Method of producing beta-lactams (versions)

专利摘要:
.beta.-Lactams having a sulfonic acid substituent in the 1-position and an amine function in the 3-position and having the formula: (see fig. I) wherein R1 is H or acyl derived from a carboxylic acid; R2 is H or alkoxy; R3 and R4, the same or different, are H, alkyl, cycloalkyl, phenyl or substituted phenyl, or one of R3 and R4 is H and the other is alkoxycarbonyl, alken-1-yl, alkyn-1-yl, 2-phenylethenyl or 2-phenylethynyl; and X is H or SO3X is SO3-M+ wherein M+ is a cation, and the use of said .beta.-lactams as antibiotics.
公开号:SU1272981A3
申请号:SU813248001
申请日:1981-02-06
公开日:1986-11-23
发明作者:Брук Сайнс Ричард；Лоуренс Паркер Вильям；Майкл Симарусти Кристофер；Генри Костер Вильям；Аллен Слусарчик Вильям；Вильям Фриц Алан；Мак Флойд Дэвид
申请人:Е.Р.Сквибб Энд Сандз, Инк (Фирма)；
IPC主号:

专利说明:

Jaz
/
NH-CH-C
Ri,
where R, -R-, R have the indicated meanings;
V is a group such as methanesulfonyl, benzene sulfonyl, toluenesulfonyl, chlorine, bromine, iodine; is subjected to sulfonation with sulfur trioxide complexes or chlorosulfonate in
organic paci 1 medium at room temperature followed by cyclization with a base such as potassium carbonate at the boiling point of the reaction medium followed by acylation of the resulting product, if R N.
4, the method according to claim 3, differs by aa yu and i, in that pyridine or dimethylformamide, or their mixture with a halogenated hydrocarbon, is used as the organic solvent of the sulfonation process.
one
This invention relates to methods for obtaining new total lactams.
2 j
(5-yaz
C-N-SOgM
tde M is hydrogen or cation;
R is hydrogen, acyl or a protected amino group;
R is hydrogen or alkoxy; R HR is the same or different and each is hydrogen, alkyl C, -C, cycloalkyl Cg-C j or one of R j and R is hydrogen, and the other is alkene-1-yl; alkin-1-yl, or 2-phenylethynyl,
which have biological activity.
The aim of the invention is to develop a method for producing new antibiotics that exhibit high activity
Beta-lactams, having a substituent of a sulfonic acid in the 1-position of the beta-lactam core and an amino-for1 1 cytotic agent in the 3-position of the beta-lactai nucleus, are active in relation to the Gram-negative and gram-positive organisms. The substituent, the sulfonic acid salt, significantly affects the activity of the proposed compounds. Compounds, in
which R and / or R are hydrogen, alkyl or, especially methyl, are the most effective.
The proposed compounds can be used
use as agents to kill bacterial infections (urinary tract infections and respiratory infections) in obstetricians such as domestic animals (dogs,
cats, cows, horses, etc), and in humans
For bacterial infections, the proposed compounds are administered to a mammal in an amount of 1.4 to 350 mg / kg / day, preferably 14-100 mg / kg / day. All previously used methods of administering penicillins and cephalosporins to the infection site are also suitable for
to the new beta-lactam family. These are oral, intravenous, intramuscular. Methods of administration, as well as administration in the form of medical suppositories.
In the proposed beta-lactams, a sulfonic acid substituent (sulfo group SOj) is usually introduced to the nitrogen atom in the 1-position of the beta-lactam nucleus. This sulfonation reaction is easily carried out using the treatment
ki beta-lactam complex sulfur trioxide or equivalent sulfating reagent - chlorosulfonate.
Commonly used sulfur trioxide complexes are pyridine-sulfur trioxide; lutidine sulfur trioxide; dimethylformamide sulfur trioxide and picoline - sulfur trioxide. It is not necessary to use a previously prepared complex, since it can be formed on site, for example, using sulfonyl triv syl silyl ester and pyridine as reagents. The sulfonation reaction is carried out in the presence of an organic solvent, such as pyridine, or in a mixture of organic solvents, preferably in a mixture of a polar solvent, such as dimethyl form amide, and a halogenated hydrocarbon, such as dichloromethane. The product originally formed by the sulfonation reaction is the sulfonated beta-lactam salt. When the sulfiding complex is pyridine-sulfur trioxide, the product originally obtained is a beta-lactamsulfonated pyridinium sulfonated beta-lactam salt, in which M is a pyridinium ion. These complexes can be converted to other salts of sulfonic acids using conventional techniques, for example, using ion exchange resins, crystallization or extraction of ion pairs. These conversion techniques are also used in cleaning products. It is especially advisable to convert the pyridine salt to the potassium salt using potassium phosphate or potassium ethylhexanoate; to tetrabutylammonium salt using acidic tetrabutylammonium sulfate; or in the zwitterion (M-hydrogen) using formic acid. The sulfonation reaction, through which the sulfonic group is attached to the nitrogen atom of the beta-lactamic core, can be carried out at various stages of the synthesis, including its introduction, before the formation of the beta-lactam core, in the presence of the solvents mentioned, usually at room temperature. If an amino function is present, it is preferably carried out with its protection, for which protecting groups such as benzyloxycarbonyl, tert-butyloxycarbonyl, simple acyl, such as acetyl or benzoylphenyl acetyl, triphenylmethyl group can be used. You can have an amino function in the form of an azide group. The desired acyl group (R,) can then be fixed using a conventional acylation reaction. When R- is alkoxy, the acylation is best carried out using an acid chloride or acid bromide. The reaction with the carboxylic acid proceeds most easily in the presence of a carbodiimide, such as dicyclohexylarbodiimide, and a substance capable of forming an active ester in place, such as N-hydroxybenzotriazole. In cases where the acyl group (B) contains reactive functionality (such as amino or carboxyl groups), it is necessary to first protect these functional groups, then perform an acylation reaction and, finally, remove the protection of the resulting desired product. If R is lower alkoxy, such a lower alkoxy group can be introduced both after and before sulphonation using the conventional method of chlorination of the acylated nitrogen atom in the 3-position with subsequent reaction with a lower alcoholic. In this reaction contain easily removable protective groups. groups that, when removed after the reaction, give the deacylated product (-NH) o The beta-lactam ring can be formed by means of a cyclization reaction; The sulfonation reaction can be carried out before cyclization, as well as after it, i.e. The acyl group, which functions as a protective group in this reaction, can also be easily removed and produces, after removal of the -NH product. Example. (s) -N- (2-OKco-l-sulfo-3-azetidinyl) -2-phenylacetamide, potassium salt. Method I A. - (1K) -Carboxy-2-methyl (propyl) 2-oKco- (3S) -phenyl acetyl (amino) J azetidino Nickel Rene is washed with water during decantation for several hours until the pH of the water ( 5- 6-fold volume of the volume of nickel Ren) will not be 7.6. To a solution of 9.0 g of penicillin G (Na) in 500 ml of water is added 54 g
(90 ml) Rene nickel. The flask, equipped with a reflux condenser, is immersed in a bagoo at 55 ° C. Starting with reflux continues for: 15 min. The flask is immediately cooled in a bath of ice-water and the Rene nickel is removed by filtration. The pH is adjusted to 3 using Dilute HC1, the solution is concentrated 150 ml and cooled. When scratched, the oily layer crystallizes. After washing with water and drying in a vacuum 3 hours at 50 ° C, 3.83 g of the expected compound are obtained.
B.1 Acetyloxy 2-ethyl (propyl) 2 oxo- (3S) -phenyl acetyl- {amino) L azetidine.
Nitrogen is passed for 15 minutes through a stirred suspension of 608 mg (2 mmol) of the indicated compound in 20 ml of dry adonitrile. The water in the bath is used for several minutes to dissolve the entire acid. The water in the bath is removed and powdered copper acetate monohydrate (182 mg, 1 mmol) is added, followed by addition after mixing for 1 min. 886 mg (2 mmol) of lead tetraacetate. The mixture is stirred at room temperature for 20 minutes. The adetonitrile solution is decanted from the precipitate, and the solids are washed with ethyl acetate. The combined acetonitrile-ethyl acetate solution is evaporated to a residue, which is taken up in a mixture of ethyl acetate and water. The ethyl acetate layer is washed successively with water and (3 times), with aqueous sodium biocarbonate (pH 7) and again with water. The ethyl acetate layer is dried over sodium sulfate and evaporated to a residue (515 mg), which is used without further purification in the next reaction.
C.2-Oxo (3 S) - {phenyl acetyl (amino) azetidine „
To a solution of 911 mg (2.86 mmol) of the indicated compound in 21 ml of methanol is added 3.5 ml of wax, followed by the addition of 383 mg (2.86 mmol) of potassium carbonate. The mixture is stirred under nitrogen for gmin and then 160 mg (4.30 mmol) is added (sodium eohydrate. The reaction mixture is stirred at room temperature for 20 minutes. The methanol is removed in vacuo, and the residue is taken up in ethyl acetate and a small amount water. The mixture is adjusted to a pH of 2.5. The ethyl acetate layer is washed at pH 7.0 with aqueous sodium bicarbonate, then with a small volume of water and finally dried over sodium sulfate and evaporated to give a crude product (493 mg). Adding a small the amount of ethyl acetate gives 2 50 mg (43% yield) of the desired crystalline product Additional product quantities can be obtained by crystallization or chromatography.
Do (h) -K- (2-Oxo-1-sulfo-3-azetidinyl) 2-phenylacetamide, potassium salt.
The pyridine SO complex (215 mg, 1.35 mmol) is added to a stirred solution of 251 mg (1.23 mmol of the indicated product in 2 ml of dry dimethylformamide and 2 ml of dry methylene chloride under nitrogen at room temperature.) The mixture is stirred for 3 hours. The solvents are removed in vacuo and the residue is taken up in methylene chloride-water mixture. The pH is adjusted to 6.5 using 2 N potassium hydroxide. The aqueous layer is washed with methylene chloride (3 times) and filtered and evaporated to a residue. The residue is stirred in 20 ml of methanol and the potassium sulfate is removed fil by evaporation. The filtrate is evaporated to a residue that is stirred with 10-15 ml of methanol. The solids are collected and I get 49 mg of the title compound, mp 189 ° C (dec) o
Calculated,%: C 40.99; H 3.44; N 8.69; S 9.93,
С „Н ,, NOjSK
Found; %: C 45.96; H 3.83; N 9.86; S 8.99.
The compound has spectral characteristics identical to the product obtained by method I.
Method II „
A solution of 660 mg (3) -2-oxo-3 {(phenylmethoxy) carbonyl amine-azethidisulfonic acid, potassium salt (see Example 3) in 13 ml of water is stirred under a hydrogen atmosphere for 2 hours with 200 mg of palladium on charcoal. The catalyst is filtered | and the filtrate is diluted
an equal volume of acetone and cooled in an ice bath. Phenylacetyl chloride (eight 40 µg portions) and 0% potassium bicarbonate solution (pH between 5, 8) are added over 30 minutes. After 40 minutes, the solution is concentrated in a vacuum. to remove acetone and applied to a 200 ml HP 20 column. Elution with water and then with a mixture of water and acetone (9: 1) yielded .160 mg of the crude product after TLC testing of Rydon-positive fractions, followed by draining and evaporation. Crystallization from methanol / ether gives 101 mg of the title compound of the example, m.p. 210 ° C (dec) o
Calculated,%: C 39.86; H 3.65; N 8.45; S 9.68; K 11.80.
С Н N OgS К -1/2 Н, 0
Found,%: C 40.01; H 3.37; N 8.59; S 9.59; K 11.98.
NMR Spectrum (g): 3.66 (s, 3); 3.67 (doublet of doublet, J 6.4); 3.90 (t, J j); 4.90 (doublet of doublet, J 6.4); 7.36 mlNo shares (m. 5) o
Method III o
To a solution of (5) -3-amino 2 Oxo 1 -azetidine sulfonic acid, tetrabutyl ammonium salt (121 mg, see Example 6A) in dry methylene chloride (3 ml) is added 40 mg of phenylacetic acid and 61 mg of dicyclohexylcarbody imide. The mixture is stirred within 48 hours at room temperature and filtered to remove the dicyclohec sylourea. The solvent is removed in vacuo, and the remaining compound is precipitated by the addition of 5 ml of acetone saturated with potassium iodide. The top-floating layer is decanted, the residue is washed with acetone (3 times). After drying, 48 mg of product is obtained having spectral characteristics identical to the products of methods I and II.
Rv "method
A solution of 2.83 g of (3) -2-oxo-3 (phenylmethoxy) carbonyl amino} -1 -azetidine sulfonic acid, pyridine salt (see Example 2) in 36 ml of water peremepgavatsya in a hydrogen atmosphere with 707.5 mg 10% Palladium on activated carbon (175 ml of hydrogen is absorbed) After 2 hours, the suspension is filtered, the filtrate is cooled to and diluted with 46 ml of acetone (initial pH 4.25
adjusted to pH 6.7 with cold 10% NYM
potassium bicarbonate solution) Rast
A thief of 2.4 ml of phenylacetyl chloride in 10 m of acetone is added dropwise over 15 minutes. The pH is maintained between 5.2 and 5.8 by simultaneously adding a cold solution of potassium bicarbonate. After 45 minutes, the suspension is diluted with 93 ml of 0.5 M potassium phosphate (pH 4.2) and concentrated to remove acetone. The suspension is filtered and washed with water. The filtrate and washings are combined and applied to a 450 HP-20 column. Elution with 1 l of 0.5 M phosphate potassium (pH 4.2), 1 l of water, and then 2.5 l of a water-acetone mixture (9: 1) gave 1.285 g of the title compound of the example in the form of fractions 14-19 (fractions 1 -15 was 20 ml, fractions 16-21 were 100 ml) o Spectral data are identical to those obtained in previous methods
Example 2. (8) -2-Oxo-3- {and (fnilmethoxy) carbonyl amino -1-azetidine sulfonic acid, pyridine salts (1: 1)
Method I on
A.1-G (lR) -Kap6oK si-2-methyl (propyl) -2-oxo- (33) - ((phenylmethoxy) -carbonyl amino-azetidine.
A suspension of 6-aminopenicillanic acid (12.98 g, 0.06 mol) in 140 ml of water containing 5.18 g of sodium bicarbonate (stirred for approximately 10 minutes without complete dissolution) is added in one portion to a well stirred mechanical stirrer suspension. Rene Nickel (washed with water to pH 8.0, 260 ml of suspension - 130 mg) in a 70 ° C oil bath. After 15 min
the suspension is cooled, the filtrate is filtered and treated with 5.18 g of sodium bicarbonate and a solution of 11.94 g (0.07 mol) of benzyl chloroformate in 12 ml of acetone. After 30 minutes, the solution is acidified to a pH of 2.5 and the methylene chloride is extracted. The organic layer is dried, evaporated and triturated with ether-hexane. 6.83 g of the title compound are obtained.
B.1- (Acetyloxy) -2-methyl (propyl) -2-oKCo- (3S) - (phenylmethoxy) -carbonyl amino azetidine.
A solution of 6.83 g (0.0213 mol) of the indicated acid in 213 ml of acetonitrile is treated with 1.95 g (0.0107 mol) of copper acetate monohydrate and 9.5 g
(0.0213 mol) of lead tetraacetate. The suspension is immersed in a 65 ° C oil bath and stirred while barging through a slurry of a stream of nitrogen until the starting material is required. The suspension is filtered and the solids are washed with ethyl acetate. The combined filtrate and washings were evaporated in vacuo. The residue is dissolved in 100 ml of ethyl acetate and 100 ml of water and the pH is adjusted to 7. The ethyl acetate layer is separated, dried and evaporated. 6.235 g of target compound of example is obtained. ,
C. (8) - (2S-3-gazididilil) carbamic acid and its vinyl methyl ether.
A solution of 3.12 g (0.0093 mol) of this acetate in 70 ml of methanol and 7 MW of water is cooled to -15 ° C and 1.33 g of potassium carbonate and 349 mg of sodium borohydride are added to it. The reaction mixture was stirred at -15-0 ° C. After completion of the reaction (after 2 hours), the mixture is neutralized to pH 7 with 2N. HC1 and concentrated in vacuo. The concentrate is adjusted to pH 5.8, saturated with salt, and extracted with ethyl acetate (3 times). The organic layer is spiked and evaporated in vacuo. The residue is combined with the substance from the similar experiment and triturated with ether. 3.30 g of the title compound are obtained.
Do Pyridine salt (h) -2-oxo-3- (phenylmethoxy) carbonyl | amino -I-azetidine sulfonic acid
Method I.
A solution of 440 mg (0.002 mol) of the indicated azetidinone in 2 mp of each of dry methylene chloride and dry dimethylformamide is mixed for 2 hours under nitrogen with 350 mg (0.0022 mol) of pyridine-sulfur trioxide complex. The solvent mass is then removed in vacuo and the residue is triturated with ethyl acetate. 758 mg of solid substance is obtained, which is essentially the title compound of the example.
NMR (D, o-CCsoC): 3.63 n (W, doublet of the doublet, J 6.4), 3.90 (W, t., J 6), 4.85 (1H, doublet of the doublet, J 6.4), 5.10 (2H, s.), 7.27 (5H, s), 8.0-9.0 ppm (multiplets 5H).
Method 11 „
Chlorosulfonyl trimethylsilyl ester (IS, 87 g) is added dropwise at -20 ° C to 7.9 g of anhydrous pyridine with stirring under a nitrogen atmosphere. When the addition is complete, the sweeping continues for 30 minutes at room temperature, and trimethylchlorosilane is then removed in vacuum. A solution of 20 g of the indicated aze of tidinone (method I, part C) in 120 ml of dimethylformamide and 120 ml of methylene chloride is added and stirred at ambient temperature 3 , 5 hours. The solvent is distilled off in vacuo, and the oily residue is crystallized by the addition of ethyl acetate. 31 g of the expected compound are obtained. The NMR spectrum data is identical to the product data of method I.
Example 3. Potassium salt (8) -2-oxo-3 - {(phenylmethoxy) carboni amino -1-acetidine sulfonic acid.
Method I.
The pyridine salt of (S) -2-oKco-3 I (phenylmethoxy) carbonyl α-amino-β-azidine sulfonic acid (135 mg; see Example 2) is dissolved in 2 ml of 0.5 M potassium phosphate monobasic (adjusted to pH 5.5 s). using 2N potassium hydroxide) and applied to a 25 ml HP-20AC column. The column was eluted with 100 ml of buffer, 200 ml of water and 100 ml of 1: 1 acetone-water mixture. Fractions (25 ml) 14-15 are highly Rydon-positive. Evaporation gives a BO mg of substance, which is mainly the target compound of the example. The spectral data are identical to the product data obtained below.
Method II.
The pyridine salt of (s) -2-oKco-3-I (phenylmethoxy) carbonyl amino-1-β-azethidine sulfonic acid (600 mg, see Example 2) is dissolved in 2 ml of water and mixed with 14 ml of monobasic potassium phosphate buffer at pH 5, five. A solid is formed. The suspension is cooled to, filtered, flushed with cold buffer, cold 50% ethanol, ethanol and ethyl ether. 370 mg of the title compound of the example are obtained, which according to the analysis contains an excess of potassium ion. A solution of 280 mg of salt in 10 ml of water is applied per 100 m; and an HP-20 column. The column is eluted with 200 ml of water, and then
a mixture of water and acetone (9: 1) "Fractions (50 ml) are collected; evaporation of fraction 7 gives a solid. Trituration with acetone, filtration, and drying in a b vacuum give 164 mg of the target compound of the example, t, pLo 193,196 ° C
Calculated,%: C 38.02; H 3.48; N 8.06; S 9.23; By 11.25.
S, N, SK 1/2 BUT
Found,%: C 38.19; H 3.24; N 8.15; S 9.12; K 11.53.
NMR Spectrum (D): 3.69 (1H, doublet of the doublet, J 6.4); 3.91 (1H, t., J 6); 4.76 (1H, m.); 5.16 (2H, s); 7.43 million, her share (5H, s).
Method III o
Phenylmethyl ester (s) - (2 oxo 3 azetidinyl) carbamic acid (20.0 g, see example 2C) is suspended in 200 ml of acetonitrile, 21.6 ml of monotrimethylsilyl trifluoroacetamide (25.3 g) is added, and the mixture heated to 50 ° C with stirring for 1 hour. After cooling by ice in an ice bath to 0 ° C, 17.2 g of trimethylsilylchloroyl sulfonate is added, and the solution is stirred at ambient temperature for 6 hours. To the solution is added 24, 2 g of potassium ethylhexanoate in 100 ml of butanol, and stirring continued for an additional hour. The suspension is poured into 1 liter of dry diethyl ether, and the precipitate is filtered and dried in vacuo. The compound is dissolved in 500 ml of water, the pH is adjusted to 5.0 with potassium carbonate, the insoluble material is filtered out, and the uterine liquid is frozen by freezing. The yield of the crude compound is 19.4 g. The compound contains a small amount of potassium chloride, which is removed by chromatography. Spectral data is identical to the data of the product of method II „
Example 4 o (h) C (phenylmethoxy) carbonic 1 amino 1 -azetidine sulfonic acid, tetrabutyl monium salt (1: 1),
Method 1
The pyridine salt (s) {L (phenylmethoxy) carbonyl amino I - azetidine sulfonic acid (1: 1) (34.3 g. Example 2) is dissolved in 800 ml of water. The solution is clarified with activated charcoal, 30.7 g of acid are added.
the logo of tetrabutylammonium sulfate in 80 ml of water and the pH is adjusted to 5.5 with 2 N. potassium hydroxide. The solvent is removed in vacuo until a volume of about 200 ml is reached. The precipitated tetrabutylammonium salt is filtered and dried in vacuo. The compound can be recrystallized from water or dissolved in methylene chloride, filtered and precipitated by the addition of ether. The yield of 34.3 g, so pl. 108-110 ° C.
Hi method
Kaliyev salt. (s) -2-oxo-3 | (F6 nylmethoxy) carbonyl amino -1-azethidine sulfonic acid (1: 0 (20.2 g, see Example 3) is dissolved in 500 ml of water, filtered and added 20, 3 g of tetrabutylammonium acid sulfate in -100 ml of water, the pH is adjusted to 5.5 with 1 K potassium hydroxide. The volume is reduced to 1 ml in vacuum, and the precipitated tetrabutylammonium salt is filtered off. The compound is dissolved in 30 ml of methylene chloride - read, filtered and precipitated by the addition of ether, yielding 21 g of the title compound of the example, mp 109-111 ° C.
Example 5. Phenylmethyl ester, potassium salt of (3S) -ot- (2-oxo-1 sulfo-3-azetidinyl) amino carbonyl} benzeneacetic acid (1: 1).
A (8) -3-Amino-2-azetidinone.
Phenylmethyl ester of (s) - (2-oxo-3-azetidinyl) -carbamic acid (3 g, example 2C) is hydrogenated in 100 ml of methanol in the presence of 1 g of palladium catalyst on activated carbon. When the theoretical amount of hydrogen is absorbed, the catalyst is filtered out and the filtrate is evaporated to dryness. On standing, 1.1 g of the title compound crystallizes.
B. Phenylmethyl ester (3S) -o-I (2-oxo-3-azetidinyl) amino-carboxyl | benzeneacetic acid.
. The said azetidinone (3.0 g) is dissolved in 100 ml of dimethylformamide. The solution is cooled to 0 ° C and 4.5 g of N-methylmorpholine is added, followed by the dropwise addition of 10.8 g of N- (chlorocarbonyl) benzolacetate phenylmethyl ester acid in 50 ml of acetonitrile with stirring. The mixture is stirred for "16 hours at 5 ° C." The solvent is distilled off in vacuo, and 100 ml of water is added to the residue. The aqueous suspension is extracted with twice 100 ml portions of methylene chloride. The organic layers are combined, washed with sodium bicarbonate, 2 N phosphoric acid and water, dried with sodium sulfate, filtered and evaporated to dryness. The residue crystallizes with ethyl acetate and petroleum ether to give 8.7 g of product, m.p. . C. Kaliyev salt of phenylmethyl ester (3S) -o (.- {(2-oxo-1-sulfo-3-azetidinyl) amino) base benzyl cyclic acid (1: 1). The said compound (6.9 g) is suspended in 150 ml of Adetonitrile. Monotrimethylsilyl trifluorocetamide (5.7 g) is added and the solution is heated for 30 minutes under stirring. The solution is cooled to 0 ° C and 3.9 g of trimethylsilyl chlorosulfonate is added dropwise. When the addition is complete, the mixture is heated - to 50 ° C for 5 hours. After cooling, 7.6 g of potassium ethylhexanoate in 10 ml of butanol is added and stirring is continued. for 30 minutes When adding 300m of ether, the target compound of the example is precipitated and filtered. The crude product is mixed with 1 00 ml of dry acetonitrile for 30 minutes and filtered off, yielding 4.5 g of the target compound of the example, mp 118-120 ° C. Further purification of the crude product using chromatography on HP-20 s after that, with a drying at zero temperature, gives a pure substance having rt, rc. 188190 ° C. Calculated,%: C 48.09; H 4.03; N 5.90; S 6.76. С Н N 0, SK Found,%: С 47.87; H 3.68; N 6.01; S 6.55. Example 6. The potassium salt of (S) -3-I (2 amino-4-thiazolyl) acetyl amino T-2-hydroxy-l-azethidine sulfonic acid. A, Tetrabutylammonium salt of (s) -3-amino-2 oxo 1-azetidine sulfonic acid. The tetrabutyl ammonium salt of (S) -2-oxo-3-- (phenylmethoxy) carbonyl) -1-azetidine sulfonic acid (2 g, Example 4) is dissolved in 100 ml of dimethylformamide and hydrogenated for about 30 min. 1 g of palladium on activated carbon (10%) as a catalyst. The catalyst is filtered off and the dimethylformamide is removed, leaving the title compound of the example as an oil. NMR spectrum (CDC1); 3.82 (W, t, J..5,5); 4.05 (d, GN, doublet of doublet J 5.5, 2.5 cycles ./ (s, V, Kaliev salt (s) -3 {(2-amino-4-thiazolyl) acetyl amino | -2-oxo -1-azetidine sulfonic acid. The indicated compound (2 g), 0.5 g of aminothiazole acetic acid and 0.4 g of hydroxybenzenetriazole are stirred at 0 ° C in 100 ml of dry dimethylformamide, while a solution of 0.7 g of dicyclohexylcarbodiimide in a drop is added dropwise. 10 ml of dimethylformamide. After the addition is complete, the stirring is continued for 12 hours at 20 ° C. The insoluble urea is filtered off and the solvent is evaporated in vacuo. The oily residue treatment with a solution of perfluorobutane sulfonate; 1L in 20 ml of acetone at room temperature for 15 minutes. After adding 20 ml of dimethyl ether, the target compound of the example precipitates, is filtered, dried and purified by chromatography on a 300 ml HP-20-column using water as eluent. Yield 850 ml t. PL, 300 ° C, Calculated,%: C 27.91; H 2.63; N 16.27; S 18.59. CgHgN OS K Found,%: C 27 , 60; H 2.87; N 17.12; S 18.41, Example 7, Kaliev salt of 3S (+) - 3- (formyloxy) phenylacetyl amino. -2-oxo-1-azetidine sulfonic acid. The tetrabutylammonium salt of (s) -3-amino-2-oKco-l-azetidine sulfonic acid (1.5 g, see example 6A) in 100 mp of dimethylformamide and 2 ml of oxypropylene is cooled to 0 ° C. A solution of chloroangs, CRIDA 0-formylindic acid in 10 ml of acetonitrile. The temperature is maintained for 1 hour and the solvent is then distilled off in vacuo. The oily residue is treated with a solution of 2 g of perfluorobutane - 15 ml of acetone. potassium sulphonate in. After adding 200 ml of ether, the title compound of the example crystallizes and filters out, and 1.5 g of product. The product is purified with noMODj; bK) HP 20 Chromatography, m.p. 180 185 ° C with decomp. Example 8. The potassium salt of 3S (+) l -3 (formicloxy) phenylacetyl amino 1 2 oxo 1 azetidine sulfonic acids. Following the 17 procedure of example 7, but replacing the acid chloride 0 with formyl-amino acid with the acid chloride D-0-formyl-amino-acid, get the target with, a single example, t . pl) (after drying at a temperature of C 39.34; H 3.03; Calculated,%: 7.65; K 10.67.: 0-, sK%: C 38.69; H 3.00; Found, N 7, 39; K 10,54. Example 9. The potassium salt of 3S (-) - 3 ((formyloxy) phenylacetyl amino 1 2 oxo 1 azetidine sulfonic acid. Performing the procedure of Example 7, but replacing the acid chloride 0 with formyl almond acid with L-0-formyl minindyl acid chloride gives target compound containing 1 mol of water, tpLo 203 205 ° С After thorough drying, the product melts at 228 230 ° C. X Calculated,%: C 39.34; H 3.03; N 7.65; K 10, 67. C. Found,%: C 39.90; H 2.98; 7.54; K 10.67, Example 10, Kaliev salt (S) (1 oCOOKtil) amino 1 aze tetrasulfyl ammonium salt (s) 3 amino 2 oxO 1 azetidine sulfonic acids (1.5 g, cm 6) 6 ml of dimethylformamide and 2 ml of propylene oxide are cooled to 0 ° C. At this temperature, 0 is added dropwise. 8 g of acid chloride and caprylic acid in 20 ml of dry acetone, and stirring is continued for 30 minutes, the solvent is evaporated in vacuo, and the oily residue is treated with 2 g of potassium butanesulfonate perfluoride in 15 ml of aetone. Acetone is distilled off in vacuo. The residue is dissolved in 5 ml of water and xp is matched using 300 MP HP 20 resin and a mixture of water 8116 acetone (9: 1) as eluent, to give 0.9 g of the title compound, m.p. 173 180 ° C after freeze-drying. Calculated,%: C 39.98; H 5.80; N 8.48; S 9.70; K 11.83. Na,%: C 39.53; H 5.67; N 8.38; S 9.33; K 11.84. Example 11. Potassium salt 3S (Z) (2 amino 4 thiazolyl) oxy (phenylmethoxy) phosphinyl labels si amino acetyl amino | 2 ca. Ti-sulfin-sulphonic acid. Tetrabutylammonium salt (s) 3 amino 2 oxo 1 azetidine sulfonic acid (0.8 g, see Example 6A) in 30 ml of dimethylformamide, 0.9 g (g) 2 amino ox (phenylmethoxy) phosphine methyl tomino1,4 thiazo-acetic acid , 0.3 g of hydroxybenzotriazole and 0.7 dicyclohexylcarbodimydez stir for 24 hours at room temperature. The precipitated urea is precipitated and the solvent is removed in vacuo. The remaining oil is treated with an equivalent amount of potassium perfluorobutane sulfonate in 10 ml of acetone. The target compound is filtered and purified using HP 20 resin and water as eluent to give 500 mg, m.p. 210 with razl. Calculated,%: C, 31.43; H 3.79; N 11.46; S 10.47; P 5.07, C ,. H. CRH Found,%: C 31.68; H 3.58; 17; .P N 11.48; S 11.17; .R 5.56. Example 12 of the Kaliev salt of t3S (Z) (2 amino 4 thiazolyl) (pathoxyimino) acetyl amino | 2 oxo azetidine sulfonic acid, tetrabutylammonium salt (3) -3-amino 2 oxo 1 azetidine sulfonic acid (1.5 g, see example 6A) in 100 ml of dimethylformamide, 0.6 g of oxybenetriazole, 1 g of dicyclohexylcarbodiimide and 0.8 g ) -2 amino c / (ethoxymino) 4 thiazolycyclic acid is stirred at room temperature for 24 hours. The solvent is distilled off, and the residue is dissolved in 30 ml of acetone. Urea is filtered off, and the mother liquor is treated with a solution of 2 g of potassium perfluorobutane sulfonate in 20 ml of acetone. After addition of 200 ml of ether, the desired compound precipitates and is filtered and dried. Cleaning
This is obtained by chromatography using HP 20 Columns and voi as eluent, yielding 1.1 g of spit fusion compound, mp. (different) o5
Calculated,%: C, 29.93; H 3.01; 17.45; K 9.74. C N N OgS K
HaVeHo,%: C 29.34; H 3.10; 16.87; K 8,64.10
Example 13, Kaliev salt ЗЗ (Е) -3 {(2-amino 4 thiazolyl) (ethoxyimino) acetyl amino 2 oxo az e tidine sulfonic acids.
The procedure of Example 12 is carried out. Replacing (2) 2 amino o ((ethoxyimino) 4 thiazo-acetic acid (E) 2-amH (ethoxyimino) 4 thiazo-acetic acid gives the target compound, for example, 160 160 ° C pos 20 le freeze-drying
Calculated,%: C 29.92; N W., 01; N 17.49; K 9.74. CioH.s WsOgS,
Found,%: C 29.04; H 3.07; 25
N16.90; By 9.45.
Example 14. Potassium salt 3S (Z) -3 {(2 amino O 4 thiazolyl) (2,2,2 trifluoroethoxy) imino acetyl amino | 2 oxo 1 azetidine sulfonic gold
Performing the procedure of Example I2 and replacing (g) 2 amino-o (- (ethoxyimino) -TIazoleacetic acid (g)) Ho-d- (2,2,2-trifluoroethoxy) imino-35 -4-thiazoleacetic acid gives the target with t. pl. 160-170 ° C after drying at a temperature below 0 ° C.
Calculated,%: C, 26.37; H 1.99; N 15.38; F 12, K 5.58.40
С Н FjN О 3,2
%,%: C 25.24; H 2.11; N 15.02; F 11.96; K 7.68.
Example 15. Potassium salt 45 (S) -2 OKco-3 L (1 oxopropyl) amino 1-azetidine sulfonic acid
Method 1
Tetrabutylammonium salt (S) amino 2-oxO 1 azetidine sulfes (acids (1.5 g, see example 6A) in 100 ml of dry dimethylformamide and 4 ml of propylene oxide are cooled to 0 ° C with stirring. At this temperature 0, 5 g of propionic acid chloride in 55 ml of acetonitrile is added dropwise with the mixture. The mixture is stirred for 2 hours. The solvent is distilled off
The mixture is treated in vacuo, and the oily residue is treated with an equivalent amount of potassium perfluorobutane sulfonate of 5 M.P. of acetone. Upon addition of the ether, the target compound crystallizes and is filtered off, yielding O, 8 g of product, m.p. 135 - 140 ° C after drying at a temperature below OS.
Method 11c
The tetrabutylammonium salt of (s) -2-oxo-3 {(phenylmethoxy) carbonyl amine Hol-1-azetidine sulfonic acid (4 g, see Example 4) is hydrogenated in 100 ml of diglyme using 1 g of palladium on activated carbon. The hydrogenation is complete after 2.5 hours. The catalyst is filtered off and 2 ml of propylene oxide is added. After cooling to 0 ° C, 0.5 g of propionic acid chloride in 10 ml of dry diglyme is added with stirring. After 30 minutes, the solvent is removed in vacuo, and the oily residue is treated with an equivalent amount of potassium perfluorobutane sulfonate in 20 ml of acetone. After the addition of ether, the desired compound crystallizes, is filtered off and is recrypted from the water-acetone mixture to give 0.9 g of product. TC pl 156-160 ° C (decomp.)
 Calculated,%: C 27.68; H 3.49; N 10.76; S 12.32.
Cb-HgKN S
Found,%: C 27.24; H 3.57;
N 10.39; S 11.64.
Example 16. Potassium salt 3S (+) - 3- | hydroxyphenylacetyl amino | - -2-oxo-1-azetidine sulfonic acid.
Tetrabutylammonium salt of (s) -3-amino-2-oxo-1-azetidine sulphoxide. lots (1.5 g, cm of Example 6A) in 100 ml of dry dimethylformamide is stirred for about 16 hours with 1.5 g of dicyclohexylcarbodiimide, 0.5 g of hydroxybenzotriazole and 0.6 g of mandelic acid. The solvent is removed in vacuo, and the residue is dissolved in 20 ml of Adeton. The precipitated urea is filtered off, and the mother liquor is treated with an equivalent amount of 1salium perfluorobutane sulfonate. After the addition of ether, the desired compound precipitates and is filtered off.
giving 1.4 g of crude product. After recrystallization from water, the product has a m.p.
Calculated,%: C 37.07; H 3.68; N 7.86; S 9.00,
C ,, H.KN.
Found,%: C 37.31; H 3.40; N 7.90; S 8.78,
Example 17, Kaliev salt of (S) -3- (cyanomethyl) thio acetyl amino1 2-oxo71 azetidine sulfonic acid,
The tetrabutylammonium salt of (s) -3 amino 2 oxo 1 aetidine sulfonic acid (1.5 g, see Example 6A) and 0.72 g of (cyanomethyl) thio acetic acid are dissolved in 70 ml of acetonitrile, where solution 1 is added dropwise, 04 g-dicyclohexylcarbodiimide, the mixture is stirred for about 16 hours at 0 ° C, and the precipitated dicyclohexyl urea is filtered off, the filtrate is evaporated, and the oily residue is dissolved in acetone. Upon addition of the complete solution of potassium iodide in acetone, the title compound precipitates, giving 1.1 g of product. That is 150 155 ° C,
Calculated,% g C 25.00; H 3.0; N 12.5; K 1 1.6.
. C, N N O S
Found,%: C 26.43; H 3.29; N 11.42; K 10.79,
Example 18. Kaliyev salt (s) -2-OKCO 3 (1H tetrazole 1 Ilac til: amino 1 -azetidinsulphonic acid
To a solution of 0.005 mol of tetrabutyl ammonium salt (3) 3 amino 2 oxo -1 azetidine sulfonic acid (see Example 6A) in 70 ml of dimethylformamide is added 0.77 g of SH-tetrazole 1 acetic acid and a solution of 1.13 g of dicyclohexylcarbodiimide in 5 ml dimethylformamide o The mixture is stirred for about 16 hours at room temperature and the solvent is removed in vacuo. The remaining oil is dissolved in 20 ml of acetone and 0.006 mol of a solution of calcium perfluorobutane sulfonate in acetone is processed. Obtain 1.5 g of the target compound, t, pl. 170-175 ° C (decomp.)
Calculated,%: C, 26.20; H 2.90; K 11.30; N 29.70; B 9.30.
CgH KNgOgS -1/2 acetone
Found,%: C 25.96; H 2.94; to 10.84; N 21.11; S 8,87,
Example 19, Potassium salt (S) -2 - oKCO 3 (2H-tetrazole 2-ylacetyl) amino -1 azetidine sulfonic acid,
Performing the procedure of Example 18 and replacing 1H-tetrazole-1-acetic acid with 2H-tetrazole-2-acetic acid gives the desired compound, mp, 175- (decomp).
Calculated,%: C 22.90; H 2.70; K 12.40; N 26.70; S 10.20,
Found,%: C 24.37; H 2.60; K 11.18; N 24.23; S 9.29,
Example 20, the Potassium salt of (S) -2-oxo-3 (2 thienylacetyl) amino 1 -aze of sulfonic acid,
Performing the procedure of example 18 and replacing 1H-tetrazole-l-acetic acid with 2-thiopheneacetic acid gives the target compound, t, mp, 180-190 ° C (decomp.) O
Calculated,%: C 32.90; H 2.70; N 8.50; S 19.50. CgHgN O S -K
Found,%: C 31.84; H 2.78; N 8.56; S 19.29,
Example 21, the potassium salt of 3S (Z) -3- (2-amino-4-thiazolyl) methoxyimino) acetyl-amino-2-oxo-1 - α-azidine sulfonic acid,
Tetrabutylammonium salt of (s) -amino-2-ca co-1-azetidine sulfonic acid (prepared as described in PIR7 6A, from 7.9 g of tetrabutylammonium salt (s) -2-oxo-3 (phenylmethoxy carbonyl amino aminoazidine sulfonic acid) is cooled to 0 ° C, and 3.53 g of (Z) -2 amine o (- (methoxyimino) -4-thiazole acetic acid is added followed by the addition of a solution of 3.27 g of dicyclohexylcarbodiimide in 10 ml of dimethylformamide. The mixture is stirred for 16 hours at 5 ° C, filtered, and the solvent is removed in vacuo. The residue is dissolved in acetone and filtered. After adding 60 ml of 10% 4.7 g of crude product is crystallized from a solution of potassium perfluorobutanesulphonate potassium in acetone. The crude product is purified by chromatography on HP-20, 100-200 mesh, to give 3.0 g of the title compound, t, mp,
Calculated,%: C 25.53; H 3.33; N 16.54; S 15,, 14.
C9H, oN50gS, .K 21 1 Found: C 26.15; H 2.99; N 15.78; S 15.03. Example 22. Dikaliev salt (GF) - o (| (2 oxo-1 sulfo 3-azeti dinyl) amino carbonyl | benzeneacetic acid. 100 g of potassium salt of phenylmethyl ester (GC) (2-oxo 1 sulfo-S-a 3 e thidinyl) amino to arboneyl jbE n-acetic acid (see Example 5) is dissolved in 20 ml of anhydrous methanol. Palladium on activated carbon (10 mg, 10%) is added and the mixture is treated with hydrogen for 15 minutes. The catalyst is filtered off and the methanol is evaporated in a vacuum. The residue is dissolved in 5 ml of water, and the pH is adjusted to 6 with 1 c of potassium hydroxide. A crude product is obtained below OS. The crude material is chromatographed on HP-20 (water as eluent) to give 60 g of the title compound with mp 80-85 ° C. Calculated,% C 35.64 H 2.49; N 6.83; K 19.34. 2K C H N N Alchego,%: C 34.33; H 2.68; 6.71; K 17.89. Example 23. Potassium salt (3) -3 - (Acetylamino) -2-oxo-1-azetidine sulfonic acid. Method 1o Kaliyev salt (h) 3-amino-2-oxo-1-azetidine sulfonic acid. Potassium salt (h) -3- (benzyloxycarbonylamino) -2-oxo-1- Azetidinsul phonic acids (169 MP, see Example 3) is dissolved in 4.0 ml of water and hydrogenated with over 37 mg of 10% palladium on a saturated carbon for 1 h 40 min. The catalyst is removed by filtration and rinsed with 1 ml of 50% aqueous adeton. B. Kaliyev salt (3) -3 ™ (acetylamo) -2-ox-o-1-aze tidine sulfonic acid. This free solution is diluted with 3.5 ml of acetone and stirred in ice water. Over a period of approximately 15 minutes, alternate the addition of small portions of Adetyl Chloride (320 µl) and solid potassium bicarbonate to maintain a pH of 6.6-7.2. After 30 minutes, a silica gel TLC in acetone-acetic acid (19: 1) and a Rydon test indicated that the reaction 1 was essentially over. 6 ml of 0.5 M potassium phosphate buffer with a pH of 5.5 tons is added and the solution is acidified to pH 4.8 with 2N hydrochloric acid. The acetone is removed in vacuo, and the aqueous solution thus obtained is passed through a 50 ml HP-20A column, yielding 2.197 g of a solid. This material is dehydrated with methanol, giving 282 mg of extractable material, which still contains a small amount of salt. The product is further purified by passing through 1 RC-50 column followed by acidification to pH 3.8 and stripping with steam under vacuum. Trituration with acetone gives 64 mg of the desired product containing approximately 0.5 eq. inorganic potassium salts. Final passage through a 200 ml HP-20A column with subsequent lyophilization from 0.5 ml of water; 22 mg of the product is in the form of an amorphous powder, which is dried under vacuum for 2 hours at 50 ° C, Then nxt, 170-180 ° C after softening at 100 ° C. Calculated,%: 24.38; H 2.87; 11.37; K 5.9. C5H, OgN, SK Found,%: C 26.06; H 3.14; And 9.96; K 18.04. Method II о A solution of 2 g of pyridine salt (s) -2-oxo-3- | (phenyl. methoxy) carbonyl} amino | -1-azetidine sulfonic acid (see Example 2) in 25 ml of water is hydrogenated over 500 mg of 10% alladium on charcoal. After 2 hours, the solution is filtered, cooled to 0 ° C and 40 ml of acetone is added. The pH of the solution is maintained between 5.2-5.8 by the simultaneous addition of adethyl chloride and cold 10% potassium bicarbonate solution. The pH of the solution is adjusted to 4.2 with acetyl chloride, and the solution is concentrated on a rotary evaporator to remove acetone. Chromatography on a 300 ml column of HP-20 AG (melted water – 25 millimeter fractions) gives 900 mg of the compound in fractions of 13 and 14 contaminated with some potassium acetate of about 23. Repeat chromatography on HP-20 AG gives an analytical sample , t. Sh 205-210 ° C. Calculated,%: C 24.38; H 2.86; ° N 1 1.38; S 13.02; By 15.88. CgH NjOjSK Found,%: C 24.23; H 2.81; N 1 1.25; S 12.86; K 15.74. Example 24, Potassium salt (S) (phenoxyacetyl) amino 1 azetidiisulfonic. The tetrabutylammonium salt of (s) -3 amino 2 Oxo 1-azetidine sulfonic acid, 1.5 g (see example ba) in 100 ml of dry dimethylformamide is cooled to. Propylene oxide (2 ml) is added and 1 g of phenoxy acetic acid chloride is added dropwise with stirring. The reaction is completed in 1 hour. The solvent is removed in vacuo and the residue is treated with an equivalent amount of potassium perfluorobutane in 20 ml of acetone. When ether is added, the target compound (1 g) crystallizes and is filtered off and then dried. After recrystallization from boiling water, the target compound has a melting point of 176-180 ° C. Calculated,%: C 37.07; H 3.67; N 7.86; S 9.60. C ,, n ,, p o, SK —but Found,%: C 37.17; H 3.68; N 7.89; S 8,82. Example 25. Potassium salt Гз (R) З - (furanylmethylene) amino - (2-oxo-1-imidazolidinyl) carbonyl amino phenylacetyl ami1: with -2-oxo-1-azetidine sulfonic acid. The tetrabutylammonium salt of (S) -2 - oxo 3 {(phenylmethoxy) carbonyl amino 1 1 azetidine sulfonic acid (3 g, see Example 4) is hydrogenated in 100 ml of dimethylformamide with 1.5 g of palladium on activated carbon. After 0.5 h, the catalyst is filtered off and 1.8 g of dicyclohexylcarbodiimide, 2 g of (R) cC {3 (nylmethylene) amino 2 oxo 1 imidazolidine 1-carbonyl amino benzene acetic acid and 0.9 g of hydroxybenzotriazole are added. After 3 hours, the reaction mixture is evaporated to dryness, dissolved in 50 m of dry acetone, and dissolved, and the urea is removed by filtration. An equivalent amount of potassium perfluorobutane sulfonate in 20 ml of 81 acetone is added and the title compound precipitates. The crystallization is completed by the addition of 200 ml of ether. After filtration, the target compound is redrawed from the water, yielding 2 g, so pl. 220,225 ° C (decomp. L) Calculated,%: C 43.86; H 3.78; N 15.20; S 5.71 Found,%: C 47.82; H 3.49; N 14.88; S 5.77. Example 26. Kaliev salt 33 (k) (dazolidinyl) carbonyl amino phenylacetylamino 1 azetidine sulfonic acid. Tetrabutylammonium salt (s) -2 (phenylmethoxy) carbonyl amino [azech; insulfonic acid (3 g; see example 4) hydrogenated in 100 ml of dry dimethylformamide with 1.5 g of palladium on charcoal, the catalyst is filtered out after 30 minutes. (R) -o (.- {(imidazolidinyl) carbonyl amino acid ben-acetic acid (1.8 g) is added , 1.3 g of dicyclohexylcarbodiimide and 0.9 g of hydroxybenzotriazole, and p The solution is stirred for 2.5 hours. The solvent is removed under vacuum, and the residue is dissolved in 50 ml of acetone. The precipitated urea is filtered off and the uterine liquid is treated with an equivalent amount of potassium perfluorobutane sulfonate in 20 ml of acetone. The target compound crystallizes and is filtered out after adding 200 ml of ether to give 1.8 g of product, mp 2 10-215 ° C after recrystallization from water / acetone. Calculated,%: C, 38.54; H 3.88; N 14.98; S 6.86. Found,%: C 38.63; H 3.74; N 14.87; S 6.68. Example 27. Potassium salt 3S (Z) (methoxyimino) phenylacetyl amino 2 oxo 1 azetidine sulphonic acid. A. 35 (g) (methoxyimino) phenylacetyl amino 2 azetidinone. . (3g) -o (.- (methoxyimino) benzene-acetic acid (3.58 g) is dissolved in methylene chloride, cooled to 5 ° C and treated with a solution of 4.53 g of dicyclohexylcarbodiimide in 50 ml of methylene chloride. The mixture is stirred 30 min at 5 ° C, then add a solution of 1.72 g of 3 amino2 azetidinone 25 (see Example 5A) in 100 ml of methylene chloride. The reaction mixture is kept at 5 ° C for 1 hour and 2 hours at room temperature. After cyclohexylurea is removed by filtration, the filtrate is evaporated, yielding 6.6 g of the crude product. This substance is purified by chromatography Fial on 750 g of silica gel using methylene chloride-ethyl acetate (7: 3) as eluent, yielding 2.9 g of product. B. Kaliyu 3S (Z) salt (methoxyimino) phenylacetyl amino | Z-oKco -1 azetidine sulfonic acid. Pyridine (0.5 ml) is dissolved in 5 ml of absolute methylene chloride, cooled before and a solution of 0.93 ml of trimethylsilylchlorosulphonate in 5 ml of methylene chloride is added.The mixture is stirred at room temperature for 30 minutes and evaporated in vacuo to dryness. The residue is dissolved in 10 ml of dimethylformamide and treated at room temperature with a solution of 1.23 g of the said azetidinone in 10 ml of dimethylformamide. After re-exchanging for 2 hours at room temperature, the solution was evaporated to dryness, yielding 2.1 g of neoE1, pyrogened (Z) -3- (labeled siimino) phenyl acetyl amino -2 ok with O -1-azetidine sulfonic acid. Treatment of the pyridine salt with an acidic tetrabutylammonium sulfate gives the corresponding tetrabutylammonium salt, which is extracted with methylene chloride and after evaporation remains as an oil. Processing tetrabutylammonium co. If an equimolar amount of potassium perfluorobutane sulfonate in acetone was obtained, evaporation and treatment of the residue with ether gave 1.6 g of the expected potassium salt, which was purified by chromatography on HP-20. The elution is carried out with a water-acetone mixture of 90:10, and gives a product having a melting point of 220 ° C (decomp.). Calculated: C 39.44; H 3.31; N 1 1.50; S 8.77. C ,,, H KNjOg S Found,%: C 39.65; H 3.85; N 11.03; S 9.83. Example 28, Potassium salt 13S (Z) 1 -3- {(2-amino-4-thiazolyl :) 2- (diphenylmethoxy) -, 1-dimethyl-2-ok8126 soethoxy imino acetyl amino -2 ox) I-azetidine sulfonic acid ( 1: 1), Solution of 0.005 mol of tetrabutylammonium salt (8) -3 - lmino-2-oxo-1 - azetidine sulfonic acid (see Example 6A) and 0.006 mol (;) - 2-amino (diphenylmethoxy) - :, 1 -dimethyl-2-oxoethoxy. amka-4-thiazoleacetic acid in 60 ml of dimethylformamide is treated with 0.7 g of hydroxybenzotriazole) and 1.13 g of dicyclohexylcarbodiimide. The mixture is stirred at ambient temperature for 16 hours, filtered, and the filtrate is evaporated. The residue is dissolved in 30 ml, filtered and treated with 20 ml of a solution of 10% potassium perfluorobutane sulfonate in acetone. After adding petroleum ether, the target compound precipitates, is treated with ether and filtered, yielding 3.8 g of product, m.p. 190 ° C (with decomposition). Example 29 Dikalium salt 3S (Z) -3- (. ( 2-amino-4-thiazolyl) (1 -carboxy-1 methylethoxy imino acetyl amino -2-oxo-1-azetidine sulfonic acid. Potassium salt 3S (Z) 3-- (2-amino-4-thiazolyl) 2- (diphenylmethoxy) - 1, -dimethyl-2-oxaethoxy imino-acetyl amino} -2-oxo-1-azetidine sulfonic acid (2 g, see Example 28) is suspended in 5 ml of anisole. Next, 25 ml of trifluoroacetic acid are added at -10 ° C. The mixture is stirred 10 in. at -10 ° C. Ether (100 ml) is added slowly at -10 ° C, and subsequently 50 ml of petroleum ether are added. The precipitate is filtered off, yielding 1.6 g of trifluoroacetic acid salt. in 20 ml of water at 0 ° C, adjusted to pH 5.5 with dilute potassium hydroxide and purified on an HP-20-column. The target compound is eluted with water and has a melting point of 225 ° C (with decomp.) , 01; H 3.21; N 13.12; S 12.02. C ,, H, K O Found,%: C 27.76; H 2.92; N 12.92; S 11.54. Example 1 € 30 Kaliyev salt 3S (Z) -3- (2-amino-4-thiazolyl) G 2- (diphenylmethoxy) -2-oxoethoxy imino acetyl amino f-2-oxo-1-azeti - dinsulfonic acid. Completion of the procedure described in Example 28 and the replacement of (Z) -2-amino
27
-ol. (2 (diphenylmethoxy) -1, 1-dimethyl - 2 oxoethoxyimino | 4 thiazoleacetic acid (7.) - 2 amino o. (D. Phenylmethoxy 2-oxoethoxy1imo | 4 thiazoleacetic acid gives the target compound, so pl. Decomp.
Example 31, Potassium salt 3S (+) - 3 (azidophenylacetyl) amino 2 oxo 1 azetidine sulfonic acid.
Method I.
A., Ci-o / .- Azido H-2-oxo 3 aze tidinyl (benzene-acetamide)} 3 amino 2 azetidinone (2.15 g. See Example 5A)
and 2, 1 g of sodium bicarbonate are dissolved in 50 ml of a mixture of acetone and water (2: 1). (+) - 6L-azidobenzeneacetyl chloride (5 g) is added dropwise while maintaining the temperature at, the pH is maintained at 6.8 sodium bicarbonate. After stirring for 1 hour, the acetone is distilled off, and the remaining aqueous solution is adjusted to pH 8 with sodium carbonate and extracted with three 50 ml portions of methylene chloride. Evaporation of the dried organic layers of sodium sulfate gives 3.6 g of the title compound as an oil, which crystallizes after trituration. simple ether. Recrystallization from a mixture of methylene chloride - ether gives the target compound, so pl. ,
B. Kaliev salt of 3S (j) -3- (azidodophenyl-acetyl) -amino -2-oxo-1-azetidine sulfonic acid.
I
A solution of 2.45 g of the azeti named
dinone and 3 g of monosilyl trifluoroacetamide in 20 ml of acetonitrile are held for 1 hour at 40 ° C. After cooling to 0 ° C, the solution is treated with 1.88 g of trimethylsilyl chlorosulfonate and stirred for 5 hours under argon atmosphere. Finally, 6.12 ml of 2N are added. a solution of potassium 2-ethyl hexanoate in n-butanol, and stirring is continued for 45 minutes. The solution is taken up in 300 ml of ether and the precipitate is filtered off. A filtered solution of 1.2 g of precipitate in phosphate buffer (pH 5.5) is chromatographed on 100 ml of HP-20. The elution is carried out in the following sequence: 20 ml of buffer, 200 ml of water, 200 ml of water-acetone (9: 1), 200 ml of water-acetone (3: 1) o. Elution is controlled using those (Rydon-TecT on oxy7298128
Si Flint). 25 mm fractions are selected and 280 mg of the title compound is obtained from fractions 15 and 16. A second chromatography on column 5 of this substance gives 120 mg of the title compound, so pl. 148 ° C (decomp.).
Calculated,%: C 39.87; H 3.04; N 21.14; K 11.80.
C 0 Found,%: C 39.21; H 2.52;
N 21.33; K 13.01. Method But
Tetrabutylammonium salt of (s) -3-amino-2-OKco-l-azetidine sulfonic acid
5 (2.03 g, see Example 6A) and 0.9 g of (j) -oL-azidobenzene-acetic acid are dissolved in 30 ml of acetonitrile, then a solution of 1.03 g of dicyclohexylcarbodiimide in 10 ml of acetonitrile is added. The temperature is maintained for 1 hour at 0 ° C and for 10 hours at room temperature. After filtering off the precipitated precipitate, the solvent is distilled off in vacuum and
5 liters of the residue is dissolved in 20 ml of acetone and 1.70 g of potassium perfluorobutane sulfonate in acetone is treated. The addition of 10 ml of ether causes the crystallization of the target compound.
Q Neni, so pl. 149 ° C (decomp.). Method III.
o - Azidophenylacetyl chloride (2.5 g) is added to a solution of 4.06 g of the 3-amino-2-oxo- tetrabutylammonium salt. -1-azetidine sulfonic acid (see Example 6A) and 5 g of propylene oxide in 30 ml of acetonitrile. After stirring for 2 hours, the solvent is distilled off in vacuo and the oily residue is absorbed, working one equivalent of the amount of potassium perfluorobutane sulfonate in acetone. After the addition of ether, the title compound crystallizes, which is filtered off; mp. 148-149 ° С (decomp.,) „
Example 32. Kaliev salt
3S (D) -3- {(4-methoxyphenyl) methoxy-carbonyl amino phenylacetyl amio--2-oxo-1-aza tidine sulfonic acid.
To a solution of 2.03 g of tetrabutylammonium salt of 3-amino-2x co-1-azetidine sulfonic acid (2.03 g, see example BL) and 1.58 g of D-oL - {(4-methoxyphenyl) methoxy-5 carbonyl amino | benzeneacetic acid in 50 ml of acetonitrile is added dropwise a solution of 1.03 g of dicyclohexylcarbodiimide in 10 ml of acetone
nitrile. The temperature is maintained for 1 h and is equal to 6 hours at room temperature. Separating the sample with dicyclohexyl urea and distilling off the solvent gives the target compound as an oily residue. Treatment of this oil in an admeton with potassium perfluorobutane sulfonate and ether gives 2.4 g of product, mp. lOe-lll C (decomp.).
Examples 33-37. Performing the procedure of Example 32 and replacing (c) (| (4 methoxyphenyl) methoxy carbonyl amino benzene acetic acid (c) -c1- {(4 methoxyphenyl) methoxy carbonyl amino 2-thiophene acetic acid) gives the potassium salt 3S (D) l-3 (f (4 methoxyphenyl) methoxy carbonyl NIL amino -2-thienylacetyl amino -2-oxo) -azetidine sulfonic acid, t, pl. 144-146 C (decomp.); (+); no-o1- (4-methoxyphenyl ) methoxy carbonyl-amino-4-thiazoleacetic acid - 3S (+) - 3 - ((2-amino-4-thiazolyl) - (4-methoxyphenyl) methoxy-carbonyl amino acetyl amino -2-oxo-1; -azetidine sulfonic acid, potassium salt ,, mp. 232 - 234С; ((- ((4-methox Ifenyl) methoxy carbonyl aminoj-2-furanacetic acid - 3S (O-3- ((2-furanyl) (4-methoxyphenyl) methoxy carbonyl amino acetyl | amino-2-oxo-1 azetidine sulfo-acid, potassium salt, t „pl 124-126 ° C (decomp.); (L) -d- (methoxyphenyl) methoxy carbonyl amino | benzeneacetic acid - (CZ, CHI) -3- {(4-methoxyphenyl) methoxy carbonyl amino -2-phenyl acetyl amino - 2-OXO-azetidine sulfonic acid, potassium salt, t. Pl. 172-175C; (B) -Y- {(4-methoxyphenyl) -methoxy carbonyl amino -2-thiophene-acetic acid — potassium salt (3S) (L) (methoxyphenyl) methoxy-carbonyl amino.-2-thienyl acetyl-amino} -2-oxo- 1-azetidine sulfonic acid, t, mp 146-148 ° C.
Example 38. (3S) (Methylthio) thioxomethyl thiophenylacetyl j amino -2 oxo-1-azetidine sulfonic acid, its tetrabutylammonium salt.
A solution of 1.03 g of (2) - (/ - / (methylthiothioxomethyl thiobenzeneacetic acid and 1.63 g of tetrabutylammonium 3 amino acid 2-oxo-1-azetidinsulfonic acid, (see Example 6A) in 30 ml
72981: And)
acetonitrile is treated (.It is added to 0.8 dichlorohexylcarbodiimide, dissolved in a mixture of 10 ml of acetoshyl). After stirring for approximately 16 hours, the dicyclohexylurea is filtered off and the mother liquor is evaporated. The residue is dried. silica column
10 (ethyladetate-methanol-Boda 8.5: 1: 0.5 is the eluent), giving 1.3 g of the title compound.
Example 39, Kaliev salt 3 (S) -3- {(methylthio) thioxomethyl
15 THoJphenyl-acetyl-amino} -2-oxo-1 - -a-z etid in sulboc and ate.
The tetrabutylammonium salt of 3 (s) ((methylthio) thioxomethyl thiophenyl acetyl amino -2-co-1-aze tidin20 sulfonic acid (1.3 g, see example 38) is dissolved in acetone and treated with an equivalent amount of potassium perfluorobutane sulfonate. The addition of ether gives crystallization
5 of the target compound that is filtered out. Product Code O, 18 g, so pl. (different).
Example 40. The potassium salt of ZE (c) -3 - {(4-ethyl-2,3-dioxo-1-piperazinyl) carbonyl amino -2-thienyl adylethyl amino [-2-oxo-1-azetidine sulfonic acid.
(D) -O (.- {(4-Ethyl-2,3-dioxo-1-piperazinyl) carbonyl amino -2-thiophene5 acetic acid (3.25 g), 4.20 g of 3-amino-2-tetrabutylammonium salt - -oxo-1-azetidine sulfonic acid (see Example 6A) and 1.3 g of N-hydroxybenzotriazole are dissolved in 25 mt of acetonite.
0 reel. The dropwise addition of 2.06 g of dicyclohexylcarbodiimide, dissolved in 10 ml of acetonitrile at -10 ° C, takes 20 minutes, stirring lasts about 6 hours. Formed with
5, the urea is filtered off and the solvent is evaporated in vacuo. The remaining oil is dissolved in 50 ml of acetone and after treatment with an equivalent amount of perfluorobutane sulfonate.
0 Potassium target compound crystallizes, m.p. 185-187 ° C (decomp.).
Example 41, Potassium salt of 3S (+) - 3- (bromophenylacetyl) amino -2 OXo-1-az et) women of sulphonic acid.
5 o (β-Bromophenylacetyl chloride (1.4 g) in 10 ml of acetonitrile is added dropwise to a solution of 5 mmol of tetrabutyl ammonium salt of 3-amino-2-oxo-1-azethidine sulfonic acid and 3 g of propylene oxide in acetonitrile at O C. After stirring for 3 hours, the solvent is distilled off, and the remaining oily residue is dissolved in 30 ml of acetone. An equivalent amount of perfluorobutane sulfonate is added in acetone. Addition of ether gives crystallization of the target compound, mp 135 137 ° C (decomp.) P r and m, e 42. Potassium salt 3S (j) (aminocarbonyl) amino -2 thienylacetyl amino | 2 oxo 1-azetidine sulfonic acid. Method 1o To a solution of 2 g of tetrabutylammonium salt (8) 3-amino 2 oxo azetidine sulfonic acid and 1.5 g of propylene oxide in acetonitrile, 1, 1 hydrochloride () 2 amino 4 - (2-thienyl 5- (4H) -oxozolone. After stirring for 3 hours at 0 ° C and for 11 hours at room temperature, the solvent is distilled off, and the oily residue is dissolved in 30 ml of acetone. When adding the equivalent the amount of potassium perfluorobutane sulfonate in acetone the target compound crystallizes. Purification by chromatography on an HP-20 column using water as eluant gives the desired compound, t.p. 218-222 ° C (decomp.). Method Ho Suspension 2 g of (+) -y .- {aminocarbonyl amino -2-thiopheneacetic acid, 10 mmol of tetrabutylammonium salt (8,) - 3-amino-2-oxo-1-azetidine sulfonic acid and 10 mmol of I-hydroxybenzotri 10 ml of dicyclohexylcarbodiimide dissolved in 15 ml of acetonitrile are added with stirring in 50 ml of acetonitrile at 0 ° C. The potassium continues for 1 hour at -15 ° C and about 16 hours at room temperature. After the dicyclohexyl urea is filtered off, the solvent is evaporated and the oily residue is dissolved in 50 ml of acetone. Adding an equivalent amount of potassium perfluorobutanesulfonate in acetone gives a crystalline product. Purification by chromatography on an HP-20 column using water as eluant gave the title compound, mp. 220-223 ° C. Example 43. 3S (j) -3 - ((methyl, amino) to arbonyl amino} -2-thienylacetyl, amino} -2 oxo 1-azeT1-zincyl sulfonic acid, potassium salt. (+) - (Methylamino) carbonyl amino -2- thiophene acetic acid (0.54 g) and 1, 00 g of tetrabutylammonium (S) -3-amino-2-oxo-1-azetidine sulfonic acid (see Example 6A) dissolved in 20 ml of acetonitrile, then added 0.5 g of dicyclohexylcarbodiimide is added. After stirring for 8 hours, the dicyclohexylurea is filtered off and, after distilling off the solvent, the oily residue is dissolved in 50 ml of acetone, then an equivalent amount is added. potassium perfluorobutane sulfonate.The crystalline product is filtered off and purified on HP-20 using water S as eluent, mp 205 ° C (decomp.) Example 44. 3S (j) -3- | (Aminooxoacetyl) amino - 2-thienylacetyl amino -2 Oxo-1-azetidine sulfonic acid, potassium salt. Following the procedure of example 42 (method II), but replacing (+) -o (- (aminocarbonyl) amino 3-2-thiophenoacetic acid (+} -ci. - (aminooxoacetyl) amino 2-thiopheneacetic acid, get the target compound, so pl. 218-222 C. C. Example: 45 (n) -3- {(4-Ethyl-2, 3-dioxo-1-piperazinyl) -carbonyl amino-phenylacetyl-amino-2-ox- 1-azevtindinsulfonic acid, potassium. Following the procedure of Example 40, but replacing (D) -di- {(4-Ethyl-2,3-dioxo-1 piperazinyl) carbonyl amino-thiophenoacetic acid (k) -oC - (((4-ethyl- 2, 3-dioxo-1-piperazinyl) carbonyl amino | -2-benzeneacetic acid, the title compound is obtained, mp 155-157s (decomp.) Example 46. Potassium salt of 3- (acetylamino) -3-methoxy-2 -oxo-l- -azetidine sulfonic acid Method I A. 3- (N-acetyl-N-chloro) amino -2-yuxo 1 azetidine sulfonic acid mixture of sodium and potassium salts To a solution of the potassium salt of 3- (acetylamino) -2 - oxo-1 -azetid insulfonic acid (172 mg, see example 23) in methanol (17 ml) containing 4% sodium borate decahydrate, to (-10) - (-15) s, an additional 33 tert-butyl hypochlorite (110 µl) is added. The mixture is stirred in the cold for 1 h 45 min, poured into a 0.5 M solution of potassium monobasic phosphate (50 ml), and The pH is reduced to 5.5, the Solvent is removed under vacuum, and the residue is dissolved in a minimum amount of water and chromatographed on HP-20AG, 100-200 mesh. (140 ml). Elution with water gives an oil (63 mg which crystallizes on standing. Trituration with methanol-ether mixture and then gives ether (53 mg) with ether. Mp. 124 ° C (slow decomposition). V. Kaliev salt 3 - (acetylamino) -3-methoxy-2-oxo-1-azetilinsulfonic acid. 3-C (N-acetyl-N-chloro) amino -2-occo-1-azetidine sulfonic acid B of its mixed salt (37 mg) is dissolved in 1 , 5 Nm of dry dimethylformamide and added: to a solution of lithium methylate (50 mg) in methanol (1 ml) at. After stirring for 15 min at -78 ° C, a 0.5 M solution of monobasic phosphorus is added sulphate oil (10 ml) and the solution is then acidified to pH 4 with 1N hydrochloric acid. Acid tetrabutylammonium sulfate (70 mg) is added to the solution, and the solution is extracted four times with methylene chloride. The combined extracts are dried with sodium sulfate and the solvent. removed in vacuo. Pol (from 55 mg of oil. Chromatography on 5.5 g of silica gel gives an oily product (41 mg) as a tetrabutyl ammonium salt (eluted with 8% methanol, 92% methylene chloride). The oil (31 mg) is dissolved in water and passed through an ion exchange column (5 ml of AG 50W-X2, K-form, 200-400 mesh, 0.6 meq / ml). Removal of the water in vacuo gives an oil that crystallizes from a mixture of methanol and ether. Rubbing the dvanr; s with ether gives the product in vvde colorless powder (11 mg); m.p. 182-183s (decomp.) „Method II. A. Tetrabutylammonium salt of 3-amino 3-methoxy-2-oxo-1 -azetidine sulfoquielty 4% sodium borate decahydrate in methanol solution (100 µl) is added to a suspension of 10% palladium on activated carbon (3D mg 8134 in methanol (2 ml), and a mixture of iiepeMeiijH- is kept in a hydrogen atmosphere for 15 minutes. The tetrabutylammonium salt of 3-methoxy-2-oxo-3- (phenylmethoxy) carbonyl JaMHHo -1-azetidine sulfonic acid (60 mg, see example 49) in methanol (2 ml) and the mixture is stirred vigorously for 15 minutes under a hydrogen atmosphere. The catacter is removed by filtration through zeolite and a milli pore filter (0.5 mmk), and the solvent is removed from the filtrate under vacuum, and the residue is extracted with methylene chloride. Removal of the solvent under reduced pressure gives 35 mg of the title compound as an oil. B. Potassium salt 3- (acetylamino A) -3-methoxy-2-oxo-1-azetidine sulfonic acid. To a solution of the tetrabutylammonium salt of 3-amino-3-methoxy-2-oxo-1-azetidine sulfonic acid (35 mg) in methylene chloride (10 ml) at 0 ° C is added propylene oxide (2 ml) and acetyl chloride (74 µl). After 2 hours, the solvent is removed under reduced pressure, and the residual oil is chromatographed on silica gel (4 g). Elution with 6–8% methanol in methylene chloride gives an oil (18 mg), which is dissolved in water and passed through an ion exchange resin (3 ml of AG 50W-X2, K®-form, 0.6 meq./ml) o Removing the water from the eluate in vacuo gives the desired product (10 mg). PRI. MER 47. Kaliev salt of N- (3-methoxy-2-oxo-sulfo-3-azetidinyl) -2-phenylacetamide. The N- (3-me-Itoxy-2-oxo-1-sulfo-3-azetidinyl) -2-phenylacetamide tetrabutylammonium salt (91 mg, see Example 47) is dissolved in water and passed through an ion exchange column (10 ml AO 50W). -X2, K-form). The eluate is concentrated in vacuo and the residual oil is solidified by stirring with a mixture of methanol - acetone - ether. After trituration twice with ether, the product is obtained as a solid (53 mg) 1762, 1665 cm. NMR spectrum (CDjOD), S: 3.41 (s, 3N, OCH); 3.59 (s, 2H, CH); 3.84. (ABq, J 6.3 Hz, 2H, HJ; 7.30 (m, 5H, aromatics). Calculated,%: C 39.88; H 3.62; N 7.75. 7.7Sc 1 |;: ; 1/2 and „o) 2 1L 62 Found,%: C 39.62; And 3.65; N 7.60. Example 48, Tetrabutylammonium salt 3, methoxy2 oxo 3 GKfe, nilmethoxy) carbonyl amino 1-azeti dinysulfonic acid. Method I, A.Tetrabutylammonium salt SI-chloro-N- (phenylmethoxy) carbonyl aiijHHo -1 -azetidine sulfonic acids. Tetrabutylammonium salt (s) -2 Oxo-3-f (phenylmethoxy) carbonyl amino 1 azetidine sulfonic acid (0.9 g, see Example 4), dissolved in 80 ml of methylene chloride, is added to the decagid cooled to a mixture of 3.17 g Add sodium borate and 11.8 ml of a 5.25% solution of sodium hypochlorite in 70 ml of water. The reaction mixture is stirred vigorously for 55 minutes while cooling in an ice bath. After the mixture was added with a 0.5 M solution of potassium mono-basic phosphate, the product was extracted with methylene chloride (three 150 ml portions). Combining the extracts, drying with sodium sulfate and removing the solvent in vacuo gives the desired compound as an oil (, 0.94 B. Tetrabutylammonium salt 3-me TOXI-2-OXO-3- (phenylmethoxy) -carbonyl amino} -1-azetidine sulfonic slots A solution of 2-oxo-3-K-chloro-K (phenylmethoxy) carbonyl amino} 1-azetid is added to a stirred solution of lithium methylate (667 mg) in anhydrous methanol, (10 ml) at -78 ° C tetrabutylammonium insulphonate (0.94 g) in dry dimethylformamide (10 ml); After stirring the mixture at -78 ° C for 1 h, it is poured into a 0.5 M solution monoaxially potassium phosphate and extracted with methylene chloride (three 150 ml portions). The combined extracts are dried with sodium sulfate and the solvent removed in vacuo. An oil (0.83 g) is obtained. After chromatography of the oil on silica gel (100 g) and elution with 4- 5% NaM in methylene chloride gives 513 mg of the desired product (pure): 1767, 1720 cm. MQKC NMR spectrum (CDClj), S: 3.40 (s OSS), 3.03 (ABq, J 6.5 Hz, N.); 5.08 (s, OH,); 6.00 (s, Ш); 7.27 (s, aromatics) Method II 81 To a solution of the potassium salt of 3-benzyl carbonate and icarbonylamino-3-methoxy-2-oxo--1-azetidine sulfonic acid (400 mg) in water is added a 0.1 M solution of tetrabutylammonium bisulfate (10.9 ml, adjusted to pH 4.3 with potassium hydroxide), the mixture is extracted three times with methylene chloride, the extracts are combined, dried with sodium sulfate, and the solvent is removed in vacuo to give a foam (625 mg), and spectral characteristics approximating the characteristics of the product of method I, Example 49 about Kaliev salt of 3-methoxy-2-oxo-3- (phenylmethoxy) carbonyl amino -1-azetidine sulfonic acid. Method I. A. Kaliev salt of 2-oxo-3-N-chloro-N- (phenylmethoxy) carbonyl-amino--1-azetidine sulfonic acid. To a solution of the potassium salt of (s) -2-oxo-3- (phenylmethoxy) carbonyl aMH but -1-azetidine sulfonic acid (1.00 g, see Example 3) in methanol (90 ml) containing 4% borate decahydrate sodium, yri is added with tert-butyl hypochlorite (420 µl). After stirring for 2 hours at 10 ° C, a 0.5 M solution of potassium phosphate monobasic (100 ml) is added and the pH is adjusted to 61 n. hydrochloric acid. After concentration of the solvent in vacuo to 30 ml, the aqueous solution is chromatographed on nR-20AC, 100-. 200 msec (200 ml) After passing the solution, monobasic potassium phosphate (50 g) in water (1000 ml), followed by washing with water (2000 ml), the product is eluted with a mixture of 10% acetone and 90% water. The solvent is removed in vacuo, and the title compound crystallizes from water, giving a solid (530 mg), t, pl. 173 175 ° C, B, Kaliev salt of 3-etoxy-2 oxo-3- (phenylme-to-si) carbonoyl amino} -1-azetidine sulfonic acid. To a solution of lithium methylate (874 mg) in dry methanol (10 ml) at 78 ° C is added the potassium salt of 2-oxo 3H-chloro-K (phenylmethoxy) carbonyl amino} -1-azetidine sulfonic acid (857 mg) in dry dimethylforimide ( 13 ml). After 15 minutes at -78 ° C, the mixture is drunk in a 0.5 M solution of potassium phosphate monobasic (200 ml) and the pH is adjusted to 5.5 with 1N. hydrochloric acid. The aqueous mixture is washed with methylene chloride (three 100 ml portions) and tetrabutylammonium bisulfate (1.169 g) is added. The product is extracted with methylene chloride (three 200 ml portions), dried with sodium sulfate, filtered and concentrated in vacuo. The residual oil is chromatographed on silica gel (150 g) and the product eluted with 2-4% methanol in methylene chloride, giving the tetrabutylammonium salt of the product as an oil (701 mg). A portion of the oil (51 mg) is dissolved in water and passed through an ion exchange. column (3 ivtn AG 50W-X2, 200-400 mesh, K®-form, 0.6 meq / ml). Concentration of the eluate in vacuo gives oil (30 mg), which crystallizes when mixed with acetone: (KVg): 1760, tc f 1725 cm, NMR spectrum (0,), S: 3.48 (s, 3N OCH); 3.92 (s, 2H, H); 5.20 (s, 2H g for I-UJ .kl. I.J 4) -... CH, j); 7.42 (s, 5H, aromatics), mp 196-198 ° C. Method II, AO 1 Chloro-3-G-chloro-H- (phenylmethoxy) carbonyl -2-aetidinone. A solution of 3- (phenylmethoxy) carbonyl and amino -2-azetidinone (440 mg cm, Pro 2c) in 40 ml of 4% methanol borax is cooled to, 0.5 ml of tert-butyl hypochlorite is added to it. After 30 minutes at 0 The solution is poured into 200 ml of cold water and extracted with two 100 ml portions of ethyl acetate. The combined ethyl acetate nish layer is washed with water, dried and evaporated to give 546 mg of the title compound as an oil, B. 3-Methoxy-3- (phenylmethoxy) carbonyl 1-amino 2-azetidinone. A solution of 730 mg (0.0025 mol) of 1-chloro-3-M-chloro-H- (phenylmethoxy) carbonyl amino 2-azetidinone in 5 mp tetrahydrofuran cooled to-78 4 ml of methanol containing 285 mg of methylate was added. lithi. After 20 minutes at -78 ° C, 0.6 ml of acetic acid and 0.6 ml of trimethylphosphite are added. The solution is stirred for 5 minutes at -78 ° C, allowed to warm to ambient temperature and stirred for 30 minutes. The resulting solution is diluted with ethyl acetate, washed with 5% sodium bicarbonate, water, 5% sodium bisulfate, water, brine, and dried. Removal of the solvent gives an oil that is applied to four silica gel plates having a size of 20x20 cm x 1 mm. The appearance of a 1: 1 mixture of benzene and ethyl acetate and the removal of the main UV active band from R / 0.25 gives 91 mg of an oil that crystallizes from ether. A solid is obtained. Recrystallization from ether gives the desired compound, m.p. 112-114 ° C. C. Kaliev salt of 3-methoxy-2-ox-so-3- (phenylmethoxy) carbonyl amino - -1-azetidine sulfonic acid. A solution of 25 mg of 3-methoxy-3- (phenylmethoxy) carbonyl of amino -2-azetidinone in 0.175 ml of dichloromethane and the same amount of dimethylformamide is mixed 24 hours with 55.4 mg of the pyridine-sulfur trioxide complex. The resulting suspension is diluted with 5 ml of cold 0.5 M potassium phosphate monobasic (adjusted to pH 4.5) and extracted with ethyl acetate. The aqueous layer is applied to a 40 ml HP-20 AG column. Elution with an additional amount of buffer, water, and a water-acetone mixture (9: 1) gave 32 mg of the title compound as an oil, which slowly solidified. Crystallization from acetone gives the target compound with mp. 196-198 C (decomp.) Example 50. Potassium salt 3 of 1,3-dioxo-2-phenyl-3- (phenylmeto-toxi) propyl amino-3-methoxy-2-ox-1-azetidine sulfonic acid. A, Tetrabutylammonium salt of 3- - l, 3-dioxo-2-phenyl-3- (phenyl marks C) propyl amino-3-methoxy-2-oxo-1-azethidine sulfonic acid. The crude Tetrabutylammonium salt of 3-amino-3-methoxy-2-oxo-1-azetidine sulfonic acid (431 mg, see example 74), containing borax, is dissolved in 30 ml of dry acetonitrile. Dry pyridine (µL) is added, and the solution moves well at -10 ° C in a dry nitrogen atmosphere. Is added dropwise with -benzyloxycarbonylphenylacetyl chloride (568 mg) in 3 ml of dry acetonitrile. A slurry chromatography shows that the reaction is complete after 15 minutes. Potassium phosphate buffer (0.5 M, pH 5.5, 17 ml) is added, and more. part of the acetonitrile is removed in vacuo. The residue is diluted with water and
: 59
extracted three times in equal volumes of methylene chloride. The extract is dried with over anhydrous sodium sulphate and evaporated in vacuo to give 1.032 g of the crude product, which is dissolved in 3 ml of ketylene chloride and chromatographed on a silica column using methylene chloride methanol. 470 mg of the title compound are obtained.
B. Kaliev salt, 3-dioxo; 2-phenyl 3 (phenylmethoxy) propylamino-3 methoxy 2 oxo 1 azetidine sulfonic acid.
Tetrabutylammonium salt, 3 Dioxo 2 phenyl 3 (phenylmethoxy) pro saws amino 3 methoxy 2 oxo 1 azeti dinysulfonic acid (470 mg) is dissolved in 15 ml of acetone: water and passed through a Dowex 50WX2 column (form) using the same solvent as eluent. The entire eluate is evaporated in vacuo to give 345 mg of an amorphous solid, which is lyophilized to an amorphous powder, m.p. WITH.
Calculated,%: C 49.37; H 3.94; N 5.76; S 6.59
Found,%: C 49.08; H 4.00;
N 5.58; S 6.29.
Example 51. Potassium salt 3 (+) -3 - (cyanomethyl) thio acetyl 1 amino | 3 methoxy 2 oxo 1 azetidinsul fokieloty.
To a solution of 3 amino 3 methoxy 2 oxo 1 aze tidinsulfonic acid tetrabutylammonium salt (414 mg, see DIRECT 74) in dry acetonitrile (50 ml) at 20 ° C is added diethylaniline (210 µl) and cyanomethylthioacetyll reed (169 mg) o Through U The solvent is removed under reduced pressure at the Scientific Research Institute, and a 0.1 M solution of tetrabutylammonium sulfate (22.8 ml) is added to pH 4.3 with LIA hydroxide. The product is extracted with three 50 MP portions of methylene chloride, dried with, filtered and concentrated under reduced pressure. The oily residue is purified on silica gel (60 g), and the product is eluted with a mixture of methanol and methylene chloride. The purified product is passed through an ion exchange resin (16 mp AG 50W-X2 (K®-form), 0.6 meq / ml mesh). Removal of water gives 164 mg of partially purified product. Product dopol
7298140
Purified relatively well on Diaion AG (100 ml) using water as eluent. The solvent is removed under reduced pressure, to give 126 mg of product, which is diluted with ether. 76 mg of the title compound are obtained. Mp. 110 125С,
Calculated,%: C 27.66; H 2.88; , 0 N 12.10; S 18.44.
.N.S.
n / a,%: C 27.25; H 3.00 N 10.84; S 17.53.
Examples Following d, the procedure of example 42, method II, but using (+) -oL (aminocarbonyl) amino 2 thiophenacetic acid instead. (+) o (. (aminooxoacetyl) amino 2 furanacetic acid) gives the potassium 2 nd salt 3S (+) - 3 (amino oxo acetyl) amino 2 furanyl amino amino 2 oxO 1 azetidine sulfonic acid, mp, C (decomp.). As a result, using (+) - o (.- {(cyanomethyl) am JC but oxoacetyl amino 2 thiophenoacetic acid) gives the potassium salt 3s (+) (cyanomethyl) amino oxo acetyl amino -2-7 thienylacetyl amino 2 oxo 1 azetidine sulfonic acid, mp 195 197 C (dec.); (R) -o (, - (aminooxoace
30 thyl) amino benzene acetic acid potassium salt 3S (R) (amino oxo acetyl) amino phenylacetyl amino} 2 oxo 1 azetidine sulfonic acid, so pl. 207 209C.
 (K) -Y- (aminocarbonyl) amino benzene acetic acid, potassium salt 3S (R) (aminocarbonyl) amino phenylacetyl amino 2 oxo 1 azetidine sulfonic acid, t. Pl. 225 ° C (decomp.). Example 56. Potassium salt C (j) (2 methylthio) -1 oxopro sawed amino -2 oxo 1 azetidine sulfo acid.
Following the procedure of Example 31, method 5 IIIJ but replacing (+) -o-aaidobenzene acetic acid (+ U-2- (methylthio) propanoic acid, it is possible to obtain the target compound with mp 173s (decomp.).
Example 57. Potassium salt 0 3S (R) 2,3 dioxo 4 (phenyl methylene) amino-piperazinyl 1carbo NILE 1 amino phenylacetyl amino 2 oxo 1 azetidine sulfonic acid,
(R) -o (- {2,3 dioxo-H (phenylmethylpylen) amino 1-piperazinyl-Ccarbonyl amino-benzeneacetic acid (0.7 g) and (3) -3 amino 2-oxo-1 azetidine sulfonic acid in the form of tetrabutylammonium 41 salts (0.8 g, see Example 6A) are dissolved in 20 ml of acetonitrile. While stirring, 0.4 g of dicyclohexylcarbodiimide is added dropwise at. The stirring is continued for 18 hours. After filtration, the solvent is distilled off. An oily residue is left which dissolves in acetone and treated with potassium perfluorobutanesulfonate to precipitate the target compound. chromatography on a HP-20 column using water as eluent gives the target compound, mp 193-194 ° C. Example 58, Potassium salt f3S (Z) J-3 - ((2-amino-4-thiazolyl (2-methoxy-2-bxoethoxy) imino acetyl amino -2-oxo-1-azetidine sulfonic acids., (D) 2-amino-o1- (2-methoxy-2-oxoethoxy) imino-4-thiazo-acetic acid: lot (1.3 g) and (8) -3-amino-2-oxo-1-azetidine sulfonic acid tetrabutyl ammonium salt (2.03 g, see example 6A) is dissolved in 50 mp of acetonitrile. 1.03 g of dicyclohexylcarbodiimide, dissolved in 5 ml of acetonitrile, is added at 0 ° C. After stirring for 15 hours and filtering off the decyclohexylurea, the solvent is distilled off. The remaining oily substance is dissolved in acetone and treated with an equivalent amount of potassium perfluorobutane sulphate. The target compound is isolated and purified by column chromatography on HP-20 using water as eluant to give the title compound with a mp of 195-198 ° C. Example 59. The potassium salt of 3S (R) (4-chlorophenyl) me: tyleno amino -2-oximidazol 1 dinyl, carbonyl amino phenylacetyl amino [-1. Azetidine sulfonic acid. Tetrabutylammonium salt of (S) -3-amino-2-oxo-1-azetidine sulfonic acid (1.5 g, see Example 6A) in 100 ml of absolute diglyme (diethylene glycol dimethyl ether), 1.5 g i R) 3- (4-chlorophenyl) methylene amino -2-oxo-1-imidazolidinyl carbonyl benzene acetic acid, equiv., Penta amount of dicyclohexylcarbodiimide and 0.5 g of oxybenzotriazole are stirred for 12 hours. The solvent is removed in vacuo, and the residue is dissolved in 50 ml acetone and filtered. The acetone is distilled off and the residue is dissolved in 200 ml of methylene chloride. The solution is washed with aqueous sodium bicarbonate and then with an aqueous solution of sodium chloride. The methylene chloride layer is dried over sodium sulfate, evaporated to dryness and crystallized by the addition of ether. The compound is recrystallized from acetone-ether. The resulting white crystalline powder is dissolved in acetone and treated with an equivalent amount of potassium perfluorobutane sulfonate in acetone. The title compound precipitates and is filtered off, to give 1.4 g of product with m.p. 217-222c. Calculated,%: C 42.42; H 3.88; 13.49; S 5.14. C AoClKN. Found,%: C 42.77; H 3.62; N 12.72; S 5.16. Example 60. Potassium salt t3S (R) -3- {2-oxo-3- (phenylmethylene) -amino -1-t midazolidinyl carbonyl amino. Phenylacetyl} amino 1 -I-azetidine sulfonic acid. Tetrabutylammonium salt of (s) -3-amino-2-oxo-1-aetidine sulfonic acid (2.25 g, see Example 6A) in 100 ml of dry dimethylformamide (DMF), .- equivalent amount of dicyclohexylcarbodiimide, 2.5 g (R) -oL- {2-oxo-3-. - (Phenylmethylene) amino -1-imidazolidinyl carbonyl amino-benzene acetic acid and 0.85 g of oxybenzotriazole are stirred at ambient temperature for 12 hours. After that, DMF is removed in vacuo, and the residue is dissolved in 50 ml of acetone. The precipitated urea is filtered off, and the mother liquor is treated with an equivalent amount of potassium perfluorobutane sulfonate in 20 ml of acetone. After adding 100 ml of ether, the title compound precipitates and is filtered off. Purification is performed by dissolving the compound in a mixture of DMF - acetone and precipitating with water. "1.5 g of product is obtained, m.p., 224226 ° C (decomposition) calculated:%: C 44.89; H 4.28; N 4.38; S 5.44 C „H ,, 5 Found,%: C 44.97; H 3.81; N 14.30; -S 5.13. i) i and m e p 61. Kalievl salt SG; (L) -3 - {I 3 (methylsulfonyl) 2 oxo 1 imidazolidinyl carbonyl amipophenylacetyl amino | 2-oKco-l azetidine sulfonic acid. The tetrabutylammonium salt of (s) -3-amino 2-oxo 1 azetidine sulfonic acid (2.25 g, see example bl) and 60 ml of dimethylformamide are stirred for 12 hours from 1.9 g of (n) -o. (Methyl sulfonic) -2 oxo 1 imidazolidI nylbenyl a benzo acetic acid, 0.75 g hydroxybenzotriazole and 2.3 g dicyclohexylcarbodiimide. The solvent is removed in vacuo, and dissolved in 20 ml of acetone filtered. The mother liquor is treated with 1.87 g of potassium fluoride perfluorobutansul and 20 ml of acetone. After the addition of ether, a precipitate of 2.0 g of the title compound precipitates out, which is purified by recrystallization from water and has a melting point of approx. 240 245С (decomp.) Calculated,%: C 35.22; H 3.69; N 12.84; S 11, 75, C., Found,%: C 35.15; H 3.35; N 12.82; S 11.26. Example 62. The potassium salt of 3S (R) -3 (oxophenylacetyl) amino 2 oxo 1 azetidine sulfonic acid. Tetrabutylammonium salt of (s) -3 amino 2 oxo1 azetidine sulfonic acid (1.5 g, see Example 6A) and 100 ml of dry dimethylformamide is stirred for about 16 hours with 1.5 g of dicyclohexyl carbodiimide, 0.5 g of oxybenzotriazole and 0.6 g e-o (.-hydroxybenzeneacetic acid. The solvent is removed in kuum, and the residue is dissolved in acetone 20. The precipitated urea is filtered off, and the mother liquor is treated with an equivalent amount of potassium perfluorobutane sulfonate. After adding simple ether, the target compound precipitates sediment and filtered out by giving 1.3 crude product. The product is purified using chromatography using HP-20 and a mixture of water and acetone (9: 1) as eluent and has a melting point of 145-150 ° C (decomp.) Calculated: C 38 , 03; H 3.48; N 8.06; S 9.23. C, H „KI, C S / QH O Found,%: C 38, G2; H 3.23; N 8.10; S 8 , 94. 81 Example 63. Kaliev salt of 3S (P /) (hydroxyphenyl-acetyl) amino 2 oxO 1 azetidine sulfonic acid. Executing the procedure of Example 63 and replacing (k) -ooxyxybenzeneacetic acid (5) -o (-oxybenzoacetic acid) gives the target compound, t pl. 195 197С. Calculated,%: C 39.04; H 3.38; N 8.28; S 9.48 n; Found: C 38.85; H 3.29; N 8.25; S 9.17. Example 64. Potassium salt (1: 2) 38 (+) (phenylsul foacetyl) amino -1 azedine sulfates of the slot. The tetrabutylammonium salt of (s) -3 amino 2 oxo azetidine sulfonic acid (2.25 g, example 6A) in 100 ml of dry diglyme, 2.4 g of triethylamine and 0.3 g of dimethylaminopyridine are cooled to 0 ° C. (k) -o (- (lorcarbonyl) benzenemethanesulfonic acid (1.8 g) in 20 ml of diglyme is added dropwise. The temperature is maintained for 2 hours, the solvent is distilled off in a vacuum, and the residue is dissolved in acetone. Undissolved the precipitate is filtered off and the mother liquor is treated with an equivalent amount of potassium perfluorobutane sulfonate. After adding ether, the target compound precipitates and is filtered off, yielding 1.4 g of crude product, pieces 240-245 ° C (dec.) after recrystallization from a mixture of water - acetone. Calculated,%: 29.99; -H 2.79; N 6.36; S 14.56. Cii H ,,, Found,%: C 29.07; H 2.35; N 6.16; S 13.71. Example 65. Potassium salt 3 S (Z) (2 amino 4 thiaz olyl) (diethoxyphosphinyl) methoxy imino acetyl amino | 2 oxo 1 azetidine sulfo acid. / Tetrabutylammonium salt (s) -3-amino-2-oxo 1-azetidine sulfonic acid (2.25 g, see example 6A) in 100 ml of dry dimethylformamide are treated with 1.87 g (g) -2 amino-o (.- (diethoxyphenyl) methoxy-imino-4-thiazoleacetic acid, 0.75 g oxybeis triazole and 2.29 g of dicyclohexylcarbodiimide for 12 hours with stirring. The precipitated urea is filtered off and the solvent is removed in vacuo. The remaining oil is treated with an equivalent amount of LIA perfluorobutanesulfonate in 20 ml of acetone. After adding ether, the target compound precipitates and is filtered off, yielding 2.77 g of crude product, the purification of which by chromatography using FIP-20 and a mixture of water - acetone (9: 1) gives the target compound as eluent, „Pl. 155-160 ° C (decomp.) O Calculated,%: C 29.82; H 3.66; N 3.88; P 5.92; S 12.25. with „n„, Found,%: C 29.91; H 3.36; N 12.45; P 5.40; S 12.09. Example 66. Potassium salt G35 (b) -3- (2-amino-4-thiazole1) 2- (1-dimethylethoxy) -2-oxo-1-phenyl-ethoxy} ynino acetyl amino -2-oxo-1- -azetidine sulfonic acid. The tetrabutylammonium salt of (S) -3-amino-2-oxo-β-azidine sulfonic acids (2.25 g, see Example 6A) in 60 ml of dimethylformamide is stirred at room temperature with 2.4 g of (z) -2-am (1, 1-dimethylethoxy) -2-oxo-1-phenylethoxy-imino-4-thiazoleacetic acid, 1 g of hydroxybenzotriazole and 1.5 g of dicyclohexylcarbodiimide for 12 hours. The solvent is removed in vacuo, and the residue is dissolved in 50 ml of acetone . The precipitated urea is filtered off and the mother liquor is treated with an equivalent amount of perfluorobutanesulfone and potassium. After the addition of ether, the target compound crystallizes and is filtered off. Purification of the compound is performed by chromatography on an HP-20 Column using a mixture of water - acetone (7: 3) c. as eluent, giving 1 g of product, so pl. 250 ° C (decomp.). o and e R 67. Kaliev salt state, / g, p ggGo 3S (Z) 1 -3 - {(2-amino-4-thiazolyl) (1H-getrazol-5-1methoxy) imino acetyl amino -2- oxo-1-azetidine sulfonic acid Tetrabutylammonium salt of (S) -3-amino-2-oxo-1-azetidine sulfonic acid (1.9 g, see Example 6A) 1.4 g of 146 (Z) -2-amino e (.-. 1 H-tetrazol-5-ylmethoxy) imino-4-thiazoleacetic acid, 0.7 g oxybenzotriazole and 1.4 g dicyclohexylcarbodiimide with stirring for 24 hours. After the solvent is removed in vacuo, the residue is dissolved in acetone and the precipitated urea is filtered off appears. The mother liquor is treated with an equivalent amount of potassium perfluorobutane sulfonate in 10 ml of acetone. The pellet compound is precipitated by adding 200 ml of ether. Purification is carried out by chromatography on a HP-20 column using HP-20 resin and water as eluent, and gives 2.05 g of product, m.p. 250 ° C (decomp.) O Example 68. Kaliev salt t3S (z) -3- ((2-amino-4-thiazolyl) (phenylmethoxy) imino acetyl amino} -2-ox-1-azetidine sulfonic acid. Tetrabutylammonium salt of (s) -3-amino-2-oxo-1-azetidine sulfonic acid (1.5 g, cm, Example 6A), 1.23 g of (Z) -2-amino-N- (phenylmethoxy) imino - -4-thiazoleacetic acid, 0.57 g of oxybenzotriazole and 1.14 g of dicyclohexylcarbodiimide are stirred in 60 ml of dimethylformamide at room temperature for 24 hours. The precipitated urea is filtered off, the solvent is removed and the residue is treated with an equivalent amount of perf. potassium orbutane sulfonate in 10 ml of acetone. After adding 200 ml of ether, the target compound precipitates, is filtered and purified by HP-20 column chromatography using water: acetone (9: 1) as eluent, to give 1 g of material with t mp 200 C (decomp.) o Example 69. The potassium salt of 3S (Z) -3-C (2-amino-4-thiazolyl) (carboxymethoxy) imino acetyl amino -2-oxo-azethidine sulfonic acid (1: 1). 3S (Z) l-3- | (2- (l4ino-4-thiazolyl) tC (2-diphenylmethoxy) -2-oxoethoxy1 imino acetyl amino -2-oxo-1-azetidine sulfonic acid, potassium salt (3 g, see example 30) is mixed with 5 ml of anisole. At -15 ° C, 25 ml of trifluoroacetic acid is added, and the mixture is stirred for 10 minutes. At 10 ° C, simple ether (100 ml) is added, followed by 50 ml of petrol ether. Sediment suspending agent
u ..
Children with ph.i.zh.plniey in a 20 ml node and adjusted to a pI of 5.0 diluted with potassium hydroxide. The product was purified by chromatography on an HP-20-column to give 3.0 g of the title compound, m.p., 230-250 ° C (decomp.).
Example 70. Potassium salt (3B (Z) -3 {(2 amino 4 thiazolyl) oxo-2 (phenylmethoxy) ethoxy imino adyl amino amino | 2-oxetidine sulfonic acid).
Following the procedure of Example 28, but replacing (Z) -2 aMHHO ol 2- (diphenylmethoxy), 1 dimethyl 2 oxoethoxy imino 4 thiazo-acetic acid (z) 2 aMHHOti ((phenylme TOXI) ethoxy-imino 4 thiazo-acetic acid, gives the target compound , t. pl. (dec) ,.
Example 71. Potassium salt t3-S (Z) -3 - {(2-amino-2 Oxoxytoxy imino (2-amino-4-thiazolyl) acetyl amino [-2-oxo-1-azetidine sulfonic acid.
Performing the procedure described in Example 28, replacing (Z) -2-amino-o 2- (diphenylmethoxy) -1,1-dimethyl -2-oxo ethoxy-imino-4-thiazole-x-hydrochloric acid (Z) -2- amino-o (- (2-amino--2-oxoethoxy) imino-4-thiazoleacetic acid gives the target compound of mp 205-210 C (decomp.).
Calculated,%: C, 27.80; H 2.50; N 19.50; S 14.80.
,, .S,
Found,%: C 27.72; H 2.69; N 19.47; S 14.95.
Example 72. The potassium salt of 3S (Z) -3- (2-amino-4-thiazolyl) (oxiimo) -acetyl amino 2-oxo-1-azetidine sulfonic acid.
A solution of 0.6 g of 90% hydroxybenzotriazole in 100 ml of dimethylformamide is stirred for 1 hour with 10 g of 4A molecular sieves, filtered, and the filtrate is added to a solution of 0.004 mol of the tetrabutylammonium salt of (S) -3-amino -2-oxo-1-azetidine sulfonic acid (see Example 6A) in dimethylformamide. (Z) -2-amino-ci- (oxyimino) -4-thia-zoluc cy C is added to the acid (0.89 g), followed by the addition of 0.91 g of dicyclohexylcarbodiimide. The mixture is stirred for about 16 hours, evaporated in vacuo, the residue is dissolved in 20 ml of acetone and filtered. Adding a solution of potassium perfluorobutanesulfonate
7298148
There is a selection of the target compound. Chromatography on HP 20 SMOLE gives 0.44 g of product, mp. .
Example 73. Potassium salt of 5 3-methoxy-2-oxo-3-1 (2-thienylacetyl) amino -1-azetidine sulfonic acid.
A. Tetrabutylammonium salt-3-amino-3-methoxy-2 Oxo-1-azetidine sulfonic acid.
10 30% acetone-water mixture is passed through a column from Dowex 50WX2 (k) and eluted with the same solvent. The total eluate is evaporated to give 95 mg of product which is lyophilized. An amorphous powder is obtained, mp. 120-135 ° C.
Calculated,%: C 33.51; H 3.09; N 7.82; S 17.89.
Syun ,, .K
20 Found,%: 33.46; H 3.08; N 7.92; S 17.64.
Example 74. The potassium salt of 3S (Z) -3- (2-amino-4-thiazolyl) (carboxymethoxy) imino acetyl amino} - 25 -2-oxo-azethidine sulfonic acid.
Potassium salt 3s (Z) -3- | (2-amino-4-thiazolyl) 2-oxo-2-phenylmethoxy-cistoxy imino acetyl amino} -2-oxo-1-azetidine sulfonic acid (0.1 g, see 3Q Example 71) is dissolved in a mixture of 5 ml of ethanol and 5 ml of water and hydrogenated at room temperature in the presence of 0.2 g of palladium on charcoal. After 2 hours, the catalyst is filtered off and the remaining solvent is dried at a temperature below 0 ° C to give the title compound, m.p. 235 ° t (dec,),
Example 75. Kaliev salt
0 3 - {(s) - (aminocarbonyl) amino -2-thienylacetyl amino j-3-methoxy-2-ca co-1-azetidine sulfonic acid, isomers. A solution of tetrabutylammonium salt of 3-amino-3-methoxy-2-oxo-1-aze 5 tidinsulfonic acid (277 mg, see Example 46, method II, part A) is added in 15 ml of dry acetonitrile at -20 ° C to add pyridine (71 µl) (0,888 mmol) and hydrochloride (o) - 2-amino-4 -2-tie
0 NIL-5- (4H) -oxazoline (166 mg). The mixture is stirred for 10 minutes and another dose of pyridine (71 µl) and oxazoline (166 mg) is added. After another 10 minutes the solvent is removed.
5 under reduced pressure, and the residue is dissolved in a water-acetone mixture and passed through an ion exchange resin (20 ml of AG 50W-X2, K®-form, 20 (b
49
400 mesh.) C. Removal of water from fractions 2-3 gives a mixture of diastereomers (248 mg).
The product is purified, the diastereomers are separated at Diaion AG HP-20 (130 mg) and eluted with water. Isomer A eluted in fractions 23-28 (30 mg) and Isomer B in fractions 3 45 (30 mg) (8 ml fraction). Medium fractions (10 mg) are combined with fractions from other experiments. The total amount of 35 mg of isomer A and 59 mg of isomer B is given. Analysis of isomer A: t. Sh1. 158 165 ° C.
Calculated,%: C 31.05; H 3.29; N 13.18.
C, 1 H..K 1/2 BUT
Found,%: C 30.95; H 2.97; N 12.98.
Analysis of the isomer B: m. Pl. (different).
Calculated,%: C 31.05; H 3.29; N 13.18; S 15.05.
C ,, H ,,., 1/2
Found,%: C 31.17; H 3.09; N 13.13; S 15,09 „
Example 76c Dikaliev Sol 3 methoxy 2-oxo 3 (phenylsulfoacetyl) amino 1 azetidine sulfonic acid
To a stirred solution of the crude 3-amino 3 methoxy 2X) tetrabutylammonium salt of Xo 1 azetidine sulfonic acid (366 mg, see example and 38 mg of borax in 35 ml of dry acetonitrile under a nitrogen atmosphere, add 0.53 ml of dry pyridine followed by two minutes of adding a solution of sulfophenylacetyl chloride monoether (348 mg) in 8 ml of acetonitrile. After 20 minutes, the solvent is removed in vacuum} and the residue is treated with 35 ml of 0.5 M with a pH of 5.5 of potassium phosphate buffer. Tetrabutylammonium acid sulfate (383 mg) and the mixture is extracted three times. lenhloridom. The methylene chloride layer was dried with sodium sul fop uparivaets to give 685 mg of crude product.
The crude product is combined with mg of the crude product from another test, and the combined substance is purified on a USSCC-CC-4 column using methylene chloride, and then 2.4, 6.8 and 10% methanol in methylene chloride as eluent is a mixture of about 6 : 1 raceme
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diastereomers in the form of a tetrabutylammonium salt, is converted to the potassium salt by passing through Dowex 50W-X2 (K-form)
5 Resin using 20% acetone in water as a solvent. The product is lyophilized, giving 171 mgmg of the title compound, t, pl. 205210 ° С (decomp.) About
0 Calculated,%: C 29.51; H 2.89; N 5.74; S 13,10.
C ,, H ,, N, 0 S, K. Found,%: C 29.45; H 2.74; N 5.61; S 12.82.
15 Example 77. Dikalium salt of 3- (carboxyphenylacetyl) amino-3-methoxy-2-oxo-1-azetidine sulfonic acid.
Kaliev salt, 3-dioxo-2-
20 t |) enyl-3- (phenylmethoxy) propyl amino-3-methoxy-2-oxo-1-azetidine sulphonic acid (39 mg, see Example 51) is dissolved in methanol (5 ml). Anhydrous potassium carbonate is added.
5 (3.9 mg) and 10% palladium on carbon (19 mg), and the mixture is hydrogenated at atmospheric pressure for 20 minutes. The catalyst is removed by filtration, and the filtrate is evaporated in vacuo to 30 ° a glassy residue (34 mg), which is lyophilized to an atmospheric powder, m.p. 178-190С (decomp.
Calculated,%: C 35.20; H 3.18; H 6.32; S 7.23
5, - 0.5 N, 0
Found,%: C 35.51; H 2.96; N 6.29; S 6.92.
Example 78. The potassium salt of 3S (z) -3- (2-amino-4-thiazolyl) 2 - (1,1-dimethoxyethoxy) -1- (methylthio) -2-oxoethoxy imino acetyl amino} -2-oxo- 1-azetidine sulfonic acid.
The procedure of example 73 and the replacement of (z) -2-amino-o (.- (oxyimino) -.
J. -4-thiazoleacetic acid (z) -2-amino-o-o (-G (2- (1, 1-dimethylethoxy -1 - (tetylthio) -2-oxoethoxy} imino1-4-thiazole acetic acid gives the target compound , mp 130 ° C (decomp.).
Example 79. The potassium salt of (+) -3-butoxy-3- (phenylmethoxy) carbonyl amino -2-oxo-1-azetidine sulfonic acid.
A solution of 185 mg of tetrabutylammonium salt-2-oxo-3-N-chloro-N- (phenyl-methoxy) carbonyl} amino -1-azetidine
sulfonic acid (see example 49A) in 1 ml of dimethylformamide is cooled to 78 ° C and 0.73 n. lithium p-butoxide (3.8 ml) in p-butanol is added at 78 ° C. After 15 minutes, 0.5 M monobasic potassium phosphate buffer is added, and the product is extracted into dichloromethane (3 portions of 40 ml), dried over sodium sulfate, filter, and concentrate in vacuo. 179 mg of the corresponding tetrabutyl monium salt of the title compound are obtained.
To a solution of 109 mg of tetrabutylammonium salt in acetone is added potassium perfluorobutyl sulfonic acid (60 ml) in acetone. The solvent is removed in vacuo and ethyl acetate is added. The product is crystallized, collected and dried. 66 mg of the title compound are obtained, mp. 186.5 187.5 ° С (decomp.) „
Calculated,%: C, 43.89; H 4.67; N 6.85; S 7.81.
C ,, S-.K
Found,%: C 43.69; H 4.73; N 6.69; S 7.75,
Example 80. Potassium salt Z + (E) -3 methoxy 3 {(methoxyimino) 2- (phenylmethoxy) carbonyl amino 4 thiazolyl acetyl amino 2 oxo 1 azetidine sulfonic acid.
Suspension of 3 amino 3 methoxy 2 oxo 1 aze tidinsulfonic acid tetrabutylammonium salt Example 46, Method II, Part A) (0.175 mmol) and sodium borate (0.0175 mmol) in 2 ml of dichloromethane at 0 ° C are treated with 28 μl of pyridine and 0.175 (E) -c (, - (methoxyimino) -2- (phenylmethoxy) carbonyl amino 4 thiazolyl acetyl chloride. After 1 h, the mixture is diluted with dichloromethane and cooled rapidly with water. The organic layer is washed with water, saturated salt, dried and evaporated in vacuo. Residue purified on Mullinkrodt SILI-CARA CC-4 silica gel (20 g), giving 43 mg of the corresponding trabutilammonievoy salt of the title compound.
The tetrabutylammonium salt (43 g) is dissolved in 0.5 ml of acetone, to which is added 20 mg of potassium perfluorobutane in 0.5 ml of acetone. After adding 3 ml of ether, the solid is collected and dried in vacuo to give 28 mg of the title compound, m.p. 144-146 ° C (decomp.,).
98152
Calculated,%: C 39.20; H, 27; N 12.70; S 11.61.

Found,%: C 38.81; H 3.88;
N 1 1.51; S 11.14.
Example 81. The potassium salt of 3+ (Z) -3 methoxy 3 {(methoxyim HoTt 2 (phenylmethoxy) carbonyl amino 4 thiazolyl acetyl amino 2-oxo 1 azetidine sulfonic acid.
Following the procedure of Example 81, but replacing (E) -ci (, - (methoxyimino) -2 phenylmethoxy carbonyl amino 4 Thiazolyl acetyl chloride (Z) -ot- (methoxyimino) -2- (phenylmethoxy) carbonyl amino 4 thiazolylacetyl chloride, the desired compound, so pl. 168 172 ° C (decomp.).
Calculated,%: C 39; 13; H 3.85; N 11.70; E 10.70.
 N OgS, K. H ,, 0 12 acetone. Found,%: C 38.92; H 3.63; N 11.34; S 10.80.
Example 82. Potassium salt 3 ((R) -O (- G (, 3 dioxo 1 -piperazinyl) carbonyl amino Snhe NIL acetyl amino 3 methoxy 2 oxO 1 aze tidine sulfonic acid.
to the stirred solution
0.69 mmol of tetrabutylammonium salt 3 amino 3 metoxy 2 ok with 1 azetidine sulfonic acid (Example 46, method II, part A) in 30 ml of dry acetonitrile
At 20 ° C, 242 µl of dry pyridine is added under a nitrogen atmosphere followed by the addition of a solution of 352 mg (R) (, 3 dioxy 1 piperazinyl) carbonip amino phenylacetyl chloride
reed in 4 ml of acetonitrile. After 1 h, 84 µl of pyridine is added, followed by the addition of 117 mg of the named acid chloride in 1 ml of aceto-nitrile. Stir the Reaction Mix
within 20 minutes, diluted with 24 ml 0.5 M pH 5.5 monobasic potassium phosphate buffer and concentrated in vacuo to remove acetonitrile. The aqueous residue is extracted
Three times with methylene chloride, the combined extracts are dried (Na 30) and evaporated. 546 mg remains of residue. Passing the residue through a silica column using methylene chloride and then 2, 4, and 6% methanol in methylene chloride gives two fractions (285 and 173 mg) of the corresponding tetrabutylammonium salt of ce- 53. Passing the left-hand fraction through 4.5 g of floWex 50 X2 resin (k) using an acetone / water mixture as eluent, gives 119 mg of the title compound, 104 mg of this substance is applied to a column of resin AG in water. Sequential elution with water and acetone in water gives 60 mg of the product as a mixture (approximately 1: 1) of diastereomers. Lyophilization with 60 mg of the fraction gives a solid, t, pl. 171-172 C (decomp.). Example 83. Tetrabutyl monium salt of N- (3 hydroxides 2 occa and cylfo 3 azethidinyl) r2 phenylacetic amide. Following the procedure of Example 80, but replacing the tetrabutylammonium salt 2 of OXO-3-SC-chlor-H- (phenylmethoxy) carbonyl amino 1 azetidine sulphoxide with the tetrabutylammonium salt of N-chloro-K- (2 oxo 1 sulfo 3 azetidinyl) -2 phenylacetamide (cm , Example 47A of the preparation of the corresponding potassium salt), the desired compound is obtained in the form of an oil. 3.62 (s., 2H, RR Spectrum (CDC1,); 4.03 (ABg, 2H, V - 7 CEC S, 1I, NN) and fishing / s, CH); 6.98 7.30 ppm (s, 5H5 Cgiig / c Example 84, Kaliev salt (R) -3 methoxy 2 oxo 3 (phenylacetyl amino J - 1 azetidine sulfonic acid, 1 M solution of the complex dimethyl form amide sulfur trioxide is prepared by slow adding trimethyl silyl sulphate to dimethyl forms at 0 ° С, followed by vacuuming at 0.1 mm for 30 min and at 0 25 ° С „50 mg (k) - (3 methoxy 2 oxO 1 a3 tetydinyl) phenylacetamide in In an argon atmosphere, dissolve in 0.2 ml of anhydrous dimethylformamide and cool to 0 ° C. A cold 1 M solution of a mixture of dimethyl forms sulfur trioxide is added. (0.428 ml), the mixture is stirred for 2 hours and poured into 15 ml of 0.5 g of monobasic kg sium phosphate. The solution is extracted twice with dichloromethane (added) and 73 mg of tetrabutylammonium bisulfate is added. Extraction with methane (three 10 ml portions) gives a viscous oil after drying and vacuuming in vacuum. Chromatography on Mallinerodt-CC 4 silccag. (50: 1) using 2% methanol in di 8154 chloromethane as eluent gives 34 mg of tetrabutylammonium salt (K) -3 methoxy 2 oxo 3 (phenylacetyl) amino 1 azetidine sulfonic acid. Ion exchange on Dowex 50W-X2 (K, 10 eq.) Gives the target potassium salt after lipidation of the aqueous eluent, mp. 130 ° C (decomp.) Oi + 52 ° (C 0.5 water), Example 85. Potassium salt (S) 1 ethyl 4 hydroxy 3 methyl 1H pyrazolo (3.4 B pyriline 5 il carbo NIL amino phenylacetyl amino 2 oxo 1 azatidine sulfonic acid Following the procedure of Example 73, but replacing (Z) -2 amino o1 (oxyimino) -4 thiazo-acetic acid / (1-ethyl 4 hydroxy 3 methyl 1H pyrazolo (3.4 B pyridine 5 yl) carbonyl amino benzoyl acetic acid, get t. M., A fine compound, (decomposition) about C 39.20; H 4.80; Calculated ,% Ы 13,, 06; S 4.98, C. Found,%: C 39.40; H 3, 74; N 12.76; S 4.94 Example 86. Potassium salt of (E) -3 acetylamino 3 methoxy 2 Oxoethidine sulfonic acids .A about 3 Acetylamino 1 1 carboxy 2 methyl (propyl) - (3R) -3 methoxy 2 oxo-acetic acid. To a solution of bB-cis 7 acetylamino 7 methoxy 3 methyl 3 oxo 5 thia 1 azabicyclo 4.2.0 oct 2 en 2 carbonic acid (650 kg) and sodium bicarbonate (191 mg) in water are added to a suspension (11 ml) Rene nickel of pro grade (0.6 g / ml), which was previously washed to neutrality with water. The mixture was placed in an oil bath, preheated to l7Q ° Cf and brought to reflux temperature for min. At the same time, the bath temperature is maintained at 150-170 ° C. After heating under reflux for 15 minutes, the reaction is quenched by cooling in a bath. The catalyst is removed by filtration through zeolite, and the filtrate is adjusted (pH 11) to pH 2 with 1 N hydrochloric acid. After extruding the aqueous solution five times with ethyl acetate, the combined extracts are dried with sodium sulfate, the solvent is removed in vacuo. Oil is obtained (487 mg) “Chromatography on silica gel gives the product (eluted in chloroform) as an oil (381 mg), B.3-Acetylamino 1 1 (acetyloxy) -2; -methyl (propyl) (3R) - 3 methoxy 2 oxoazetidine. The indicated azitidinone (464 mg) was mixed in dry acetonitrile (15 ml and the solution was flushed with argon for 15 minutes. Copper acetate (359 mg) was added, the mass was stirred for one minute to dissolve the salt and added lead tetraacetate. (797 mg). While argon continues to bubble through the mixture, the reaction temperature rises by immersing the flask n and an oil bath preheated and maintained at 55-65 ° C for 15 minutes. The mixture was allowed to cool to room temperature, filtered through zeolite, and the filtering agent was thoroughly rinsed with acetonitrile. Remove the solvent in a vacuum from the combined filtrate and washing liquids. The residue is taken up in water and extracted four times with ethyl acetate. The combined extracts are dried with sodium sulphate and the solvent is removed in vacuo. The desired product is obtained in the form of an oil (382 mg). C. (R) -N- (3-Methoxy-2-oxo-1-azetidinyl) acetamide. This oil is dissolved in methanol (10 ml): water (1 ml), cooled in an ice / methanol bath at (10) - (- 15) ° C. Next, potassium carbonate (194 mg) is added, followed by sodium borohydrate (53 mg). After stirring at (-15) - (-8) ° C for 1 min, the solvent is removed in a vacuum, the residue is taken up in water, and the solution is brought to pH 6 with 1 n hydrochloric acid. Exhaustive extraction with ethyl acetate, drying with sodium sulfate, and removing the solvent in vacuo gives an oil (224 mg). Chromatography of the oil on silica gel, elution with a mixture of 5% methanol, 95% methylene chloride gives an oil (169 mg). The title compound crystallizes from a mixture of ether and pentane, to give 131 mg of a substance with m.p. 106 112 ° С (sintering 103.5 ° С). D. Potassium salt of (K) -3-acetylamino-3-methoxy-2-oxo-1-azetidinesulfonic acid In an atmosphere of argon 50 mg of (R) -3-acetylamino-3-methoxy-2-OXO-1-azetidine is placed into a flask and cooled to 0 ° C. Then a 1 M solution of the dimethylformamide-sulfur trioxide complex in dimethylformamide (0.95 ml) is added, and the solution is stirred for 15 minutes. The contents of the flask are poured into 40 ml of 0.5 N K, the HPO solution and extracted twice with 10 ml of methylene chloride. Tetrabutylammonium sulfate (1.2 equivalent-a) is added to the aqueous solution. The resulting mixture is extracted with four 10 ml of methylene chloride portions. The extracts are then dried over sodium sulfate and concentrated to give 39 mg of product. The tetrabutilammo. Nieva salt is converted to the target potassium salt by passing it through a Dowex 50X2 (K) column. Concentration of the aqueous fraction gives 19 mg of the potassium salt with an NMR spectrum identical to that of the product obtained by EX461 by isolation from natural sources (Example 165). Example 87. The potassium salt (nk) of 3-acidophenylacetyl) amino-3-methoxy-2-oxo-1-azetidine sulfo x-acid. Calculated,%: C, 36.90; H 3.26; N 17.45; S 7.98. C ,, K.O-5n о Found;%: 35.94; H 3.07; N 17.24 f 8.02. Example 88. The 3-Kazidophenylacetyl) amino-3-methoxy-SI-2-OXO-1-azetidine sulfonic acid potassium salt, isomer A. The 1: 3 mixture of racemic distereoors prepared according to example 88B is left in deuterated form room temperature. Isomer A crystallizes. After cooling, the mother liquor is removed, the crystals (28 mg) are dried in vacuum at 40 ° C, To m. 130C (decomp.), As a monodeuterate. Calculated,%: C 34.78; H 3.64; 16.90; 5 7.74. C ,,, H, OOgN, SK-H О Found,%: C 34.66; H.3.28; 16.88; S 7.70. Example 89. Potassium salt, 3+ (R) 1-3-C (4-ethyl-2,3-t; ioxo 1 piperazinyl) caronyl amino phenyl
acetyl amino 3 methoxy 2-oxo-1
azetidine sulfonic acid.
To a stirred solution of 3 methoxy 2 oxo 1 azetidine sulfonic acid as its etrabutylammonium salt (0.69 mmol, see Example 74A) in 30 ml of dry acetonitrile at 20 ° C under nitrogen atmosphere is added 242 µl of dry pyridine with the subsequent addition of a solution 352 mg of (k) -oC- (, 3 dioxo 1 pipovrasin) carbonyl amino phenylacetyl chloride in 4 ml of acetonitrile. After 1 h, 84 µl of pyridine is added, followed by the addition of 117 mg of acid chloride in 1 ml of acetonitrile. The reaction mixture is stirred for 20 minutes, diluted with 24 ml of 0.5 M monobasic potassium phosphate buffer at pH 5.5 and concentrated in vacuo to remove acetonitrile. The aqueous residue is extracted three times with methylene chloride. The combined methylene chloride extract is dried with sodium sulfate and evaporated to a residue (546 mg). Passing this substance through a column of SilicaAR CC using methylene chloride and then 2, 4, and 6% methanol in methylene chloride gives two fractions (285 m and 173 mg) of the purified product in the form of tetrabutylammonium salt.
Passing 173 mg portions through 4.5 g. Dowax (K) resins using this material nano sieve on a HP 20 AU resin column in water. Sequential elution with water and acetone in water gives 60 mg of the product as a mixture (approximately 1: 1) of distereomers and 21 mg of the product as a mixture (approximately 9: 1) of diastereomers. Lyophilization with a 60 mg fraction gives the target compound, m.p. 171-172 C (rael.)
Calculated,%: C, 41.23; H 4.37; N 12.65; S 5.78 CieHai B SK —but Found,%: C 41.39; H 4.2; N 12.58; S 5.63.
Lyophilization of a 21 mg fraction gives the target compound with a mp. (different)
Calculated,%: C, 41.23; H 4.37;
N 12.65
C, H NgO SK. Naidio,%: C 41.43; H 4.11; N 12.28.
A treatment of the 285 mg fraction of the tetrabuyl ammonium salt fraction with Dowex 50 X2 resin (k) gives 145 mg of potassium salt, which is combined with the remaining 15 mg of the mentioned 119 mg portion of potassium salt obtained using Dowex resin. Passing this material through, as already described, gives an additional 31 mg of product as a mixture (approximately 1: 1) of distereomers and an additional 42 mg of product as a mixture (approximately 9: 1) of diastereomers. The total amount of the mixture of diastereomers (1: 1) is 91 mg and the total amount of the mixture (9: 1) of diastereomers is 63 mg.
Example 90. Potassium salt 33 (g) (methoxyimino) 12 - (((phenylmethoxy) carbonyl amino-4-thiazolyl acetyl amino-2-oxo-1-azetidine sulfonic acid)
To a solution of tetrabutylammonium salt (3) -3 amino 2 oxo 1 azatidine sulfonic acids (0.170 mmol, see Example 6A) and sodium borate 0.170 mmol in 2 ml of methylene chloride, pyridine (64 μl) and (Z) -o ;-( Metoxyl) -2- (phenylmethoxy) carbonyl aminoJ 4 Tiazolacetyl chloride (0.51 mmol). After 40 min, the reaction mixture was diluted with methylene chloride and water, followed by the addition of 0.1 M tetrabutylammonium sulfate, buffered to pH (5.1 ml). The organic layer is separated and washed with water, adjusted to pH 2, washed with water, adjusted to pH 7, then washed with water saturated with sodium chloride, dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified on silica-C-4 silica gel (10 g) and the product is eluted with a mixture of 10% methanol-methylene chloride.
The tetrabutylammonium salt, after being dissolved in the acetone-water mixture, is passed through an ion exchange resin (8 MP, AG 50W-X2, K-form 100200 mesh). Removal of water in vacuo from fractions 1–4 yields 40 mg of the title compound, so pl. 172-174 C (decomp.).
Calculated,%: C 37.84; H 3.33; N 12.99; S P, 87.
CuHisNgOeSgK
H, 0 C 37.95; H
Found, 12.73; S 11.53.
59
Example 91 “Potassium salt (+) - 3 butoxy 2 oxo3 Zfanilace til) amino 1 azetidine sulfonic acid.
A.Tetrabutylammonium salt 3 - chlorine (phenylacetyl) amino Z-okco 1 azetidine sulfonic acid.
A solution of tetrabutylammonium salt {S) (phenylmethoxy) carbo NIL ja ino l azethidine sulfonic acid (350 mg, cm, example 4) in methylene chloride (3 ml) is added to a suspension of sodium borate (1.27 g) in 5, sodium hypochlorite solution ( 4,72 ml) and water (20 ml) at. After 1 hour, 0.5 M monobasic potassium phosphate (25 ml) is added and the mixture is extracted three times with methylene chloride (50 ml portions). The organic extracts are dried over sodium sulfate, filtered and concentrated in vacuo to give 344 mg of the title compound. . .
B. Tetrabutylammonium salt (j;) - 3 si-2 oxo-3 (phenylacetyl) amino -1-azetidine sulfonic acid buckets.
A solution of tetrabutylammonium cate (phenylmethoxy) carbonyl amino -1-aetidine sulfonic acid (344 mg) in imethylformamide (5 ml) is added to 0.73 n. lithium butylate vn -butanol (6 ml) and dimethylformamide (1 ml) under an inert atmosphere. After 10 minutes, the mixture is diluted with a 0.5 M solution of potassium phosphate monobasic (175 ml). After extracting three times with methylene chloride, the organic extract is dried over sodium sulfate, filtered, and the solvent is removed in vacuo. The residue was purified on SILICAR SS-4-cage (80 g) and the title compound (130 mg) was eluted with 4-8% methanol in methylene chloride.
C. Kaliev salt of (+) - 3-butoxy-2 oxo-3- (phenylacetylTamino - β-azethidine sulfonic acid
The tetrabutylammonium salt of (+) - 3-butoxy 2 oxo-3- (phenylacetyl) amio-1-azetidine sulfonic acid (43 mg) is dissolved in a water-acetone mixture (9: 1) and applied to the cation-exchange film (Dowex AG MP 50W-X2 , 100200 mesh, 5 g,) opMa). The product is eluted with water and the eluate is concentrated in vacuo to give 20 mg of the desired compound, m.p. 122-125C.
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Calculated,%: C 44.66; H 4.96; N 6.95; S 7.94.
C, 5H, and iOb-K- 1/2 Found,%: C 44.77; H 4.76; 5 N 6.76; S 7.75.
Example 92. The potassium salt of (+) - 3-ethoxy-2-OXO-2-3-G (phenylacetyl) amino1-1-azetidine sulfonic acid is you.
The tetrabutylammonium salt of 0 (phenylacetyl) amino -2-oxo-1-azetidine sulfonic acid (200 mg, see example 92A) in dimethylformamide (4 ml) is added to 0.5N. lithium ethylate in ethanol (12.20 ml) at -78 ° C in 5 inert atmosphere. After 10 minutes, the mixture was diluted with a 0.5 M solution of potassium phosphate monobasic (15 ml). After extraction three times with methylene chloride, the organic layer was dried over sodium sulfate, filtered, and the solvent was removed in vacuo. The residue is purified on SILISAR SS-4 silica gel (20 g), and the tetrabutyl ammonium salt of the product (40 mg) is ale 5 and treated with 2% m methanol in methylene chloride.
The tetrabutylammonium salt is dissolved in a water-acetone mixture (9: 1) and placed on a cation-exchange column (Dowex AGMP 50W-2X, 100,200 mesh, 5 g, K - form). The product is eluted with water. The eluate is concentrated in vacuo to give 25 mg of the title compound, m.p. 94-96 ° C. Calculated,%: C 42.62; H 4.10;
five
N 7.65; S 8.74.
C ,, H, 5N ,,
Found,%: C 40.36; H 3.66; N 6.77; S 8.44.
40
Example 93. The potassium salt of 3+ (Z) -3-С (2-amino-4 Thiazolyl) (netoxyimino) acetyl amino-3-methoxy--2-ok-co-1-aze tidine sulfosulfate.
The tetrabutylammonium salt of 3-amino-3-methoxy-2-oxo-1-azetidine sulfonic acid (see Example 46, method II, part A) is dissolved in acetonitrile (20 ml) and pyridine (1 ml) and added
to a vigorously stirring suspension (g) -c11 .- (methoxyimino) -2 amino-4 thiazoleacetyl chloride in acetonitrile (20 ml), cooled to 0-5 ° C. After stirring the cold mixture in
The mixture is diluted with a 0.5 M solution of potassium phosphate monobasic (100 mlCrN 4.8 mixture) for 1 hour and the solvent is removed in vacuo. Mixture 61 is taken to the minimum amount of water containing the highest amount of acetone. Chromatography on an ion exchange resin (AG50W-X2, 100-200 mesh. K-form, 200 ml) gives the crude will pass in the form of potassium salt after elution with water. Further purification on an HP-20 resin (200 ml of water using eluent gives 59 mg of the product as a powder after trituration with acetonitrile ether and then twice with ether. The product is an amorphous powder that slowly melts and decomposes at temperatures above. Calculated,%: C 28.77; H 2.90; N 16.78; S 15.36; K 9.37. C ,, .SK Found,%: C 27.77; H 2, 82; N 15.87; S 13.63; K 10.11. Example 94, Kaliev salt ZE (K) and 3S (S) -3 - {(aminocarbonyl) amino, phenylacetyl amino-3-methoxy-2- oxo-1-azetidine sulfonic acid, A,. Internal salt (+) 3- (amine ester n and l) amino-3-me current with i-2-ca co-1-azetidine sulfonic acid. Potassium salt {+) - 3- (azidophenyl acetyl) amino si-2-ca co 1 - β-azidine sulfonic acid (209 mg, see example 88) is dissolved in 60 ml of dry methanol. Anhydrous trifluoroacetic acid (0.6 ml) and 10% palladium-carbon (105 mg) are added, and the mixture is hydrogenated for 1 hour. The catalyst is removed by filtration and the filtrate is evaporated in vacuo to give 271 mg of crude product. B. Kaliyev salt of Zn (k) and 3S (S ((aminocarbonyl) amino phenylacetyl amino-3-methoxy 2 oxo-1-azetidine sulfonic acid, Potassium salt (+) - 3- (aminophenylacetyl) amino Z-methoxy-2-oxo - in tidinsulfonic acid (271 mg) dissolved in 6.5 ml of water. C. added, and potassium hydroxide (87 mg), and the mixture is stirred at room temperature for 3 hours. The solution is concentrated in vacuo to 2 ml and chromatographed per 100 ml of an AG column using water as eluent. After freeze-drying, isomer A was analyzed (29 mg), mp times Calculated,%: C 36.44; H 3.99; N 13.07; S 7, 48, 81 C ,, SK Found,% : C 36.35; H 3.79; N 12.81; S 7.32. Example 95. Potassium salt t3R (s) and 38 (H) (aminocarbonyl) amino phenylacetyl amino} 3-methoxy-2 oxo-1 Azetidine sulfonic acid. Along with the potassium salt of ZR (k) and 3S (S) -3- (aminocarbonyl) amino phenylacetyl amino-3 methoxy-2-oxo-1-azetidine sulfonic acid, obtained in Example 95, 2G mg of the potassium salt 3R (S ) and 3S (R) -3 - {(aminocarbonyl) amino phenylacetyl amino 3 methoxy 2-oxo-1-azetidine sulfonic acid in vi, e lyophilisate, t. pl. 160 ° C (dec) Calculated,%: C 35.69; H 4.14; N 12.81; S 7.33 sesquihydrate 13 -if. Found,%: C 35.98; H 3.87; N 12.50; S 7.32. Example 96. Potassium salt of 3-.- (3) .- 3.methoxy-3- {(2-oxo-3 (phenylmethylene) amino 1-imidazolidinyl carbonyl amino 2-thienylacetyl amino -2-oxo-1-azetidine sulfonic acid. K a stirred solution of the tetrabutyl ammonium salt of 3-amino-3-labels of SI-2-OXO-1-azetidine sulfonic acid (306 mg of a crude substance, containing an estimated 274 mg of organic substance, prepared as described in Example 74) in 20 ml of dry acetonitrile at - 0.30 ml of dry pyridine is added under a nitrogen atmosphere, followed by the addition of 484 mg of (s) - (2-oxo-3-phenylmethylene) amino-1 imidazo lidinyl carbonyl amino-2-thienylacetyl chloride, partially dissolved and suspended in 10 ml of dry acetonitrile. The reaction mass is stirred and allowed to stand until it reaches 0 ° C for 1 hour. The reaction mixture is diluted with a large volume of methylene chloride, and 22 ml of 0.5 M pH 5.5 monobasic potassium phosphate buffer is then treated, the aqueous layer is washed with methylene chloride, and the combined methylene chloride extract is washed with water, dried with sodium sulfate and evaporated to a residue (508 mg). The residue is chromatographed on 50 g of SILISAR CC-4 using methylene chloride, and then 2 and 4% Me. Tanol in methylene chloride. Get
63
251 mg of the tetrabutylammonium salt of the target compound.
To this salt (251 mg) in acetone, a solution of 107 mg of potassium perfluorobutanesulfonic acid in several milliliters of acetone is added. Ethyl acetate is added, the precipitate is washed three times with ethyl acetate and centrifuged, dried in vacuo at mm for 2 h, to give 95 mg of the required potassium salt as a mixture of (approximately 1: 2) diastereomers having a melting point of 20 ml. 200 C, with decomp.
Calculated,%: C 42.85; H 3.60; N 14.28; S 10.87,
C 2 Found,%: C 43.02; H 3.74;
N 13.94; S 10.71.
Example 97. The potassium salt of (+ cis) -4 methyl 2 oxo 3 (phenylmethoxy) carbonyl amino 1 azetidinsulfkio ate.
AO B-Benzyloxy tert. threoninamide. The term bock is used to mean butoxycarbonyl.
A solution of 6.9 g d, 1 tert-sided allo-threonine and free .amine, obtained from 5.3 g 0 benzylhydroxylamine x HCl approximately 0.033 mol, released using ethyl acetate – sodium bicarbonate, in 80 ml of tetrahydrofuran is treated with 4.82 g N -oxybenzotriazole and 6.5 g of dicyclohexylcarbodiimide in 20 ml of tetrahydrofuran. After stirring for about 16 hours at room temperature, the suspension is filtered, concentrated in vacuo and chromatographed on a 400 ml column of silica gel. Elution with ethyl acetate in chlorofor did not give 6.8 g of the title compound as fractions (20 ml each) 7-22.
B. (cis) N-Benzyloxy 3 tert butoxycarbonylamino 4 methylaze dinone.
A solution of 6.8 g of K-benzyloxy tert-side allotreoninamide in 200 ml of tetrahydrofuran is stirred for approximately 16 hours with 5.24 g of triphenylphosphine and 3.2 ml of diethyl azodicarboxylate. The solvents are evaporated in vacuo and the residue is chromatographed on: 500 ml of a silica gel column. Elution with methylene chloride followed by crystallization from ether yields a total of 2.65 g of azetidinone. Rech
7298164
A rotograph of the mother liquor and mixed fractions gives an additional 0.6 g of product. Crystallization of a portion twice from ether () 5 gives an analytical sample of the target compound Art. square 140 142s.
C. (3c) -3 tert. Butoxycarbonyl amino 1 oxo 4 methylazedinone.
A solution of 3.2 g of cis K-benzyloxy 3
fO tert butoxycarbonylamino 4 methyl azetidinone in 200 ml of ethanol is stirred in a hydrogen atmosphere with 0.7 g of palladium on carbon. After 40 min, slurry suspension
15 Route (consumption 249 ml) and filter
war is evaporated and triturated
rum, given in the form of two films 2.05 g
solid matter, so pl. WITH.
Do (+ cis) -3 tert Butoxycarbonyl
20 amino 4 methylazetidinone.
A solution of 2.05 g of cis 3 tert butyl sicarbonylamino hydroxy 4 methylamine dynone in 60 MP of methanol is treated in total 90 ml of 4.5 M am5 mono acetate (40, 20 and 30 ml of the portion) and 45 ml of 1.5 M titanium trichloride (20 10 and 15 ml portions). The second and third additions are made after 15 and 20 minutes, respectively. After 135 min solution
0 is diluted with an equal volume of sodium chloride and extracted with three 300 ml portions of ethyl acetate. The combined organic layer is washed with a mixture of sodium bicarbonate and saturated salt (100 ml each),
5 is dried and evaporated. Trituration with ether gives two portions of 1.65 g of solid. The first portion of the collection is recrystallized from
.-ester, giving analytical software. m.p. , 5 ° C.
E. (+ cis) 3 Benzyloxycarbonyl but 4 methylazedinone.
A solution of 1.55 g cis 3 tert butoxy
-Carbonylamino 4 methylazetidinone in 4 ml of methylene chloride and anisole, taken separately, cooled to 0.5 seconds and 50 ml of cold trifluoroacetic acid was added. After 90 minutes, dissolve the evaporated under vacuum (benzene is added and evaporated three times). The residue is dissolved in 25 ml of acetone, the initial pH (2.5) is adjusted to 7 with sodium bicarbonate.
- and add 2 ml of benzyl chloroformate. The solution is left for 4 hours at 0 ° C and a pH of 7, the acetone is removed in vacuo, giving a suspension, which filters to 65 seconds. The filtrate is saturated with salt and extracted with methylene chloride. TE: The solid is dissolved in methylene chloride and dried. The organic layers are combined, concentrated, and the oC chromatograph is chromatographed on a 200 ml silica gel column. Elution with a mixture in a ratio of 3: 1 chloroform and ethyl acetate gives 850 mg of the target compound as fractions (100 ml each). Crystallization of a small sample from ether gives an analytical sample, mp 166 ° C. F. (+ cis) 4HChetyl 2 Oxo 3 (phenylmethoxy) carbonyl jaMHHoJ-1-aaeTH- dinosulfonic acid, potassium salt To a suspension of cis 3 benzyloxycarbonylamino 4 methylacetate 1, inona {O, 75 g in 7 ml of dimethylformamide (dried after sieving a 4A sieve, incubated at 320 ° C for 15 hours in a stream of argon) and methylene chloride (dried with AC base O,), separated separately, 1.66 g of pyridine-sulfur trioxide complex is added. After 3 hours of stirring at room temperature under a nitrogen atmosphere, an additional amount (1.66 g) of the pyridine-sulfur trioxide complex is added. The reaction mixture is then stirred at room temperature B for about 16 hours. Dimethyl formamide is removed in vacuo to give 4.6 g of a residue, which is dissolved in 300 ml of a 0.5 M solution of potassium phosphate monobasic (40 ° C for 10 minutes). 15 minutes). The solution is cooled, passed through a column of HP-20 resin (3 X 60 cm) with 400 ml of 0.5 M monobasic potassium phosphate and 1 liter of distilled water with a ratio of 14: 1 water / acetone mixture, giving 280 mg of product per fractions 13 and 26 (100 ml each). Crystallization from MeOH petroleum ether gives 757.5 mg of analytical sample. T. pl. 2 4 215С (decomp.) Calculated,%: C 40.90; H 3.72; N 7.95; S 9,10 ;, K 11,10. , jN, 2SOgK; Found: C, 40.43; H 3.60; N 7.89; S.8,69; To 10.82. Example 98. Kaliev salt (33-trans) 4 metsh1 2 oxo 3 | (phenylmethoxy) carbonyl J amino -1 aze dinosulfonic acid. 8166 Following the procedure of Example 98, but replacing d, 1-tert-side-allotreonin with l-tert-side-threonine, the desired compound is obtained, so pl. 133-135 ° C. Calculated,%: C 40.90; H 3.72; N 7.95; S 9,10; K 11.10. R T-T C SK 12 SK; Found,%: C 40.72; H 3.60; N 7.99; S 8.80; To 10.82. Example 99. The potassium salt of (3S -trans) -4-methyl-2-oxo-3- (phenylacetyl) amino - 1 -a-tidine sulphonic acid. A. (3s) -3-Amino 4-methyl-2-oxo-1-α-azididine sulfonic acid, tetrabutyl-a-monium salt. The potassium salt of (48-trans) -4-methyl-2-oxo-3- (phenylmethoxy) carbonyl amino -1-azetidine sulfonic acid (352.4 mg, see Example 99) is dissolved in 20 ml of distilled water and processed 373, 5 mg mmol) acidic ammonium tetrabutyl sulfate. After stirring at room temperature for 10 minutes, the solution is extracted three times with 10 ml portions of methylene chloride after saturation of sodium chloride. The methylene chloride layer is dried over sodium sulfate and evaporated in vacuo to give 536 mg of tetrabutylammonium salt, which is hydrogenated using 270 mg. 10% - palladium on activated carbon in 25 ml of dimethylformamide. The mixture is filtered through zeolite, and washed twice with 2.5 ml portions of dimethylformamide, giving the title compound in solution. B. Kaliyev salt of (33-trans) -4-methyl-2-oxo-3- (phenylacetyl) amino -1-α-a tidinsulfone sulfonic acid. The crude (3S) 3-amino-4-methyl-2-oxo-1-β-azetidine sulfonic acid tetrabutylammonium salt from Part A (combined filtrate and wash water) is treated at 206 mg of dicyclohexylcarbodiimide, 153 mg of N-hydroxybenzotriazole and 133 N-oxybenzotriazole and 8), and 153 mg of N-oxybenzotriazole and 136 N-hydroxylcarbodiimide; The reaction mixture is stirred for 1 hour and then at room temperature for 2 hours. The precipitate is filtered, the filtrate is evaporated in a vacuum, the residue is diluted in 10 ml of acetone and filtered. The filtrate is treated with 25 ml of acetone, saturated potassium iodine.
67
and then 200 ml of ether. The resulting solid (752.7 mg) is a mixture of the potassium and tetrabutylammonium salts of the target compound. The solid is dissolved in 50 ml of 0.5 M potassium monobasic phosphate and applied to an HP 20 column. Elution with WATER and then with water / acetone gives several fractions that are combined and evaporated to give a purified tetrabutylammonium salt. An aqueous solution of this material is passed through Dowex 50W-X2 (K-form) to give the desired potassium salt (121.4 mg). Rubbing with a mixture of acetone - hexane gives 104.6 mg of the target compound, m.p. 211 213 ° CciCalculated,%: C 41.72; H 4.09; N 8.11; S 9,28; By 11.32. hemihydrate and
Found,%: C 41.70; H 4.01; N 8.07; S 9.01; K 11.02.
Example 100. Potassium salt (cis) with O-3- (phenyl acetyl) amino 1 azetidine sulfonic acid.
A solution of 320 mg of the alium salt (nn) CIS 4 methyl 2 OK co-3 (phenylmethoxy) carbonyl amino l-azetidine sulfonic acid (cm, EP 98) in 20 ml of water containing 483 mg of acid tetrabutylammonium sulfate is prepared and adjusted to pH 5.5. Extraction with six 25 ml portions of methylene chloride gives 517.3 mg of oil. A solution of this substance in 15 ml of dimethylformamide is stirred with 400 mg of palladium on charcoal in a hydrogen atmosphere for 90 minutes. The catalyst is filtered off and the filtrate is stirred with 150 mg of phenylacetic acid, 1b9 mg of N-hydroxybenzotriazole and 247 mg of dicyclohexylcarbodiimide for 7.3 hours. The solvent is removed in vacuo, and the residue is dissolved in 20 ml of acetone and filtered. The filtrate is treated with 25 ml of 0.044 M potassium iodide in acetone. Dilution with an equal volume of ether gives a solid (330 mg), which is applied to a 50 ml HP-20 column in 20 ml of 0.05 M monobasic potassium phosphate. Elution with 200 ml of water and then with a mixture of 1: 9 acetone-water gave a coolo positive material in fractions (50 ml) 6-10. Evaporation
7298168
fractions 7–9 gives 81 mg of a solid. Recrystallization from acetonitrile-water gives 46 mg of the title compound, which decomposes
5 at a temperature of more than 205 ° C. A second crop (6 mg) is obtained from the filtrate. An additional 5 mg is obtained from fractions 6 and 10 by evaporation and recrystallization.
10 Calculated,%: C 42.84; H 3.89; N 8.33; S 9.53; K 11.62. S „N.OSK
Found,%: C 42.75; H 3.82; N 8.32; S 9,26; K 11.63.
15 Example 101. Potassium salt (Z), 4 (2-amino-4-thiazolyl) (methoxyimino) acetyl amino 4-methyl-2 - oxo-1-azetidine sulfonic acid.
20 A. Tetrabutylammonium salt of (3S-trans) -4-methyl-2-oxo-3- (phenylmethoxy) carbonyl amino -1-azetidine sulfonic acid.
The potassium salt of (35-trans) -4-methyl 5 -2-oxo-3 f (phenylmethoxy) carbonyl amino 1-1 azetidine sulfonic acid (352.4 mg, see example 99) is dissolved in 20 ml of water, and added tetrabutylammonium acid sulfate
0 (373.5 mg). The aqueous solution is extracted three times with methylene chloride, and the combined extracts are dried over sodium sulfate. After removal of the solvent, 534.6 mg of the targeted
5th compound.
B. Kaliyev salt 3S-Zo (. (Z), 4p} -3-f2-amino-4-thiazolyl) (by methoxyim) but acetyl} amino-4-methyl-2-oxo-I-azetidine sulfonic acid.
0
A solution of 534.6 mg of tetrabutylammonium salt of (3S-trans) -4-methyl-2-ox-so-3 (phenylmethoxy) carbonyl amino -1 -1 azetidine sulfonic acid in 20 ml
5 dimethylformamide is hydrogenated from 220 mg of 10% palladium on activated carbon at atmospheric pressure for 2.75 h; hydrogen absorption is 26.3 ml. The mixture is filtered
0 and washed twice with 2.5 ml of dimethylformamide. The filtrate and washed water (approximately 25 ml in total) are stirred under a nitrogen atmosphere with 161 mg of (Z) -ct- (methoxyimino) -2-amino-4-thia 5 zolacetic acid, 136 mg of N-oxybenzotriazole and 164.8 mg dicyclohexylcarbodiimide. The mixture is stirred under nitrogen for about 16 hours.
69
Dimethylformamide is removed under vacuum and the gummy residue dissolves in acetone and filtered to remove Lenin urea. To the filtrate is added a solution containing 272 mg (0.8 mmol) of potassium perfluorobunsulfonic acid in 0.8 ml of acetone. The suspension is diluted with an equal volume of ether and filtered to give 325.5 mg of crude product, which is purified by chromatography on 75 ml of HP-20 AG. Elution with 400 ml of water and 400 ml of a mixture (9: 1) water - acetone with 50 ml fractions gave 335 mg in fractions 3-10. After trituration with a mixture of acetone and hexane from fractions 3–5, 97.3 mg of an analytical sample are obtained. Similar trituration of fractions 6-10 gives an additional 90.4 mg of product as a solid.
Calculated,%: - C 29,, 92; H 3.01; 17.45; S 15.97; K 9,, 74.
N
Cho
Found,%: C 30,32; H 3.49 ;;
S 15.82; S-13.95; K 10.45,
NMR spectrum (° J 7); 3.97, (3N, s): 4.30 (IH, quartet doublet, J 7.3), 4.70 (1H, d, J 7); 6.95 ppm (1K, s). ;
Example 102. Dikaliyev. 3S-3oL (L) salt, 4 (2-amino-4-thiazolyl) (1-carboxy 1 methyl; ethoxy) imino acetyl amino 4 methyl 2-oxo-1-azetidine sulfonic acid
A. N-Benzyloxy-tert-side threonine amide.
A solution of 8.76 g of tert-bob-threonine and free amine from 6.4 g of O-benzyloxyamine hydrochloride (released by a mixture of ethyl acetate-sodium bicarbonate) in 100 ml of tetrahydrofuran is treated with 6.12 g of N-hydroxybenzotriazole and 8.24 g of dicyclohexylcarbo - diimide in 20 ml of tetrahydrofuran. The mixture is stirred under nitrogen for 26 hours, filtered and evaporated in vacuo. The residue is chromatographed on a 300 g silica gel column (eluted with chloroform and mixture: 1 soluorof ethyl acetate 3: 1), to give 7.2 g of the compound. Crystallization from a mixture of ether and hexane gives 4.18 g of the desired compound.
B. (ZZ-trans) -I-Benzyloxy-3-tert-butoxycarbonylamino-methyl-azetidinone.
7298170
A solution of 12.67 g of amide K-benzyloxy-tert-side-threonine, 11.5 g of triphenylphosphine and 6.23 ml of diethyl azodicarboxylate in 380 ml of tetrahydrofuran
5 is stirred under nitrogen for about 16 hours. The solution is evaporated and chromatographed on a 900 g silica gel column. Elution with a mixture of chloroform and ethyl acetate
10 (3: 1) gives 13.69 g of a compound, which crystallizes from a mixture of ether and hexane, giving 9.18 g of the target compound.
C, (3Z-trans) -3-tert-Butoxycarbo 15 Nylamino-1-oxn-4-methylazetidinone.
A solution of 9.18 g of (3S-trans) -N-benzyl-3-tert-butycoxycarbonyl-amino-4-methylazetidinone in 300 ml of 95% ethanol is stirred in an atmosphere of
20 D of hydrogen from 1.85 g of 10% palladium on activated carbon. After 141 minutes, the suspension is filtered and evaporated in vacuo. The residue is recrystallized from a mixture of ether.
25 hexane, giving 5.2 g of the title compound.
S, (ZZ-trans) -3-tert-Butoxycarbonylamino-4-metsh1azetidinono
A solution of 4.98 g of (3S-trans) -3-tert -butoxycarbonylamino-1-hydroxy-4-methylazetidinone in 200 ml of methanol is treated with 132 ml of 4.5 M ammonium acetate, and then 66 ml of 1.5 M three - titanium chloride and stirred for 4.5 hours. The aqueous solution is diluted with an equal volume of 8% sodium chloride and extracted with ethyl acetate, to give 3.48 g of the crude product. Recrystallization from ether-hexane gives 3.3 g of the title compound.
E. (38-trans) -3-Benzyloxycarbo, Nylamino-4-methylazetidinone,
A solution of 3.3 g of (3s-trans) -3-tert-S butoxycarbonylamino-4-methylazetidinone in 10 ml of each of dichloromethane and anisole is cooled to 0 ° C and 112 ml of trifluoroacetic acid are added. The solution is stirred for 90 minutes and evaporated in vacuo (benzene is added and evaporated three times). The residue is dissolved in 70 ml of acetone, and the solution is adjusted to pH 75 with bicarbonate solution. 55 rub. Only 5.33 g of benzyl chloroformate is added over 1 hour at a pH of 6.5-7.5. The mixture is stirred for 30 minutes at pH 7, diluted with 100 ml.
saturated salt and extracted with ethyl acetate (three 400 ml portions). The residue obtained by evaporation was chromatographed on a rotary puff column. Elution with chloroform / ethyl acetate (4: 1) gave 2.19 g of the compound. Crystallization from a mixture of ether and hexane gives G, 125 g of the target compound.
FO Tetrabutylammonium salt (3S Trans) -4 - methyl 2-Oxo 3 phenylmetoxy carbonyl amino -1 azetidine sulfonic acid.
A solution of 600 mg (38 trans) of zyloxycarbonylamino-4-methylazetidinone in 2 ml of dimethylformamide is cooled down and 4 ml of 0.8 M of sulfur trioxide in dimethylformamide is added. The solution is stirred at room temperature of nitrogen for 1 hour and poured into 80 ml of cold 0. 5 M monobasic potassium phosphate (adjusted to pH 5.5) The solution is extracted with three 50 ml portions of methylene chloride and 868 mg of tetrabutylammonium bisulfate is added. The resulting solution is extracted with four 75 ml portions of methylene chloride. The combined organic layer was washed with 8% aqueous chloride 1M sodium, dried, and evaporated in vacuo to give 1.54 g of the title compound.
C. Kaliev salt (z), (2-amino-4-thia zolyl) - (1-diphenylmethoxycarbonyl-1-metshIethoksi) imino-acetyl-amino-4-methyl-2-oxo-1 - -azetidine sulfonic acid
Solution 1.54; g of tetrabutylammonium salt of (3s-trans) -4-methyl-2-oxo- -3- (phenylmetoxy) carbonyl amino - 1 -azetidine sulfonic acid in 45 ml of dimethylformamide is stirred under a hydrogen atmosphere with 800 mg of 10% palladium on charcoal for 2 hours. The catalyst is filtered off, and the filtrate is stirred for about 16 hours with 1.24 g (g) -2-amino-c (- (l-diphenylmethyl-aparboles-1-methyl-1) -imino-4-thiazole acetic acid, 0 4 g of N-hydroxybenzotriazole and 580 mg of dicyclohexylcarbodiimide. The suspension is evaporated in-vacuum and the residue is triturated with 20 ml of acetone and filtered. The filtrate (plus 2 ml romtnyh water) obrabatyuaets 868 mg of potassium perfluoro butanesulfonate in 3 ml of acetone dilution of 75 ml of ether gave a solid
a substance which is separated by decantation of the mother liquor, triturated with ether, and filtered to give 0.91 g of the title compound. Matochna. the liquid is diluted with an additional 100 ml of ether, giving a second collection of 0.45 g of the desired compound.
H. Dikaliev's salt (Z), 4 P -3- (2-amino-4-thiazolyl) (1 carboxy-1-methlethoxy) imino-acetyl-amino-4-methyl-2-ca-1-azaididine sulfonic acid.
A suspension of 140 mg of potassium salt (. (Z), (2-amino-4-ti
azolyl) (1-diphenylmethoxycarbonyl-1-methylethoxy) imido acetyl amino-4-methyl-2-oKco-l-azetidine sulfonic acid (first collection) in 0.5 ml of anisole is stirred at -12 ° C in an atmosphere,
nitrogen. 2.5 ml of cold (-10 sec) trifluoroacetic acid are then added. After 10 minutes, 10 ml of ether and 5 ml of hexane are added, and the resulting suspension is stirred for
5 min at -12 ° C, then warmed to room temperature. The solid is separated by centrifugation and washed twice with simple ether. The solution of this solid is
5 ml of cold water is immediately adjusted to pH 5.5 with 0.4 n. potassium hydroxide and then applied to an 80 ml AO column. Elution with water gave 72 mg of the title compound in fractions (10 ml) 7-11 after evaporation (acetonitrk was added and evaporated three times) and triturated with simple ether, m.p. approximately (decomp.).
Calculated,%: C 30.51; H 2.95;
N 13.69; S 12.53; By 15.28.
C, H gNjOgSgK Found,%: C 29.63; H 3.20; N 12.96; S 11.94; K 12.78.
NMR spectrum (Vl); 1.46 (s, 6H); 1.58 (1H, d, s 7); 4.28 (Ш, doublet of the quartet, s 7, 2.5); 4.67 (IH, d, s 2); 6.95 ppm (s, IH). The remaining 1.22 g of potassium salt (z), (2-amino-4-thiazolyl) (1-diphenylmethoxycarbonyl-1-methylethoxy) amino-acetyl amino-4-methyl 2-scso-1-azetidine sulfonic acid (charges 1 and 2) treated as described above: 4.2 ml of anisole, 16 ml of trifluoroacetic acid, 13 minutes at. Chromatography on a 300 ml nR-20 AO column gives 694 ml of the desired compound in 73 fractions (60 ml) after processing as described. Examples about the implementation of the procedure of example 11 with the replacement of column I 104. 2 Amino-H 2 (1, 1-AHMeTHn oxy) -1 methyl 2-oxoethoxy-imino-4 thiazo-acetic acid 105. (R) (4-Ethyl-2 , 3 dioxo-lipiperazinyl) -carbonyl amine-4thibenzeneacetic acid 106. (+) - o / - (, 3 dioxO 1 - piperazinyl) -carbonyl amino 2 -furanacetic acid 107. (k) -o / -1 ( 4-Ethyl 2,3 dioxo piperazinyl) -carbonyl amino 1,4 Cyclohexadienoacetic acid 108. (R) -ci-2,3 Dioxo 4 (phenylmethylene) amino 1 piperazinyl carbonyl 3 amino 1 4-hydroxybenzo-acetic acid 109. {g) - 2 Aminoes, 1 methyl etho imino 4-thiazole-succinic acid PO. (Z) -2-Amino- (phenoxyimine-4 thiazo-acetic acid 111. (R) -d-YY 3 (4-Oxyfennl) methylene amino 2-oxo 1 imidazolide NILE carbonyl 3 amine benzene acetic acid 81 (Z) -2 aMHHO o (. hydroxy (phenylmethoxy) phosphinyl-methoxy-imino 4 thiazole hydrochloric acid, the acids listed in column I give the compounds listed in the column No Column II 3S (Z) -3 (2 amino 4 thiazolyl. 2 (1.1 dimethylethoxy) - I methyl 2 oktoethoxyzimino acetyl amine 2 oxo - 1 azetidine sulfonic acid, potassium salt, hydrate (1: 1), mp, (decomp.), Calculated,%: C 34.67; H 4.27; N 13.48 ; - S 12.34; K 7.57 ... .. -.C. 33.84; H 3.80; Found, N 12.94; S 11.10; K 7.67. B ((, 3 dioxo 4 - piperazinyl) carbonyl amino (4 hydroxyphenyl) acetyl amino) KCO 1 azetidine sulfonic acid, potassium salt, mp 197 ° С (decomposition). 3S (4) -3 (, 3- dioxo 4 piperazinsh1) carbonyl amino 2-U ranylacetyl amino 2 oxo 1 azetidine sulfonic acid, potassium salt, mp 169 171 ° C. 3S (R), 4-cyclohexadiene-1 IL (, 3 dioxo 1-piperazinyl) carbonyl amino acetyl aMHHoj2 OK CO 1 azetidine sulfonic acid, potassium salt, so pl. 185 C (decomp.). 3S (R) -3 (2,3 dioxo 4 Pipa razinyl) carbonyl amino (4 hydroxyphenyl) acetyl amino 2 oxo 1 azetidine sulfonic acid, potassium salt, so pl. 194 97 ° С (decomp.) About 3S (z) -3 (2 - amino 4 thiazolyl) (1 methyltoxy) imino acetyl amino 2 oxo 1 azetidine sulfonic acid, potassium salt, so pl. 195 ° C (decomp.). 3S (z) -3- (2 amino 4 thiazolyl) (phenoxyimino) acetyl amino 2 OXO 1 azetidine sulfonic acid, potassium salt, so pl. 165 ° С (decomp.) Calculated,%: C 35.97; H 3.02; N 14.97; S 13.72 C, H KNjO.S; Found: C 35.69; H 2.72; .. N 13.99; S 13.18. 3S (R) -3 3 (4 hydroxyphenyl) methylene amino 1 imidazolidine n 1 carbon 4 amino phenyl and schistil 1 amino 2 oxo 1 aze 1 din sulphonic acid, potassium salt, m.p. (different). Calculated,%: C 45.04, - H 3.95: N 14.33; S 5.47. OgS
112. (R) - (V - f f (4 piperidinylmethylene). Amino 1 imdazolidinyl J carbonyl amino benololuxus. On cns lot
113. (Z) -Z-AMHHO- t 1 methyl. (Phenylmethoxy) ethoxy by them but 4-thiazoleacetic acid
114. (Z) -2 lmino T5 {cyclopentyl oxy) amino 4-thiazoleacetic acid
115. (k) -o (. (Phenylmethoxy) carbonyl amino-methyl amino 6-benzoacetic acid
116. 2-Ouranacetic acid
117. (P) (2 Oxo 3 phenyl 1 imidazolidinyl) carbonyl amino benzeneacetic acid
118. (R) - (5 / - {f (2 0ксо-3 (phenylmethyl) -1 imidazolidinyl} carbonyl amide io 11 benzeneacetic acid
Found,%: C D4,54; H 3.83; N 19.79; S 5.30
3S (R) -2-oxo-3. l Nmidazolidinyl carbonyl amino (4-pyrindinemethylene) amine -phenylacetyl a shno 1-azetidine sulfonic acid, potassium salt, so pl. 230 C (decomp.,).
Calculated,%: C, 45.56; H 3.64; N 17.71; S 5.79.
/ -1 tt LTJ - s
Found,%: C 45.9; H 3.93; 17.90; S 5.36,
3S (Z) 3 (2 amino 4 thiazolyl) (. (Phenylmethoxy) etoxy imine acetyl amino - 2 ok CO 1 -azetidine sulfonic acid, potassium salt, mp 110-115 ° C (decomposition). Calculated,%: C 40.36; H -; N 13.08; E 11.97
C ,, H, KN, 0
92
Found,%: C 39.10; H.-; N 12.36; S 11.33.
Zy (k) -2 (2 amino 4 thiazolyl) (cyclopentyloxy) imino acetyl amino - 2 oxo 1 1 azetidine sulfonic acid, potassium salt, so pl. 200 ° C (decomp.).
3S (R) phenyl, phenylmethoxy) carbonyl amino acetylamino acetyl amino azazidine sulfates, potassium salt, m.p. (different) about
Calculated,%: C, 47.70; H 4.60; N 10.60; S 6.00
- c ,, (s
Found,%: C 47.50; H 3.75; N 10.54; S 5.68.
(S) -3 (2 furanyl acetyl) amino 2 oxo azetidine sulfonic acid, potassium salt, so pl. 110 ° C (dec,).
Calculated,%: C 34.60; H 2.90; N 8.90; S 10.20
Gn kn o
H 6
Found,%: C 34.13; H 2.70;
N 8.99; S 10.19.
(3S) С CL (2 oxo 3 fe111l 1 imidazolidinyl) carbonyl amino2phenylacetyl7amino 1 azetidine sulfonic acid, potassium salt, so pl. 217 (different).
Calculated,%: C, 44.91; H 4.31; N 12.47; S 5.71
. S
Found,%: C 45.06; H 3.92; N 12.69; S 5.14.
3R (R) (phenylmethyl) 1 Imidazolidinyl carbonyl amino phenylacetyl amino 1 119..c (3g {(2H & uranylmethylene) amino 2-oxo 1 imidazolidinyl carbonyl} amino A OXibenzene acetic acid 120. (R) -d-tfp-S3 - (2-Furanyl) -propenylideneJamino -2-occo-l-imide zolidinyl cans amine -benzeneacetic acid
1 21 „(Z) -2 AMHHO d (ethyl but) carbonyl oxy imino 4 thiazoluc acid
122. (° R) -o (.- 2,3 Dioxo 4 (phenylmethyl) -1 piperazinyl carbonyl almino benzeneacetic acid
123. (E) (1 Methylethyl) -2.3 dioxo 1 piperazinyl} carbonyl amine benzeneacetic acid
124. (Z) -oi.- (methoxyimino) -2-1 furan acetic acid
125. (R) -ol. - 3- (Dimethylamino) methylene amino -2-oxo-1 Imidazolidine carbonyl amino benzeneacetic acid
126. (E) -L1- (3-Ethyl-2 Oxo 1-imidazolidinyl) carbonyl amino benzeneacetic acid
3S (Z) -3 (2 amino 4 thiazolyl) (ethylamino) carbonyl oxy-imino adyl amine 2 oxo 1-a zetidine sulphonic acid, potassium salt, so pl. 230 ° C (decomp.).
(R) -3 2,3 dioxo 4 (phenylmethyl) -1 piperazinyl carbonyl amino phenyladethyl amino 2 oxo 1 azetidine sulfonic acid, potassium salt, t. Pl 158-159 ° C (decomp.).
38 (k) .. (-methylstil) -2, 3 dioxo 1 piperazinyl carbonyl amino-3-3-phenymethyl amino-2 oxo-1-azetidine sulfonic acid, potassium salt, t.p 185-187С.
3S (Z) -3- (2- (1) uranyl) (methoxyimino) adetyl-amino-2-ox-o-1-a z e-tidinsulfonic acid, potassium salt, so pl. 160 ° C (decomp.).
Calculated,%: C 33.70; H 2.80; N 11.80; S 9.00
C.cH.oKNjOTS
Found,%: C 33.79; H 2.82; N ll, 94; S 8.72.
ZS (R) -. (Dimethylamino) methylene amino -2-oxo-1 imidazolidinyl carbonyl amino phenyladethyl amino -2-oxo-1-azetidine sulfonic acid, potassium salt, so pl. 195 ° C (dec,).
. 33 (k) -. 3- (3-ethyl-2-oxo-1-imidazolidinyl) carbonyl amino-phenyladethyl amino -2-oxo-1-azetidine 81 -azetidine sulfostra, potassium salt, so pl. 195-200С. Calculated,%: C 47.39; H 4.34; N 12.56; E 5.75. C J1 KN O S BUT Found%: C 47.00; H 4.33; N 12.53; S 5.58. (3S) -i, (2 furanylmethylene) amino 2 oxo 1 Imidazolidinyl carbonyl Mamino (4-hydroxyphenyl) acetyl amino 2 oxo 1 azetidine sulfonic acid, potassium salt, m.p., 244 ° С (dil.) About 3S ( R) -3 3 3 (2 uranyl) -2 propenylidene amino 2 oxo 1 imidazolidinyl 3-carbonyl amino phenylade, amino amino 2-oxo 1-azetidine sulfonic acid, potassium salt, so pl. 195 C (decomp.) S Calculated,%: C 43.16; H 3.79; N 13.34; S 5.88; Found: C 43.70; H 4.16; N 13.90; S 5.30.
79
127. (yO-d- (f (A Methoxyphenyl) methoxy carbonyl amiko} acetylJaMHHo, benzeneacetic acid
1.28. (R) -oL- (Phenylmethoxy) carbonyl JamoJ l Imidazolide carbonyl} amino benzole cyclic acid
129. (g) -2 Amino b1 C (2 amino-1, dimethyl 2 oxoethoxy) imino -2 thia zylacetic acid
130. (b) -o ((1 1 shch1 ethyl) 2, 3 dioxy 1 piperazinyl 3-carbonyl amino 4 hydroxybenzeneacetic acid
131. (K) (1 Methylethyl) -2oxo 1 Imidazolidinyl3 carbonyl amino benzeneacetic acid
132. (g) -2-Amino-ъ (2 (diphenyl methoxy) - -methyl 2 oxoethoxy Ymino 4 thiale-acetic acid
133. 5 - Methyl 3 phenyl 4 isoxazole carboxylic acid Examples 133-134. Perform the procedure of Example 70, but replacing the potassium salt t3s (Z) l-3- (2-amino-4-thiaz olyl) 2- (biphenylme-Toe) Column I 133. (g) -3-: C2- Amino-4-thiazolyl) (1,1-1) methylmetoxy) -1- (methylthio) -2-oxoethoxy-imino acetyl-J amino -2-OXO-1-azetidine sulfate, potassium salt (see Example 78) 134. (RM-2 -Oco-3- C 2 -o-co-Zp (phenylmethoxy) arbonyl amino -1-imidazolidinyl carbonyl amino phen7298180
sulfonic acid, potassium salt, so pl. 185 190C (decomp.).,
(3S (RM -3 (4 methoxy-NILE) methoxy carbonyl, amio-Acetyl} amino phenylacetylMamino 2 oxo 1 azetidine sulfonic acid, potassium salt, mp. 268 ° С (decomp.).
3S (R) -2 oxo 3 12-oxo 3 (phenylmethoxy) carbonyl amino 1 imidazolidinyl carbonyl amino phenylacetyl amino 1 azetidine sulphonic acid, potassium salt, m.p. 175 C (decomp.).
Calculated,%: C, 44.79; H 4.09; N 18.30; S 13.90
Found,%: C 44.66; H 4.03;
N 17.19; S 12.66.
33 (g) -3 (2 amino 1, 1-dimethyl, 2 oxo-ethoxy) imino (2 amino 4-thiazolyl) acetyl-amino 2 oxo 1 -azetidine sulfonic acid, potassium salt, m.p. 210 ° C (decomp.)
3s (R) (1 methylstil) -2, 3-dioxo piperazinyl3carbonyl amino (4 hydroxyphenyl) acetyl amino 2 oxo 1-azetidine sulfonic acid, potassium salt, so pl. 201-203 ° C. (different).
Z3 ((1 metsh1Etil) 2 oxo 1-imidazolidinyl carbonyl amino phenylacetyl amino -2 oxo 1
-azetidine sulfonic acid, potassium salt. That pl. 195 200 ° C (decomp.)
f3s (z) J-3 (2 amino-4 thiaz olyl) 2 (diphenylmethoxy) -1 methyl-2 oxo ethoxy-imino-acetyl J amino-2-oxo-1 - azetidine sulfonic acid, potassium salt, so pl. 145-150 ° C.
(S) -3 t (5-methyl-3-phenyl-4-isoxazolyl) carbonyl amino -2-oxo-1-azepetics sulfonic acid, potassium salt, so pl. 230-232 C Contra.). soethoxy imino acetyl amino -2-oxo-1-azetidine sulfonic acid; the compounds listed in column I give the compounds listed in column 11. Column II 3S (Z) -3- (2-amino-4-thiazolyl) -carboxy (methylthio ) methoxy imino acetyl amino -2-oxo-1-azetidine sulfonic acid, potassium salt (1: 2), so pl. 165 ° C (decomp.). 3 (S) -3- (3-amino-2-oxo-1-imidazolidinyl) carbonyl amino-phenylacetyl-amino} 2-oxo-1-azetidine sulfo
811272981В2
. Nylacetyl amino-1 azetidine sulfonic acid, potassium salt, m.p. 250 ° C lot of potassium salt (see, example 127). (different). Example 135. 3 (Z), 4oi} - 3- (2-Amino 4-thiazolyl) (methoxyimino) acetyl amine tyl ™ 2 oxo 1 azetidine sulfonic acid, potassium salt. A solution of 51.8 mg of potassium salt (cis) 4-methyl 2 oxo-3 (phenylmethoek si) carbonyl amino1--1 azetidinsulfonic acid and 51 mg of tetraH-bisulfate - ammonium bisulfate in 5 ml of water is extracted with methylene chloride (four 10 ml portions), giving 81 mg of oil. The oil is stirred under a hydrogen atmosphere for 2 hours with 40 mg of 10% palladium on charcoal in 4 ml of dimethylformamide. The catalyst is filtered off and washed with 1 ml of dimethylformamide. The filtrate and washings are combined and stirred for about 16 hours with 31 mg (z) -2 amine of ((methoxyimino) -4 thiazoleacetic acid, 27 mg of N-hydroxybenzotriazole, and 31.5 mg of dicyclohexylcarbodiimide. The solution is evaporated in a vacuum, and the residue is triturated with 3 ml of acetone. The resulting suspension is centrifuged, and the solution is treated with 51 m potassium perfluorobutane sulphate. Dilution of 5 ml of ether and filtration gives a solid. Chromatography on AG (40 ml) gives Rydon-positive material in a fraction qi x (20 ml) 3-5 (el1-) water treatment Evaporation and grind with ether, it gives 23 mg of the product as a hygroscopic solid. Calculated,%: C 29.91; H 3.01; N 17.44 CloH, Navdeno,%: C 29.30; H 3.31 16.66 ( D, J: 1.40 (3N, d. NMR Spectrum J7); 3.97 (3N, J); 4.46 (1H, high pentet, H7), 5.37 (1H, d, J 7); 6.97 ppm (W, s). EXAMPLE 136. (3S-cis) but 4 methyl 2 octo l azetidisulfonic acid. A. tert-bok-1 Allotreonin. Suspension 6, 72 g of 1-allotreonin in 70 ml of aqueous dioxane are treated with 9.45 ml of triethylamine and 18.1 g of tert-butyl pyrocarbonate. The resulting mixture is stirred at room temperature for 4 hours and then diluted with 70 ml of water and 140 ml of ethyl acetate. After thoroughly shaking, the layers are separated, and the organic lipo layer is washed with 30 ml of a 2: 1 water / lute solution. The combined aqueous layers are then reversed with 70 ml of ethyl acetate. The aqueous layer is cooled in an ice bath and the potassium bisulfate solution is added to a pH of 2.3. The acidified solution is extracted with ethyl acetate (four 150 ml portions). The combined organic layers were dried over anhydrous sodium sulfate and stripped of the solvent, yielding 9.13 g of the title compound, B.H-Methoxy tert-1 allotreaninamide. tert-bok-1 allotreonin (9.13 g) is dissolved in 85 ml of water and 41 ml of 1N potassium hydroxide solution. Methoxyamine hydrochloride (5.22 g) and 8.67 g, 3 (dimethylaminopropyl) carbodiimide HCl are added. The mixture is stirred at room temperature for 4 hours and then injected with sodium thiol tartrate. The resulting mixture is extracted with ethyl acetate (four 150 ml portions), the organic layer is dried with anhydrous sodium sulfate and stripped from the solvent, yielding 7.38 g of the title compound as a solid C.OAP Ethanesulfonyl-M-methoxy Tert 1 allotreoninamide . N-methoxy tert-side 1 allotreonin amide (7.32 g) is dissolved in 40 ml of pyridine and cooled to -20 ° C in a nitrogen atmosphere. Methanesulfonyl chloride (3 ml) is added dropwise with a syringe over 15 minutes. The receiving mixture is slowly heated to and stirred at this temperature for 3 hours. Ethyl acetate is added (500 ml), and the solution is washed with 250 ml of ice-cold 3 He, a solution of HCl, then with 100 ml of 5% sodium bicarbonate solution. The ethyl acetate layer was dried over anhydrous sodium sulfate and evaporated from the solvent, giving 8.64 g of the title compound as a white solid. 83 D. (Zb-cis.) 3 Tert Butoxycarboni amino-1 methoxy 4 methylazet 11 dinone. Amide 0 methanesulfonyl H-methoxy-tert 1 allotreonin (8.64 g) is dissolved in 530 ml of acetone and added AND g of solid potassium carbonate. The mixture slowly heats up to 65 ° C under nitrogen and stirred at this temperature for one hour. The reaction mixture is then filtered through a zeolite, and the filter cake is washed with ethyl acetate. The filtrate is concentrated, and the residue is taken up in 250 ml of ethyl ta. The ethyl acetate solution is washed with 100 ml of 1N hydrochloric acid solution and 100 ml of 5% sodium biconate solution. The ethyl acetate layer was sewed over anhydrous sodium sulfate and stripped from the solvent to give 6.63 g of the crude product. E. (38-cis) -3-tert-Butoxycarbonylamino-4-methylazetidinone. Sodium (1.35 g) is dissolved in approximately 300 ml of liquid ammonia at, and 5.87 g of (GF-cis) -F-tert-butoxycarbonylamino-1-methoxy-4-methylazetidinone are added dropwise with a syringe. in 35 ml of tetrahydro furan. An additional 10 ml tetrahydrofuran is used for rinsing. Before the end of the addition, about 100 mg of additional sodium is added. The mixture is stirred for another five minutes, then cooled rapidly by adding 3.35 g of solid ammonium chloride in one portion. The ammonia is distilled off with a stream of nitrogen and 250 ml of ethyl acetate is added to the residue. After filtering and washing the solid with ethyl acetate, the combined filtrate was evaporated from the solvent, giving 4.82 g of the desired compound, FO (3S-cis) -3-tert-butyroxycarbonyl amino 4 - - ethyl 2-oco-1-azetidine sulfoacetomethane-4-α-ethyl-2-sulfonyl amino-tetramethylsulfonate. (3S, 4k) -3-tert Butoxycarbonylamine-41 tethylazetidinone (4.98 g) is dissolved in 30 ml of dimethylformamide. The pyridine sulfur sulfur complex is added in an amount of 11.9 g, and the mixture is stirred at room temperature under a nitrogen atmosphere. After 14 hours of transfer, an additional 1.8 g of the complex of pyridine and trioxide 8 / sulfur are added, and stirring is continued for 80 hours. The reaction mixture is poured into 700 ml of a 0.5 M solution of one-. potassium phosphate and washed with methylene chloride (three 300 ml portions). Tetra-and-butylammonium bisulfate (8.45 g) is added to the aqueous solution, and the mixture is extracted with methylene chloride (four 300 ml portions). The combined methylene chloride layers are dried over anhydrous sodium sulfate and evaporated from the solvent to give 10.76 g of the desired gum compounds. G. (38-cis) -3-Amino-4-methyl-2-oxo-1-azetidine sulfonic acid. 10.76 g of the tetrabutylammonium salt (3-cis) -3-tert-butoxycarbonylamino-4-methyl-2-oxo-1-azethidine alkylphenol is dissolved in 50 ml of 95-97% formic acid and stirred for 4 h in nitrogen atmosphere. A small amount of product from the previous reaction is added as a seed, and the mixture is stirred for an additional hour. The mixture is stored in a refrigerator (freezer) for about 16 hours, and the frozen mixture is heated to room temperature and stirred for an additional hour. The resulting solid is filtered and rinsed with methylene chloride to give 282 mg of the title compound. The filtrate is diluted with 1 liter of methylene chloride and kept at -20 ° C for 4 hours. The precipitate that forms is recrystallized from water-methanol-acetone, giving an additional 167 mg of the title compound. NMR spectrum (): 1.63 (3N, d, J - 6.5 cycles per second); 1 R (Nujol) 1776 cm. Example 137. The potassium salt (. (Z), (2-amino-4-thiazolyl) - (methoxy-imino) acetyl-amino-, -4-methyl-2-oxo-1-azetidine sulphoxy acid, A solution of 201 mg (g) -2-amino o (- (meoxyimino) -4-thiazoleacetic acid 153 mg of K-hydroxybenzotrizol monohydrate in 3 ml of dimethylformamide is formed in 206 mg of dicyclohexylcarbo imide. The mixture is stirred at the temperature of 206 minutes for 20 minutes nitrogen solution, and 180 mg of (3H-cis) -3-amino-4 "e yl-2-OXO-1-azetidine sulfonic acid and 0.14 ml of triethylamine in 2 ml of dimethylformamide (an additional 1 ml of dimethylformamide and This mixture is stirred for about 16 hours. The suspension is evaporated under vacuum, triturated with 12 ml of acetone, centrifuged, and the liquid is treated with 338 mg of potassium perfluorobutane sulfonate. Dilution of 10 ml of ether and filtration gives a solid product which is chromatographed on 200 ml of NR 20 resins with water elution. Fractions (20 ml each) 18-30 are combined and lyophilized to give 274 mg of the title compound as a hygroscopic solid. Calculated,%: C 29.91; H 3.01; N 17.44 C, oHi.V6S.K Found,%: C 30.03; H 3.21; N 17.06, NMR spectrum (J 6.5); 3.98 (3N, s); 4.48 (W, double triplet, J 6.4 5.5); 5.36 (1H, d, J 5.5); 6.97 (IH, s). Example 138. (38-trans) -3-Amino-2-oxo-1 ™ azetidine sulphoxide Lot A. Threonine methyl ester hydrochloride. Under nitrogen, a flask containing 500 ml of methanol is cooled to -5 ° C (ice / brine), and 130 ml (excess) of thionyl chloride is added at such a rate as to maintain the reaction temperature between 0 and 10 ° C. After cooling again to -5 ° C, 59.5 g of 1-threonine is added and the mixture is heated to room temperature and stirred for 16 hours. The mixture is then concentrated and evacuated at 10 Torr for 2 hours, giving a viscous oil. This material is used in the next step. B. Treninamide, The crude product of part A is dissolved in 2.5 L of methanol and cooled to -5 ° C (ice / saline). The solution is saturated with ammonia gas, the cooling bath is removed and the sealed vessel is left to stand for 3 days. After removing all unreacted ammonia, 100 g of sodium bicarbonate and 50 ml of water are added through an aspirator and the mixture is stripped to a viscous oil. C. Amide benzyloxycarbonyltreonine. The crude product of part B (already containing the required amount of sodium bicarbonate) is diluted to a volume of 1 liter with water. To this rapidly stirred solution is added, with 94 g (88 ml of 90% purity of the substance) benzyloxycarbonyl chloride as a solution with 80 ml of tetrahydrofuran over 1 hour. The reaction mixture is then stirred for an additional 16 hours and extracted with ethyl acetate ( one 500 ml portion, two 250 ml portions) The combined extracts are dried over magnesium sulphate and concentrated. The crystalline residue is then dissolved in 250 ml of hot ethyl acetate. 300 ml of hexane is added, followed by boiling until the solution is clear. Cooling and filtering the crystalline mass after drying gave 104 g of the desired compound. D, O-mesylate benzyloxycarbonyl-threoninamide. Under an argon atmosphere, 100 g of benzyloxycarbonyltreoninamide is dissolved in 400 ml of anhydrous pyridine and cooled in an ice / salt bath. 36.8 ml (54.5 g) of methanesulfonyl chloride is added to the stirred solution over 15 minutes. After stirring for 2 hours, another 0.3 equivalents of methanesulfonate chloride is added. The reaction mixture is then stirred for 1 hour and poured into a mixture of 1.5 liters of ice and 2 liters of water. The resulting suspension is stirred for about 30 minutes and filtered. Drying the crude product at 60 ° C for about 16 hours in a vacuum oven gives 109 g of the desired compound. E. Tetrabutylammonium salt of N-sulfonyl-benzyloxycarbonyltreoninamide-O-mesylate. A solution of 2-picoline (17.8 ml) in 90 ml of methylene chloride is cooled to -5 ° C (ice / saline). 5.97 ml of Chlorosulfonic acid are added at such a rate as to keep the internal reaction temperature below 5 ° C. The resulting solution is added through a tube to a suspension of 7.65 g of benzyloxycarbonyltreoninamide 0-t esylate.
87
in 120 ml of methylene chloride. The resulting heterogeneous mixture is heated under reflux for about 16 hours, and a clear solution is obtained. The solution is drawn out in 500 ml of phosphate buffer of pH 4.5 (0.5 M) and further diluted with 120 MJ1 of methylene chloride. The separated organic layer is then washed once with 100 ml of a buffer solution, and the combined aqueous phases are treated with 10.2 g of acidic sulphate (tetramine H butylammonium and extracted with methylene chloride in one 300 ml portion and two 150 ml portions). After drying the combined organic extracts over sodium sulfate, the solution is concentrated, giving 12.7 g of a foam.
FO (3-B-trans) -3 Amino 4 methyl-2 oxO 1-azetidine sulfonic acid
The mixture, containing 5.52 g of carbonate and potassium in 20 ml of water and 160 ml of 1.2 dichloroethane, is brought to the boil under reflux. Next, add 15.5 mmol of tetrabutylammonium salt of 0 N-sulfonyl benzyloxycarbonyltreoninamide mesylate in 20 ml of 1.2 dichloroethane (20 ml is used as a rinse). After heating under reflux for 30 minutes, the mixture is poured into a separatory funnel, diluted with 50 ml of water and 100 ml of methylene chloride, and the phases are separated. The organic phase obtained is dried over sodium sulfate and concentrated to give the crude (33 trans) -3 benzyloxycarbonyl e-tidine sulfo Column I tetrabutylammonium salt.
139. (R) (2 Furanylmethyl) amino 2 oxo 1 ImidazolidinP carbonyl amino benzene acetic acid
140. (R) -ot- (4-Ethyl 2,3 dioxo -1 piperazinyl) carbonyl amino J benzene acetic acid
141. (g) -2-Amino-o (((hydroxyimino) -4-thiazoleacetic acid
72981 8
; Acids. The crude azetidinone is treated in 250 ml of ethanol, 0.8 g of palladium on charcoal as a catalyst, and hydrogen
5 bubbled through the solution. After 90 minutes, the mixture is filtered through a zeolite using 50 ml of ethanol as a rinse. Addition of 1.2 ml of formic acid to this
0 solution causes immediate precipitation of the target zwitterion, which is filtered out after stirring for 1 h, allowing after drying at 10 Torr for 1 h 1.1 g
15 products. A second collection of the product is obtained after concentration of the filtrate and the repeated addition of the mous of viric acid, yielding 1.3 g of the desired zwitterion, mp 218C
0 (different). , 41.1 (with 1, BUT). NMR Spectrum (D): 1.58 (3N, d, J 7); 4.80 (2H, m).
Calculated,%: C 26, 66; And 4.44; N 15.55; S 17.77.
5 Q,
Found,%: C 26.62; H 4.72; : N 15.47; S 17.49.
Examples Performing the procedure of Example 138 with the replacement of (33-cis) 3 amino 4 methyl 2 OXO 1 azetidine sulfonic acid (38-trans) 3 amino 4 metidine sulfonic acid and (d) -2 amine O with; (methoxyimimino) -4 Thiazoleacetic acid with the acids listed in column I gives compounds listed in column II.
Column II
(R, (3-L (2 furanylmethylene) amino 2 oxo 1 IMI dazolidinyl carbonyl amino phenyl acetyl amino 4 methyl 2 oxo aze tidine sulfonic acid, potassium salt, mp 213 C (decomp.).
ZZ-SZ-OTK K-), (.til 2,3 dioxo 1 piperazinyl) carbonyl aminophenylacetyl amino 4 methyl 2 octo l of sulfonic acid, potassium salt, so pl. 177 ° C (decomp.).
Potassium salt (. (Z), 4/3 -3-G (2 amino 4 thiazolyl) - (oxime but) acetyl-J amino 4-methyl-2-oxo-1 azetidine sulfonic acid, mp 230 ° C.
Calculated,%: C 26.60; H 2.40; N 17.20; S 15.80
CgH. Hjo
89
42. (+) - o ((Aminooxyazetil) amino} -2 thiopheneacetic acid.
Examples 143 o Executing the procedure of Example 138 with the replacement of (Z) -2-aminopz-(methyimino) -4 tia Column I
143. (, 3-Dioxo 4 (phenylmethoxy) carboxyl amine l Piperisinyl carboxyl Jamino benzyl cyclic acid
144. (n) (2 Furanylmethylene) amino 2 ok from imidase olidinyl to arbonyl amino benzeneacetic acid
145. (n) (, 3-dioxo piperazinyl) -carbonyl amino benzeneacetic acid
Example 14fi. Potassium salt (Z), (2 amino 4 thiazolyl) (1-carboxy 1 methylethoxy) imino acetyl amino 4 methyl 2 oxo 1 azetidine sulfonic acid (1: 2),
A. Kaliyev salt 3S-t3o (. (Z) ,, cJ-} -3- C (2 amino 4 thiazolyl tC 1 diphenyl methoxycarbonyl 1 methyethoxy) imino acetyl amino 4 methyl 2 oxo 1 azetidine sulfonic acid.
A solution of 440 mg of (Z) 2 - aMHHonc (-t (l-carboxylic acid and l-ethyl acetate) and in 4 types of azolic cyclic acid and 153 mg of mono-
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Found,%: C 26.62; H 2.95; N 16.59; S 15.58
The potassium salt of (+), (aminooxoacetyl) aminoZ 2 thienylacetyl amino 4-methyl 2 oxo 1. azetidine sulfonic acid, so pl. 135 ° C (decomp.).
acetic acid, the compounds listed in column I give the compounds indicated in column II.
Column II
Potassium salt 35-SZo1 (K), g with 2 (4 methyl 2 oxo 1 sulfo 3 W-azetidinyl) amino} 2 oxo 1 phenyl ethyl) amine carbonyl 2,3 dioxo 1 piperazinsh13kar1.shnovoy acid, enylmethyl ether, t. PL . 191 ° C (decomp.).
Calculated,%: C, 45.58; H 4.13; N 12.76; S 4.87
С, 5Н5, Цо5-К
Found,%: C 45.16; H 4.05; N 12.60; S 4.97.
Kaliev salt SZB 43o1 (c), 4oi L C 3 (2 furanylmethylene) amino 2 oxo 1 imidazolidinyl carboyl amino 3 phenylacetyl amino 4 methyl 2 2 oxo 1 azetidine sulfonic acid
Calculated,%: C, 41.30; H 4.46;
13.76; S 5.25
C, H O N S-K -SHjO Found,%: C 41.18; H 3.96;
13.59; S 5.32.
Potassium salt ZZ-l3cL (R), 3 I CC (, 3 dioxo 1 piperazinil carbonyl amino phenylacetyl amino with O 1 aze tidinsul ′ phoquielots
Calculated,%: C 41.07; H 4.72; N 12.60; S 5.77;
9 "22 ° 8 5S K - 2H, 0 Found,%: C 41.08; H 4.11; N 12.91; S 6, P.
hydrate of N-hydroxybenzotriazole in 3 ml of imethylformamide is treated with 206 mg of didiclohexylcarbodimide. The mixture is stirred at room temperature.
temperature for 30 minutes in the atmosphere of nitrogen. Next, a solution of 180 mg of (35-cis) 3 amino4 methyl 2-oxo 1 azetidine sulfonic acid (see Example 137) and 0.14 ml of triztilamine are added.
2 ml of dimethylformamide (Additionally, 1 ml of dimethylformamide is used for rinsing), and the mixture is stirred for about 16 hours. The suspension is evaporated in vacuo and triturated with 12 ml of acetone. The suspension is filtered and the solid is washed with acetone (two 3 ml portions). The combined filtrate and industrial waters are treated with 338 mg of potassium perfluorobutane sulfonate. Diluting a field with 30 ml of ether gives a gum-shaped solid that slowly solidifies. The solid is filtered and washed with ether to give 656 mg of the title compound.
B. Kaliyev salt 3S-f3o ((Z), (2 amino 4 thiazolyl) (1-carboxy-1-methylethoxy) imino acetyl amino-4 methyl 2-oxo-1-azetidine sulfonic acid (1: 2).
A suspension of 656 mg of potassium salt (. (Z), -3 - (; (2-amino-4-tzazolyl) - (i-diphenylmethoxycarbonyl-1-methylethoxy) imido acetyl-4 methyl 2-oKco-l-azetidine sulfonic acid in 2.3 ml of distilled anisole is cooled to -12 ° C. Next, 11.5 ml of trifluoroacetic acid is added, previously cooled to -10 ° C. The solution is stirred for 15 minutes, 46 ml of ether are added, and then 23 ml of hexane. 15 minutes at -10 ° C and stirring for I5 minutes at room temperature, the solid is filtered and washed with ether, giving 457 mg of a highly hygroscopic resin. This substance is dissolved in 6 ml of cold water and immediately adjusted to pH 5.6 with 0.4 N. potassium hydroxide solution. The solution is applied to 200 ml HP-20 resin, eluted with water. Fractions (50 ml The commands are combined and lyophilized to give 239 mg of the title compound as a solid.
Calculated,%: C 29.99; H 3.10; N 13.45; S 12.32.
 / 2 Found,%: C 29.94; H 3.30;
N 13.30; S 11.93.
NMR spectrum (DIZO): (ZN, d.,
J 7.5); 1.46 (6H, s); 4.48 (1H,
double triplet, J 7.5, 6.5); 5.34 (1H, d, J 5.5), 6.96 ppm (1H, s).
EXAMPLE 147. (j) -3-Amino, 4 dimethyl 2-x-cs-1 aze tidinsulfonic acid.
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A. (+) - 4, i-Dimethyl-2-oxo-1-azetidine-t-butyldiphenylsilane.
A solution of 40.5 ml of tert-butylchloridephenylsilane in 112 ml of dimethylforma-5 is cooled to 0 ° C. To this solution is added 22 ml of triethylamine. To a cooled solution of triethylamine is added dropwise over 10 minutes a solution of 12.87 g of 4,4-di-
10 methyl-2-azetidinone in 25 ml of dimethylformamide. The resulting turbid solution is stirred for 18 hours under argon atmosphere. This mixture is poured into 400 ml of ice water and
15 is extracted with three 150 ml portions of a 2: 1 mixture of ether / ethyl acetate. The combined extracts are washed with four 100 ml portions of 0.5 M monobasic potassium phosphate buffer,
20 with one 150 ml portion of sodium bicarbonate solution, two 150 ml portions of water, and one 150 ml portion of the complete sodium chloride solution. The solution is dried over sodium sulfate.
25 and concentrated in vacuo to give 33.03 g of the title compound as a solid.
B. (4) -3-Azido-4,4-dimethyl-2-oco-1-azetidine-t-butyldiphenylsilane.
 A solution of 4.25 ml of 1.6 M (in hexane)
- butyl lithium and 1 1 ml of dry rofuran tetrahydride is prepared at -50 ° C. under argon in a 100 ml three-neck flask. The solution is added.
5 0.083 g of triphenylmethane in 1 ml of tetrahydrofuran. The resulting solution is cooled to -60 ° C, and I, 0 ml of diisopropylamine is added dropwise with a syringe. The mixture was stirred for 15 minutes and then cooled to -78 ° C. The solution is added slowly using a syringe.
2.3 g (j) -4,4-dimethyl-2-oxo-1-aze tidin-tert-butyldiphenylshistana in 8 ml
5 tetrahydrofuran. The resulting solution is stirred for 20 minutes at -78 ° C, during which time a heavy substance is precipitated and uniform mixing becomes difficult.
0 nym. A solution of 1.33 g of p-toluenesulfonyl azide in 5 mp tetra.hydrofuran is added dropwise. The resulting mixture was stirred for 20 minutes, then dropwise to 5 drops of 2 ml of trimethylsilyl chloride. The reaction mixture is warmed to ambient temperature and stirred for 1 hour. The mixture is then cooled to OC, and poured into 150 ml of ethyl acetate at 0 ° C. In order to make both the aqueous and the organic layer light (clean), a residual amount of 0.5 M of monobasic potassium phosphate buffer is added. The two layers are separated, and the organic layer is washed with three 150 ml portions of 0.5 M thieves. monobasic potassium phosphate, one 150 ml portion of sodium chloride solution, one 150 ml portion saturated solution of sodium chloride and dried over sodium sulfate. The solvent is concentrated in vacuo to 2.83 g of an oil, which, after mixing with hexane, gives 1.67 g of the title compound as a solid. C, (+) - 3- Azido 4.4 dimethyl 2-oxo -1 azetidine, 1.52 g of (+) - 3 azido 4.4 Dimethyl 2 oxo 1 aze tidine dissolved in a 50 ml three-neck flask in 25 ml of acetonitrile. tert butyldifensilsilane. To the stirred solution is added 0.25 M of 48% hydrofluoric acid. This mixture is stirred at ambient temperature. Every 60 minutes, 0.5 milliliter portions of hydrofluoric acid are added until 3.25 m of hydrofluoric acid is added after 6.5 hours. The reaction mixture is then cooled to 0 ° 0, neutralized with saturated sodium carbonate and extracted with 120 ml of ethyl acetate. The organic layer is then washed with 100 ml of water, with 100 m of a saturated solution of sodium chloride and dried over sodium sulfate. The dry solution is concentrated in vacuo to give 1.34 g of oil. This crude oil was chromatographed on 27 silica gel, eluting with hexane and then 33% ethyl acetate in gox, to give 0.358 g of the title compound as a solid. D. Tetrabutylammonium salt (} -3-azido-4, 4-dimethyl-2-oxo-1-azetidine sulfonic acid, K 0.100 g (+) - 3-azido-4,4-dimethyl 2-oxo-1- azetidine 2.8 ml of a 0.5 M complex of dimethylformamide with sulfur trioxide is added under argon atmosphere. The mixture of diathes can be heated to ambient temperature and stirred for 19–45 minutes. The solution is poured into 20 ml of a 0.5 M single-base potassium phosphate buffer pH 5.5. This substance is washed with three 20 ml portions of methylene chloride (discarded), and 0.237 g of acid tetrabutylammonium is added to the aqueous solution. sulphate. The substance is extracted with four 20 ml portions of methylene chloride, and the combined organic extracts are washed with 20 ml of 8% sodium chloride solution. The methylene chloride solution is dried with sodium sulfate and concentrated in vacuo to give 0.31 g of oil, which according to NMR data is 50% dimethylformamide and 50% of the target compound. E, (+) -3-Amino 4,4-dimethyl-2-oxo-l-azetidine sulfonic acid A solution of 0.155 g of tetrabutylammonium salt (+) - 3 azido 4,4-dimethyl- -2-oxo 1-azetidine sulfonic acid in 0.6 ml of methanol is hydrogenated over 10% palladium on charcoal for 20 minutes at a pressure of 1 atm. The catalyst is filtered off and rinsed with methylene chloride, which is combined with the methanol solution. This clear solution is treated with 0.123 ml of 97% formic acid. Upon addition of the acid, the solution immediately becomes cloudy. After standing for 1 hour at 5 ° C, the solid is filtered off, yielding 0.0664 g of the title compound, t, pl. 200-202С (decomp.). NMR spectrum (DJO): 1.64 (3N, s): 1.68 (3N, s); 4.42 (1H, s). IR spectrum (KVg): 1765. Calculated,%: C 30.92; H 5.20; 14.43; S 16.50, Found,%: C 28.79; H 5.70; N 13.28; S 15.44. Example 148. Potassium salt G3 + (L) -3- (2-amino-4-teazolyl) (methoxyimino) acetyl amino-4,4-dimethyl 2-oxa-1-az e tidine sulfonic esters. A solution of N-hydroxybenzotriazole hydrate (50 mg) and (s) -2-amino-T3 (- (methoxyimino) -4-thiazoleacetic acid (0.323 mmol) in 0.5 ml of dimethylformamide is treated with 67 mg of dicyclohexylcarbodiimide in an atmosphere of - ™ on at ambient temperature. The resulting mixture is stirred for 1 hour.
(+) 3 - amino 4, having O 1 -azatidine sulfonic acid (57 NH, see Example 153) as a solid, followed by dropwise addition of triethylamine (0.05 ml). The reaction mixture is transported at ambient temperature for 16 hours. Dimethylformamide is removed under a deep IMC vacuum at 30 ° C, and the residue is suspended in 4 ml of acetone and filtered. The filter cake is flushed with an additional 4 ml of acetone and potassium perbutane sulfonate (-85 mg) is added to the filtrate, followed by the addition of ether. Mixing the obtained resin with ether gives 40 mg of a tan solid which is chromatographed on a 70 ml AG column. Elution with water gave 20 mg of the target compound in fractions (5 ml) after evaporation, trituration with a 1: 1 mixture of acetone and hexane and the substance, t, Sh1. 225 ° C (decomp.).
Calculated,%: C 31.80; H 3.40; N 16.86; S 15.43.
11 14
Found,%: C 29.48; H 3.48;
N 14.98; S 13.35.
Example 149. The potassium salt of (+) -4.4 dimethyl 2 oxo 3 (phenyl acetyl) amino 1 ethidine sulfonic acid.
A solution of N-hydroxybenzotriazole hydrate (45 mg) and phenylacetic acid (40 mg) in 0.5 ml of dimethylformamide is prepared with dicyclohexylcarbodymium (61 mg) under argon at ambient temperature. The resulting mixture is stirred for 1 hour. Next, (+) -3 amino-4.4 Dimethyl -2 OX-1 azetidine sulfonic acid (52 mg, see example 153) is added as a solid (see Example 153) and the dropwise added triethyla on (0.04 ml). The reaction mixture is stirred at ambient temperature for 24 hours. Dimethylformamide is removed under high vacuum and the residue is suspended in acetone and filtered. Potassium fluorobutane sulfonate, ether, is added to the filtrate, and the mixture is cooled. The resulting solid is washed with acetone, hexane and sups, giving the title compound as a powder.
Calculated,%: C 44.55; H 4.32; N 8.00; S 9.15; K 11.16.
.SK
13 15-
  ),%: C 43.83; H 4.16;
Found, N 7.96; S 8.76; K 11.43.
NMR Spectrum (Dj): 1.33 (s, 3N); 1.58 (s, zn); 3.68 (s. 3N); 4.70 (s, 1H); 7.56 ppm (broad s, 5H).
Example 150. Potassium salt 33-trans 3 (2 amino 4 thiazolyl) oxide with acetyl amino 4-methyl 2 oxo 1 azetidine sulfonic acid.
To a solution of diphenylphosphinylchloride (1.85 g) in dry dimethylformamide (15 ml), cooled, valuable in an ice / methanol bath at (-15) - (-20) ° C, to Reduce the triethylamine salt (2 amno-4 thiazolyl) β-glyoxylic acid (2.14 g). After stirring for 0.5 h, a solution of (38-trans) -3 amino 4-methyl-2-ox-1 azetidine sulfonic acid (1.08 g, see Example 139) and triethylamine (1) are added to a cold solution of the mixed anhydride. , 92 ml in dry dimethylformamide (5 ml), and the reaction mixture is stirred at 5 ° C for 24 hours. The solvent is removed in a vacuum, the residual dark oil is dissolved in water and chromatographed on a Dowex 50 x 2 400 resin ( form, 200 ml) After elution with water (15 ml fractions), the neo-schenny product is collected in fractions (3.37 g) by chromatography on HP 20 resin (200 ml), eluting with water (15 fractions) gives the desired product in fractions. Removing the water in vacuo gives the desired compound as an amorphous powder.
Calculated,%: C 29.02; H 2.44; N 15.04; S 17.22; K 10.50.
CgH-N O SK (372,42)
Found,%: C 28.87; H 2.62; N 14.85; S 15.09; To 10.81.
Example 151. 3S (R) -3 C (amino-acetyl) amino-phenylacetyl amino 2 oxo 1 azetidine sulfonic acid, potassium salt, trifluoroacetate (1: 1) salt.
The release of the potassium salt of 133 (B) (4-methoxyphenyl) methoxy carbonyl} amino acetyl amino phenylacetyl amino 2 Oxo 1 azet1G of dynesulfonic acid (see example 127) using trifluoroacetic acid and anisole gives the target compound, v. Sh1. which is 165 ° C (decomp.).
97
Calculated,%: C 34.22; H 3.45; N 10.64; s: 6.09; F 10.83.
 KN, H, 0
Found,%: C 34.86; H 3.41; N 10.69; S 6.08; F 10.51.
Example 152. Potassium salt (38 Trans) -3 methoxy 4 methyl-2 oxo 3 {(phenylmethoxy) carbonyl amino} 1 azetidine sulfonic acid.
A. (38 trans) -4-ethyl 3 methoxy -2 oxo 4 {phenylmethoxy) carbonyl amino azetidino
A solution of 2.5 g (0.0106 mmol) of (3R trans) -4 - methyl 2 oxo 3 (phenylmethoxy) carbonylZamino3 azetidine (prepared from D-threonine with a yield of 12.6%, mainly as described for racemic The cis isomer in about 98 s) in 112 ml of borax in methanol is cooled to 0 ° C and 3.5 ml of tert-butyl hypochlorite are added. After 20 minutes, the solution is poured into
1 l cold water and extracted
two 750 ml portions of cold ETHIL
acetate. The organic layer is washed with cold water (two 750 ml portions), saturated with salt, dried and evaporated, giving 3.05 g of crude H, K-dichloroamide.
A solution of 426 mg of lithium methylate in 20 g of dry methanol is cooled to 78 ° C and diluted with 40 ml of dry tetrahydrofuran. Over 30 seconds, a solution of the indicated chloramide in 20 ml of rofuran tetrahydride (78c) is added via syringe. After 20 minutes at 78 ° C, the solution is added.
2 ml of acetic acid and trimethylphos phyta. After 40 minutes at room temperature, the solution is taken up in 500 ml of water and extracted with ethyl acetate (two 300 ml portions). The organic layer is washed with water, dried and evaporated to give an oil. Chromatography on a 200 ml silica column eluted with 3: 1 chloroform / ethyl acetate gave a total of 1.25 g of the desired diene compound.
In “Kaliev salt (38 trans) toxo 4 methyl 2-oxo 3-- j (phenylmetoK si) carbonyl a.mino 1 azetidine sulfosate.
A solution of 800 mg (0.00303 mol) (33-trans) A methyl 3 Methoxy 2 oxo 4 (phenylmethoxy) carbonyl amino azetidine in 2 ml of dimethylformamide
7298198
cooled to 0 ° C and add 4 ml. complex of dimethylformamide and sulfur trioxide. After 1 h incubation at 0 ° C and 4 h incubation at room
At a temperature of 5, the solution is poured into 80 ml of 0.5 M monobasic potassium phosphate adjusted to pH 5.5 and extracted with methylene chloride (two 50 ml portions, discarded).
The 10th layer is treated with 1.04 g of tetrabutylammonium sulfate and extracted with dichloromethane, giving 1.42 g of oil. This oil is dissolved in acetone and treated with 1.04 g of peroxide.
15 potassium fluorobutane sulfonate in 10 ml of acetone. Dilution of 250 ml of ether and intensive trituration of an oily-solid solid yields 584 g of crude product. Chromatography
20 per AG (200 ml) gives 418 mg of the purified product in fractions (100 ml) 13-16 (elution with 1 l of water and then a mixture of 9: 1 water and acetone). Rubbing 114 mg of this material with
25th ether gives 104, mg analytical sample about
Calculated,%: C 39.06; H 4.04; N 7.01; S 8.03; K 9.78. ,, .SK-
3Q Found;% 38.91; H 3.62; N 6.91; S 8.06; K 9.51.
NMR Spectrum (): 1.33 (3N, d, J 7); 3.46 (3N, s); 4.22 (2H, doublet of doublet, J 6); 5.18 (2H, s); 7.43 ppm about shares (5H, s) o
Example 153. Kaliev salt (35-trans) -. 3 methoxy 4 methyl 2 oxo (phenylacetyl) amino 1 azetidine
40 sulfonic acids.
Tetrabutylammonium salt (35 ™ -trans) 3 amino 3 methoxy-4 methyl 2 oxo 1 azetidine sulfonic acid is prepared by catalytic
45 whom hydrogenation of potassium salt (33-trans) 3 methoxy 4 methyl 2 OKCO 3 t Kfbnylmethoxy) carbonyl amino 1 n zetidine sulfonic acid (see example 158) after the conversion of tetrabutyl
50 ammonium salt. Following the procedure of Example 88, but using the (33 trans) -3 amino C-tetrabutylammonium salt of tetrasulfonic acid and phenylacetyl chloride
55 read, get the target compound. Calculated,%: C 42.61v And 4.31; N 7.65. ., C jHisK ASK Found,%: C 39.67; H 4.09; N7.30. NMR spectrum (): 1.29 (3N, d, J 7); 3.45 (3N, s); 3.73 {2H, s); 4.36 (2Hj doublet of doublet, J b); 7.38 ppm (5H, s.). Example 154. Potassium salt (Z), 4 3 (2 amino 4 thiazolyl) L12- (diphenipmethoxy) soethoxy imino-Acetyl-amino 2 Methi 4 oxo 1-azetidine sulfonic acid. Performing the procedure of Example 138 but replacing (g) -2 amino - L (methoxy immuno) -4-thiazoleacetic acid (Z) -2-amino-tz (. 2 (diphenylmethoxy) oxoethoxyimino3 4 thiazo-acetic acid and treating it first (3S -Cis) 3 amino 4 methyl 2 oxo 1 azetidine sulfonic acid with triethylamine gives the title compound, mp PL 155 160 ° C (decomp.). Calculated: C 47.12; H 3.63; N 11, 45; S 10 , 48. C. K. Found,%: С 46.91; H 4.03; N 11, 36; S 9.52. Example 155. Dikalieva salt. (Z), 4E1} -3 (carbox simethoxy) imino (2 amino 4 thiazolyl) acetyl amino 4-methyl - 2 sk with 1 azetidine sulfonic acid. Release of the potassium salt 3S-3d (Z), 4 j8 3 i ( 2 amino 4 thiazolyl) 2- (diphenylmethoxy) -2 oxoethoxy imino acetyl amino 2 methyl 4 OK with 1 azetidine sulfonic acid (see CHAPTER 170) using trifluoroalkyl acid and anisole gives the desired compound, which decomposes at a higher temperature. Example 156. The Kashiev salt of (S) -3 (2.6 dichloro 4-pyridine) and acetyl amino 2 oxo 1 azetidinsul phonic acids Acylation of the tetrabutylammonium salt of (S) -3-amino 2 oxo 1 azetidine sulfonic acids (see Example 6A) with phenylbutyl ether (2.6 dichloro 4-T1IRIDINIL) TIO of acetic acid with P following treatment with perfluorobutane Column I 159.2.6 Dimethoxybenzoic acid 160. azoluacetic acid 98100 potassium sulfonate gives the target compound with so pl. 212 L14 ° C. Calculated,%: C 27.15; H 2.27; N 9.50; S 14.50. C KClKNjOS Found,%: C 27.38; H 1.97; N 9.66; S 14.55. Example 157. The potassium salt 38 (K) -3 (4 amino 2,3 dioxo 1 piperazinyl) carbonyl amino phenyl acetyl 4 methyl 2 oxo 1 aze tidine sulfonic acid. The potassium salt of the phenylmethyl ester of 3S (R) 2- (4 methyl 2 oxo 1 sulfo 3 azetidinyl) aminoJ 2 OK co l phenyl Ethyl amine carboxyl 2, 3 dioxo 1 piperazinyl carbamic acid (see Example 149) is hydrogenated using gaseous water kind and palladium on activated carbon as a catalyst, giving the title compound Art. square 165 ° C (decomposition) o Calculated,%: C 39.32; H 4.36; N 15.61; S 5.85 - Found,%: C 38.92; H 4.03; N 16.02; 5 6.11. Example 158. Sodium salt (1: 2) ZS (Z) l-3 (2 amino 4 thiazolyl) (1 carboxy 1 methylethoxy) im-acetyl amino 2 oxo 1-azetidine sulfonic acid. The tetrabutylammonium salt of C3S (L) j-3 (2 amino 4 thiazolyl 2- (diphenyl methoxy) -, 1 dimethyl 2-oxo-toco-imino acetyl-amino 2 oxo 1 azeti-dinsulfonic acid (see Example 28) is deblocked using three fluoro-acetic acid and anisole, dava target compound, mp 185 C (decomp.) after conversion to the disodium salt with aqueous sodium hydroxide and purification with HP-20. Example 159-162. Execution of the procedure of example 11, but with (Z) -2 -amino t; - hydroxy (phenylmethoxy) phosphinyl-methoxy-imino-4-thiazo-acetic acid, indicated in column I, gives compounds listed data in column II. Column II Kaliev salt (8) -3 (2.6 dimets sibenzoyl amino -2 oxo-1 azetidine sulfonic acid, mp 180 ° С (dec.). Potassium salt 3S (Z) -2 - (2-amino-4 thiazolyl) 4- (diphenylmethoxy) -4-oxobutoxy imino acetyl amino 161. 2 (Phenylmethoxy) carb amino methyl benzoic acid 162. o - C 4 Oxy-2- (4-amyl perazinyl ) pyrido (2,) pyrimidi -yl j carbonyl amino benzeneacetic acid
Example 163. (Trans) -3-Ami no-α-ethyl 2-oxO 1 azetidine sulfonic acid.
A "t-side M-Methoxy | B Treostilserinamid.
, L-methylserine (1.33 g) is diluted in 10 MP 2 N. Potassium hydroxide and 5 ml of tert-butanol. After adding 2.46 g of di-tert-butyl pyrocarbonate, the biphasic mixture is stirred for 4 hours at ambient temperature. Methyl hydroxylammonium chloride (1.25 g) is added and the pH is adjusted to 41 n. hydrochloric acid. Hydrochloride of 1-ethyl-3 (3-dimethylaminopropyl saw) carbodiimide (1.92 g) is added, and the pH is clearly adjusted to 4. After peremestiya within 1 h, the reaction mixture is saturated with sodium chloride and extracted with four 50 ml portions of ethyl acetate. The ethyl acetate extracts are combined and dried over magnesium sulfate. Removal of the solvent in vacuo gives I g of the title compound.
B. tert-side-O-methanesulfonyl-N-methoxy-A-treopropionamide about
tert-side-N-methoxy-p-threoethylsarinamide (10.5 g) is dissolved in 65 ml of pyridine. Methanesulfonyl chloride (4.65 ml) is added dropwise with. After stirring for 3 hours at ambient temperature, the reaction mixture is drunk
200 g of ice in 300 ml 2 n. hydrochloric acid. The pH is adjusted to 4 with concentrated hydrochloric acid. After extraction with three 85 ml portions of ethyl acetate, the combined extracts are dried over magnesium sulfate and concentrated in vacuo. The residue is treated with carbon tetrachloride and concentrated again. Stirring with ether followed by filtration afforded 6.9 g of the title compound.
C. (trans) -3-tert-Butoxycarbonyl amino-4-ethyl-1-methoxy-2-azetidinone.
Anhydrous potassium carbonate (4.15 g) and 125 ml of dry acetone are heated to reflux and 3.4 g of tert-side-O-methanesulfonyl-N-methoxy-p-threopropionamide in 25 ml of acetone is added. After one hour, the reaction mixture is cooled and filtered. The filtrate is concentrated in vacuo. The oily residue is stirred with hexane, to give 2.2 g of the target compound.
D. (trans) -Block-Butoxycarbonylamino-4-ethyl-2-azetidinone.
(trans) -3-tert-ButoxycarboxylateMino-4-ethyl-1-mutoxy-2-azetidinone (3 g) is added to 170 mp of ammonia at 78 ° C in nitrogen. Next, add 1.68 g of sodium in five portions with stirring for more than 5 minutes. Stirring is continued for 30 minutes. Then, 02 2 oxo 1-azetidine sulfonic acid compounds, m.p. 125-130 ° C (decomp.). Calculated,%: C 48.22; H 4.53; N 11.25; S 10.30 S, -240 Found: C 47.66; H 40.1; N 10.94; S 9.42. Potassium salt (s) 2 C (phenylmethoxy) carbonyl amino methyl benzoyl amino 1 azetidinsulfonic acid, m.p. 234.5 ° C (decomp.) Calculated,%: C 48.39; H 3.85; N 8.91; S 6.80 Found: C 47.81; H 3.75; N 8.86; S 6.31. The potassium salt of (3S) -3 5-hydroxy 2- (4 formyl-1 piperazinyl) pyrido (2,) pyrimidine 6 yl carbonyl amino-phenylacetyl amino 3-2 oxo aze dinesulfonic acid, m.p. 265 270 ° C (decomp.).
ammonium chloride until the reaction mixture turns blue. After removal of ammonia under nitrogen, the solid is extracted with two 100 ml portions of ethyl acetate. Removal of the solvent, followed by drying in vacuo, afforded 2.7 g of the title compound.
E. Tetrabutylammonium salt of (trans) -3-tert-butoxycarbonylamino 4 Ethyl-2-oxo 1-azetidine sulfonic acid.
To .2 ml of absolute pyridine in 20 ml of dry dichloromethane is added with trimethylsilyl sulfonyl chloride (3.7 ml) in 5 ml of dry dichloromethane. The addition is completed at C under nitrogen for more than 10 minutes. After stirring for 30 minutes at ambient temperature, the flask is evacuated, giving the pyridine sulfur trioxide complex (trans) -3 - tert butoxycarbonylamino-4 ethyl 2-azetidinone (2.67 g) and 20 ml of extremely dry pyridine are added to the flask, which then placed in an oil bath heated to 90 C. After 15 minutes, a clear solution is obtained and injected into 200 ml of a 1M solution of two basic potassium phosphate. After adding 27 g of dibasic potassium phosphate and 100 ml of water, a clear solution is obtained. The solution is extracted with two portions of 60 ml of ethyl acetate each. Tetrabutylammonium is added.
sulphate to water layer, water
The organic layer is extracted with three portions of 100 ml of dichloromethane each and the combined organic layers are dried over magnesium sulfate. Concentration in a vacuum gives 6.9 g of the title compound.
 .
FO (trans) -3 Amino 4 Ethyl 2 oxO I azetidine sulfonic acid.
(trans) -3 Tert Butoxycarbonyl but 4 ethyl 2 oxo 1 azetidine sulfonic acid, Tetrabutylammonium salt (6.75 g) in 40 MP of formic acid is stirred for 3 hours at ambient temperature. Dichloromethane (60 ml) is added, and the mixture is cooled for about 16 hours. The resulting precipitate is separated by filtration and then dried in vacuo to give 0.85 g of the title compound, m.p. 185С (decomp.) About
Example 164. Dikaliev salt (trans, b) -3 P (2 amino 4 thiazolyl)
1 carboxy 1 methylztoxy) imino acetyl amino 4 ethyl 2 oxo 1 azetidine sulfonic acid.
A. Dikaliev salt of (trans, b) -3 (2 amino 4 thiazolyl) (1 diphenyl methoxycarbonyl 1 methylethoxy) imino acetyl amino 4 ethyl 2 oxo 1 azeti dinysulfonic acid.
(trans) -3 Amino 4 ethyl 2 oxo 1 azetidine sulfonic acid (0.55 g) and 335 mg of triethylamine are dissolved in 50 ml of dry dimethylformamide. (2) -2 amino o ((1-diphenylmethoxycarbonyl I methyl-toxo) -imino 4 thiazoleacetic acid (1.14 g) is added with stirring at 0 ° C followed by the addition of 450 mg of oxibenzotriazole and then 0.69 g of di-cyclohexylcarbodiimide After stirring for about 16 hours at 0 ° C, the colum is evacuated. Dry acetone (25 ml) is added to the solid with stirring .. The mixture is filtered and 0.94 g of potassium perfluorobanesulfonate is added and the filtrate is followed by the addition of 100 ml of ether. After standing for 1 hour at 0 ° C, the solid is filtered off The product is washed with simple zfir and dried in vacuo to give a mixture of 1.58 g of the title compound.
. trans, (2 amino 4 TI azolyl) G (1 carboxy 1 methylethoxy) imino acetyl amino-4-methyl-2-oxo-1.-azetidine sulfonic acid, dipotassium
;SALT.
To a suspension of 1.31 g of trans, (2 amino 4 thiazolyl) (1 diphenyl methoxycarbonyl, methylethoxy) they are but acetyl amino 4 ethyl 2 Oxo-1 azetidine sulfonic acid in the form of dipotassium salt in 10 ml of anisole is added 5 ml of trifluoroacetic acid over 10 minutes at 15 ° C, after stirring for 2 hours at -10 ° C, a clear solution is obtained. When 80 ml of dry ether is added, the resulting precipitate is filtered off and then treated with 5 ml of water. The pH is adjusted to 5.5 with 1 n. potassium hydroxide at, and the mixture filtered to remove unconverted starting material. The filtrate is chromatographed on HP-20 with water as the solvent. Lyophilization yielded 185 mg of the title compound, m.p. 160 ° C (decomp.) Example 165. Potassium salt 3S (L) -3 (2 amino 4 - thiazolyl) (4 OKCH 4 OKCo6yTOKCHJ imino acetyl amino 2 oxo 1 azetidine sulfoxide. Lots. Release of the potassium salt 33 (b) -3 (2-amino 4-thiazolyl) A (diphenylomethoxy) -4 oxobutoxy imino acetyl amino 2-oxO 1 azetidine sulfate slots (see Example 166) using trifluoroacetic acid and anisole give the target compound, so more. 166o Inner salt of (S) -3 2 (aminomethyl) benzene amino 2 oxo azetidine sulfonic acid, Release of the potassium salt () -2 -H) 2- T (phenipmethoxy) carbonyl amino methyl benzosh1 amino-azididine using hydrogen gas, palladium on activated carbon and hydrochloric acid gives the target compound, mp 162 ° C. Example 167. Potassium salt (S) 2 (4 formyl 1 piperazinyl) -5 oxypyrido 2, pyrimidine 6 yl carbonyl Amino 1 azetidinsul phonic acid. The tetrabutylammonium salt of (S) -3 -amino 2 0xo-1 -azetidine sulfonic acid (see Example 6A) is combined with 2- (4 formyl 1 piperazinyl) -5-hydroxy-6 (4 nitrophenoxy) carbonyl Zpirido f2.3 o pyrimidine and treated potassium perfluorobutanesulfonate in acetone, giving the target compound, mp 290 ° C (decomp.) "Example 168. Dikalieva salt (33 trans) -o (- (4P 1 methyl 2 - oxo 1 sulfonic 3 azetidinyl) amino carbonyl 1 benzeneacetic acid. (33 Trans) -3 Amino 4 methyl 2 Oxo 1 azetidine sulfonic acid (see DIRECT 39) combined with ° C- (carboxyl) benzeneacetyl chloride and treated with triethylamine and perfluorobutan potassium phonate to obtain the target compound, t, mp 147 ° C (sect.). Example 169. (3S-trans) -3 Amino 4 cyclohexyl 2 oxo 1 aze dinsulfonic acid. A. (tert Butoxycarbonylamino) -A-cyclohexyl Oxytreopropion: ovic acid. Cyclohexyl o (.amino p-hydroxy threo propionic acid (15 g) is suspended in 150 ml of acetonitrile and 70 ml of water. Triethylamine 17.8 g is added and the mixture is heated with stirring until. At this temperature, a clear solution is obtained and 21.0 g of di-tert-butyl pyrovarbonate is added. Stirring at 60 ° C is continued for another 1.5 hours. The solvent is removed in vacuo and 50 ml of water is added. The aqueous layer is extracted with ethyl acetate at a pH of 2, which is achieved by adding 3 parts of HC1. The organic layer is separated, dried over sodium sulfate and evaporated to dryness. The remaining crystalline substance is filtered with petroleum ether, giving 20.4 g of the title compound, m.p. 113-115C. B.Y- (tert-Butoxycarbonylamino) -cyclohexyl- / 3-hydroxy-N-methoxy-treo-propionamide. oi- (t-butoxycarbonylamino) -cyclohexyl-oxytreopropionic acid 20.2 g and 7.6 g of 0-methylhydroxyl-amine hydrochloride are suspended in 350 ml and 175 ml of t-butanol. The pH of the mixture is adjusted to 4.0 with potassium carbonate. 1-Ethyl-3- (3-dimethyl; 1 aminopropyl) carbodiimide (16.4 g) is added and the pH is maintained at 4 with stirring for 1.5 hours. The tert-butanol is removed in vacuo, the remaining aqueous solution is saturated with sodium chloride and extracted twice with 100 M.P. portions of ethyl acetate. The organic layers are combined, dried with sodium sulfate and evaporated to dryness. The remaining crystals are filtered with petroleum ether. 18.6 g of the expected compound are obtained, m.p. 125-127 ° C. I C. (tert-Butoxycarbonylamino) - -cyclohexyl-) - (methane sulfonyloxy-N-methoxy-threo-propionamide. (Tert-Butoxycarbonylamino) -cyclohexyl-oxo-H-methoxy-threo Propionamide (18.3 g) solution With stirring in 100 ml of dry pyridine. The solution is cooled with stirring to 0 ° C and 9.3 g of methanesulfonyl chloride is added dropwise. After an hour, an additional 3.3 g of methanesulfonyl chloride is added at 0 ° C and stirring is continued for more than one The solution is poured into 300 ml of ice water, added with 20 ml of ethyl acetate and the pH is adjusted to 3 seconds. using dilute sulfuric acid. The organic layer is separated, dried with sodium sulfate and boiled.
the solvent is removed in vacuo. The remaining solid is collected by petroleum ether, thus obtaining 19.0 g of the compound, m.p. 150 152C.
D. (38-trans) -3- (tert Butoxy-carbonylamino) -4 Diclohexyl OL 1 methoxy 2 azetidinone.
0 (tert-butoxycarbonylamino) -diclohexyl; B (methanesulfonyloxy) -C-methoxy-threo-propionamide (18.7 g is dissolved in 500 ml of dry alcohol. Then LIA carbonate (9.8 g) is added and the suspension heats to a temperature of refluxing with stirring at a scientific research institute for 5 hours. Insoluble inorganic substance is filtered. The solvent is removed in vacuo, the remaining oil is dissolved in 30 ml of ethyl acetate. After the addition of petroleum ether, the compound is precipitated and filtered off (12.9 g), mp 110-112 ° C.
E, (3-3-trans) -3- (t-Butoxy-carbonylamino) -4-diclohexyl-2-aze tidinone.
 (35-trans) -3- (tert-Butoxycarbonylamino) -4 Diclohexyl 1-methoxy-2-azetidinone (1 g) is added to 50 ml of liquid ammonia with stirring. Sodium (0.154 g) is added in 5-6 portions over 5 minutes. After that, additional sodium (0.025 g) is added, and stirring is continued for another 5 minutes. Ammonium chloride 0.89 g is added and ammonia is removed. The residue is extracted with warm ethyl acetate. The organic extract is evaporated to dryness and the remaining crystals of the target compound are filtered with petroleum ether to give 0.5 g, so pl. 130.
FO Pyridine salt of (33 trans) 3 - (tert-butoxycarbonylamino) -4-cyclohexyl 2-oxy-l-azethidine sulfonic acid.
(ZZ-trans) -3- (tert-Bytoksikarbonil of shno) -4-cyclohexyl-2-azetidinone (5.3 g) is dissolved in 20 ml of methylene chloride and 80 ml of dimethyl forms and. After adding 60 mmol of the pyridine-sulfur trioxide complex, the solution is stirred for 6 hours at room temperature. Removal of the solvent in vacuo gave 11.3 g of the title compound as an oil.
G. (38-trans) -3- (tert-Butoxycarbonylamino) -4-cyclohexyl-2-oxo-1-α-azidine sulfonic acid, tetrabutylammonium salt.
The pyridine salt of (38-trans) -3- (tert-butoxycarbonylamino) -4-CIC-loexyl-2-oxo-1 azetidine sulfonic acid (11.3 g) is dissolved in 230 ml of water. Tetrabutylammonium acid sulfate 9.0 g is added with stirring, and the pH is adjusted to 6.5 with 1N. potassium hydroxide. The aqueous solution is extracted twice with 200 ml portions of methylene chloride. The organic portions are dried with sodium sulfate, filtered and the solvent is distilled off to obtain 8 g of the title compound, m.p. 135-138 ° C.
H. (38-trans) -3-amino-4-cyclohexyl-2-oxo-1-azetidine sulfonic acid.
(3Z-trans) -3- (tert-butoxycarbonylamino) -4-cyclohexyl-2-oxo-1-azetidine sulfonic acid, tetrabutyl ammonium salt (3.8 g) is stirred in 20 ml of formic acid for 3 hours, then added 20 ml of methylene chloride. The title compound precipitated as a precipitate (1.0 g) is filtered off, mp. 217-219 ° С o
Calculated,%: C 43.53; H 6.50; N 11.38; 3 13.91,
C, color N, 0.3
Found,%: C 43.36; H 6.61; N 11.04; 3 12.58.
Example 170. Potassium salt GZ-1ZY (b), 4 p -3-2-amino-4-thiazolyl (methoxyimino) acetyl-amino-4-cyclohexyl-2-oxo-1 azetidine sulfonic acid.,
I
 (33 trans) -3-Amino-4-i; iclohexyl 2-oxo-1-aze tidinsulfonate (0.25 g) is dissolved in 30 ml of dry dimethylformamide and 0.12 g of triethylamine with stirring. After obtaining a clear solution, (Z) -2 amino-o1- (methoxyimino) acetic acid (0.2 g), 0.16 g of hydroxybenzotriazole and 0.42 g of dicyclohexylcarbodiimide are added. Stirring is continued for 48 hours at ambient temperature. The precipitated urea is filtered off and the solvent is removed in vacuo. The residue is dissolved in 10 ml of acetone and 0.41 g of potassium perfluorobutanesulfonate is added. After addition of 50 ml of ether, the compound precipitates and is filtered. Chromatogra
1 09
Phi on a column using HP-20 and a water-acetone mixture (9:11) as eluent gives 0.36 g of product, t. 200 to 205 ° С (after lyophilis-1); -
Example 171: 13G; 3H (b), 4p) (2 Amino 4-thiazolyl) b-carboxH 1 methylethoxy) imino acetyl-amino-4 cyclohexyl 2 oxo 1 aze1vdine sulfonic acid, dipotassium salt,
A.Kaliev salt (z), (2 amino 4 thiazolyl) (1-diphenylmethoxycarbonyl 1 methylethoxy) imino
acetyl amino 4 cyclohexyl 2 oxo -1-azetidine sulfonic acid.
(38 - trans) .mino 4 cyclohexyl 2 oxo 1-azetidine sulfonic acid (0.2 g, see Example 175) is dissolved in 30 ml of dimethylformamide and 0.09 g of triethylamine with stirring. Add hydroxybenzotriazole (0.12 g), 0.30 g (g) -2-amino c /. (l Diphenylme Toxic B-1-methyl ethoxy) Imino 4 thiazoleacetic acid and 0.33 g of dicyclohexylcarbodiimide, and stirring at ambient temperature for 12 hours. The precipitated urea is filtered. the mother liquor is evaporated. The remaining oil is dissolved in 5 ml of acetone, treated with 0.3 g of potassium perfluorobutanesulfonate and poured into 100 ml of simple ether with stirring. The potassium salt (z), -3 (2 amino 4 thiazolyl) - (1 dipheyl methoxycarbonyl 1 methylethoxy) -ami but acetyl amino 4 cyclohexyl 2 oxo 1 azetidine sulfonic acid (0.61 g) precipitates and filters off.
B. Dikaliev salt (z),
4 p 1 3 (2-amino 4 thiazolyl) (1 carboxy 1 methylethoxy) imino acetyl amino 4 cyclohexo azetidine sulfonic acid,
The potassium salt of 3S-l3o (- (Z), (2 amino 4 thiazolyl) - (1 diphenyl methoxycarbonyl 1 methylethoxy) igchins acetyl amino 4 cyclohexane 1 azetidine sulfonic acid (0.61 g) is suspended in 6 ml of anisole, cooled to 15 C, 5 ml of trifluoroxy hydrochloric acid is added dropwise with stirring. The temperature is kept the same for 1 hour and then lowered to. About 100 ml of dry ether are added.
72981110
so fast that the temperature does not exceed. The precipitated compound is filtered and chromatographed using
5 NR-20-RESIN and mixtures of water and acetone (9: 1) as eluent. Obtain 0.3 g of the target compound, so pl. 1 1-120 ° C, decomp. (after lyophilization) ..
0 Example 172 “Kaliev salt, (Z) 4p l-4 Cyclohexyl 3 G (2-furanylmethylene) amino -2-oxo-1-imidazolidinyl1-carbonylamino-phenylacetyl amino -2-oxo-1-aseti) 5 dinsulfonic acid.
(3S-trans) --3-Amino-4-cyclohexyl-2-oxo-1-azetidine sulfonic acid (0.1 g) (see Example 175) is dissolved in a mixture of 30 ml of dry dimethylforma-
20 amide and 0.05 g of triethylamine with stirring. G (2-furanylmethylene) amino -2-oxo-1-imidazolidinyl carbonyl amino-phenylacetic acid (0.14 g), 0.06 g of hydroxybenzo25 triazole and 0.17 g of didiclohexylcarbimide are added, and the solution is stirred for 5 days at room temperature. temperature The solvent is removed in vacuo, the residue is dissolved in 10 ml of acetone
JQ and the precipitated urea is filtered off. The mother liquor is stirred with 0.15 g of potassium phosphate perfluorobutane and diluted in 50 ml of ether. The precipitate is filtered and chromatographed with HP-20 resin using a water: acetone (9: 1) mixture as eluent. Obtain 0.14 g of the product, t. 1gl. 195-200 ° C, decomp. (after lyophilization) about
Example 173. Potassium salt (R) 4/3 -4-cyclohexyl-3 (4-methyl-2,3-dioxo-1-piperazine NILE) -1,3-dioxo-2-phenylpropyl-amino-2 oxo-1-azetidine sulfonic acid. (3S-trans) -3-amino-4-cyclohexyl
-2-oxo 1 azetidine sulfonic acid
(0.1 g, see example 175) is dissolved; in 30 ml of dimethylformamide and 0.5 g of triethylamine with stirring. Before-
50 bavles (k) o (- G (4-et1sh-2,3-diox-c 1 piperazinyl) carbonyl amino benzene-succinic acid, 0.06 g oxyben zotriazole and 0.17 g dicyclohexyl carbodiimide, and the mixture is stirred
55 seconds at about 16 hours at room temperature. The solvent is distilled off in a vacuum and the remaining oil is dissolved in 10 ml of acetone.
Ill
the urea is filtered off, the uterus is mixed in liquid with 0.15 g of potassium perfluorobutane sulfonate and diluted with 50 ml of ether. The precipitate is filtered off and the chromium is combined with HP-20 resin using water / acetone (9: 1) as eluent. 0.15 g of the title compound is obtained, mp. 175 180 ° С (after lyophilization) „
Example 174, Potassium salt (trans.Z) -3- (2 amino 4 thiazolyl) (methoxyimino) acetyl amino 4 ethyl 2 OKCO-l-zetidine sulfonic acid.
Following the procedure of Example 170, part A, but substitutions (Z} -2 - aMimo d (1 diphenyl labels Sicarbonyl 1 methyl ethoxy) imino 4 thiazole-acetic si lot (Z) -2 amino s / (methoxyimino) 4 thiazo-acetic acid, the desired compound is obtained , t PL 190 With (decomp.),
Example 175 about (4) - (trans) -3g-Amine with 1 -az e-tyd in sulfonic acid
A. (O- (trans) -2 Oxo 4 Fensch1 1 azetidine-tertbutyldiphenyl silane ”
The solution of tert-butylchlorodiphenylsyl per (20.56 g) in dimethylformamide (45 ml) is cooled to 0 ° C in an argon atmosphere and treated with triethyl amine (10.4 ml) and then (+) 4 fensh1 1 azetidine. After a few hours at a temperature O, the mixture obtained is treated with an additional amount of triethylamine (1 ml) and tert-butylchlorodiphenylsilane (2.11 g). Stirring is continued B for 65 h at 5 ° C. The reaction mixture was poured into ice water (300 ml) and extracted with ether: ethyl acetate 3: 1 (three 125 ml portions). The organic extracts are washed with pH 4.5 phosphate buffer (three 50 ml portions), saturated sodium bicarbonate solution (50 ml), water (two 50 ml portions), saturated sodium chloride solution, and dried with sodium sulfate. Filtration and concentration in vacuo gives a solid, which is washed with hexane, giving, after drying (high vacuum), 15 g of the title compound as a solid.
B. (j;) - (Tranc) -3-Azido-2-oxo-4-
-4-phenyl-1-aze tidine tert-butyldiphenylsipan.
72981 2
A 50 ml flask, equipped with a stirrer, gas inlet and a septum, is dried with an argon flame and charged with n-butyllithium (0.65 ml
5 1.6 M solution in hexane), which is cooled to and dissolves B tetrahydrofuran (2 ml). Diisopropylamine 0.16 ml is added dropwise. The resulting mixture is stirred in
10 for 30 minutes and cooled to -78 ° C. A solution of () - (trans) -2-oxo-4-phenyl-1-azetidine-tert-butyldiphenylsilane (400 mg) in tetrahydrophorofuran (1.5 ml) is added dropwise over about 5 minutes. After stirring for an additional 20 minutes, the solution is treated with -toluene sulfoxide (204 mg) in tetrahydrofuran (0.5 ml). The resulting mixture
20 for 10 minutes at -78 ° C and treated dropwise with chlorotrimethylsilane (0.4 ml) o After an additional 10 minutes of stirring, the cooling bath is removed and the reaction mixture
25 is stirred at ambient temperature for 2.5 hours. Then, with cooling at 0 ° C, ethyl acetate (20 ml) is added, followed by the addition of phosphate buffer with a pH of 4.5.
0 (8 ml-) o The organic layer rinses with additional buffer (two 8 ml portions), 5% sodium bicarbonate solution (three 10 ml portions), 50% sodium chloride solution (10 ml), sodium chloride solution (10 ml) and dried with sodium sulfate. Filtration and concentration in vacuo gives 500 mg of oil which is chromatographed with
... spray with 5% ethyl acetate hexane to give the title compound
; (253 mg) o
C. (+) - (trans) -3-Lzido-2-oxo-4-phenyl-1-azetidine,
5 A solution of 1–7 g of crude (j) - (trans) -3-azido-2-oxo-4-phenyl-1-aza tidin-t-butyldiphenylsilane is dissolved in methanol (240 ml) and treated dropwise at 0 ° WITH
0 of concentrated HCI (35 ml) "The cooling bath is removed, the reaction mixture is stirred at ambient temperature for 1 hour, and re-cooled to 0 ° C,
5, after which a saturated solution of sodium bicarbonate is added until neutrality.  The resulting mixture is extracted with ethyl acetate (one 300 ml of 113 portions and four 100 ml portions), and the organic extracts are washed with a mixture of (1; 1) sodium bicarbonate and sodium chloride solution S with saturated sodium chloride solution and sups over sodium sulfate.  Filtration and concentration in vacuo gives 15 g of a heavy oil, which is chromatographed on 100 g of silica gel using a mixture of 20% ethyl acetate hexane, and 460 mg of target compound D, Tetrabutylammonium salt (j ;;) - (trans) -3-azido 4 phenyl 1-azetidine sulfonic acid.  A solution of (4) - (trans) -3 azido-2-cx-4 phenyl 1 azetidine {300 mg) in dimethylformamide (3 ml) is cooled to 0 ° C under a stream of argon and treated dropwise with a complex of dimethyl formamide and trioxide sulfur (4.78 ml of 0.5 M solution in dimethylformamide).  The cooling bath is removed, the reaction mixture is stirred at ambient temperature for 2 hours and poured into 80 ml of 0.5 M potassium phosphate basic (pH 5.5).  The solution is extracted with dichloromethane (discarded) and 541 mg of tetrabutylammonium bisulfate are added. The resulting mixture is extracted with dichloromethane, the organic extracts are washed with sodium chloride solution, and dried with sodium sulfate.  vacuum filtration and concentration gives 800 mg of oil; about 40% of the desired product, the rest dimethylformamide.  The mixture is used without purification in the next step.  E. (+) - (trans) - 3-Amino 4 Phenyl 1 azetidine sulfonic acid.  A solution of the tetrabutylammonium salt of (n) - (trans) -3-amino-4 phenyl-H azetidine sulfonic acid in 4 ml of meta ™ nola is hydrogenated over 30 mg of platinum oxide at 1 atm and room temperature.  After 15 minutes, the system is pumped out and fresh hydrogen is introduced.  After an additional 45 minutes, the reaction is completed and the system is purged with nitrogen.  After several days at room temperature in a mixture of dichloromethane-methanol (4: 1, 200 ml), the catalyst aggregation is completed and filtration is carried out.  The filtrate is concentrated in vacuo to 18 ml and 8111 0.2 ml of formic acid is added.  After cooling for several hours, the solid obtained is filtered off and washed with dichloromethane, yielding 150 mg of the target compound as a solid in a form of solid vep1; After drying, 150 mg of C 44.62; H 4.17; N 11, 57; S 13.23.  SdSd, S Found,%: C 43.36; H 4.31; N 11.09; S 13.02.  Example 76: Kaliev salt (+) - (trans) -2 oxo 4 phenyl 3- (phenylacetyl) amino 1 azetidine sulfate slots.  BUT.  Tetrabutylammonium salt of (+) - trans - 2 oxo 4 phenyl 3-- (phenylacetate) amino -1-azetidine sulfonic acid.  A solution of M-hydroxybenzotriazole monohydrate (52 mg) and phenylacetic acid (46 mg) in dimethylformamide (0.3 ml) is treated with solid dicyclohexylcarbodiimide (70 mg) under argon at 0 ° C.  The cooling bath is removed and the resulting mixture is stirred at ambient temperature for 1 hour.  After dilution with additional formamide (0.3 ml), (- (trans) -3-oxo-4-phenyl-azethidine sulfonic acid is added as a solid (75 mg) (see  example 181). followed by dropwise addition of triethylamine (0.05 ml).  The reaction mixture is stirred at ambient temperature for 23 hours, filtered and the filter cake is washed with dimethylformamide. The filtrate is added to 20 ml of 0.5 monobasic potassium phosphate (pH 4.5), the mixture is washed with three 8 ml portions of ethyl acetate ( is discarded) and is added with 105 mg of tetrabutylammonium bisulfate (0.31 mmol).  The resulting mixture is extracted with dichloromethane (three 15 ml portions).  The extracts are washed with a 10% solution of sodium chloride (two 15 ml portions), a saturated solution of sodium chloride (10 ml) and dried sodium sulfate.  Filtration and concentration in vacuum gives (after heating at 32 ° C under high vacuum) 165 mg of oil; about 40% is the desired compound and 60% is dimethylformamide.  115 V.  The potassium salt of (+) - trans 2 oxo 4 phenyl 3 (phenylacetyl) amAo - - azetidine sulfonic acid.  A solution of the tetrabutylammonium salt (+} -trans-2 oxo 4 phenyl 3 (phenylacetyl) amino-I aze tidine sulfonic acid in I, 5 ml of acetone is treated with 41 mg (0.121 mmol) of potassium fluoride fluoride-butane-sulfate.  Dilution with 12 ml of ether gives glass, which, after trituration with ether, yields 43 mg of a solid containing about 20% of the impurities that contain the tetrabutylammonium part.  The solid is dissolved in 50% aqueous acetone and passed through a Dowex 50W-X2 K -ion exchange resin (1 ml).  Removal of the solvent gives a solid, which is washed with acetone, hexane and dries I (60 ° C, high vacuum).  Yield of the target compound 15 mg.  Calculated,%: C, 51.23; H 3.80; N 7.03; S 8.05; K 9.81.  C-K Found,%: C 50.44; H 4.20; N 7.01; S 7.59; K 9.40.  Example 177.  Potassium salt (4) - (trans-Z) -3- (2 amino 4 thiazolyl) (methoxyimino) acetyl amino 2 oxo 4 phenyl 1 azetidine sulfonic acid.  A solution of N-hydroxybenzotriazole hydrate (52 mg) and (g) 2 amino o (methoxyimino) -4-thiazoleacetic acid (69 mg) in dimethylformamide (0.3 ml) is treated with solid dicyclohex silcarbodiimide (70 mg) under argon at temperature the environment.  The resulting mixture is stirred for 1 hour, and (+) - (trans) -3-amino 2 ca. 4 phenyl I az e tidine sulfonic acid (75 mg, cm.) Is added as a solid.  Example 181 followed by the dropwise addition of triethanolamine (0.05 ml).  The reaction mixture is stirred at ambient temperature for 23 hours. Dimethylformamide is removed under high vacuum at 30 ° C and the residue is triturated with 2 ml of acetone and filtered.  The filter cake is washed with an additional amount of acetone (two 3 ml portions), and KALIUM perfluorobutane sulfonate (86 mg) is added to the filtrate. Dilution with 10 ml of ether gives the cam a deformable solid, which is 981 triturated, washed with acetone and hexane, After drying, 82 mg of the title compound are obtained as a solid.  Calculated,%: C 40.26; H 3.16; N 15.65; S 14.33; K 8.74.   H, NjO.  S K Found,%: 38.60; H 3.19; N 15.07; S 13.87; Go to 7.5.  Example 178.  Potassium salt (cis) 2 oxo 4 phenyl 3 (phenyl tyl) amino 1 azetidine sulfonic acid, A.  N-Benzylidene 2,4 dimethoxybene zylamine.  12.0 g of 2.4 dimethoxybenzylamine hydrochloride is added to 100 ml of 1 N.  sodium hydroxide solution, and the mixture is extracted with 125 ml of ethyl acetate.  The organic layer is dried over anhydrous sodium sulphate and is evaporated from the solvent, giving 10.2 g of 2.4 dimethoxybenzylamine as an oil.  This amine is dissolved in 150 ml of benzene; 6.47 g benzal dehydrate and 0.6 g monohydrate, luolsulfonic acid are added.  The mixture is heated at reflux with water being removed with a Dean-Stark separator and after two hours the calculated amount of water (1.1 ml) is removed.  The mixture is cooled to room temperature.  After further cooling, some precipitate forms from the benzene solution.  The benzene is removed under reduced pressure and 60 ml of petroleum ether is added to the residue. The Brownish layer is separated with an additional amount of precipitate.  Benzene (10 ml) is added to make the layer homogeneous and the remaining precipitate is filtered.  The filtrate is stripped, the solvent gives 14.2 g of the title compound as an oil, B, (4) - (cis) -4 phenyl 1 (2, tobibenzyl) -2 oxo-3 azidoazetidine, o-azidoacetic acid (1.62 g ) dissolved in 25 ml of methylene chloride under a nitrogen atmosphere. To this solution, 3.24 g of triethylamine, 1.02 g (4.0 mmol) of imine E-benzyl, 4 dimethoxybenzylamine are dissolved in 10 ml of methylene chloride.  The mixture is cooled in a water bath and 3.36 g of trifluoroacetic anhydride are slowly added.  The solution becomes dark in color.  After stirring in a bath, the mixture is heated to room temperature and stirred for an additional 15 minutes. The solution is then washed with water (60 ml of NaHCO solution (two portions of 50 ml each) and 1 and.  with a solution of HC (60 ml. The organic layer is dried over anhydrous sodium sulphate and stripped from the solvent, giving 1.72 g of the crude product as a dark cadmium.  The gum is processed several times with activated carbon.  The resulting brown mixture is chromatographed on 40 g of silica gel. eluted with CIw I: 1 petroleum ether and ethyl acetate.  The combined fractions give crystals after a quick freeze or in a bath of dry ice with acetone.  Using them as a seed, the product is recrystallized from a mixture of petroleum ether and ethyl acetate, obtaining 817 mg of the target compound in the form of needles, which melt after heating them to room temperature C.  (+) - (cis) 4-t 1enyl 2-oxo 3-azi doazetidine.  (+) - (cis) 4 Phenyl 1 (sibenzyl 2,4-dimetok) -2 oxo 3 azidoazetidine (737 mg) is dissolved in 25 ml of acetonitrile and heated to C under nitrogen atmosphere.  Over the course of 1 hour, 943 mg of potassium persulfate and 750 mg of potassium hydrogen phosphate, both dissolved in 25 ml of water, are added to the resulting solution.  After the addition, the mixture is further heated at 80-83 ° C for 7 hours.  The mixture is cooled, and the pH is adjusted to a solid Kahsh phosphate.  Most of the acetonitrile is removed under reduced pressure, and the resulting mixture is extracted with 60 ml of chloroform.  The chloroform layer is washed with water (60 ml), dried over anhydrous sodium sulphate and evaporated from the solvent, giving the crude product as an oil.  The crude chromatography is carried out on 40 g of silica gel, eluting with 1: I petroleum ether-ethyl acetate.  The combined fractions give crystals, and the product is recrystallized from petroleum ether-ethyl acetate to give 267 mg of the title compound.  D.  The tetrabutylammonium salt of (+) - (cis) -4-phenyl-2-0X00-3-azido-azethidine sulfonic acid, NO 81118 (+) - (cis) -4) enyl-2-oxo-3-azidoazetidine (162 mg) is cooled to O C in a stream of nitrogen, and 3.5 ml of approximately 0.5 M solution of a complex of dimethylformamide and sulfur trioxide are added dropwise using a syringe.  The resulting bright solution is stirred at 0 ° C for 15 mn.  The mixture is then poured into 50 ml of a 0.5 M solution of monobasic potassium phosphate and washed with methylene chloride (three 50 ml portions).  Tetra-i-butylammonium bisulfate (292 mg) is added to the aqueous solution and the mixture is extracted with methylene chloride (six 50 ml portions).  The combined methylene chloride layers are dried over anhydrous sodium sulfate and distilled from the solvent, giving 272 mg of the title compound as a gum.  E.  The potassium salt of (+) - (cis) -2-oxo-4-phenyl-3- (phenipacetyl) amino -1-azetidine sulfonic acid.  The tetrabutylammonium salt of (+) - (qi with) -4-phenyl-2-oxido-1-aza ethyl-sulfonic acid (293 mg) is dissolved in 4 ml of ethanol and hydrogenated using 80 mg of an oxide-platinum kata. 1 scrubber at atmospheric pressure. After stirring for 1 hour, the catalyst is filtered through a Millipore filter with zeolite; some catalyst particles pass through the filter, giving a black filtrate.  The ethanol is removed under reduced pressure, and the residue is dissolved in 4 ml of dimethylformamide.  N-hydroxybenzotriazole monohydrate (81 mg), 78 mg of phenylacetic acid and 117 mg of dicyclohexylcarbodiimide are added and the mixture is stirred for about 16 hours under a nitrogen atmosphere.  The suspension is evaporated in vacuo and triturated with 10 ml of acetone. The resulting suspension is filtered through a Millipore filter with a zeolite pad, and the brown filtrate is treated with 193 mg of potassium fluorobutane sulfonate.  After adding 20 ml of ether, the resin is separated.  The liquid is removed and the resin is made simple with ether.  The resin is dissolved in 10 ml of methanol. After adding ether, some precipitate forms.  The mixture is filtered, and the colored filtrate is treated with an additional amount of ether.  The precipitate formed is filtered off and recrystallized twice in the mixture of ether ether, giving 26 mg of the title compound.  Calculated,%: C, 46.99; H 4.41; N 6.45.  C, 2HgO Found,%: C 47.24; H 4.19; N 6.34.  Example 179.  Potassium salt of (cis, S) -3- (2 amino-4 thiazolyl) (methoxyim-o) acetyl JaminoJ 2 oco 4 phenyl 1 azetidine sulfonic acid.  The potassium salt of (cis) (phenylacetyl) amines of the dinysulfonic acid network (560 mg, cm of DIRECT 184, part D) is dissolved in 5 ml of ethanol and hydrogenated using 110 mg of the oxinoplatinum catalyst at a pressure of 1 atm.  After stirring for one hour, the catalyst is filtered through a Millipore filter with zeolite; catalyst particles pass through a filter, giving a black filtrate. This NOL is removed under reduced pressure, and the residue is dissolved in 4 ml of dimethylformamido. N-hydroxybenzotriazole hydrate (168 mg) 221 mg (g) -2-amino o (. (methoxyimino) -4 thiazoleacetic acid and 227 mg of dicyclohexylcarbodiimide, and the mixture is stirred for about 16 hours under nitrogen atmosphere.  The suspension is evaporated in vacuo and triturated with 15 ml of acetic acid. The resulting suspension is filtered through Millipore with zeolite, and the filtrate is treated with 372 mg of potassium perfluoroblutobansulfonate.  After addition of 15 ml of ether, the resin is separated.  The liquid is removed, and the resin is washed with ether. The resin is dissolved in 5 ml of water and applied to 150 ml of resin while zoned with water.  The fractions (30 ml each) 16-34 are combined and lyophilized, giving 201 mg of the title compound as a solid. Calculated,%: C 36.73; H 3.49; N 14.28; S 13.07; K 7.97.   N. S K 1.5 BUT Found,%: C 36.65; H 3.00; N 13.99; S 13.48; To 8.30.  Example 180  (Cys) -Z-Amin -2-oxo-4 (2-phenylethenyl) -azetidine sulfonic acid.  BUT.  K- (3enyl-2-propenylidene) -4-methoxyaniline.  Para-anis1adine (12.32 g) was dissolved in 160 ml of methylene chloride, and 20 g of anhydrous magnesium sulfate was added.  The mixture is cooled in an ice bath and 13.22 g of trans-cinnanaldehyde is added.  The mixture is stirred under nitrogen for 2 hours and then filtered.  The filtrate is evaporated to give the product as a solid.  The crude product will recrystallize from a mixture of methylene chloride and petroleum ether, giving 20.96 g of the title compound as a solid o. B.  (+) - (cis) -3-Azido-1- (4-methoxyphenyl) -2-oxo-4- (2-phenylethenyl) azetidine.  2-Azidoacetic acid (24.26 g) is dissolved in 100 ml of methylene chloride and cooled in an ice bath.  To this solution, 48.57 g of triethylamine and 14, 24 g of N- (3-phenyl-2-propenylidene) -4-methoxyaniline dissolved in 250 ml of methylene chloride are added.  To the resulting solution, 50.41 g of trifluoroacetic anhydride is added dropwise over a one-hour period.  After stirring for one hour in an ice bath, the mixture is warmed to room temperature and stirred for approximately 16 hours.  The mixture is then diluted with 250 ml of methylene chloride and washed with water (750 ml), a 5% solution of bi-.  sodium carbonate in two 750 ml portions and 1 and.  HCl solution (750 ml).  The organic layer is dried over anhydrous sodium sulphate and stripped of solvent to give a solid.  The crude product is recrystallized from ethyl acetate to give 11.39 g of the title compound as a solid, Co (H;) - (cis) -3-Azido-2-oxo-4- (2-phenyl-methyl) azetidine.  To a solution of 10.22 g of cerium ammonium nitrate in 13 ml of water at 0 ° C is added 1.99 g of (+) - (cis) -3-azido-1- (4-methoxyphenyl) -2-oxo-4- ( 2-Phenyl-ethenesh1) -azetidine dissolved in 65 ml of acetonitrile within 15 minutes (an additional 10 ml of acetoiitrile is used for poloskanz).  The mixture is stirred for another 15 minutes at 0 ° C,:, diluted with 750 ml of ethyl acetate, passed through with water (six 600 ml portions), sutured over anhydrous sodium sulfate, and stripped from the solution, dried, giving an oil.  The crude product is chromatographed on 90 g of silica gel, eluting first with 250 ml of a 30% ethyl acetate / petroleum ether mixture, then with ethyl acetate / petroleum ether.  The fractions (50 ml each) 11-16 are combined and evaporated to give 802 mg of the title compound as an oil.  D.  Tetra N (+) - (cis) 3 azido 2 oxo 4 (2-phenyl ethenyl) -1-azetidine sulfonic acid butyl ammonium salt.  (+) - (cis) -3-Lzido 2 - oxo 4 (2-phenylethenyl) -azetidine (334 mg) is dissolved in 3 ml of dimethylformamide, and 868 mg of pyridine and sulfur trioxide are added.  The mixture is stirred at room temperature for 40 hours under nitrogen, and then poured into 200 ml of a 0.5 M solution of potassium phosphate monobasic and 300 ml of methylene chloride is added. Tetra-butylammonium bisulfate (530 mg ), and the mixture is extracted with methylene chloride (four 50 ml portions).  The combined organic layers are backwashed with water (two 100 m portions), dried over anhydrous magnesium sulphate and evaporated from the solvent, giving 824 mg of the title compound as a gum or resin.  E.  (-1 -) - (cis) 2 3-Azido-2-oxo-4- (2-phenylethenyl) -1-azetidine sulfonic acid.  .  The tetra-n-butylammonium salt of (+) - (cis) -3-azido-2-oxo 4- (2-phenylethylene) -1-azetidine sulfonic acid (300 m is dissolved in 4 ml of tetrahydrofuran and stirred rapidly.  600 mg of zinc dust is added to the mixture, followed by the addition of 0.8 ml of 1N.  solution of monobasic potassium phosphate.  The mixture is heated to 45 ° C at this temperature for 3 hours.  The mixture is then filtered, and the filtrate is placed in 40 ml of methylene chloride and 10 ml of water. The aqueous layer is further extracted with methylene chloride (three 40 ml portions), and the combined methylene chloride layers are stripped from the solvent; this gives 256 mg of foam.  The crude product is dissolved in a small amount of the mixture (30% acetone-water) and applied to Dowex resin (K) (7.5 ml5 0.7 meq / ml), 40 ml water is eluted. The eluent is evaporated to give 151 mg of foam, which is a solution in ml of water and acidified to pH 2 1 n.  hydrochloric acid solution.  A small amount of acetonitrile is added to dissolve the precipitate, and the resulting solution is applied to 15 ml of HP-20 resin, eluted with 150 ml of water, then with a mixture of 10% acetone-water.  The fractions (15 ml each) 2-13 are combined and evaporated.  101 mg of the title compound are obtained as a foam.  Example 181  The potassium salt (b) - (cis) -3- t (2-amino-4-thiazolyl) (methoxyimino) acetyl amino -2-oxy-4-2 phenylethenyl -1-azetidine sulfonic acid.  A solution of 68 mg of (Z) -2-amino-oL- (methoxyimino) -4-thiazoleacetic acid and 51 mg of N-oxobenzotriazole monohydrate in 2 ml of dimethylformamide is treated with 69 mg of dicyclohexylcarbodiimide.  The mixture is stirred at room temperature for 30 minutes under a nitrogen atmosphere (cis) -3-amino-2-oxo-4- (2-phenylethenyl) -azetidine sulfonic acid (90 mg, see  Example 186), 34 mg of triethylamine are added, and the mixture is stirred for 20 hours under a nitrogen atmosphere.  The suspension is evaporated in vacuo and triturated with 10 ml of acetone.  The suspension is filtered, and the filtrate is treated with 113 mg of potassium perfluorobutane sulfonate. Dilution with 30 ml of ether and filtration gives 169 mg of solid product, which dissolves in a small amount of approximately 30% of a mixture of acetonitrile and water and is applied to 34 ml of HP-20 resin. with elution with 150 ml of water, then with a 10% mixture of acetone and water.  Fractions 16-19 (15 ml each) are combined and stripped of the solvent, giving 110 mg of the title compound as a solid. Calculated,%: C 40.23; H 3.57; N 13.80; S 12.63; K 7.70 C HvO W C Found,%: C 40.03; H 3.05; N 13.61; S 12.31; K 7.56 Example 182.  (cis) -3-Amino-4- (methoxycarbonyl) -2-pkso-1-azetidine sulfonic acid.  BUT.  (4-Methoxy-phenyl) amino-acetic acid methyl ester.  A 3-neck dry 1-liter flask equipped with a nitrogen inlet and a stirrer was charged with 56.88 g of magnesium sulphate followed by the addition of a solution of recrystallization of anisidine (19.43 g) in dichloromethane (25Q No. 1).  After cooling to 0 ° C, a solution of methyl gnnoxate semi-acetal (19.92 g) in dichloromethane (250 ml) is added over 1.5 hours.  After stirring for an additional 20 minutes at 0 ° C, the reaction mixture is filtered with suction, dried over magnesium sulfate, filtered and concentrated under vacuum to one-fourth volume.  Hexane (300 ml) is added and the solution is concentrated to an oil that solidifies by half while standing under high vacuum at 5 ° C.  AT.  (cis) -3- (1, 3-dihydro-1,3-dioxy-2H-isoindol-2-yl) -4-methoxycarbonyl-2-oxy-1- (4-methoxyphenyl) azetidi Dry 3-throat A 500 ml flask equipped with a stirrer, funnel for addition, septum and nitrogen intake is charged with a solution of methyl ester (4-methoxyphenyl) imino acetic acid (21.09 g) in dichloromethane (150 ml) and cooled to 0 ° C.  Triethylamine (19.2 ml, 0.14 mol) is added dropwise, followed by addition of a solution of the acid chloride (N-phthalimido) acetic acid 28.4 in dichloromethane (150 ml) over 1 hour.  The resulting mixture was stirred for 1.5 hours at 0 ° C and diluted with 2.5 liters of dichloromethane.  The organic solution is washed with monobasic potassium phosphate with a pH of 4.5 (two 500 ml portions), sodium bicarbonate (two 500 ml portions), and a saturated solution of sodium chloride (500 ml) and dried over sodium sulfate.  Filtration and concentration in vacuo gave a solid, which was washed with ethyl acetate with cold acetone and hexane, to give 18.65 g of product.  WITH.  (cis) -4- (methoxycarbonyl) -1- (4-methoxyphenyl) -2-oxo-3- (phenylmethoxy) carbonyl amino azetidine.  A dry 500 ml flask equipped with nitrogen, a stirrer and a septum is charged with 18.65 g (cis) -3- (1,3-dioxo-2H-isoidol-2-yl) -4-methoxycarbonyl-2-oxo- 1- (4-methoxyphenyl) azetidine and 325 ml of dichloromethane. The resulting suspension is cooled before and methyl 11razine (3.52 ml) is added dropwise.  The reaction mixture is heated to 0 ° C and stirred for 1 hour. An additional amount of 0.4 ml of methyl methyl is added, and the mixture is stirred for 10 minutes.  This sequence is repeated with a total amount of methyl hydrazine added of 2.9 eq, (7.7 ml). The solvent was removed in vacuo, 200 ml of fresh dichloromethane was added, and the mixture was again concentrated.  This sequence is repeated twice, e two times, the resulting foam is dried under high vacuum for 20 minutes, re-dissolved in 225 ml of dichloromethane, and left to stand at ambient temperature for about 16 hours, during which significant amount of solid matter.  The mixture is filtered under nitrogen, the filtrate is cooled to 0 ° C (nitrogen atmosphere) and treated with diisopropylethylamine (17 ml) followed by) dropwise with benzyl chloroformate (7 ml).  The reaction mixture is stirred at 0 ° C for 30 minutes.  then nprf ambient temperature for 1.5 h.  The mixture is washed with two 300 ml portions of a monobasic potassium phosphate buffer of pH 4.5 with 5% sodium bicarbonate (two 300 ml portions), saturated sodium chloride (300 ml), dried with sodium sulfate and filtered.  Concentration in vacuo gives a foam which.  trituration with ether gives 9.9 g of the target compound as a solid.  D.  (cis) -4- (methoxycarbonsch1) -2-ox-so-3-C (phenylmethoxy) carbonyl amino -1-azetidine.  A solution of ammonium cerium nitrate (8.59 g) and 60 ml of a 1: 1 mixture of acetonitrile and water is treated with a suspension of 2 g of (cis) -4- (methoxycarbonyl) -1- (4-methoxyphenyl) -2-oxo-3- (phenylmethoxy ) carbonyl-amino acetydine in 50 ml of acetonitrile over 10 minutes.  The reaction mixture is stirred for an additional 10 minutes at ambient temperature and diluted with ethyl acetate (100 ml).  The separated aqueous layer was washed with ethyl acetate (three 40 ml portions), and the combined organic extracts were washed with 50% sodium bicarbonate (three 70 ml pores
125
qi mi). The main washings are backwashed with ethyl acetate (50 ml), and the combined organic extracts are washed with aqueous sodium sulfite, 5% aqueous sodium carbonate (100 cells), 5% aqueous sodium chloride solution (two 100 ml portions), saturated sodium chloride (two 50 ml portions) and stirred over charcoal charcoal C-60 for 30 minutes. Sodium sulfate is added, and the mixture is filtered and concentrated in vacuo to give an oil, which, when triturated with ether, gives 685 mg of the title compound as a solid.
E. Tetrabutylammonium salt of (cis) 4- (methoxycarbonyl) 2-oxo-3- (phenylmethoxy) carbonyl amino 1-azetidine sulfonic acid.
A mixture of (cis) -4- (methoxycarbonyl) -2-oxo-3- (phenylmethoxy) carbonyl1 amino1 1-azetidine (100 mg) and 172 mg of a complex of pyridine and sulfur trioxide in 1 ml of pyridine is stirred under argon flow for 3 hours at 80 ° C. The reaction mixture is poured into 70 ml of 0.5 M oArfoocHOBHoro potassium phosphate (pH 5.5) and extracted with four 30 ml portions of dichloromethane (refined Bates). The acidic tetrabutylammonium sulfate (122 mg) is added to the aqueous extract, which is then extracted with dichloromethane (four 30 ml portions). The organic extracts are washed with sodium chloride solution, dried over sodium sulfate and filtered. Concentration in vacuo gives 186 mg of the title compound as a viscous oil.
F. (cis) -3-Amino-4- (methoxycarbonyl) -2-OXO-1-azetidine sulfonic acid.
A solution of 186 mg of the (cis) -4- (methoxycarbonyl) -2-oco-3 1 (phenylmethoxy) carbonyl amino -1 -1 azetidine sulfonic acid tetrabutylammonium salt in 2 ml of methanol is hydrogenated over 10% palladium on activated carbon (95 mg) for 1.5 h at a pressure of 1 atm. The catalyst is filtered off and washed with dichloromethane, the filtrate is treated with 97% formic acid and cooled to -50 s (the presence of seed; crystals at this stage is necessary in order to cause crystallization 72981126
ration). After the start of crystallization, the mixture is left to stand for about 16 hours at 10 ° C. The resulting solid is washed with dichloromethane, 5 hexane and dried in vacuo, to give 50 mg of the title compound.
Example 183. The potassium salt of (cis) -3- (2-amino-4-thiazolyl) l- (diphenylmethoxycarbonyl) -; - methyl 10 ethoxyimino acetyl amino-4- (methoxycarbonyl) -2-oxo-1-azetidine sulfonic acid.
N-hydroxybenzotriazo hydrate solution. la (34 mg) and 101 mg of 2-amino- - 115 - (diphenylmethoxycarbonyl) H-methylethoxyimino-4-thiazoleacetic acid in 0.75 ml of dimethylformamide is treated with solid dicyclohexylcarbodiimide (45 mg), and the mixture is stirred under an argon current in 45 min at ambient temperature, (cis) -3-Amino-4- (methoxycarbonyl) -2-oxo-1-azetidine sulfonic acid (45 mg, see Example 188) is then added as a solid, followed by triethylamine (0.03 ml) is added dropwise. The reaction mixture is stirred at ambient temperature for about 16 hours. Di3 Q methyl formamide is removed under high vacuum at 30 ° C and the residue is triturated with acetone. The surface layer is treated with potassium perfluorobutane sulfonate (67 mg). Dilution
5 m ether gives a solid which is washed with ether and dried in vacuo to give 93 mg of the title compound.
Example 184. Dikaliev salt
0 (cis) -3- (2-amino-4-thiazolyl) (hydroxy-1 -methyl ethoxy) imino acetyl amino-4- (methoxycarbonyl) -2-oxo-1 -azetidine sulfonic acid.
Potassium salt (cis) -3- suspension
5 - 12-amino ™ 4-thiazolyl) -1- (diphenylmethoxycarbonyl) -1-methylethoxy-imino acetyl amino) -4- (methoxycarbonyl) -2-oxo-1-azetidine sulfonic acid in 0.4 ml of anisole is stirred at
50 -12 ° C under argon flow, then 0.9 ml of cold () trifluoroacetic acid is added. After 1.5 hours, 4 ml of ether and 2 mg of hexane are added. The mixture obtained is
5 is stirred for 1-5 minutes at -10 ° C, then 15 minutes at ambient temperature. The solid is separated by centrifugation and
Mitsya simple aetherstm. The PI of the suspension of the given water in 0.5 As cold water is adjusted to 6 with 1 n. potassium hydroxide and then applied to a 30 MJ IIP-20 AG-column. Elution with water gives 30 mg of the title compound after evaporation (acetonitrile is added and evaporated twice).
Calculated,%: C 31.15; H 2.81; N 12.98.
YY; - 1 1525 3 2
Found,%: C 29.08; H 3.03; N 12.19.
Example 185. (S) - (trans) -3-Amino-4-etrshyl-2-oxo-1-azetidine sulphuronic acid.
A.2- (Trimethylsilyl) ethinyl magnesium bromide.
In a flash-dried 50 ml flask, held in a positive nitrogen pressure, 20 ml of dry tetrahydrofuran, 2.20 ml of trimethylsilylacetylene and 5.05 ml of 3.06 M solution of methyl magnesium bromide in ether are added. The mixture is stirred for 140 minutes to give the title compound.
B. (5) - (trans) -4- 2- (Trimethylsilyl) ethynyl-2-oxo-3-C (triphenylmethyl) amino-azetidine.
In a flame dried 250 ml 3-necked flask, 6.0 g of (s) - (cis) -4- (methylsulfonyl) -2-oxo-3- - L {triphenylmethyl) aminoazetidine is added. The flask is purged with nitrogen and then maintained with a positive
nitrogen pressure. After the re
the stock mixture is cooled to dry
a bath of ice and isopropane is added dropwise with a syringe with rapid stirring 4.65 ml3, the volume solution of methylmagnesium bromide in ether. A solution of 2- (trimethylsilyl) -ethylnummagnesium bromide prepared in Part A is added through a Teflon tube at a positive nitrogen pressure (the flask containing the reagent is rinsed with 7 ml of tetrahydrofurm). When the addition is complete, the cold bath is removed. After 45 minutes, a solution of 3.5 g of potassium bisulfate in 20 ml of water is added. Most of the tetrahydrofuran is removed on a rotary evaporator. The residue is transferred to a separatory funnel and washed with ether and water. The aqueous layer is separated and extracted twice with ether. OBSDINRNKYO
the ether layers are washed with one grade aqueous chloride chloride, dried with sodium sulfate and triturated. Removal of the solvent gives a foam which is chromatographed on a silica column. Elution of 2 l of dichloromethane, 1 l of 1% ether - dichloromethane, 2 l of 2% ether - dichloromethane
Q tan and 1.5 l - 10% mixture: 1 fi r - dichloromethane (fraction 1 1000 b, fraction 2.3 500, fraction 4 - last 250 ml) gives 1.30 g of the target compound in fraction 2-8 and 1.80 g
5 corresponding trans isomer in
fractions 12-19. Fractions 9-11 contain 1.19 g of a mixture of cis and trans-isomers.
C. () - (trans) -4-ethynyl-2-oxo-3 (triphenylmethyl) acetidine.
Q (PO- (trans,) - 4-2 (Trimethylsilyl)
ethynylT-2-oxo-3-C triphenylmethyl) amino-azetidine (2.97 g) is dissolved in 30 ml of dichlorometap and 330 mg of tetrabutylammonium fluoride are added, containing
5 20-25% of water. After 20 minutes, the solvent is removed in vacuo. The residue is taken up in ethyl acetate and water. The organic layer is separated, washed once with water and once with saturated aqueous sodium chloride, dried over sodium sulfate and filtered. Removal of the solvent gives an oil that is stirred for 15 minutes with 60 ml of pentane, to give 2.35 g of the title compound as a powder (after
 drying in a vacuum) about
D. (s) - (trans) -3-Amino-4-ethynyl-2-oxo-1 azetidine sulfonic acid.
In a 25 ml flask, (s) - (trans) -4-ethin # 1-oxo-3- (triphenylmethyl) amino azetidine (404 mg), 560 mg of pyridine complex and sulfur trioxide are introduced. After the flask prod
With nitrogen, 4.0 ml of dry pyridine is added, and the mixture is heated at 80-85 ° C for 3 hours. The mixture is added to a quickly stirred mixture of 4.0 ml of concentrated salt. hydrochloric acid, 50 ml of water and 50 ml of ethyl acetate. The pH is adjusted to 3.15 with sodium carbonate. The aqueous layer is separated and extracted once with ethyl acetate; the organic layer is washed once with cbmteHHbiM with aqueous sodium chloride, dried over sodium sulfate and filtered. Removal of the solvent in vacuo gives a foam which is taken up in 10 ml of dichloromethane. Formic acid is added (, 8 ml). After 15 minutes, the mixture was concentrated to 4 MP and 10 ml of methane dichloride was added, giving a solid, suspended in solution. Filtration gives 100 ml of the title compound as a solid (both are clearly highlighted with melting at a temperature above 180 s). Example 186. Potassium salt 3S-So1 (Z), 4 uZ (2 amino 4 TI azolyl) (methoxyimino) acetyl amino 4 ethynyl 2 oxo 1 azetidine sulfonic lot. (Z) -2 Amino1. (Methoxyimino) -4-thiazoleacetic acid (100 mg), 85 mg of N-hydroxybenzotriazole monohydrate and 113 mg of dicyclohexylcarbodiimide are weighed into a 10 ml flask. The flask is purged with nitrogen and cooled in a bath of ice and water. Then, 0.6 ml of dimethylformamide and the mixture is stirred for 10 minutes. At this point, an additional 0.6 ml of dimethylformamide (s) - (trans) - 3-amino- 4 ethynyl-2 6 C 1 azetidine sulfonic acid (95 mg, see Example 191) is added as a solid to 1.0 ml of dimethyl form amide and 56 µl of triethylamine. The cold bath is removed and the mixture is stirred for 22 hours. Acetone (3 ml) is added and the solids present are removed by filtration and washed with an additional 4 ml of acetone. All solvents were removed in vacuo, the residue was taken up in 5 ml of methanol, 162 mg of potassium perflutobansulfonate were added and the residue was dissolved. After standing, the solid precipitates out and is then centrifuged, yielding 68m of the title compound with m.p. 230С. Calculated,%: C 30.75; H 2.79; N 16.30; S 14.92. C H N.0 I K. H O 11 -10 -5 6 2 2 Column I 188. (R) - (Aminooxoacetyl) amino - (4-hydroxyphenyl) acetic acid lot 190. (R) - (Aminooxacetyl) amino-phenylacetic acid 81, 130 Found, %: C 31.01; H 2.43; N 16.34; S 14.67. Example 187. Potassium salt (S) -3-C (2, 5-dichlorophenyl) thio} acetyl-amino 2 Oxo-1-azetidine sulfonic acid. 3-amino-2 oxo-1-azetidine sulfonic acid (100 mg) is dissolved in dry dimethylformamide (2 ml) with triethylamine (0.083 ml). Filtered and solvent removed in vacuo. The residue is taken up in water and filtered. The filtrate is washed with ethyl acetate, layered with dichloromethane, then tetrabutylammonium bisulfate (4.2 mmol) is added. After three extractions with dichloromethane, the combined extracts are dried over sodium sulfate and the solvent is removed in vacuo to give an oil (920 mg). Potassium perfluorobutane sulfonate (946 mg) dissolved in acetone is added to the oil solution in acetone. The solid is slowly precipitated, collected, washed twice with ether and dried to give a powder (306 mg). Chromatography on an HP-20 resin (100 ml column) with elution with 20% acetonitrile: 80% water (mixture) gives the desired product, which crystallizes after evaporation of the water-methanol mixture. Rubbing the residue with acetone gives a powder (233 mg), t pl. 212-213s (decomp.) O Calculated,%: C 32, 2.54; N 6.41; C 16.21; S 14.66. CirH ,, N About C1, S, K Found,%: 3, 91; H 2.60; N 6.42; C1 16.50; S 13.77. Examples 188-190. Following the procedure of Example 138, but replacing (3S-cis) -3-amino-4-methyl-2-oxo-1-β-azethidine sulfonic acid (38-trans) -3-amino-4-methyl-2-oKco-l-azetidine sulfonic acid and (Z) -2-amino-oC- (methoxyimino) -2 thiazoleacetic acid with the acid indicated in column I, and the compounds shown in column 11, column II of the potassium salt (c), 4p31-3- G (aminooxoacetyl) amino - (4-hydroxyphenyl) acetyl amino3-4-metil-2-Oxo-1-azetidine sulfonic acid, so pl. 199 ° C (decomp.). Potassium salt 3S-t3 (R),. (Aminooxoacetyl) aminoZphenylacetyl Zamino-4-methyl-2-oxo-1-azetidine sulfonic acid, mp. 18 / C (dec). Example 191. The potassium salt of Zo (P,) -3- (aminooxacia L) amine but (4 hydroxymethyl) acetyl amino 2 ox -1 -1 azetidine sulfonic acid. Following the procedure described in procedure 28, but replacing (7.) - 2 amino C (2 (diphenylmethoxy) -1,1 dimethyl 2 oxoethoxyimino - 4 thiazoleacetic acid (R) - (aminooxoacetyl) amine (4 hydroxyphenyl) - acetic acid, get a celled compound with mp 128 ° C (decomp.) "Example 192, Potassium salt 3S (R) -3 (2 amino 4 thiazolyl) 3- (2 furanylmethylene) amino with 1 imidazolidinyl carbonyl amino acetyl7 amino 2 oxO 1 azetidinsul phonic acids. The procedures in Example 6 are complete, but the amino-thiazoleacetic acid (R) 2 amino o / 3 substitutes, 3 (2 furanylmethyl) amino 2 oxO 1-imidazolidinyl carbonyl amino 4 t with acetic acid, a target compound is obtained with a melting point of 250 ° C. Biological activity. To determine the minimum ingibiruating concentration (MIC) of the proposed beta lactams, use the following method. a) by inoculating (in the tubes) into the broth loops of the body with BHI (Difco) on oblique agar. The inoculated tubes are incubated at 37 ° C for an hour. It is assumed that these cultures contain 10 units forming colonies (K E) per milliliter. The cultures are diluted to a degree of 1: 100, giving the final degree of inoculum Yu; dilution is done with broth. The compounds are dissolved in a suitable diluent at a concentration of 1000 µg / ml. Twice dilutions are made in K 10 broth, ultimately giving dilutions in the internally from 1000 to 0.5 µg / ml. 1.5 ml from each dilution is placed in individual square Petri dishes, to which 13.5 ml of p is added. The final concentration of the drug in agar fluctuates in the terminal and, 05 µg / ml. Control plates with a growing organism, containing only agar, are prepared and inoculated before and after the plate test. The organisms are applied to the surface of the agar of each plate using a Denley Multipoint Jnoculator, which produces approximately 0.001 ml of each organism, resulting in a final CFU level of 10 cmU. The plates are incubated tots at 37 ° C for 18 hours, and the MIC values are determined. K-10-broth is a mixed yeast and meat broth containing: i, g: Meat extract 1.5 Yeast extract 3.0 Peptone 6.0 Dextrose 1.0 Distilled water Up to 1 L contains: g: Meat extract 1 , 5 Yeast extract 3.0 Peptone6.0 Dextrose1.0 Agar15.0 Distilled waterUp to 1 L The table shows the results of testing the proposed beta lactams against various microorganisms. The number following the calzdoid organism is referred to the number of organisms in the collection of the company E.R. Squibb & Sons, nk., Princeton, New Jersey. The icon -) means that the test compound did not show activity against an oncreative organism at 100 µg / ml. T - not tested.

权利要求:
Claims (4)
[1]
1. A method for producing β-lactams of the general formula r ₂ r „Ri-RH-Cd-Rj 0 = с-те-з0зм ⁺ where M ⁺ is hydrogen or a cation;
R is hydrogen, acyl or R ^ -NH-protected amino group;
R is hydrogen or alkoxy C;
R ^ and - are the same or different, and each represents hydrogen, alkyl C ₁ -, cycloalkyl C ₅ —C _t , or one of R ₃ and is hydrogen, and the other is alkene — I — yl; alkyn-I-yl or 2-phenyl-ethynyl; characterized in that the compound of the general formula
B ₂ .A
Rl-HN-tCR, „II 0 = С — NH where R ,, R ^, and R have the indicated meanings, are sulfonated with sulfur trioxide complexes or chlorosulfonate in an organic solvent at room temperature, and the target product at R ₍ - Н is converted to its acyl derivative.
[2]
2. The method of pop. I, characterized in that pyridine or dimethyl formamide or a mixture thereof with a halogenated hydrocarbon is used as an organic solvent.
[3]
3. A method of obtaining lactams of the General formula Rif
Rnnh-ft-d-fh
Il _.
0 = C — N-S0 ₃ M where M ⁺ is hydrogen or a cation;
R, is hydrogen, acyl or R, -NH-protected amino group;
R ^ is hydrogen or alkoxy C;
B ^ and B ^ are the same or different, and each represents hydrogen, alkyl C _f —C ^, cycloalkyl C ₅ —C or one of and is hydrogen, and the other is alkene — I — yl, alkine — I — yl or 2 — phenylethynyl;
characterized in that the compound of the general formula
Q <o
SU, „> 1272981> cm
V
Ri-NH-CH-C <L ⁰
IR (jo = c-nh ₂ where R, R, R have the indicated values 1 S 4;
V is a group such as methane sulfonyl, benzene-sulfonyl, toluenesulfonyl, chlorine, bromine, iodine; subjected to sulfonation with sulfur trioxide complexes or chlorosulfonate in an organic paci environment at room temperature, followed by cyclization with a base such as potassium carbonate at the boiling point of the reaction medium, followed by acylation of the resulting product if R ₁ = N.
[4]
4. The way to pop. 3, characterized in that pyridine or dimethylformamide, or a mixture thereof with a halogenated hydrocarbon, is used as an organic solvent for the sulfonation process.
^R 3 ^HR 4 which are nost.

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引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

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WO1982001873A1|1980-12-05|1982-06-10|Takeda Chemical Industries Ltd|1-sulfo-2-oxoazetidine derivatives and process for their preparation|

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US4675397A|1980-12-05|1987-06-23|Takeda Chemical Industries, Ltd.|1-sulfo-2-oxoazetidine derivatives and their production|

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US4782147A|1980-12-05|1988-11-01|Takeda Chemical Industries, Ltd.|1-sulfo-2-oxoazetidine derivatives and their production|

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US4673739A|1980-12-05|1987-06-16|Takeda Chemical Industries, Ltd.|4-carbamoyloxymethyl-1-sulfo-2-oxoazetidine derivatives and their production|

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US4572801A|1981-04-30|1986-02-25|Takeda Chemical Industries, Ltd.|4-Carbamoyloxymethyl-1-sulfo-2-oxoazetidine derivatives and their production|

法律状态:

优先权:

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申请号 | 申请日 | 专利标题

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US11927680A| true| 1980-02-07|1980-02-07|

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