Method of producing azetidine compounds

专利摘要:
Antibiotic activity is exhibited by ???-lactams having an <IMAGE> substituent (and esters and salts thereof) in the 1-position and an acylamino substituent in the 3-position.The analogues having an optionally protected NH2 group in the 3-position are also claimed.
公开号:SU1329617A3
申请号:SU833635150
申请日:1983-08-03
公开日:1987-08-07
发明作者:Брейер Герман；Штрауб Хеннер
申请人:Е.Р.Сквибб Энд Санз,Инк (Фирма)；
IPC主号:

专利说明:

113296
This invention relates to the field of synthetic organic chemistry, namely, to a new method for the preparation of non-general azetidine compounds of general formula
2 L
R.-NH-C-C-R-i,, 5
s-s-d-soon
° R5 Kb
Where
R, is hydrogen or acyl group,
where the acyl group is
a) aliphatic group of general formula
Ra-C- 0
where Kd is C, is C4-alkyl;
c) a carbocyclic aromatic group of the general formula
CgH 5 CH2.C 1
about
and CeHsCH-cШ2 (3
where RP is hydrogen or C -C-alkoxy,
c) a heteroaromatic group of the formula
C1

K (F5CHN2S- SG O
d) (4-substituted-2, 3-dioxo-1-piperazinylcarbonylamino) phenylacetyl - group of the general formula
- CH-sh-C-NQN-Rc About SbH5,000
where R. C, - C elkyl,
e) an oxyimino acetyl formula
-C-C N-0-Re II I O Rd
,
0
15
0
five
17.2
where RJ is 2-amino-4-sol, 5-amino--1,2,4-thiazolyl or 2,6-dichloro-4-pyridyl;
Rg - C, - C4 lkyl or 1,1-dimetho-1-2-fench1methoxy-2-oxo-3 thyl;
R is hydrogen;
R and R are hydrogen, or one of the radicals Rj and K is alkyl, and the other is hydrogen; - hydrogen or C, -C4-alkyl, their esters or alkali metal salts, which have antibacterial activity and can be used as agents for controlling bacterial infections (including urinary tract infections and respiratory infections) in various mammalian species, for example in domestic animals (dogs, cats, cows, horses, etc.) and humans.
The purpose of the invention is to search for new derivatives in the range of acetidine, which have antibacterial activity.
Example I. I, 1-Dimethylethyl ester 3S (Z) -3- (2-amino-4-thiazolylmethoxyiminoacetylamino) 2-oxo-1-azetidinyloxyacetic acid,
A) O- (tert-Butyloxycarbonylmethyl) -CX: - N- (benzyloxycarbonyl) -L-serinehydroxamate.
0
Dicyclohexylcarbodiimide solution
(57.5 g, 0.28 mol) in dry tetrahydrofuran (60 ml) is added dropwise to a solution of NO; - (benzyloxycarbonyl) -L-serine (66.9 g, 0.28 mol ), 1-hydroxybenzotriazole hydrate (42.0 g,
0.28 mol) and tert-butylaminooxyacetate (41.2 g, 0.28 mol) in dry tetrahydrofuran (1.4 g) at 0–5 ° C. The mixture is stirred overnight at room temperature. The precipitate (dicyclohexyl urea) is removed by filtration and the filtrate is evaporated under vacuum. The residue is dissolved in ethyl acetate, washed with 5% NaHCOi and water. Conducted over sulfate
magnesium, then filtered off, evaporated and get: - crude oil which is cured by treatment with ice-cooled mixture (1: 2) of sulfuric and petroleum ethers. The output of 83.6 g, so pl.
64-68 0.
c) (S) - (3-Benzyloxycarbonylamino-2-oxo-1-azetidynyloxy) acetic acid 1,1-dimethylethyl ester.
- one
Method I.
Trifeiyl (} n) spine (26.2 g, 0.1 mol) is added to a solution of O- (tert-butoxycarbonylmethyl) -ob-M- (benzyloxycarbonyl) -L-serine hydroxamate (36.8 g, O, 1 mol) in 500 ml of dry acetonitrile. A solution of triethylamine (20.9 ml, 0.15 mol) and carbon tetrachloride (9.7 ml, 0.1 mol) in 50 ml of dry acetonitrile was added dropwise at room temperature, the mixture was stirred overnight and evaporated under vacuum. The residue is dissolved in chloroform, washed with aqueous pH 4 buffer (citrate, HCl), dried over magnesium sulfate, and filtered. The solvent is then removed under reduced pressure and the residue is chromatographed on silica gel using sulfuric ether: ethyl acetate (2: 1). By recrystallization of the product from sulfuric ether / petroleum ether, colorless crystals are obtained; yield 20.6 g, m.p. 87-88 ° C.
Method I I.
Dry pyridine (4.75 g, 60 mmol) was added to a solution of O- (tert-butoxycarbonylmethyl) -oC-N- (benzyloxycarbonyl) -L-serine hydroxamate (11.05 g, 30 mmol) in 150 ml of dry dichloro - tana. A solution of methanesulfonyl chloride (6.8 g, 60 mmol) in 6 ml of dichloromethane is added dropwise to this mixture at 0 ° C. The mixture is stirred overnight at room temperature, poured into ice water and re-extracted with dichloromethane. The combined organic layers are washed twice with dilute HC1, water, 5% NaHCOj, water, and dried over max sulfate. By filtration and concentration under vacuum, an oil is obtained which is solidified with sulfuric ether. Yield 9.4 g, m.p. 92-94 S.
This product is combined with the product of the second series (total amount 11.2 g, 26 mmol) in 50 ml of dry acetone and added dropwise to a suspension of anhydrous potassium carbonate boiling with refluxing cooler (21.1 g, 0, 15 mol) in 100 ml of dry acetone. The mixture was vigorously stirred and refluxed for 1.5 hours, then cooled to room temperature, filtered and evaporated under vacuum. The residue is dissolved in sulfuric ether, washed with water and dried over sulfate.
174
magni. Filtration and scrubbing under vacuum give the above compound in its raw form, which is recrystallized from a mixture of sulfuric ether / non-net ether and yields a yield of 7.41 g, m.p. S2-85 ° C.
c) 1, 1-Dimethyl ethyl ester 3S (Z-Z- (2-amino-4-thiaoolylmethoxyimine-acetylamino) -2-oxo-1-azetidinyl-hydroxy acetic acid.
(5) - (3- -Benzyloxycarbonylsmino-2-oxo-1- -azetidynyloxy) acetic acid 1,1-dimethyl ethyl ester (1.4 g, 4.0 mmol) is dissolved in 25 ml of dry dimethylformamide and hydrogenated using 1 g of 10% palladium on activated carbon as a catalyst. After 20 minutes, the catalyst was filtered off and a mixture of (Z) -2-amino - ":, - (methoxyimino) -4-thiazoleacetic acid (4.4 mmol), 1-hydroxybenzotriazole hydrate (0.15 g, 1.0 mmol), dicyclohexylcarbodiimide (0.81 g, 4.4 mmol, and 30 ml of dry dimethylformamide. The mixture is stirred overnight at room temperature. The precipitated dicyclohexyl urea is filtered off and the solvent is removed under vacuum. The residue is dissolved in ethyl - acetate, followed by 5% NaHCOj and dried over magnesium sulphate. By filtration and evaporation under vacuum get the target soy Disinfection, which is cured by stirring with a mixture of sulfuric and petroleum ether; t, mp 120 C (with decomposition).
Examples 2-5. Analogously to Example 1C, but using instead of (Z) - -2-amino-ob- (methoxyimino) -4-thiazoleacetic acid, the compounds indicated in column I of the table. 1, the compounds listed in column II are obtained.
In the compounds listed in the table, the stereochemical properties of the oxime group correspond to these configurations.
Example 6. (35-trans) - (3-benzyloxy-carbonylamino-4-methyl-2-oxo-1-azetidispoxy) acetic acid 1,1-dimethylethyl ester.
A) O- (tert-Butyloxycarbonylmethyl) -o (, -N- (benzyloxycarbonyl) -L-threonineHyroxamate.
Analogously to Example 1A, but using N- (5i- (Benchyloxycarbonyl) -L-threonine instead of N-ai, - (benzyl51
loxycarbonyl) series gives the desired compound as an oil, which is cured by stirring overnight with a mixture of dichloromethane petroleum ether; m.p. 57-58 c.
c) (3S- -trans) - (3-benzyloxycar6-aminylamino-4-methyl-2-oxo-1-azetidinyloxy) acetic acid 1,1-dimethyl ethyl ester.
Analogously to Example 1B (procedure I, but using O- (tert-butyloxyxarbonylmethyl) -oi-N- (benzyloxycarbonyl) -L-threonine hydroxamate instead of O- (tert-butyloxycarbonylmethyl) -ot-N- - (benzyloxycarbonyl) - The L-serine hydroxamate is the target compound.After chromatography, the oil product crystallizes after one week of storage in a refrigerator, mp approx.
Example 7. (35-trans) -2- (3-benzyloxycarbonylamino-4-methyl-2-oxo-1-azetidinyloxy) -2-methylpropionic acid diphenylmethyl ester,
A) O- -Methyl-1- (diphenylmethoxycarbonyl) ethyl - “L-N- (benzyloxycarbonyl) -L-threonine hydroxamate.
Analogously to Example 1A, but using N-ci- (benzyloxycarbonyl) -L-threonine and diphenylmethylaminoxy isobutyrate instead of N-ot- (benzyloxycarbonyl) -L-serine and tert-butylaminooxyacetate, the said compound is obtained, which is dissolved in dry acetonitrile, dry over molecular sieves (ЗА), evaporate in vacuo and obtain crude oil.
c) Diphenylmethyl ester (3S- -trans) -2-- (3-benoyloxycarbonylamino-4-methyl-2-oxo-1-azetidinyloxy) -2- -methyl propionic acid.
Analogously to Example 1B (procedure I) but using O-l-methyl-1- (difennl-methoxycarbonyl) ethyl - "iN- (benzyloxycarbonyl) -L-threonine hydroxamate instead of O- (tert-butyloxycarbonylmethyl) -o -N- (benzyloxycarbonyl) -L-serine hydroxamate, the title compound is obtained. By recrystallization of the chromatographically purified product from a mixture of sulfuric and petroleum ethers, colorless crystals are obtained, m.p. 115 C (with decomposition).
Example 8. (35-trans) - (3-tert-butyloxy-carbonylamino-D-methyl-2-oxo-1-azetidinyloxy) acetic acid diphenylmethyl ester.
17 .6
A) O-I-Methyl- 1 - (diphenyln-toxycarbolyl) ethyl-a: - N- (tertbutyloxycarbonyl) -L-threonine hydroxamate.
Analogously to Example A, but using N-oi- (tert-butyloxycarbonyl) -L-threonine and diphenylmethylaminoxyacetate in place of N-oi- (benzyloxycarbonyl) -L-serine and tert-butylaminooxyacetate, this compound is obtained, m.p. 87-92 p.
c) Diphenylmethyl ester of (35-trans) - (3-tert-butyloxycarbonyl but-4-methyl-2-oxo-1-azetidinyloxy} acetic acid.
Analogously to example 1B (method I) but using O-1-methyl-1- (diphenylmethoxycarbonyl) ethyl (tert-butyloxycarbonyl) -L-threonine hydroxamate instead of O- (tert-butyloxycarbonylmethyl) -ob-N- (benzyloxycarbonyl) -L —cepine hydroxamate, the title compound is obtained as a colorless oil, which is crystallized by stirring with petroleum ether; m.p. 73-74 S.
Reference Example 1
(35-Trans) - (3-Benzyloxycarbonylamino-4-methyl-2-oxo--1-azetidynyloxy) acetic acid methyl ester.
A) O- (Methoxycarbonylmethyl) -oi-N-. - (benzyloxycarbonyl) -L-threoiin and methylaminooxyacetate instead of N-oi- (benzyloxycarbonyl) -L-serine and tert-butylaminooxyacetate, the title compound is obtained, m.p. 99-100 C.
c) (35-trans) -I L 3- (benzyloxycarbonyl) amino-4-methyl-2-oxo-1 -azetidinyloxyacetic acid methyl ester.
Analogously to example 1B (procedure I), but using O- (methoxycarbonylmethyl) (benzyloxycarbonyl) -L-threonine hydroxamate instead of 0- (tert-butoxycarbonylmethyl) -oi.-N- (benzyloxycarbonyl) -L-serine hydroxy samata, Said compound as a colorless oil.
Example 9. Diphenylmethyl ester (S) -2- (3-phenylacetylamino-2-ox-1-azetidynyloxy) -2-methylpropionic acid.
A) O-Ll-methyl-1- (diphenylmethoxycarbonyl) ethyl -ai-N- (phenylacetyl) -L-sirinehydroxamate.
Analogously to Example 1A, but using N-oi- (phenylacetyl) -L-serine and di-phenylmethylamino-oxyisobutyrate instead of N- (benzyloxycarbonyl) -L-serine and
tert-butylaminoxylacetate, the indicated compound is obtained (during chromatography, using a mixture of chloroform: acetone as an eluent in the form of an oil, which is dissolved in dry acetonitrile, dried over molecular sieves, and then evaporated under vacuum,
c) Diphenylmethyl ester of (S) -2- (3-phenylacetylamino-2-oxo-1-azetidini-oxy) -2-methylpropionic acid.
Analogously to example 1B (procedure I) but using O-LI-methyl-I- (diphenylmethoxycarbonyl) (phenyl acetyl) -L-serine hydroxamate instead of 0- (tert-butyloxycarbonylmethyl) -ti-N- (benzyloxycarbonyl) -L- serine hydroxamate, the indicated compound is obtained, mp, 63-73 ° C (with decomposition).
Example 10. (35-trans) -2- (3-phenylacetylamino-4-methyl-2-oxo-1-azetidynyloxy) -2-methylpropionic acid diphenylmethyl ester.
A) O-l-methyl-1 - (diphenylmethoxy bonyl) ethyl-ci-N- (phenylacetyl) -L-threonine hydroxamate.
Analogously to Example 1A, but using N-oi- (phenylacetyl) -L-threonine and diphenylmethylaminoxyisobutyrate in place of N-ftt- (benzyloxycarbonyl) -L-serine and tert-butylaminooxyacetate, this compound is obtained, m.p. .
c) 3S- -trans) -2- (3-phenylacetylamino-4-methyl-2-oxo-1-azetidynyloxy) -2-methyl-propionic acid diphenylmethyl ester.
Analogously to example 1B (procedure I) but using O-l-methyl-1- (diphenylmethoxycarbonyl) ethyl -o6-N- (phenylacetyl) -L-threonine hydroxamate instead of 0- (tert-butyloxycarbonylmethyl) -oi-N- - (benzyloxycarbonyl) -L-serine hydroxamate, the indicated compound is obtained, m.p. 78 C (with decomposition).
Example 11. Potassium salt 35 (Z) (2-amino-4-thiazolylmethoxyiminoacetylamino) -2-oxo-1 -azetidi-nyloxy acetic acid.
N-Methyl-N-trimethylsilyltripter-acetamide (0.20 g, 1.0 mmol) (hereinafter referred to as MSTFA) was added to a suspension of 3-S (Z) J-3 (2-amino-4- thiazolylmethoxyiminoacetylamino) -2-oxo-t-azetidi-niloxy-acetic acid (0.20 g, 0.5 mmol; example 1) in 5 ml of dry acetonitrile at O C. Mixing,
five
ABOUT
0
five
Q
five
five
continue for 30 minutes at 0 ° C and iodotrimethylsilane (0.10 g, 0.5 mmol) is added. After stirring for 30 minutes at room temperature, the mixture is evaporated under vacuum. The residue is taken up in 5 ml of absolute ether and 0.5 ml of methanol is added. After 30 min, the precipitate is filtered off, suspended in 5 ml of ice water and the pH is adjusted to 6.5 with IN potassium hydroxide. This suspension is treated by reverse phase chromatography on HP-20 resin using water as eluant, the corresponding fractions are dried, and 120 mg of the title compound are obtained; m.p. 170 ° C (with decomposition).
Example 12. The sodium salt of 3S (R) - .- (4-ethyl-2, 3-dioxo-1-piperamyl carbonyl amine) phenyl-cethylamino -2-oxo-I-azetidynyloxy | acetic acid.
Removal of the ester group from 3S (R) 1,1-dimethyl ethyl ester (4-α-ethyl-2,3-dioxo-1-piperazinylcarbonylamino) -2-oxo-1-azetidynyloxy acetic acid (Example 3) is carried out using MSTFA and iodotrimethylsilane, as described in Example 11. After decomposing the crude silylated product in ether with α-methanol, 0.5 ml of propylene oxide and ice water are added and the pH is adjusted to 6.5 with 5% NaHCOj. The organic layer is separated and the aqueous phase is lyophilized; after chromatography on HP-20 using a mixture of water / acetone (3: 4) as eluent, 230 mg of product are obtained; m.p. 160 ° C (with decomposition).
Example 13. 1,1-Dimethylethyl ether (R), p -G3-foi- - (4-ethyl-2,3-dioxo-1-piperazinylcarbonylamino-phenylacetylamino-4-methyl--2-oxo-1 -azetidinyloxy acetic acid.
(3S-Trans) - (3-Benzyloxycarbonylamino-4-methyl-2-oxo-1-azetidynyloxy) acetic acid 1,1-dimethyl methyl ester (1.53 g, 4.2 mmol Example 6) is dissolved in 20 ml of dry dimethylformamide. After adding 1.4 g of catalyst, which is 10% palladium on activated carbon, a stream is bubbled through the solution for about 1 hour.
hydrogen. After filtering the reaction mixture (30 min, O C) containing (R) -oi- (4-ethyl-2, 3-dioxo-1 -piperidinylcarbonylamino) benzeneacetic acid (1.34 g, 4.2 mmol), 1-hydroxybenzotriaeol hydrate (0.70 g) and dicyclohexylcarbodiimide (0.92 g, 4.4 mmol) in 30 ml of dry dimethyl formamide are added and the mixture is stirred overnight at room temperature. The precipitated urea is filtered off, the solvent is removed under vacuum, and the residue is chromatographed on silica gel using ethyl acetate as eluent. The oily product is crystallized by treatment with petroleum ether.
Yield: 0.25 g, m.p. 103-1 (with decomposition).
Reference Example 2
The sodium salt of (Z), -3- (2-amino-4-thiazolnolmethoxyimine-acetylamino) -4-methyl-2-oxo-1-azetidynyloxy acetic acid.
MSTFA (0.43 ml, 2.2 mmol) at 0 ° C is added to a solution of (35-trans) -benzyloxycarbonylamino-4-methyl-2-oxo-1-azetid nyloxyacetic acid 1,1-dimethyl ethyl ester (0.73 g, 2.0 mmol; example 6) in 20 ml of dry acetonitrile. After 30 minutes, iodotrimethylsilane (0.56 ml, 4.4 mmol) was added at O C and stirring was continued for 30 minutes at room temperature. After evaporation in vacuo, the residue is dissolved in 15 ml of dry tetrahydrofuran, and (Z) -2-amino-o-methoxyimino-4-thiazole acetic acid 1-hydroxybenzene ester (0.64 g, 2.0 ml) is added. mmol) and the mixture is stirred for overnight at room temperature. The solvent is removed in vacuo. After the addition of sulfuric ether and ice water, the pH was adjusted to 6.5 with NaHCGj. The organic layer is separated and the aqueous phase is lyophilized. Chromatography on HP-20 using water / acetone as the eluent affords the title compound (260 mg).
Example 14. Disodium salt of (Z), (2-amino-4-thiazolyl) -ftl- (1-carboxy-1-methyl-ethoxyimino) acetylamino-4-methyl-2-oxo-1-azetidinyloxy acetic acid.
29617. ten
Similar to reference example 2, but using 1-hydroxybenzotriazole ester of (Z) -2-aMHHo-oi- (2-diphenylmethocr. Si-1, 1-dimethyl-2-oxoethoxyimino) -4-thiazole acetic acid instead of 1-oxibenzotriazole (Z) -2-aMH- (methoxyimino) -4-thiao-acetic acid ester, sodium salt of 10 (Z), (2-aMHHo-4- -thiazolyl) -oi is obtained. (2-Diphenylmethoxy-1,1-dimethyl-2-oxo-ethoxyimino) acetyl-amino-4-methyl-2-oxo-1-azetidinyl-hydroxy | acetic acid. The product was dried and suspended in a solution of trifluoroacetic acid (10 ml) and anisole (1 ml) at -10 ° C. After 10 minutes at 0 ° C, the trifluoroacetic acid was distilled off, sulfuric ether and ice water were added and the pH was adjusted. t to 6.5 with NaHCOj. After freeze drying the aqueous phase, the crude product is chromatographed on HP-20 using water as eluent; m.p. 200 C (with decomposition).
Example 15-17. Similar to reference example 1, but using (35-trans) - (3-benzyl 30 hydroxycarbonylamino-4-methyl-2-oxo-1-α-azididinyloxy) acetic acid methyl ester (Example 10) instead of 1,1-dimethyl ethyl ester ( S) (3-Benzyloxycarbonyl-amino-2-oxo-1-azetidinyloxy) acetic acid and the acid indicated in column I of the Table. 2 instead of (Z) -2-amino-cb-methoxyimino-4-thiazoleacetic acid, the compounds shown in column II are obtained (Table 2).
40
Example 18. Sodium salt
(Z), 4/3 (2-amino-4-azolyl) "i- (1-carboxy-1-methyl-ethoxy) imino-acetylamino-4-methyl-2-oxo45 -1-azetidynyloxy | acetic acid. Using trifluoroacetic acid, anisole and sodium bicarbonate (as indicated in Example 14), this compound is obtained from methyl ester (Z), 4 / - (2-amino-4-thiazolyl) (2-diphenylmethoxy-1,1 -dimethyl-2-oxy-ethoxyimo-) acetylamino-4-methyl-2-oxo-1-azetidinyloxy acetic acid; m.p.
55 o Kolo (with decomposition),
Example 19. The sodium salt of (S) - (2-oxo-3-phenylacetylamino-1 - -azetidynyloxy) acetic acid.
II13
(5) - (3-Phenylacetylamino-2-oxo-1-azetidinyloxy) acetic acid diphenylmethyl ester (1.78 g, 4.0 mmol Example 11) was dissolved in 30 ml of absolute methanol and hydrogenated using 1, 2 g of 10% palladium on carbon as a catalyst. After 10 minutes the catalyst is filtered off and the filtrate is evaporated under vacuum. The residue was dissolved in a mixture of sulfuric ether and ice-water, and the pH was adjusted to 6.5 with NaHCO. Reverse phase chromatography of the lyophilized aqueous phase on HP-20 using water / acetone as eluent and lyophilic drying of the corresponding fractions gives 255 g of the indicated compound, mp. 56-70 ° C (with decomposition).
Example 20. Sodium salt of (S) -2- (2-oxo-3-phenylacetylamino-1-β-azetidinyloxy) -2 methylpropionic acid.
Analogously to example 19, but using 4.0 mmol of (S) - (3-phenylacetylamino-2-oKco-1 -azetidinyloxy) -2-methylpropionic acid diphenylmethylene ether (S) (example 12) instead of 4.0 mmol of (S) - diphenylmethyl ether (3-phenyl-acetylamino-2-oxo-I-azetidinyloxy acetic acid, 630 mg of the title compound are obtained, mp 88 C.
Example 21. Sodium salt of (3 $ -trans) - (4-methyl-2-oxo-3-phenyl-acetylamino-1-azetidynyloxy) acetic acid.
Analogously to Example 19, but using (3 $ -trans) - (3-phenyl acetylamino-4-methyl-2-oxo--1-azetidynyloxy) acetic acid diphenylmethyl ester instead of diphenylmethyl ester (S) - - (3-fe1-acetylamino-2- oxo-1-azeti-D1 niloxy) acetic acid, receive the specified connection, so pl. 77 - 130 C (with decomposition).
Example 22 Sodium salt of (35-trans) -2-4-methyl-2-oxo-3-phenyl-acetylamino-1-azetidynyloxy-2-methylpropionic acid.
Analogously to Example 11, but using (35-trans) -2-3-phenylacetylamino-4-methyl-2-oxo--1-azetidynyloxy-2-methylpropionic acid diphenylmethyl ester (Example 10) instead of (S) - ( 3-phenylacetyl-amino-2-oxo-1-azetidynyloxy) acetic acid, obtain the specified soy
Q g 0
five
ABOUT
Q g
Q
five
five
dynenie, so pl. 135-145 ° С (with decomposition).
Example 23. (35-trans) -2- (3- -Benzyloxycarbonylamino-4-methyl-2- -oxo-1-azetidynyloxy) -2-methylpropionic acid.
(35-trans) -2-(3-benzyloxycarbonylamino-4-me-TIL-2-OXO-I-azetidinyloxy) -2-methylpropionic acid diphenylmethyl ester (1.51 g, 3.0 mmol example 7) is stirred with with a solution of 1 ml of anisole in 10 ml of trifluoroacetic acid at -10 s for 10 min. The mixture is evaporated under vacuum and the residue is dissolved in sulfuric ether. A precipitate formed after the addition of petroleum ether is collected; yield 0.85 g, so pl. 125-126 C (with decomposition).
Example 24. Sodium salt of 35-3 (2), 4 / i (2-amino-4-thiazolylmethoxyiminoacetylamino) -4-me-TIL-2-OXO-1-azetidinyloxy -2-methylpropionic acid.
Similar to reference example 2, but using (35-trans) -2-3-benzyl-oxycarbonylamino-4-methyl-2-oxo-1-α-azididinyloxy-2-methyl-propionic acid (Example 29) instead of 1,1-dime - (35-trans) - (3-benzyloxycarbonylamino-4-methyl-2-oxo--1-azetidynyloxy) acetic acid methyl ethyl ester, this compound is obtained, mp, 190 ° C. (with decomposition).
Example 25. Methyl ether, sodium salt of (Z) 4рЗ -2- - (2-amino-4-thiazolyl) - "6- (1-carboxy-1-methylethoxyimino) acetylamino-4-methyl-2-oxo- I-azetidynyloxy | -2- -methylpropionic acid.
Similar to reference example I and example 18, but the outcome is (3 $ -trans) -2- (3-benzyloxycarbonylamino-4-methyl-2-oxo-1-azetidinyloxy) -2-methylpropionic acid methyl ester (Example 21) , receive the specified connection, so pl. 150 C (with decomposition).
Example 26. Diphenylmethyl ester of (35-trans) - (.3-tert-butyloxyxycarbonylamino-4-methyl-2-oxo-1-azetidinyloxy) acetic acid.
A) (35-trans) -3-tert-butyloxycarbonylamino-1-hydroxy-4-methyl-2-aetidininone,
(3S-trans) -3-tert-butyloxycarbonylamino-1-benzyloxy-4-methyl-2-azetidinone (10.2 g, 33.3 mmol) is dissolved in dry methane and hydrogenated using The clutch collector is 1.66 palladium nl coal (10%). After 45 minutes the catalyst is filtered off and the filtrate is evaporated to a dry residue under reduced pressure. By mixing the residue (6.94 g) with a mixture of sulfuric and petroleum ethers, said compound is obtained; yield 6.60 g; m.p. 144 C (with decomposition)
c) Diphenylmethyl ester of (35-trans) - (3-trit-butyloxycarbonyl but-4-methyl-2-oxo-1-azetidinyloxy) acetic acid.
Triethylamine (0.61 g, 6.0 mmol) was added dropwise to a solution of (35-trans) -3-tert-butyloxycarbonyl-1-hydroxy-4-methyl-2-lzetidinone (1.08 g , 5.0 mmol) and diphenylmethyl chloroacetate (1.43 g, 5.5 mmol) in 10 ml of dry dimethylformamide. The mixture is stirred overnight at room temperature. The precipitate is removed by filtration and the solvent is evaporated under vacuum. The residue is dissolved in ethyl acetate, filtered, washed with 5% NaHCO3 and water, dried over magnesium sulphate, evaporated under vacuum to give a colorless oil; output 2.0: When kept in the refrigerator, said compound crystallizes, m.p. 73-74 C,
Example 27. 1,1-Dimethyl ethyl ester of (35-trans) - (3-amino-4-methyl-2-oxo-1-azetidinyloxy) acetic acid.
I, 1-dimethyl ethyl ester of (35-trans) - (3-tert-butyloxycarbonylamino-4-methyl-2-oxo-1-azetidynyloxy) acetic acid (1.44 g, 4.4 mmol) in a mixture of 8.8 ml of trifluoroacetic acid and 0.88 ml of anisole at -10 ° C. After 10 minutes at 0 ° C, the solution is evaporated under vacuum and the residue is stirred with ether and filtered off, dried over and colorless trifluoroacetate crystals are obtained. salts of this compound; yield 0.61 g, mp 111-112 ° C. (with decomposition).
The salt (1.38 g, 4.0 mmol) is suspended in dry lcetonitrile at 0 ° C. N-methyl-N-trimethylsilyl-trifluoroacetamide (1.56 ml, 8.0 mmol) is added and transferred to persm (: stitching in 30 min at room temperature. After adding methanol (0.32 ml, 8.0 mmol) at 0 ° C, the precipitation is indicated
five
0
five
0
five
0
five
0
five
} The south of the compound is completed by adding dry sulfuric infirl. The colorless precipitate is collected and dried over; yield 0.92 g, mp, 115 ° C (with decomposition).
Example 28. (R), -p- (oi-aminophenylacetylamino) -4-methyl-2-oxo-I-azetidiiyloxy acetic acid.
Patria salt (), i (R), (4-methoxyphenylmethoxycarbonylamine ()) phenylacetylamino-1-4-methyl-2-oxo-1-azetidinyloxy acetic acid (0.493 g, 1.0 mmol) (obtained from crude acid with using NaHCO 3 with 11 consecutive purification on PR-20), the mixture is trifluoroaceous (H1 acid (2 ml) and anisole (0.2 ml) mixture. After 10 minutes at about C, the solution is evaporated under vacuum, the residue is stirred with sulfur ether and receive triptoreline SOL11 specified coeditleni, so pl.
 55 C (with decomposition).
MSTFA (o, 29 ml, 1.5 mmol) is added to a suspension of salt (0.21 g, 0.5 mmol) in 4 ml of dry acetonitrile at 0 ° C. The resulting solution is allowed to warm to room temperature and after 30 minutes it is cooled again to 0 ° C. Dry methanol (0.06 ml, 1.5 mmol) is added and the indicated compound is precipitated by adding dry sulfuric ether, collected by filtration and dried under vacuum.
OUT1) D 0,11 g.
Example 29. 2,2-Dimethyl-propionyl-oxymethyl ester of (35-trans) - - (3-phenylacetylamino-4-methyl-2-oxo-1-azetidinyloxy) acetic acid.
The sodium salt of (35-trans) - (4-methyl-2-oxo-3-phenylacetylamino-1-azetidynyloxy) acetic acid (0.94 g, 3.0 mmol) (Example 21) is dissolved in 20 ml of dimethylformamide . Iodomethyl pivalate (1.45 g, 6.0 mmol) is added at + 10 ° C and the mixture is stirred overnight at room temperature, the Solvent is evaporated under vacuum, the residue is dissolved in ethyl acetate, thoroughly washed with water, NaHCO solution, water and then dried (). After removing the solvent under vacuum, the resulting oil is mixed with petroleum ether, insoluble oil (0.86 g) is separated and then (5 purified by chromatography on silica using ethyl acetate / sulfuric ether as a fcTB eluant (1: 3) to give a colorless oil ; yield 0,43 g
Example 30. Trifluoroacetate salt of (3 $ -cis) - (3-amino-D-methyl-2-oxo-1-azetidynyloxy) acetic acid.
A) O- (Diphenylmethoxycarbonylmethyl) -N-tert-butyloxycarbonyl-allo-L-threonine.
Analogously to example IA, but using M-tert-butyloxycarbonyl-allo-1-threonine and diphenylmethylaminoxyacetate instead of M-about- (benzyloxycarboyl) -L-serine and tert-butyl amino-minoacetate, this compound is obtained, t. square UO-IAS C.
c) (35-cis) - ((3-tert-butyloxycarbonylamino-A-methyl-2-oxO-azetidynyloxy) acetic acid) (35-cis) - (3-terc) butyl ether.
Analogously to example 1B (procedure 1), but using 0- (diphenylmethoxycarbonylmethyl) -N-tert-butyloxycar bonyl-allo-threonine instead of 0- (tert-butyloxycarbonylmethyl) -oi-N- (benzyloxycarbonyl) -L- serine hydroxamate, the indicated compound is obtained. After chromatography on silica gel using ethyl acetate / sulfuric ether as eluent, the oily product is solidified by stirring with petroleum ether; m.p. 105-108 ° C.
c) The trifluoroacetate salt of (35-1; is) - (3-amino-4-methyl-2-oxo-1-azetidynyloxy) acetic acid.
Diphenylmethyl ester (35-cis) - (3-tert-butyloxycarbonylamino-4- -methyl-2-OXO-1-azetidinyloxy) acetic acid (1.5 g, 3.5 mmol) is dissolved in a mixture of 15 ml of trifluoroacetate Acids and 1.5 ml of anisole at -10 ° C. After keeping for 10 minutes at 0 ° C, 30 ml of sulfuric ether are added, the precipitate is filtered, washed with sulfur with M ether, dried over vacuum over and a hygroscopic solid is obtained; yield 0.53 g
Example 31. (2,2-Dinetnl-1-oxopropoxy) methyl ester of (S) - (3-benzipoxycarbonylamino-2-OKCo-l-azethidinyloxy) acetic acid.
(S) - (3-benzyloxycarbonylamino-2-α-oxo-1-azetidynyloxy) acetic acid (C g) is dissolved in 200 ml of dimethylformamide and the solution is cooled to
. 1, B-diazobicyclo- (5.4.0) unde-7-ene (0.01 mol) is added, followed by 2.7 g of 2,2-dimethylpropionate iodomethyl ester. After 10 minutes, the mixture was diluted with 75 ml of ethyl acetate, cooled (ice water), washed with ice water, sodium bicarbonate solution, diluted with ice water and again ice water. After drying over magnesium sulfate, the filtrate is evaporated and 4 g of the title compound are obtained, m.p. 73-75 С
Example 32 2,2-Dimethyl-ethoxy ($) - (3-benzyloxycarbonylamino-2-oxo-1-azetidinyloxy) acetic acid (2-oximethoxycarbonyl) methyl ester.
Analogously to example 31, but using instead of iodomethyl 2,2-dimethylpropionic ester 1,1-dimethyl ethyl ester of chloroacetic acid, the reaction is carried out for 6 hours to obtain the indicated compound, mp, 90-924.
Example 33. Acetyloxymethyl ester. (Z), 4 /, (2-amio-4-thiazolylmethoxyiminoacetylamino) -4-methyl-2-oxo-1-azetidynyloxy acetic acid.
To a solution of the sodium salt -oi (Z), 4 (3- (2-amino-4-thiazolylmethoxyiminoacetylimino) -4-methyl-2-oxo-1-azetidinipoxyacetic acid (3.2 g) in 50 ml of dry dimethylformamide was added dropwise 1.86 g of chloromethyl acetate with stirring, which was continued for 5 days. The solvent was evaporated under vacuum, the residue was dissolved in ethyl acetate, washed thoroughly with ice water, ice water and sodium bicarbonate solution salt, and dried over CaSO. After filtering and removing the solvent under vacuum, the residue is chromatographed on vuokisi silica using ethyl acetate as the eluent to give 1.08 g of the title compound, m.p. -74 C (with decomposition).
Example 34. Trans- (3-tert-Butyloxycarbonyl-4-β-methyl-2-Oxo-1-azetidynyloxy) methyl thioacetic acid methyl ester.
A) Methyl ether bromine (methylthio) acetic acid.
24.0 g of methylthioacetic acid methyl ester, 32.8 g of N-bromosuccinimide and 100 mg of 2,2-azobis (2-methylpropionitrile) are heated for
17
.1 h at 100 ° C with 150 ml of tetrachloride carbon. After cooling and filtering, the solvent is removed in vacuo and the residue is distilled, yielding 26.8 g of methyl bromine (methyl lithium) acetic acid as a red oil.
c) Methyl ester of trans- (3-tert-butyloxycarbonyl-4-methyl-2-oxo-1 - -aetidynyloxy) methylthioacetic acid.
2.16 g of 3-tert-butyloxycarbonyl-amino-1-hydroxy-A-methyl-2-aetidinone and 2.20 g of methyl bromo methyl tio-acetic acid methyl ester are dissolved in 50 ml of dimethylformamide. A solution of 1.11 g of triethylamine is added over 3 hours and the mixture is stirred for 2 days at room temperature. The solvent is removed in vacuo and the residue is suspended in 20 ml of ethyl acetate. The ammonium salt is filtered off, the solution is concentrated, chromatographed on silica gel using ethyl acetate as eluent, and 2.0 g of product is obtained in the form of an oil.
IR (film): 1780, 1745, 1710
NMR (DMCO-dJ 8 1.38 (singlet, 9H) 2.22 (singlet, ZI), 3.76 (singlet, GN), 5.63 and 5.66 (2-singlet, 1H), 7.60 (wide doublet, 1H).
EXAMPLE 35 I-Methylethyl Ether (Z), (2-amino-4-thiazolylmethoxyiminoacet1-shamino) -4-methyl-2-oxo-1-azetidinyloxy acetic acid.
A) (35-trans) -3-tert-butyloxycarbonylamino-1-hydroxy-4-methyl-2-azetidinone.
10.5 g of (35-trans) -3-tert-butyloxycarbonylamino-1-benzyl-hydroxy-4-methyl-2-azetidinone are dissolved in 250 ml of methanol and hydrogenated using 1.43 g of palladium on carbon. (10%) as a catalyst. After 45 minutes the catalyst is filtered off and the filtrate is evaporated under vacuum. The crystalline product is dried in a vacuum desiccator at room temperature and yields 7.3 g of the title compound, m.p. 161-162 C (with decomposition).
c) 1-Methylate: (3-trans) - - (3-tert-butyloxycarbonylamino-4-me-TIL-2-OXO-1-azetidinyloxy) acetic acid ether.
329617
18
11.3 g of triethylamine are added dropwise to a solution of 19.5 g (3 $ -trans) -Z-tert-butyloxycarbonipamino-1-ox-4-methyl-2-azetidinone and 14.8 g of 1- - methyl ethyl chloracetic acid ester in 400 ml of dry dimethylformamide. The resulting mixture was stirred at room temperature for 3 days. The hydrochloride is filtered off with triethyles and the solvent is evaporated at 35 ° C under vacuum. The residual oil is dissolved in sulfuric ether, the extract is kept in the refrigerator for an hour, filtered and the sulfuric ether is evaporated under vacuum. The resultant compound (30 g) in the form of an oil, containing approximately 2 g of oil
neny, use at the following stage, without further cleaning.
c) The trifluoroacetate salt of (3 $ -trans) - (3-amino-4-methyl-2-oxo-1-azetidinyloxy) acetic acid t-methyl ethyl ethyl ester.
30 g of crude (35-trans) - (tert-butyloxycarbonylamino-4-methyl-2-oxo-I-azetidinyloxy) acetic acid I-methyl ethyl ester are dissolved
in a mixture of 230 ml of trifluoroacetic acid and 23 ml of anisole at -10 ° C. Stirring is continued at -2 ° C for 30 minutes. After evaporation of the trifluoroacetate solution under vacuum
at a low temperature of (-10) - (- 20) the oily residue is dissolved in 350 ml of anhydrous ether, and immediately after this the crystallization of the trifluoroacetate salt begins. The output is increased by placing the ether mixture in the refrigerator. After cleaning the indicated compound, it is washed twice with anhydrous sulfuric HIFM, then with petroleum ether (40-60 ° C) and after drying in a desiccator over PjO, 18 g of product are obtained, mp. 125.5 ° C.
l) (Z), 4, 3- (2-amino-4-thiazolylmethoxy-amino-acetylamino) -4-methyl-2-oxo-1-azetidinyloxy acetic acid 1-methyl ethyl ester.
While stirring, 5.8 g of anhydrous triethylamine dissolved in 50 ml of anhydrous dimethylformamide is added dropwise to the solution.
17.5 g of trifluoroacetate salt of 1-methyl ethyl ether (3 $ -trans) - (3-amino-4-methyl-2-oxo-1-azetidinyloxy) acetic acid (0.053 mol) and 16.9 g of 1- hydroxybenzotriuylovy ether (Z) -21913
-amino-l- (methoxyimino) -4-thiao-acetic acid (0.053 mol) in 200 ml of dimethylformamide cooled to 0 ° C After 2 hours (after the addition of triethylamine is completed) the temperature of the reaction mixture is allowed to rise slowly to 20 ° C. Stirring at this temperature is carried out for another 4 hours. The dimethylformamide is removed under vacuum, the residual oil is dissolved in ethyl acetate, shaken with an aqueous ice sodium bicarbonate solution (IN) and then with ice water. The ethyl acetate layer was dried over sodium sulfate, evaporated under vacuum, and 18.8 g of the title compound were obtained. Chromatography on silica gel using tetrahydrofuran / / ethyl acetate (1: 1) gives a pure product, mp. 87-95 with (with decomposition).
Example 36 2-Pro-11-ester (Z), (2-amino-4-thiazolylmethoxyiminoacetylamino) -4-methyl-2-OKCO-l-azetidinyloxy acetic acid,
A) 2-Propenyl ester of (35-trans) - - 3-tert-butyloxycarbonylamino-2-me-TIL-4-OXO-1-azetidinyloxy acetic acid.
To a solution of 17.3 g of (3S-Tpairc) -3-tert-butyloxycarbonylamino-1-hydroxy-4-methyl-2-azetidinone was added 12.9 g of chlorophosphoric β-propenyl ester in 350 ml of dry dime- tilformamide. The mixture was incubated for 4 days at room temperature, and then processed, shayut as described in example 35B. Crude ether yield 25.5 g.
c) The trifluoroacetate salt of (35-trans) - (3-amino-4-methyl-2-oxo-1-azetidinyloxy) acetic acid 2-preppenyl ester.
25.5 g of (3 $ -trans) - (3-tert-butyloxycarbonylamino-4-methyl-2-oxo-β-netidynyloxy) acetic acid 2-propenyl ester (3t-trans) are added to a stirred and cooled to -10 ° C. a mixture of 200 ml of trifluoroacetic acid and 20 ml of anisole. After carrying out the reaction for 25 minutes with an excess of trifluoroacetic acid, it is removed under vacuum at a low temperature of 20-25 ° C. The oily residue is dissolved in 250 ml of anhydrous sulfuric ether and stored in a refrigerator. Precipitated crystal precipitated compound7
20
It is washed, washed twice with anhydrous sulfuric ether, then with petroleum ether (40-60 °) and dried in a desiccator over. to obtain 17.7 g of product, m.p. 11 2-of S.
c) 2-Propenyl ester {3S-L3 «ii (Z) 4 H- (amino-4-thiazolylmethoxyiminoacetylamino) -4-methyl-2-oxo-1-azetidynyloxy acetic acid.
To a stirred mixture, 17.4 g of the trifluoroacetate salt of 2-propenyl ester (35-trans) - (3-amino-4-methyl-2-oxo-1-azetidinyloxy) acetic acid and 16.9 g of the 1-hydroxybenzotriazole ester (Z) -2-amino in :-( methoxyimino-4-thiazoleacetic acid in 200 ml of dimethylformamide, cooled to 0 ° C, a solution of 5.8 g of triethylamine in 40 ml of anhydrous dimethylformamide is added in portions. After that, the solution temperature is maintained at 5 C for 1 h, then at 10 ° C for 2 h, after which the solution is left to stand overnight at room temperature. The treatment is carried out the same as in example 35. Output 18 g, so pl. 75-80 C (with decomposition).
EXAMPLE 37. 2-Propynyl ester (Z), (2-amino-4-thiazolylmethoxyiminoacetylamino) -4-methyl-2-oxo-1-azetidynyloxyacetic acid.
A) 2-Propynyl ester of (35-trans) - - (3-tert-butyloxycarbonylamino-4-methyl-2-oxo-1-azetidinyloxy) acetic acid.
Analogously to example 36A, but using chloroacetic acid 2-propynyl ester (1.7 g) instead of chloroacetic acid 2-propenyl ester, 2.2 g of the above product is obtained in the form of an oil, which is used in the next step without purification.
c) Trifluoroacetate of (35-trans) - (3-amino-4-methyl-2-oxo-I-azetidynyloxy) acetic acid 2-propynyl ester.
Removal of the protective group in the oil obtained in the previous step was carried out with a mixture of trifluoroacetic acid / anisole (25 ml / 2.5 ml) as in Example 37B. Output 1.7 g, so pl. 106-197 C.
(c) 2-Propynyl ef1f 35-GZy. (1), H- (2-amino-4-thiazolylmethoxy-iminoacetylamines (1 0) -4-methyl-2-oxo-, 1-β-azididinyloxy acetic acid.
21132961722
The addition of 1.6 g of trifluoroacetate - the Solvent is evaporated under vacuum
ten
at 30 ° C, the residue is dissolved in ethyl acetate, shaken with an icy aqueous solution of sodium bicarbonate (1 N) and then with ice water. The ethyl acetate layer suptane magnesium sulfate and the indicated compound (4 g oil) are chromatographed on silica gel using ethyl acetate. Yield 3.1 g, m.p. (with decomposition).
Example 39. 2-Chloroethyl ether (Z), (2-amino-4-thiazolylmethoxyiminoacetylamino) -4 salt of 2-propynyl ether (35-trans) - (3-amino-D-methyl-2-oKco-l- -azethidinyloxy) acetic acid to 1.6 g of 1-hydroxybenzotriazole ester of (Z) -2-amino-ib- (methoxyimino) -4-thiazoluacetic acid, is carried out as described in Example 37C. Chromatography on silica gel using tetrahydrofuran / ether was used to obtain 1.1 g of the title compound, m.p. 69-75 C (with decomposition).
Example 38. Propyl ether 15-methyl-2-oxo-1-azethidinyl oxide Jyccy- ((Z), 4cJJ D (2-amino-4-thiazoic acid.
lilmethoxyiminoacetylamino) -4-methyl-A) 2-Chloroethyl ester (35-trans) -2 -2-OXO-1-azetidinyloxy-acetic (3-tert-butyloxycarbonyl-4-methyl-2-OXO-1-azetidinyloxy) acetic
A) Propyl ether (3 $ -trans) - (3-20 acids,
tert-butyloxycarbonpamino-4-methyl Analogously to Example 36A, but using 2-chloroethyl chloroacetic acid ester (4.32 g) instead of 2-propenyl chloroacetic acid ester, 5.2 g of the above compound
(When chromatographing on silica gel, a mixture of ethyl acetate / sulfuric ether (l: l) is used as eluant. c) 2-Chloro-trifluoroacetate salt) 2-chloro-ethyl-ethyl propylozoate trifluoroacetate (-3-ether) 3 $ -trans) - (3-amino-4-me-2-methyl-4-oxo-1-azetidynyloxy) hydroxy acid.
-2-OXO-1-azetidinyloxy) acetic acid.
In analogy to Example 36A, but using Chloroacetic Acid Propyl Ester (3.0 g) instead of Chloroacetic Acid 2-propenyl ester, 4.2 g of the title compound are obtained, m.p. 72 ° C.
TIL-2-OXO-1-azetidynyloxy) acetic acid.
By processing the above ester
succinic acid.
Starting from a derivative in which the amino group is protected by tert-butyloxy (4.2 g) with 50 ml of trifluoroacetic acid „carbonyl, and using trifluoroacetic acid and anisole (as described in example PbB), this compound is obtained. Yield 4.19 g,
(c) {25-L2ei, 3A (-3- (2-amino-4-thiazolylmethoxyiminoacetylamino) -2-methyl-4-oxy-1-azetidynyloxyacetic acid) 2-chloroethyl ester.
Analogously to Example 36C, an addition reaction is carried out between 2.0 g
and 5 ml of anisole according to Example 3B, 3.3 g of the title compound are obtained.
c) Propyl ester of (Z), 4 H- (2-amino-4-thiazolylmethoxy-Q imino acetylamino) -4-methyl-2-oxo-1-azaididinyloxy acetic acid.
4.88 ml of MSTFA (95%) (2.5 mmol) was added to a suspension of 3.3 g of the trifluoroacetate salt of propyl ether (3S- 45 of the trifluoroacetate salt of 2-chloroethyl-trans)) (3-amino-4-methyl -2-oxo-1-ether of (3 $ -trans) - (3-amino-4-methyl-2-β-azethidinyloxy) acetic acid in-oxo-1-azetidinyloxy) acetic acid; 60 ml of dry acetonitrile at. lots and 1.89 g of 1-hydroxybenzotriazole. Stirring is continued until solution of (Z) -2-amino-ib- (methoxyimino) ether - PIA trifluoroacetate salt. Transparent go-thiazoleacetic acid, the solution is prepared to stand overnight. 1.66 g of this compound (upon evaporation of the acetonitrile under vacuum, the remaining oil (3.39 g) is dissolved in 40 ml of dry tetrahydrofuran, 2.96 g of 1-hydroxybg gg of triazole ester (Z) -2- amino-a; .- - (methoxyimino) -4-thiazoleacetic acid (8.44 mmol) and the mixture is stirred for 4 hours at room temperature.
chromatography on silica gel using tetrahydrofuran / sulfuric ether (l: l) as eluent, mp. 84-85 ° C (with decomposition).
Example 40. Cyclohexyl ether (Z), (2-amino-4-β-thiazolylmethoxyiminoacetylamino) -4-
at 30 ° C, the residue is dissolved in ethyl acetate, shaken with an icy aqueous solution of sodium bicarbonate (1 N) and then with ice water. The ethyl acetate layer suptane magnesium sulfate and the indicated compound (4 g oil) are chromatographed on silica gel using ethyl acetate. Yield 3.1 g, m.p. (with decomposition).
Example 39. (Z) 2-Chloroethyl ester, (2-amino-4-β-thiazolylmethoxyiminoacetylamino) -4 acetic acid.
Starting from a derivative in which the amino group is protected by tert-butyloxycarbonyl, and using trifluoroacetic acid and anisole (as described in example PbB), this compound is obtained. Yield 4.19 g,
(c) {25-L2ei, 3A (-3- (2-amino-4-thiazolylmethoxyiminoacetylamino) -2-methyl-4-oxy-1-azetidynyloxyacetic acid) 2-chloroethyl ester.
Analogously to Example 36C, an addition reaction is carried out between 2.0 g
trifluoroacetate salt of 2-chloroethyl ether (3 $ -trans) - (3-amino-4-methyl-2-oxo-1-azetidynyloxy) acetic acid and 1.89 g of 1-hydroxybenzotriazole fir (Z) -2- amino-ib- (methoxyimino) - -thiazoleacetic acid, 1.66 g of the title compound is obtained (with
trifluoroacetate salt of 2-chloroethyl ether (3 $ -trans) - (3-amino-4-methyl-2-oxo-1-azetidynyloxy) acetic acid and 1.89 g of 1-hydroxybenzotriazole ether (Z) -2- amino-ib- (methoxyimino) - -thiazoleacetic acid, 1.66 g of the title compound is obtained (with
chromatography on silica gel using tetrahydrofuran / sulfuric ether (l: l) as eluent, mp. 84-85 ° C (with decomposition).
Example 40. Cyclohexyl ether (Z), (2-amino-4-β-thiazolylmethoxyiminoacetylamino) -4-
-methyl-2-с) Ксс1- 1-, g) ethidi) ni; 1pc (: and с-cycuoi i acids.
(3S-Ti) - - (3-tert-butyloxnone rbopillmio-4-me-TIL-2-OXO-1-lithiotic acid) acid (2.23 g), cyclic-hexyl ester (2.23 g), obtained as in Example 36A, stretched n solution of 25 ml of trifluoroacetic acid and 2.5 ml of anisole at -10 ° C. After 25 minutes the mixture is evaporated under vacuum and the residue is stirred with sulfuric ether, filtered, dried over, 0. and colorless trifluoroacetate acetate crystals of (3S) -3-amino-4-methyl-2-oxo-1-azetidynyloxyacetic acid are obtained (yield 1.53). The salt (1.50 g) is suspended in 30 ml of acetonitrile, MSTFA (2.37 ml) is added at 0 ° C and the solution is left overnight. After evaporation in vacuo, the residue (1.75 g) was dissolved in dry tetrahydrofuran (25 ml), 1.4 g of (Z) -2-amino- (5,, - - (methoxyimimino), 1 - hydroxybenzotriazole ester) was added. ) -4-thiazoleacetic acid, and the mixture is stirred at room temperature for 4 hours. The tetrahydrofuran is removed under vacuum at 30 ° C, the residue is dissolved in sulfuric ether, shaken with ice-cold aqueous solution of NaHCOj (IN) and twice with cold water The dried ethyl acetate layer is evaporated under vacuum, the resulting oil (2.14 g) is chromatographed on silica gel using these acetate to give 1.58 g of the title compound, mp (with decomposition).
Example 41, Cyclopentyl ester 35 (Z), (2-amino-4-thiazolylmethoxyiminoacetylamino) -4-methyl-2-oxo-azethidinyloxy acetic acid.
Analogously to example 40, but using (35-trans) - - (3-tert-butyloxycarbonylamino-4-methyl-2-oKCO-1-azetidynyloxy) acetic acid cyclopentyl ether instead of (35-trans) - (3-ter -butyloxy-carbonylamino-4-methyl-2-oxo-1-azetidinyloxy) acetic acid, to obtain the specified connection, so pl. 90-95 С
(with decomposition).
I Example 42. Piclopentylmethyl ester (Z), - (2-amino-4-thiazolylmethoxyiminoacetylamino) -4-methyl-2-oxo-1-azetidynyloxy} acetic acid.
1d1klopentylmethyls) vyg1 ester (3S-Trlns) -3-tert-butyloxycarbnyl-ns) -4-methyl-2-oxo-I -azetidynyloxy-acetic acid, obtained from (3S-trans) -3-tert-butyuksycarbonyl / am - io-1-ox and-4-methyl-2-acetidinone and cyclopentylmethyl chloroacetate, are introduced into the deprotection reaction and addition reaction to form the compound according to the procedure described in Example 35B - D, t. square 73-80 C (with decomposition).
Example 43: 2,2-Dimethylpropyl ether (, (Z), (2- -aNoiHo-4-thiazolylmethoxyiminoacetyl-amino) -4-methyl-2-oxo-1-azetidinyl-acetic acid G1.
The 2,2-dimethylpropyl ester of (35-trans) - (3-tert-butyloxycarbonyyl) yu-4-methyl-2-oxo-t-azetidinyloxy) acetic acid is converted to the corresponding trifluoroacetate salt,
and then to the indicated compound (mp. 74-76 C, with decomposition) according to the method described in Example 36A - C.
Example 44. (Z) 2-ethylbutyl ether, (2-amino-4-thiazolylmethoxyiminoacetylamino) -4-methyl-2-oxo-1-azetidinyloxy acetic acid.
Analogously to Example 36A-C, 2-ethylbutyl ether (3Z-trans) - (3-tert-butyloxycarbonylamio-4-methyl-2-oxo-1-azetidinyloxy) acetic acid is first converted into the trifluoroacetate salt, and then in the specified connection; m.p. 56-60 С (with decomposition) „
Example 45. 2,2,2-Trifluoro-ethyl ether (Z), th 3 - (2-amino-4-thiazolylmethoxyiminoacene-1-amino) -4-methyl-2-oxo-1-azetidi-
nyloxy acetic acid.
Analogously to Example 35, 2,2,2-trifluorostiloby ether (3 $ -trans) - (3-tert-butyloxycarbonylamino-4-methyl-2-oxo-1-azetidinyloxy) acetic acid is deacylated to the trifluoroacetate salt, and then reacted with (1) hydroxybenzotriazole ester of (Z) -2-amino):, - (methoxymino) -4-β-thiazoleacetic acid to obtain the above compound; m.p. 75-81 C (with decomposition).
Example 46 (Z), 4p3J - 3- (5-amiyo-1,2,4-thiadiazole-3-methylmethoxy-imine-acetylamino) -4-methia.
25
-2-oxo-I-a etidinyloxy acetic acid.
(35-trans) - - (3-butyloxycarbonylamino-4-methyl--2-oxo-1-azetidinyloxy) acetic acid diphenylmethyl ester (15 g, Mm mmol) is dissolved in a solution of 112 ml of trifluoroacetic acid and 11.2 ml of anisole at
-10 ° C
And pm-e 48. One-Satin
After 10 minutes, the mixture is evaporated under Na-10 salt. (2), 3- (b-amino-2 quum, the residue is stirred with sulfuric ether, filtered, dried over P-0, and 7.3 g of trifluoroacetate salt crystals are obtained (3S) - (3-amino-4-methyl-2-oxo-1-azetidinyloxy) acetic acid. This salt (7.3 g) is suspended in 30 ml of dry acetonitrile, 3.34 ml of MSTFA is added and the stirring is continued in for 1 hour. After evaporation under vacuum, the residue is dissolved in dry tetrahydrofuran, 2.0 g of (Z) -5-amino-1,2,4-α-thiadiazol-3-yl- 1-hydroxybenzotriazole ester is added. o6- (methoxyimino) acetic acid acid, the mixture is stirred overnight at room temperature and evaporated under vacuum. After the addition of sulfuric ether, the crude silylium product is decomposed with 0.5 ml of methanol. The insoluble product is filtered off, dissolved in tetrahydrofuran, chromatographed on silica gel using ethyl acetate / sulfuric ether (1: 1) and receive the specified connection, so pl. 165-166 C.
Example 47. 1-Methyl ethyl eff (Z), (5-amino--1, 2, 4-thiadiazl-3-ylmethoxyiminoacetylamino) -4-methyl-2-oxo-1-azetidinyl hydroxy acetic acid.
1.35 g of the trifluoroacetate salt of (35-trans) - (3- -amino-4-methyl-2-oxo-1-azetidinyloxy) acetic acid 1- -methyl ethyl ester. acids (4.1 mmol) are suspended in 25 ml of dry acetonitrile, 2.28 ml of MSTFA are added at 0 ° C, stirring is continued for another 30 minutes and the solution is left overnight at room temperature. After evaporation in vacuo, the residue (1.92 g) is dissolved in 13 ml of dry tetrahydrofuran, 1.75 g of (Z) -5-aMHHo-1,2,4-thiadiazol-3-yl-1 c1 - - (methoxyimino) acetic acid, the mixture is stirred overnight at room temperature and evaporated in vacuo. The residue is dissolved in ethyl acetate, shaken with ice water 20
25
thirty
-pyridinylmethoxyiminoacetylamino) -4-methyl-2-oxo-1-azetidinyloxy acetic acid.
Analogously to Example 46, but using 1-hydroxybenzotriazole ester of (Z) - -6-amino-2-pyridinyl) - «i, - (methoxyimino) acetic acid instead of 1-hydroxybenzo-triazole ester of (Z) -5-amino- -1, 2,4-thiazol-3-yl-ob- (methoxyimino) acetic acid, this compound is obtained in the form of the free acid. It is suspended in ice water, the pH is adjusted to 6.5 with sodium hydroxide, the clear solution is lyophilized and get salt, so pl, 140 ° C (with decomposition).
Example 49. One-sodium salt of (35-trans) (2,6-dichloro-4-pyridinylthioacetylamino) -4-methyl-2-oxo-1-azetidinyloxy acetic acid.
In analogy to Example 48, but using 2,6-dichloro-4-pyridinylthioacetic acid 4-nitrophenyl ester jfj instead of (Z) -6-amino-2-pyridinyl-ll6- (methoxyimino) acetic acid 1-hydroxybenzotriazole ester, the specified connection, so pl. 97-100 ° C (with decomposition).
Example 50. 1- (Cyclohexyl-hydroxycarbonyloxy) ethoxylic ester 35-3 (6 (Z), 4p-3- (2-amino-4-thiazo-lilmethoxyiminoacetylamino) -4-methyl--2-oxo-1-azetidinyloxy acetic acid .
The single-potassium salt (ii (Z), -3- (2-amino-4-thiazolylmethoxyiminoacetylamino) -4-methyl-2-oxo-azethidinyloxy acetic acid (o, 40 g) is dissolved in 10 ml of dry dimethylformamide. 06-chloroethylcyclopentyl carbonate (0.20 g) and 0.083 g of potassium iodide are added at room temperature, and the mixture is stirred at room temperature for 2 days. The solvent is evaporated under vacuum, the residue is dissolved in ethyl acetate, washed thoroughly with water, and a solution of NaHCO 3 , (IN), with water and then dried on
40
45
50
55
132961726
rum NaHCOj (1 N), and chamem with ice water. The JTiLnaueraTiibift layer was dried over sodium sulfate, the chromate was refined on silica gel using ethyl acetate as eluent. The yield of said compound is 1.10 g, m.p.
 J-85 ° C.
And pm-e 48. One-Satin
- 10 salt. (2), 3- (b-amino-2 salt. (2), 3- (b-amino-2
-pyridinylmethoxyiminoacetylamino) -4-methyl-2-oxo-1-azetidinyloxy acetic acid.
Analogously to Example 46, but using 1-hydroxybenzotriazole ester of (Z) - -6-amino-2-pyridinyl) - “i, - (methoxyimino) acetic acid instead of 1-hydroxybenzotriazole ester of (Z) -5-amino- -1, 2,4-thiazol-3-yl-about- (methoxyimino) acetic acid, receive the specified connection in the form of the free acid. It is suspended in ice water, the pH is adjusted to 6.5 with IN sodium hydroxide, the clear solution is lyophilized and the salt is obtained, m.p. 140 ° C (with decomposition).
Example 49. One-sodium salt of (35-trans) (2,6-dichloro-4-pyridinylthioacetylamino) -4-methyl-2-oxo-1-azetidinyloxy acetic acid.
Analogously to Example 48, but using 2,6-dichloro-4-pyridinylthioacetic acid 4-nitrophenyl ester instead of (Z) -6-amino-2-pyridinyl-ll6- (methoxyimino) acetic acid 1-hydroxybenzotriazole ester, the above connection, so pl. 97-100 ° C (with decomposition).
Example 50. 1- (Cyclohexyl-hydroxycarbonyloxy) ethoxylic ester 35-3 (6 (Z), 4p-3- (2-amino-4-thiazol-methylmethoxyminoacetylamino) -4-methyl-2-oxo-1-azetidinyloxy acetic acid.
The single-potassium salt (ii (Z), -3- (2-amino-4-thiazolylmethoxyiminoacetylamino) -4-methyl-2-oxo-azethidinyloxy acetic acid (o, 40 g) is dissolved in 10 ml of dry dimethylformamide. At a room temperature, 06-chloroethylcyclopentyl carbonate (0.20 g) and 0.083 g of potassium iodide are added, and the mixture is stirred at room temperature for 2 days. The solvent is evaporated under vacuum, the residue is dissolved in ethyl acetate, washed thoroughly with water, and a solution of NaHCO , (IN), with water and then dried on
2713
sodium sulfate. After removal of the solvent under vacuum, the resulting oil (o, 34 g) is chromatographed over silica gel using tetrahydrofuran / ether as the eluent (1: 1) to give 0.31 g of the title compound as an oil, which crystallizes upon treatment with water m.p. 85-90 C (with decomposition).
Example 51. 1- (Ethoxycarbonyloxy) ethyl ester (Z), 4 |} j- 3- (2-amino-4-thiazolylmethoxy-imino acetylamino) -4-methyl-2-oxo-1 - -azetidynyloxy acetic acid.
Analogously to example 50, but using the ";, -Iodoethyl carbonate instead of ci - chloroethylcyclopentyl carbonate, the indicated compound is obtained, mp. 120 125 C (with decomposition).
Example 52. I, 1-Dimethylethyl ester (xL (Z), (2- -amino-4-thiazolylmethoxyiminoacetyl-amino) -4-methyl-2-oxo-1-azetidinyl-hydroxy-acetyloxy acetic acid.
To a solution of sodium salt | 3 $ - - 3oi (Z), PI H- (2-amino-4-thiazolyl methoxyimino-acetylamino) -4-methyl-2-oxo-1-azetidinyloxy-acetic acid in 50 ml of dry dimethylformamide along 4.14 g of tert-butyl iodoacetate are added dropwise. Stirring is continued at room temperature for 3 hours.
The solvent is evaporated under vacuum at room temperature, the residue is dissolved in ethyl acetate, washed thoroughly with ice water, ice-cold aqueous solution of NaHCOj and ice-cold with brine, then dried over CaSO4. After filtration and removal of the solvent under vacuum, the residue: is chromatographed on silica gel using ethyl acetate as eluent, to obtain 2.9 g of the title compound, m.p. 77 C (with decomposition).
Example 53. The monosodium salt of (Z), (2-amino-4-β-thiazolylmethoxyiminoacetylamino) -4-β-methylan-2-oxo-1-azetidinyloxy acetic acid.
A solution of 0.33 g of triethylamine in 5 m of dry dimethylformamide is added dropwise to a solution of 0.33 g of the trifluoroacetate salt (3, S-cis) - (3-amino-4-methyl 2-oxo-1- azetidinyloxy) acetic acid and 0.35 g of 1-hydroxybenzotri-728
(Z) -2-amino-2- (methoxyimino) -4-thiazoleacetic acid ester in 20 ml of dimethylformamide at 0 ° C, and stirring is continued for
3h at room temperature. The solvent is evaporated under vacuum. The residue is suspended in 10 ml of n-butanol and a solution of 0.55 g of sodium 2-methyl hexanoate in 10 ml of n-butanol is added. The mixture is stirred for
4h at room temperature. The precipitate is collected by decanting, washed with n-butanol and ethyl ether and dried under vacuum over. After reverse phase chromatography using water as eluent (HP-20) and freeze drying of the appropriate fractions, the title compound is obtained; yield 0.14 g, so pl. 170 ° C (with decomposition)
Example 54. Disodium salt of (Z) salt, (2-amino-4-thiazolyl) -2- (1-carboxymethoxy-4-methyl-2-oxo-3-azetidinyl-amino) -2-oxoethylidene-amino-oxy} -2- Methylpropium acid
A) Monosodium salt of diphenylmethyl ether (Z), - (2-amino-4-thiazolyl) -2- (I-carboxy-methoxy-4-methyl-2-oxo-3-azetidinyl-amino) -2-oxoethylideneamine -2-methylpropionic acid.
1.3 ml of MSTPA were added to a suspension of 0.63 g of the trifluoroacetate salt of (35-cis) - (3-amino-4-methyl-2-oxo-1-α-azididinyloxy) acetic acid in 10 ml of dry acetonitrile at 0 ° C and Stirring is continued for 30 minutes at room temperature. After evaporation in vacuo, the residue is dissolved in 15 ml of dry tetrahydrofuran, and this solution is added to a mixture of 0.97 g of (Z) -2-amino-oi- (2-diphenyl-methoxy-1, 1-dimethyl-2-oxoethoxy). - imino) -4-thiazoleacetic acid, 0.34 g of 1-hydroxybenzotriazole and 0.45 g of dicyclohexylcarbodiimide in 10 ml of tetrahydrofuran, where they are reacted for 2 hours at. After stirring overnight at room temperature, the precipitate is evaporated under vacuum. Ice water and sulfuric ether are added to the residue and the pH is adjusted to 6.5 with 5% sodium bicarbonate solution. The organic layer and insoluble products are separated and the aqueous phase is lyophilized and dried. Column Chromatography on Resin
29
llP-20 using water quality and water / acetone (7: 3) as (1) eit) to obtain 0.56 g of pure product, m.p. 168 ° C (with decomposition).
c) Dinatriene salt, (Z), 4oi 2- 1 - (2-amino-4-thiazolyl) -2- (1 - -carboxymethoxy-4-methyl-2-oxo-3- -azetidinylamino) -2-oxoethylidene-amide- nooxy -2-methylpropiomic acid.
0.29 g (0.47 mmol) of mononatriate diphenylmethyl ester {35- - 3 °; {Z), 4o (. | - (2-amyl-14-thiazolyl) -2- (1-carboxymethoxy-4- methyl 2-oxo-3-azetidinylamino-2-oxo-ethylenenaminooxy-3-methylpropionic acid (lyophilized) is suspended in a solution of 2.1 ml of trifluoro-yKcycHoii acid and 0.21 ml of liizol at -10 ° C. After stirring in the course of 1-10 minutes at 0 C, trifluoroacetic acid is removed under vacuum; the bath temperature is 5 s). Sulfuric ether and ice water are added and the pH is adjusted to 6.5 with 5Z-Horo sodium bicarbonate solution. After freeze-drying the aqueous layer, the crude product is chromatographed on HP-20 using water as eluant to yield 0.16 g, m.p. 60 C (with decomposition).
Example 55. // 3-Pentyloxy / / carbonyl / 3S-3ci {Z) methyl ester, 4 h- (2-amino-4-thiazolylmethoxy-imine acetylamino) -4-methyl-2-oxo-1 - -azetidynyloxy acetic acid .
A) 3-Pentyloxycarbonyl 1-methyl bromoacetic acid ester.
Bromoacetic acid 3-pentyl ester (330 g, 1.6 mmol) is dissolved in 300 ml of dimethylformamide. Frequently, the potassium bromoacetate was added with stirring and the mixture was stirred overnight. The mixture is then poured into 1 liter of ice water and 500 ml of sulfuric ether are added. After washing with water, a solution of NaHCO and drying over magnesium sulfate, the sulfuric ether is evaporated. During distillation, 156 g of the starting ester and 103.5 g of the indicated compound are obtained (mp. 160-162 ° C at 12 mm Hg).
c) 3-pentyloxycarbonylmethyl ether (3 $ -trans) - (3-tert.butyloxycar bonylamino-4-methyl-2-oxo-1-azetidinyloxy) acetic acid.
(35-trans) -3-tert-butyloxycarbonyl amino-1-hydroxy-4-methyl-2-azetidinone (21.6 g) is dissolved in 250 ml of dimethyl
,
t m
-
329617
formamide. With
thirty
 26.7 g of 3-polyploxycarbo} and 1) methyl and bromoacetic acid ester were added, followed by 17 ml of triethylamine. The mixture is stirred overnight and the D1 methylformamide is evaporated under vacuum. The oily residue is dissolved in 300 ml of ethyl acetate, washed with ice-cold NaHCO, solution.
10 then three times with ice water. After drying over magnesium sulfate, the solvent is evaporated under vacuum to obtain 35.6 g of the title compound as an oil.
15 c) 3-Pentyloxycarbonylmethyl ester of (35-trans) - (3-amino-4-methyl-2-oxo-1-azetidinylphenyl) acetic acid.
3-Pentyloxycarbonylmethyl
(35-trans) - (3-tert-butyloxycarbonylamino-4-methyl-2-oxo-I-azetidinyloxy) acetic acid 2Q ester is dissolved in dichloromethane. At -10 ° C, 50 ml of trifluoroacetic acid are slowly added. The temperature is maintained at -10 ° C for 20 minutes, the solvent is evaporated under vacuum and 13 g of the title compound are obtained as an oil.
30 - D) 3-Pentyloxycarbonylmethyl ester (Z), 4p, (2-amino-4-β-thiazolyl methyloxyimino-acetylamino-4-methyl-2-oxo-I-azurethynyloxy acetic acid.
35
(Z) -2-amylo-o1- (methoxyimino) -4-thiazoleacetic acid (b g) is dissolved in 100 ml of dimethylformamide, 5 ml of triethylamine are added and, after cooling down to -25 ° C, 6.2 ml of di - phenylphosphate. The mixture was stirred at -25 ° C for 50 minutes and then added at -25 ° C to the solution obtained from 13 g of (35-trans) - (3- -amino-4-methyl-2- oxo-1-azetidinyloxy) acetic acid, 21 ml of triethylamine and 100 ml of dimethylformamide. The reaction mixture is stirred at
50 -25 ° C for 2.5 hours. The solvent is evaporated under vacuum, the residue is dissolved with 400 ml of ethyl acetate, washed with ice-water, NaHCOj solution, ice-water again, dried over magnesium sulfate, evaporated again and the indicated compound is obtained in as a solid foam, which is treated with hexane. Product yield 8.7 g, purity 83% HPLC; m.p. 76-80 s.
The term cfuib or suns denotes the salts of osipolids formed by inorganic or orth-anic bases. These salts include ammonium salts, alkali metal salts — sodium
in position 1 and the substituted amino group or acylamino group in position 3 contain at least one chiral center, namely the carbon atom (in the position of 3/5 -dactam core), to which the replacement amino group or acylmino is attached. The proposed invention relates to those
And potassium (which are preferred),
salts of alkaline earth metals calcium and magnesium, organic salts
bases, for example, the salts of dicyclohexa p-lactams, as described above, and
silumin, benzathine, M-methyl-O-gluc-in which the stereochemistry of the chiral csnmin, salt of the hydrabamine. salts with amine in position 3 ft-lactam core
I, salt of hydrabamine, salts with amino acids such as arginine, lysine, and the like. Non-toxic, pharmaceutically acceptable salts are preferred, although other salts are suitable, for example, in the isolation or purification of a product.
Salts are obtained in the usual manner by reacting the free acid form of the product with one or more equivalents of the corresponding base, giving the desired cation, in those solvents or media where the salt is insoluble, or in water, followed by removal of the lyophilic water. The free acid form or, if necessary, another salt can be obtained by neutralizing the salt with an insoluble acid, such as cation exchange resin in the hydrogen form (for example, polystyrene sulfonic acid resin, such as Dowex 50) or an aqueous acid solution and extracting with an organic solvent, for example ethyl acetate, methylene chloride, etc.
(i-Lactams, having in position 1 the efrf of the group --O-C-COOH
are involved as an integral part of the present invention. Examples of such esters include alhyl, alkenyl, alkynyl, cycloalkan, as the configuration at the 6 carbon atom of penicillins
15 of natural origin (e.g. penicillin G) and the same as the configuration at the carbon atom in position 7 of cefamycins naturally occurring; 1 app (e.g. cefamycin C).
20 / - Lactams containing a substitute

0 C-COOH (either its ester or salt) in the 1-lactam core position and the substituting acylamino group in the 3p-lactam core position, have activity against a number of gram-negative and gram-positive organisms.
thirty
 t Deputy - O - COO (either
35
its ester or salt) plays an important role in the activity of the compounds according to the invention.
The proposed compounds can be used as agents for controlling bacterial infections (including urinary tract infections and respiratory infections) in various mammalian species, for example, in domestic animals (for example, dogs, cats, cows, horses, etc. p.) and man.
In tab. 3 shows the definitions of antibacterial activity.
In tab. 3 shows the definitions of antibacterial activity.
alkyl (cycloalkyl) alkyl.
Hydrolyzable esters are
, hp of the obtained compound, are such esters as may be. „„ “.“ ,, “,
hydrolyzed in vivo to form the original carboxylic acid product, they detect antibiotic
the activity of the original carboxylic acid from about 1.4 mg / kg / day
up to 350 mg / kg / day, preferably in an amount from about 14 mg / kg / day to about 100 mg / kg / day. All known methods of administration, predating the control of bacterial infections in mammals, the proposed compounds can, if necessary, be administered to a mammal in quantitates. Non-hydrolyzable esters (esters that do not hydrolyze in vivo to the starting carboxylic acid) are used as intermediates, some of these esters also exhibit antibiotic activity.
fJ-lactams containing a substitute
R5R6
O-C-COOH (either its ester or saltJ
gc designated for delivery of penicillins and cephalosporins to the site of infection can also be used for a new group of p-lactams of the present invention. These methods having position 1 and a substituted amino group or an acylamino group at position 3 contain at least one chiral center, namely a carbon atom (at the 3/5 position –dactam core) to which a substituent amino group or acylaminogroup is attached. The proposed invention relates to those
the same as the configuration at the carbon atom in position 6 of penicillins
natural origin (e.g. penicillin G) and the same as the configuration at the carbon atom in position 7 of cefamycins natural occurs; 1 app (e.g. cefamycin C).
/ - Lactams containing a substitute

0 C-COOH (either its ester or salt) in the 1-lactam core position and the substituting acylamino group in the Zr-lactam core position, have activity against a number of gram-negative and gram-positive organisms.
thirty
 t Deputy - O - COO (either
five
its ester or salt) plays an important role in the activity of the compounds according to the invention.
The proposed compounds can be used as agents for controlling bacterial infections (including urinary tract infections and respiratory infections) in various mammalian species, for example, in domestic animals (for example, dogs, cats, cows, horses, etc. p.) and man.
In tab. 3 shows the definitions of antibacterial activity.
compound obtained,. „„ “.“ ,, “,
 from about 1.4 mg / kg / day
To combat bacterial infections in mammals, the proposed compounds can, if necessary, be assigned to a mammal in quantities designated for the delivery of penicillins and cephalosporins to the site of infection, can also be used for the new group of β-lactams of the present invention. These methods are introduced.
Days include oral, intravenous, intramuscular, and suppository administration.
Thus, a method has been proposed for the preparation of azetidine derivatives in which the nucleus of f-lactam is activated by a substituent having the form RRs Re
Mulu-Q-c-QOOH ether or a salt of this substituent) and attached to the nitrogen atom in the core of the general formula and which possess valuable antibacterial activity.

权利要求:
Claims (1)
[1]
Invention Formula
The method of obtaining azetidine compounds of General formula I
Ribt
K-YN-S-NZ
C - N-0-C-COOH
// /
оRb Nb
1329617ZA
-С-СН-ШЬС-NQN-RC
about CjHs about 00
5 where RC is C, -C4-alkyl,
e) an oxyiminoacetyl group of formula
ten
-C-C -N-0-Re II I
About sh
where R is 2-amino-4-thiazolyl, 5-amino--1,2,4-thiazolyl or 2,6-dichloro-4-pyridyl; Rg is C, -C, -alkyl or 1,1-dimethyl-2-phenylmethoxy-2-oxoethyl; RJ is hydrogen; R and R is hydrogen, or one of
the radicals R and R are C, -alkyl and the other is hydrogen; Ry RJ is hydrogen or C -C-alkyl of their esters or alkali metal salts, meaning that a compound of the general formula II
where R is a hydrogen or an acyl group, where the acyl group is
a) aliphatic group of general formula
Ra-C- O
where Rj, - C, -C-alkyl,
c) a carbocyclic aromatic group of the general formula
SbH5-CH2C- 0
or SbNySN-S-Shch about
where Rg is hydrogen or C, -C-alkoxyl,
c is a heteroaromatic group of the formula
C1 SCHoCci about
d) f (A-substituted-2, 3-dioxo-1-piperazinyl) carbonyl-amino-phenyl acetyl group of the general formula
RiB- Rrl HC-b-Jaz
thirty
sg (f b
wherein they have the indicated meanings, are alkylated with compound 35 of general formula III in an activated form:
NS COOH KB
where R and RJ have the indicated meanings, or its ether with the selection of the target
product in free form, in the form of an alkali metal salt or salt, or, if necessary, followed by acylation of the obtained compound, of the general formula I, where R is hydrogen,
the corresponding acid is general and formula
R, OH
where the acyl group R has the indicated value
or with its reactive derivative with the release of the target product in free form, in the form of ether or shsh in the form of an alkali metal salt.
(Z) -2-Amino-oi- (2-diphenylmethoxy-1,1-dimethyl-2-hydroxyethoxy-imino) -4-thiazo-acetic acid
(R) -ci- (4-ethyl-2, 3-dioxo-1-piperazinylcarbonylamino) benzene-acetic acid
Phenylacetic acid
"T, - (4-Me current of siphenylmethoxycarbonylamino) benzeneacetic acid
15
sixteen
(Z) -2-amino-in-methoxyimi-3S-L3o6 (Z) methyl ester, but-4-thiazoleacetic acid (((2-amino-4-thiazolylmethoxy-amino-acetylamino) -4-methyl-2-oxo-I-azetidinyl - s acetic acid; mp. 99 ° C (with decomposition)
Methyl ether, (Z}, 4-fl - (2-amino-4-thiazolyl) -o6 (2-diphenylmethoxy--1,1-dimethyl-2-oxoethoximino-acetylamino) -4-methyl--2- OXO-1-azetidynyloxy | -uk (Z) -2-aMHHO- «i- (2-diphenylmethoxy-1,1-dimethyl-2-oxo-ethoxyimino) -4-thiazo-acetic acid
17
(R) (4-ethyl-2,3-dioxo-methyl ester, (fl), -1-piperazinyl) carbonyl 4p - 3 - i- (4-ethyl-2, 3-diaNiHHO-benzeneacetic acid-oxo-) 1-piperazinylcarboiilot
amino) phenylacetylamino-4- -methyl-2-oxo-I-azetidinyl-oxyacetic acid; mp 100 ° C (with resolution),
(3S) (Z) (-) - - 3-ei - (2-amino-A-thiazolyl) -o- (2-diphenylmethoxy-1,1-dimethyl-2-oxoethoxy- 1,1-1,1-methyl methylether) siimino) acetylamino -2-oxo-1-azetidynyloxy acetic acid; the product is an oil
I, 1-Dimethyl ethyl ester (3S) (R) - o - {4-ethyl-2, 3-dioxo-1-piperazinylcarbonylamino) phenylacetylamino-2-oxo-1-azetidinenpoxy acetic acid so pl. 100 C (with decomposition)
(5) - (3-Phenyl acetylamino-2-oxo-I-azetidinyloxy) acetic acid 1,1-dimethyl ethyl ester; m.p. ЗЗ-Зб С (with decomposition)
(S) - (4-methoxyphenylmethoxycarbonylamino) phenylacetylamino -2-oxo-I-azetidine-nyloxy-acetic acid 1,1-dimethylstile ether; m.p. 55-62 seconds
hydrochloric acid; m.p. (with decomposition)
88-90 С
oxo-1-piperazinylcarboxylamino) phenylacetylamino-4-methyl-2-oxo-I-azetidinyl-hydroxy acetic acid; mp, 100 ° C (with separation),
Editor E, Papp
Compiled by N. Pivnitska
Tehred M, Hodanich Proofreader I. Muska
Order 4530 Circulation 371 Subscription
VNIIPI USSR State Committee
for inventions and discoveries 113035, Moscow, Zh-35, Raushsk nab., 4/5
Production: Graphic Enterprise, Uzhgorod, ul. Project, 4
Table 3

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同族专利:

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NL8302746A|1984-03-01|

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GB2125794A|1984-03-14|

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AR241158A2|1991-12-30|

---

FR2531427A1|1984-02-10|

---

CS26783A2|1985-08-31|

---

GB2125794B|1985-12-18|

---

AU1755683A|1984-02-09|

---

IT1224129B|1990-09-26|

---

AU568086B2|1987-12-17|

---

US4939253A|1990-07-03|

---

BE897466A|1984-02-06|

---

DD213919A5|1984-09-26|

---

GB8320497D0|1983-09-01|

---

DK354683A|1984-02-05|

---

RO86511A|1985-03-15|

---

NO832801L|1984-02-06|

---

DK354683D0|1983-08-03|

---

PL257440A1|1986-10-07|

---

PT77155A|1983-09-01|

---

ATA281283A|1986-07-15|

---

CS26785A2|1985-08-15|

---

IT8322430D0|1983-08-04|

引用文献:

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US4548751A|1983-08-03|1985-10-22|E. R. Squibb & Sons, Inc.|-2-propenoic acid|

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CA1243679A|1983-09-14|1988-10-25|Henner Straub|3-ACYLAMINO-2-OXO-1-AZETIDINYL-.beta.-OXYPROPIONATES|

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EP0135194A1|1983-09-16|1985-03-27|Takeda Chemical Industries, Ltd.|Azetidinones and their production|

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US4581170A|1984-08-03|1986-04-08|E. R. Squibb & Sons, Inc.|N-hydroxyl protecting groups and process and intermediates for the preparation of 3-acylamino-1-hydroxy-2-azetidinones|

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EG18314A|1985-09-26|1993-02-28|Squibb & Sons Inc|Process for preparing of 2-oxo-1amino)carbonyl)-azitidines|

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JP2008520686A|2004-11-17|2008-06-19|スミスクライン・ビーチャム・コーポレイション|Use of new antibacterial compounds|

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CA2629570C|2005-12-07|2012-11-27|Basilea Pharmaceutica Ag|Useful combinations of monobactam antibiotics with beta-lactamase inhibitors|

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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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US40494582A| true| 1982-08-04|1982-08-04|

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