Process for producing derivatives of 3-oxyvinyl cephalosporin

专利摘要:
New cephalosporins of the formula: <IMAGE> (I) in which n=0 or 1, R1 is a radical of the formula: <IMAGE> (II) [in which R4 is a protective radical and R5 is hydrogen, alkyl, vinyl, cyanomethyl or a protective radical], or R1 is a protective radical and R2 is a protective radical or an enzymatically removable radical, or R1 is an acyl radical which may be substituted in various ways and R2 is a protective radical, in the 3-oxoethyl-bicyclooct-2-ene or -bicyclooct-3-ene or 3-oxoethylidene-bicyclooctane form if n=0, and in the 3-oxoethyl-bicyclooct-2-ene or 3-oxoethylidene-bicyclooctane form if n=1, are useful as intermediates for the preparation of 3-thiovinyl-cephalosporins useful as antibacterial agents.
公开号:SU965358A3
申请号:SU802928399
申请日:1980-05-21
公开日:1982-10-07
发明作者:Фарж Даниель；Ле Руа Пьер；Мутоннье Клод；Пейронель Жан-Франсуа
申请人:Рон-Пуленк Эндюстри (Фирма)；
IPC主号:

专利说明:

Invented. relates to a method for producing β-3-oxyvinylcephaposporin derivatives, which are intermediates in the synthesis of new antibiotics of the cephalosporin series, namely, derivatives of 3-thiovinyl cephalic sporins.  A known method for producing biologically active derivatives of 3-thiome tilcephalosporins by the interaction of 3-acetoxymethyl cephalrsporins with the corresponding thiols 1.  The purpose of the invention is to obtain new intermediates in the synthesis of cephalosporin antibirds, expanding the arsenal of effects on a living organism.  The objective is achieved by a method for the preparation of 3-oxivinylcephalosporin derivatives of the formula of J-C.  it is CH-O-BS COORj where R is hydrogen, trityl, tert. -butoxycarbonyl, a radical of the formula R —CH-CR4 is phenyl or 2-thienyl; R is hydrogen or protected by tert. -butoxycarbonyl amino group, or R - radical of formula t. Г R (, is a hydrogen atom or trityl and R is methyl or vinyl; R is a hydrogen atom or ben.  hydryl; RJ is tooyl, mesyl, acetyl or ethoxymalonyl; p - O or 1; the dotted line indicates a double bond in position 2 or 3 of the cephalosporin ring, is a mixture of isomers. or.  individual ers, which is a problem with the formula Zr-n ,.  it is (H) where R and R have the indicated meanings other than hydrogen and provided that the free amino groups are protected and n has the indicated values, they are reacted with the compound of the formula (f) Rj is C1 where Rj is the indicated values, in a solvent in the basic medium at a temperature from room temperature to and, if necessary, when li 1 the S-oxide obtained is converted by reduction to sulfide or, when n the resulting sulfide is converted by oxidation to S-oxide and, if necessary, the target product obtained, where Ri is benzhydryl, translate into a target product where R2 is hydrogen and / or, if necessary, remove the R- or R group that protects the amino groups and isolate the desired product as a mixture of isomers or divide it into individual isomers.  Removal of applicants seeking an amino group of t. α-butoxycarbonyl and trityl are carried out in an acidic medium.  Preferably, trifluoroacetic acid is used at 0-20 ° C, or formic acid, anhydrous or in the form of an aqueous solution, or p-toluenesulfonic acid or methane Lioux in acetone or acetonitrile at a temperature from reflux of the reaction mixture.  Under these conditions, the product of general formula I can be obtained in the form of trifluoroacetate, formic acid solvate, methyl sulfonate or p-toluenesulfonate, from which the free compound can be isolated without affecting the rest of the molecule.   contacting npHBejqeHHeM with an ion exchange resin or an organic base.  i. Removal of the protecting carboxy group; benzhydryl1 is carried out by treatment in acidic conditions under the described conditions to remove the trilyl radical protecting the amino group. The process can be carried out in the presence of anisole.  Example 1  52.5 mg 2-benzhydryloxycarbonyl-7-tert-β-butoxy.  carbonylamino. -8-oxo-3- (2-oxo-eth-1) -5-oxide-5-thia-1-azabicyclo (4.2.2) g2-octene is dissolved in 2 cm of pyri-.  Dina.  The solution is cooled to -15 ° C, then 21 mg of p-toluenesulfonyl chloride is added.  Stir for 15 minutes at then 1 hour at a temperature of from -15 to -0 ° C.  The reaction mixture is broken into 50 cm of distilled water.  Extraction is carried out with 50 cm of ethyl acetate and the organic phase is washed twice with 50 cm of 0.1 N.  hydrochloric acid, then twice 50 cm of distilled water.  Dry over sodium sulfate, filter, and evaporate the solvent under reduced pressure (20 mmHg). Art. ) at 30 ° C.  66 mg of a mixture of forms Z and E 2-benzhydryloxycarbonyl-7-tert are obtained. -butoxycarbonylamino-8-6kco-5-oxide-3- (2. -tosyloxyvinyl) -5-thia-1-azabicyclo (4,2,0) -2-octene as a solid orange foam.  Chromatography on a silica gel plate (solvent cyclohexane-ethyl acetate 50-50 (by volume)) separated the forms Z (10 mg) and E (40 mg).  IR spectrum of form Z (СНВгз): 3420, 1800, 1720, 1505, 1380, 1370, 1195, 1180, 1050, 1010 and 730 cm.  NMR -spectrum (350 MHz, ESR. Ll d. , j in Hz) 1.49 (S, 9H.  -C (CH3) h); 2.44 (Si 3N, -CH); 3.36 and 4.04 (2d, j 19, 2H, -SCH. ); 4.44 (d, j 4,5, 1H, H in 6); 5.73 (d, j 9, 1H, -CONH-); 5.81 (dd, j 4,5 and 9, 1H.  H in 7); 6.42 (d, j T; 1H, -CH CH-OSO. i-); 6.46 (d, j 7, 1H, CH-OSOi-); 6.89 (S, 1H, -COOGH); 7.77 (d, j 9, 2H, H in the orpoyl position).  IR spectrum of the Formal E (SNVhz): 3420, 1800, 1720, 1505, 1380, 1370, 1195, 1180, 1075, 935 and 745 cm-h.  NMR spectrum (350 MHz, CDCl, (m d. , j in Hz): 1.48 (S, 9H, (CHj).  WITH-) ; 2.46 (5, 3N, -CHi); 3.16 and 3.81 (2B, j 18.2H, -SCHi); 4.46 (d, j 4.5, 1H, H in 6); 5.73 (d, j 9, 1H, -CONH); 5.8 (dd, j "9 and 4.5, 1H, H at 7); 6.83 (d. j 13, 1H, -CH CH-OSOo); 6.83 (S, GN, 2COOSNS); 7.08 (d, j 13, 1H, CH-OS07-); 7.73 (d, j 9, 2H, H in the ortho position of the tosyl).  2-Benzhydryloxycarbonyl-7-tert. -butoxycarbonylamino-8-oxo-3- (2-oxo-ethyl) -5-oxide-5-thia-1-azabicyclo (4.2.2) -2-octene can be prepared as follows.  2.7 g of 2-benzhydryloxycarbonyl-7-tert. -butoxycarbonylamino-3-2- (dimethylaxnovinyl) -8-oxo-5-thia-1-azabicyclo (4,2.00-2-octene (form E) is dissolved in 54 cm of tetrahydrofuran. 27 cm of distilled water are added successively and 2.7 cm of pure formic acid and mix the reaction mixture (K) for 40 min at 25 ° C.  After partial evaporation of the reaction mixture under reduced pressure (20 mm Hg. Art. ) and, and adding 200 cm of ethyl acetate, the organic phase is separated and washed twice with 100 cm of a saturated aqueous solution of sodium chloride. The organic phase is dried over magnesium sulfate in the presence of vegetable black, filtered and evaporated to dryness under reduced pressure (20 mm Hg). with izos. 2.3 g of product are obtained in the form of a solid orange foam, which is used without further purification.  A solution of 1.02 g of the product obtained in 100 CM methylene chloride is cooled to a temperature of (-5) to (-10) C.  A solution of 0.34 g of 85% methanchlorophosphate acid in 40 cm of methylene chloride is added dropwise over 20 minutes.  After the addition is complete, the reaction mixture is stirred for 10 minutes at a temperature of (-5) -, then. washed with 50 cm of half-saturated aqueous solution of sodium bicarbonate, then three times with 50 cm of distilled water.  After drying over sodium sulfate and the vanilla filter, the solvent is evaporated to dryness under reduced pressure (20 mm Hg). with and 30 ° C.  The residue is redissolved in 25 cm of methylene chloride.  Add 5 years. silica (0.56-0.2 mm).  Evaporated to dryness at a pressure of 400 mm Hg. Art.  and 30 ° C and place the resulting powder in a column with 25 g of silica gel (0, mm), prepared with a mixture of c-cyclohexN-ethyl acetate (80–20 volume); column height 21 cm, diameter 2 cm.  Elute with cyclohexane-ethyl acetate mixtures in the following ratios (by volume / number): 80-20 (100 cm), 70-30 (200 cm), 60-40 (40 cm), 50-50 (400 cm) and.  40-60 (400 cm), selecting fractions of 60 cm.  - c-ration 10-21 evaporated to dryness under reduced pressure (20 mm Hg. Art. ) and.  0.2 g of 2-benzhydryloxycarbonyl-7-tert is obtained. -butoxycarbonylamino-8-oxo-3- (2-oxo-ethyl) -5-OXID-5-thia-1-azabicycl (4,2,0) -2-octene as a solid orange foam.  Rf 0.32; chromatography on silica gel with eluent cyclohexane-ethyl acetate 20-80 by volume).  IR spectrum (SNBr): 2720, 1800, 1720 and 1050 cm-.  NMR spectrum (350 MHz, CDClj, sgm. d 1.47 (S, 9H, (SIZ) ZSO-); 3.37 and 3.57 (2d, AB, j 19 Hz, 2H: -CHNOSO); 3.60 and 4.20 (2d, AB, j 18 Hz, 2H: SO-CHi); 4.56 (d, j 4 Hz, 1H: H in 6); 5.24 (d, j 10 Hz, 1H: -CONH}; 5.82 (dd, j 10 and 4 Hz, 1H: H in 7); 6.87 CS, 1I: -CH (S5L) a); 7.2-7.5 (broad, 10H: aromatic); 9.55 (d, j 1 Hz, 1H: -CHO).  2-Benzhydryloxycarbonyl-7-tert. -butoxycarbonylamino-3- (2-dimethylaminovinyl) -8-oxo-5-thia-1-azabicyclo (4,2,0) -octene-2 (form E) can be obtained as follows.  To solution 2, g 2-benzhydryloxycarbonyl-7-tert. -butoxycarbonylamino-3-methyl-8-oxo-5-thia-1-azabicyclo (4.2.0) -2-octene in 12 cm of anhydrous N, N-dimethylformamide in a dry nitrogen atmosphere at 25 ° C. add a solution of dimethoxymethylaminomethane 12 cm anhydrous M, L-dimethylformamide.  The reaction mixture is heated to 80 ° C for 3 h 20 min, then poured into a mixture of 150 cm of ethyl acetate and 150 cm of distilled water.  The aqueous phase is decanted and extracted with 100 cm of ethyl acetate.  The collected organic solutions are washed twice with 100 cm of distilled water, then dried over magnesium sulfate and filtered.  After evaporation of the solvent under reduced pressure (20 mm Hg. Art. ) and get 2.7 g mass of brown color.  Analysis by thin layer chromatography (silica gel, eluent cyclohexane-ethyl acetate 60-40) and the IR spectrum indicate that 2-benzhydryloxycarbonyl-7-tert has been obtained mainly. -butoxycarbonylamino-3- (2-dimethylaminovinyl) -8-oxo-5-thia-1-azabicyclo (4.2.0) -2-octene (form E).  Rf 0.29; chromatography on silica gel s with eluent cyclohexane-ethyl acetate 50-50 (by volume).  2-Benzhydryloxycarbonyl-7-Tert.  butoxycarbonylamino-3-methyl-8-oxo-5-thia-1-azabicyclo (4.2.0) -2-octene can be prepared as follows.  To a solution of 188.6 g 7-tert. -butoxycarbonylamino-3-methyl-8-oxo-5-thia-1-azabicyclo (4.2.0) -2-octene in 2100 cm of acetonitrile is added dropwise over 45 minutes and a 25-30 ° C solution 116,. 5 g of diphenyldiazomethane 800 cm acetonitrile.  The reaction mixture is stirred for 16 hours at 22 ° C., then evaporated to dryness under reduced pressure (20 mm Hg. Art. ).  The residue is dissolved in 2 L of ethyl acetate and the solution is shed | 700 cm 2 n. hydrochloric acid, then 700 saturated aqueous solution of sodium icarbonate and 700 cm from saturated aqueous solution of chloride.  The solution is dried over atri sulfate, treated with plant extract and filtered, then the dryness is evaporated under reduced pressure of 20 mm Hg. Art. ) and.  The residue was dissolved in 600 cm of ethyl acetate at reflux temperature,.  1 L of cyclohexane is added, heated with reflux. Then allowed to cool.  The crystals formed are separated by filtration, washed three times with 250 cm of diethyl ether, and then dried.  Get it. 191 g of 2-benzhydryloxycarbonyl-7-tert. -butoxycarbonylamino-3-methyl-8-oxo-5-thia-1-azabicyclo (4.2.0) -2-octene as. white crystals (t. PLTE S).  When the mother liquor is evaporated to 500 cm, a second product fraction (32.6 tons) is obtained. payment).   7-rubs. -butoxycarbonylamino-2-carboxy-3-methyl-8-oxo-5-thia-1-azabicyclo (4,2,0) -2-octene can be prepared as follows; 371 g of 7-amino-2-carboxy-3-methyl-8-oxo-5-thia-1-azabicyclo C4,2, O) -2-octene is dissolved in a solution of 307 g of sodium bicarbonate in a mixture of 2 distilled water and 2 liters diox, on.  421 g of di-ter carbonate are added over 10 minutes. - Tyla in 2 liters of dioxane.  The reaction mixture is stirred for 48 hours at 25 ° C.  The resulting suspension is evaporated under reduced pressure (20 mm RT. Art. ) and 50 ° C to a residual volume of approximately 2 liters, then diluted with 1 liter of ethyladetate and 2 liters of distilled water.  The aqueous phase is decanted, washed.  500 cm of ethyl acetate and acidified to pH 26 with hydrochloric acid in the presence of 1500 cm of ethyl acetate.  The aqueous phase.  extracted twice with 1 liter of ethyl acetate.  The combined organic phases are washed twice with 250 cm of a saturated solution of sodium chloride and dried over sodium sulfate.  After filtration, the solvent is distilled off under reduced pressure (20 mm Hg. with and 50 ° C.  Get 486 g of 7-tert. Sicarbonylamino-2-carboxy-3-meth-8-oxo-5-thia-1-azabicyclo (4,2,0) -2 octene -buton in the form of yellow crystals (t. square  decomposed).  Note ep 2.  To a solution of 113.7 i 2-benzhydryloxycarbonyl-7-tert. -butoxycarbonylamino-3- (2-dimethyl novinyl) -8-oxo-5-thia-1-azabitocyclo (4,2,0) -2-rctene (form E) in 1 liter of trahydrofuran is added a solution of 50 cm formic acid acid c.  500 cm views.  The homogeneous plant is stirred at 20 s for 20 minutes, then it is evaporated to a quarter of the initial volume under reduced pressure (20 mm Hg.). Art. ) and. The concentrate is dissolved in 2 liters of ethyl acetate / washed twice with 500 cm of 5% chathri bicarbonate solution, two times with 500 cm of water and twice with 500 cm of saturated sodium chloride solution; dried over sodium sulfate, filtered and evaporated to dryness at 20 ° C and reduced pressure (20 mm Hg. Art. ).  112.4 g of crude product are obtained, which is treated in a solution of 250 cm of pyridine with 57.2 g of tosyl chloride.  After soaking for 30 minutes and a temperature of 5s and for 1 hour, the solution is poured into 1 liter of a mixture of water with chopped ice.  Separate the aqueous phase and wash the insoluble residue with 300 cm of distilled water.  The paste is dissolved in 200 cm 2 of ethyl acetate, washed twice with 750 cm 1. N.  hydrochloric acid, twice 750 cm of 5% sodium bicarbonate solution and four times 750 cm of water, dried over sodium sulfate and evaporated to dryness under reduced pressure: (20 mm Hg. Art. ) and.  121 g of product are obtained, consisting essentially of 2-benzhydryloxycarbonyl-7-tert. -butoxycarbonylamino-8-oxo-3- (2-tosyloxyvinyl) -5-thia-1-azabicyclo (4.2.0) -2-octene, a mixture of forms E and Z, in the form of a crude brown mass.  2-Benzhydryloxycarbonyl-7-tert. -butoxycarbonylamino-3- (2-dimethylamino-vinyl) -8-oco-5-thia-1-azabicyclo (4, 2.0) -2-octene (Form E) can be prepared as follows.  90.5 g of 2-benzhydryloxycarbonyl-7-tert is dissolved. -butoxycarbonylamino-3-methyl-8-oxo-5-thia-1-azabicyclo (4.2.0) -2-octene in 400 cm of anhydrous N, N-dimethylformamide.  The pacTBopi obtained is heated to 80 ° C under a nitrogen atmosphere.  Then a solution of 36.1 g of bis-dimethylamino-tert is quickly added. -butoxymethane 60 cm anhydrous, preheated to N, N-dimethylformamide.  The reaction mixture is maintained at -80 ° C for 5 minutes, then poured into 3 liters of ethyl acetate.  After adding 1 liter of distilled water, the organic phase is decanted, washed four times with 1 liter of distilled water, dried over sodium sulfate and filtered in the presence of vegetable black.  Evaporated to dryness under reduced pressure (20 mm Hg. Art. ) and 30 ° C and get 101 g of 2-benzhydryloxycarbonyl-7-tert. -butoxycarbonylamino-3- (2-dimethylaminovinyl) -8-oxo-5-thia-1-aza-dicyclo (4,2,0) -2-octene (formula E) in the form of an orange wt. sy. Rf 0.29; chromatography on silica gel using eluent cyclohexane-ethyl acetate 50-50 (by volume).  Example 3  To a solution of 9.3 g of crude 2-benzhydryloxycarbonyl- 7- (D t-tert.  -buto xi carbonyls of nofenilacetamido) -3- (2-dimethylaminovinil) -8-oxo-5-thia-1-azabicyclo (4.2.2) -2-lctene in 100 cm of tetrahydrofuran are added successively at 25 ° C to 50 cm distilled water and 8 cm of pure formic acid.  The reaction mixture is stirred for 50 minutes at, then partially evaporated under reduced pressure (20 mm Hg. Art. ) and 30 ° C, and 200 cm of ethyl acetate.  The organic phase is decanted; washed successively with 100 cm of distilled water, 100 cm of a saturated aqueous solution of sodium bicarbonate and 100 cm of a saturated aqueous solution of sodium chloride, then dried over magnesium sulphate and filtered.  After evaporation to dryness of the solvent under reduced pressure (20 mm Hg. Art. ) and 30 ° C, followed by drying the residue under reduced pressure (5 mm Hg. st Get 9 g of brown meringue mass. The IR spectrum of which indicates that it consists mainly of 2-benzhydryloxycarbonyl-7- (P-tert.  -butoxycar bonylaminophenylacetamido) -8-oxo-3- (2-oxoethyl) -5-thia-1-azabicyclo (4.2.2) -2-octene.  R 0.55; chromatography on silica gel with eluent cyclography. hexane-ethyl acetate 50-50 (by volume). Rf of the starting product is 0.36.  IR spectrum (solution of SSCS) 1780 (carbonyl fj-lactam); 1715 (several carbonyl bands, conjugated ester, carbamate, aldehyde) and 1695 cm (carbonyl amide).  According to the method described in example 2,. but starting from 63.8 g of the brown mass obtained under the indicated conditions and 20.5 g of tosyl chloride in 180 cm of pyridine, 68 g of a mixture consisting mainly of 2-benzhydryloxycarbonyl-7- (P-tert.) are obtained.  -butoxycarbonylaminophenyLacetamido) -8-oxo-3- (2-tosyloxyvinyl) -5-thia-1-azabicyclo (4.2.2) -2-octane, form Z iB I Form E 2-benzhydryloxycarbonyl-7- (Od ( -tr. -butoxycarbonylaminophenylacetamido) -3- (2-dimethylaminovinyl) -8-OXO-5-thia-1-azabicyclo (4.2.2 -2 -2-octene can be obtained as follows.  , A solution of 6.14 g of 2-benzhydryloxycarbonyl- 7- (Dj -t.  -butoxycarbonyl aminophenylacetamido) -3-methyl-8-oxo-5-thia-1-azabicyclo (4,2,0) -2-octene in 90 cm anhydrous N, M-dimethylformamide when treated in a dry nitrogen atmosphere 3.49 g bisdimethyl amino tert. -butoxymethane in 30 cm S, N-dimethylacetamide.  According to the procedure described in Example 2, 6.27 g of a brown mass, mainly consisting of 2-benzhyd | zyloxycarbonyl-7- (Dj-tert), are obtained.  -butoxycarbonylamino-phenylacetamido) -3-g (2-dimethylaminovinyl) -8-oxo-5-thia-1-azabicyclo (4.2.2) :: 2-octene, form E.  IR spectrum (SNVgz) :. 1760 (carbonyl / 4-lactam); 1710 (conjugated ester carbonyl); 1690 (carbonyl carbamate) and 1610 (C – C dienamine double bonds).  R 0.33; chromatography on silica gel with eluent cyclohexane-ethyl acetate 50-50 (by volume).  Example 4  A solution of 1.07 g of 2-benzhydryloxycarbonyl-7-tert. -butoxycarbonylamino-3- (2-dimethyl-: aminovinyl) -8-oxo-5-thia-1-azabicyclo (4, 2,0) -2-octene (form E) in 10 cm of ethyl acetate is stirred for 1 h at 25 ° C with 5 cm 1 n.  an aqueous solution of hydrochloric acid.  The organic phase is decanted, washed four times with 50 cm of a saturated aqueous solution of sodium chloride, then dried over magnesium sulfate and filtered.  After evaporation to dryness of the solvent under reduced pressure, 1 g of product is obtained, the IR spectrum of which shows. that it consists mainly of 2-benzhydryloxycarbonyl-7-tert. -butoxycarbonylamino-8-oxo-3- (2-oxoethyl) -5-thia-1-azabicyclo (4, 2.0) -2-octene.  Rf Of57; silica gel chromatography with cyclohexane / ethyl acetate 60-40 (by volume).  .  , IR spectrum (solution of HBVg): 2840, 1785 and 1720 cm-.  NMR spectrum (350 MHz, СНС1 з, with m d. , j in Hz): 1.47 (S, 9H: (CH3). C-0-); 3.24 and 3.55 (AB, j 18, 2H: -SCH -); 3.50 and 3.66 (AB, j 16, 2H; -CHNCNO); 4.98 (d, j 4.5, 1H: H in 6); 5.25 (d.  j 9, 1H: -CONH-); 5.65 (dd, j 4,5 and 9 ,.  1H: H at 7); 6.87 (S, 1H:; 7.2-7.5 (broad, YUN: aromatic); 9.54 (S, 1H: -CIS).  12.9 g of the product obtained by acid hydrolysis of the enamine is dissolved in 50 cm of pyridine.  The mixture is cooled to -7 ° C and 2.4 cm of methanesulfonyl chloride is added with stirring.  Stir for 1.5 hours at and for 1 hour at.  there are a mixture in. 500 cm of ice water, filter, wash the precipitate with 50 USP of water, then dissolve it in 250 cm of ethyl acetate.  The organic phase is washed with two: 100 cm times 1 n.  hydrochloric acid and twice 100 cm of a saturated solution of sodium chloride, dried with sodium sulfate, filtered and evaporated to dryness under reduced pressure (20 mm Hg. Art. ). . and 20C.  Hold the residue in a mixture of cyclohexane-ethyl acetate 80-20 (by volume) and romatograph the solution on a column with 100 g of Merck silica gel (0.05-0.2 mm), and the column diameter is 2.8 cm, height 42 cm.  lute 3 l of this mixture and collect fractions of 100 cm.  Fractions 9-21 are evaporated to dryness under reduced pressure (20 mm Hg. Art. ) and 20 "s, 5.7 g of 2-benzhydryloxycarbo are obtained. nil-7-tert. -butoxycarbonylamino-3 (2-mesyloxyvinyl) -8-oxo-5-thia-1-azabicycl (4.2.0) -2-octene as a yellow mass, form E and Z.   Crystallization from 15 cm of diethyl ether gives 1.85 g of a yellow crystalline product, the structure of which corresponds to the structure of isomer E.  IR Spectrum (SNVgz): 3420, 1790, 1720, 1510, 1380, 1370, 1185, 1085, and 770 cm:  NMR spectrum (350 MHz, CDC1, m d j in Hz): 1.47 (S, 9H, (CHOjC-); 3.04 (S, 3N, CHjSOi-); 3.48 and 3.57 (2d, j 17.5, 2H, -S -CHN-); 5.02 (d, j 5, 1H, H in 6); 5.25 (d, j 9, -CONH-); 5.66 (dd, j 5 and 9, 1H, H in 7 ); 6.94 (S, -COOPH); and 7.04 (2d, J 13, 2H,).  2-BenzgiDriloxycarbonyl-7-tert. -butoxycarbonylamino-3- (2-dimethylaminovinyl) -8-oxo-5-thia-1-azabicyclo (4-, 2.0) -2-oxy (form E can be obtained as follows.  A solution of 1.0 g of 2-benzhydryloxycarbonyl-7-tert. -butoxycarbonyl but-3-methyl-8-oxo-5-thia-1-azabicyclo (4,2,0) -3-octene in 100 cm of anhydrous H, M-dimethylformamide is heated to 80 ° C, atmosphere, nitrogen .  Then 0.86 cm of bis-dimethyl amino tert would be added. -butoxymethanol  The reaction mixture is maintained at 80 ° C for 5 minutes, then poured into 50 ethyl acetate.  After adding 25 cm of distilled water, the organic phase is decanted, washed four times with 25 cm of distilled water, dried over magnesium sulfate and filtered.  Evaporated to dryness at a lower pressure (20 mm Hg. Art. ) and 30 ° C, and 1.10 g of product is obtained, consisting essentially of 2-benzhydryloxycarbonyl-7-tert. -butoxycarbonylamino-3- (2-dimethylaminovinyl) -8-oxo-5-thia-1-azabicyclo (4,2,0) -2 -octene (form E) as an orange mass.  .  Rr 0.9; chromatography on silica gel with eluent cyclohexane-ethyl 50-50 (by volume).  IR Spectrum (SNF): 3430, 3350, 2820, 1765, 1715, 169. 0, 1615, 1540, 1505, 1495, 1465, 1370, 1240, 940, 475, and 600 cm; UV spectrum visible (ethanol) L 390 nm; € 29,000 (. -10m)  Mass spectrum: molecular peak 535 characteristic fragments m / e, 378 and 379 (fi-lactam).  NMR spectrum (350 MHz, CDCli, sym m. d. , j in Hz): 1.48 (S.  (SNz) ss-OCO-, 9H); 2.89 (S, (CH3) L–, bN); 3.17 (AB, j 14, -5-CH, -cepham, 2H); 5.0-2 (d, j 4, H in 6, 1H); 5.27 (dd, j 4 and 9, H in 7, 1H); 5.60 (d, j 9, -CONH-, 1H); 6.71 (d, j 14, -CH CH-NC, III); 6.49 (d, j 14, -CH CH-NC, 1H); 6.95 (s, -CH () ,, 1H); 7.2-7.5 (broad, aromatic, lOHj.  2-Benzhydrylxycarbonyl-7-tert. -butoxycarbonylamino-3-methyl-8-oxo-5-thia-1-azabicyclo (4.2.2) -3-octene can be obtained by esterification with 3.2 g of 7-tert. -butoxycarbonylamino-2-carboxy-3-metsh1-8-oxo-5-.  . -thia-1 gasabicyclo (4, 2,0) -3-octene by 2.1 g of diphenyldiazomethane according to the method described in example 1.  After recrystallization from a mixture of cyclohexane-ethyl acetate 90-10 (by volume), 2.3 g of 2-benzhydryloxycarbonyl-7-tert are obtained. -butoxycarbonyl-amino-3-methyl-8-oxo-5-thia-1-azabicyclo (4,2,0) -3-octene as white crystals (t. square  ).  Conversion of 8.28 g 7-t. -Biotoxycarbonyl-2-metoxycarbonyl-3-methyl-8-oxy-5-thia-1-azabicyclo (4.2.0) -2-octene get 5.4 g of 7-tert. -butoxycarbonylamino-2-carboxy-3-methyl-8-oxo-5-thia-1-azabicyclo (4,2,0) -3-octene.  T. square  200C with decomposition (after recrystallization from ethyl acetate).  Rf 0.59; chromatography on silica gel with eluent ethyl acetate T-acetone-water-formic acid 60-20-1-1 (by volume).  7-tre.  - Utoxycarbonylamino-2-methoxycarbonyl-3-methyl-8-oxo-5-thia-1-azabicyclo (4.2.0) -2-octene can be obtained by esterification of 16.7 g 7-tert. -Biotoxycarbonyl-amino-2-carboxy-3-methyl-8-o-co-5-thia-1-azadicyc (4.2.2) -2-octene, described in Example 1, with an ethereal solution of diazomethane.  This gives 13.6 g of 7-thirds. -butoxycarbonylamino-2-methoxycarbonyl-3-methyl-8-oxo-5-thia-1-azadicyclo (4,2,0) -2-octene in the form of white crystals (t. square  148 ° C).  R 0.45; chromatography on silica gel with eluent cyclohexane-ethyl acetate 60-4Q (by volume).  Example 5  10.15 g of the product obtained by hydrolysis of the enamine under the conditions described in Example 4 are dissolved in 100 cm of anhydrous pyridine.  The solution is cooled to.  1.57 g of acetyl chloride are added dropwise over 15 minutes while stirring.  The reaction mixture is stirred for 3 hours at, then evaporated to dryness under reduced pressure (10 mm Hg. Art. ) and.  The residue is diluted with 150 cm of ethyl acetate and 100 s of distilled water.  The aqueous phase is decanted and extracted with 150 cm of ethyl acetate.  The combined organic phases are washed with 100 cm of distilled water, twice with 100 cm 1 and.  water solution of hydrochloric acid and 50 cm of distilled water.  Dry over magnesium sulfate, filter, and evaporate under reduced pressure (20 mmHg.). Art. ) and 30 ° C.  The residue is dissolved in 200 cm of methylene chloride.  To the resulting solution was added 200 g of silica gel (0.560, 2 mm) and the solvent was evaporated under reduced pressure (20 mm Hg. st and 30 ° C.  The resulting powder is placed in the upper part of the column (4.5 cm in diameter) with 200 g of silica gel (0.56-.  0.2 mm).  Elute with 500 cm of a mixture of cyclohexane-ethyl acetate 90-10 (by volume).  Then 3l of a mixture of cyclohexane-ethyl acetate 80-20 (Sbomu) is eluted and fractions of 100 cm are collected.  Fractions 6-14 are combined and evaporated to dryness under reduced pressure (20 mm Hg. st and.  3.35 g of an orange mass are obtained, which are dissolved in a mixture of 75 cm of cyclohexane and 13 cm of ethyl acetate.  From the solution cooled to 4 ° C, crystals are formed, which are squeezed and washed with 10 cm of cyclohexane-ethyl acetate 90-10 (by volume), then; 10 cm of cyclohexane and dried under reduced pressure (10 mm Hg). Art. ) and 30 ° C.  2.3 g of 3- (2-aceto-Xivinyl) -2-benzhydryloxycarbonyl-7-tert are obtained. -butoxycarbonylamino-8-oxo-5-thia-1-azabicyclo (4.2.0) -2-octene (E isomer) in a bidet of yellow-beige crystals.
IR (CHBrj): 3420, 1780,. 1765, 1635, 1500, 1450, 1395, 1370, 1200 and 605 cm.
NMR spectrum (350 MHz, CDC1 3, c ppm j in Hz) 1.48 (S, 98, (CH3); C-); 2.15 (s, 511, —COCHj); 3.57 (AB, j 17, 21, -S-CHrj-); 5.02 (d, j 4, 1H, H in 5); 3.57 (LV, j 17, 2H,. -S-CHi); 5.02 (d, j 4, 1H, Hb 5); 5.62 (dd, j 4 and 10, 1H, H at 7); 5.75 (d, j 10, 1H, -CONH-); 6.95 (S, 1H, (SbH5) 7CH-); 7.02 (d, j 14, F, -CH C (1-0- (; 7.64 (d, j 14, 1H, CH-0-)).
From the mother liquor, 1.25 g of a mixture of the previous product with its Z isomer is obtained in the form of a yellow mass. The isomer Z can be isolated by chromatography of this product.
NMR spectrum of form Z (350 MHz, COI3d.d, j in Hz): 1.48 (S, 9H, (CH3) aC-); 2.11 (S, 3H, -CQCH); 3.25 and 3.32 (AB, j 17, 2H, -SCHo-); 5.02. (D, j 4, in, H in 6); 5.25 (d, j 10, 1H, -CONH-); 5.62 (dd, j 4 and 10, 1H H at 7); 6.01 (d, 3 7, 1H,
6.96 (S, 1H, (QH5) o CH-); 7.10 (d, j 7, 1H, CH-0-).
ID fractions 15-31, combined and evaporated to dryness under reduced pressure (20 mm Hg), and 3.68 g of a yellow mass consisting of a mixture of 3- (2-acetoxyvinyl) -2-benzhydryloxycarbonyl-7- tert.-butoxycarbonylamino-8-oxo-5-thia-1I-azabicyclo (4.2.0) -2- and 3-octenes; (mixtures of Z and E isomers).
Example 6. A solution of 10 g of 2-benzhydryloxycarbonyl-7-tert.-butoxycarbonyl-3- (2-oxoethyl) - 8-oxo-5-thia-1-azabicyclo (4,2,0) -2-octene and 4 57 g of p-toluenesulfonyl chloride in 100 cm of methylene chloride is stirred at 20 s. A solution of 3.1 cm of triethylamine in 10 cm of methylene chloride is added over 5 minutes. The mixture is stirred for another 1.5 h at 20 ° C. The solution is then washed twice with 150 cm of a saturated aqueous sodium bicarbonate solution, then twice with 150 cm of water. The organic phase is dried over magnesium sulphate and evaporated to dryness under reduced pressure (20 1M Hg) and 40 ° C. This gives 14.2 g of a brown residue, which is chromatographed on a column (diameter 24 mm) containing 60 g of silica gel. Elute 1000 cm of a mixture of ethyl acetate-cyclohexane 3-7 (by volume) and collect fractions of 100 cm. Fractions 5 and 6 are combined and evaporated to dryness under reduced pressure (20 mm Hg) and. A mixture of four products is obtained:
A is 2-benzhydryloxycarbonyl-7-tert.-butoxycarbonylamino-8-oxo-3- (2-tosyloxyBiNIL) -5-thia-1-azabicyclo (4, 2.0) -3-octene (form E) 40%;
B is 2-benzhydryloxycarbonyl7-tert.-butoxycarbonylamino-8-oxo-3- (2-tosyloxyvinyl) -5-thia-1-azabicyclo (4, 2.0) -2-octene (form E) 35%;
C - 2-benzgadryloxycarbonyl-7-tert.-butoxycarbonylamino-B-oxo-3- (2-tosyloxyvinyl) 5-thia-1-azabicyclo (4,2,0) -3-octene (form Z) 15%;
D is 2-benzhydryloxycarbonyl-7-tert.-butoxycarbonylamino-8-oxo-3- (2-tosyloxyvinyl) -5-thia-1-azabicyclo (4.2.2) -2-octene (form Z) 10%. . .
NMR spectrum (350 MHz, COC11, etc. j in Hz): 1.48 (S, (CH3) sC-, A + BfC-S) 2.41 (S, -CHj (tosyl), B + D ); 2.43 (§-СНз (tosyl), А + С); 3.39 and 3; 47
18, S-CH, -, B); 3.67 and 3.73
(2cl,,
18, -SCHi-, D); 4.92 (d, j (2d, j
 4, Hfe, D); 4.96 (d, j 4, H., B); 4, 5, 05 (S, HI, A); 5.08 (s, ho,
5.21 (d, j 4, Hfe, A); 5.24 (d, j 7
-CH-CH-0-C); 5.25-5.40 (m, H ,, A and C, -NH-, A-t-B - “- C + D); 5.55 (dd, j 4 and 9 H ,, D); 5.62 (dd, j 4 and 9, H7, B) {5.91 (d, j 12, -CH CH-0-, AJ; 6.14 (d. Y 7, -CH CH-0-, D); 6.21 (S, H4A); 6.42Cd, j "7, -CH CH-0-, C); 6.44 (d, j 7j -CH CH-0-, D); 6.55 (s, h4, c); 6.76 (d, j 12, A); 6.80 (S, 5CH- (benehydryl), e); 6.85 (S, CH-Sbenzhydryl), D); 6.87. CS, (benzgydryl), A); 6.88 (d,
: j 12, -GH "cH-o-, B); 6.90. (S,:; cH- (benzhydryl), B); 6.95 (d,; 12 -CH CH-O-, B); 7.20-7.45 and 7.65-7.85 (2m, aromatic).
2-Bvnzgidryloxycarbonyl-7-tert.-butoxycarbonylamino-8-oxo-3- (2-oxoethyl) -5-thia-1-as6-cyclo (, 0) -2-octene can be obtained as follows. in a way.
A solution of 5.5 g of 2-benzhydryloxycarbonyl-7-trzt. -Butoxycarbonylamino-3- (2-dimethylaminovinyl) -8-oxo-5-thia-1-azabicyclo (4,2,0) -2-octene (form E} , prepared according to example 1, in 40 cm of pure formic acid is kept for 3 minutes at, then diluted with 300 cm of ethyl acetate and treated with 100 cm of distilled water. After decanting, the organic phase is washed successively with 100 cm of distilled water, 100 cm of saturated aqueous sodium bicarbonate - and 100 cm of a saturated, aqueous solution of sodium chloride. Then it is dissolved over magnesium sulfate and fil ruyut. After evaporation of the solvent under reduced pressure gave 5.1 g of an orange-brown mass which index m are identical indicators obtained in Example 4.
Example 7: Solution of 0.833 g of isomer syn-2-benzhydryloxycarbonyl-7-C2-methoxyimino-2- (2-tritylamino-4-thiazol) acetamidoZ-8-oxo-3- (2-oxoethyl) -5-thia-1 - azabicyclo (4,2,0) -2-octene and 0,228 g of p-toluenesulfonyl chloride in 16 cm of methylene chloride is cooled to an ice bath. A solution of 0.155 cm of triethyl is added over 15 minutes to 8 cm 3 of methylene chloride, kept at 3 ° C for another 20 minutes, then the temperature is allowed to rise to 30 minutes. After this, the reaction mixture is washed with two ras of 20 cm2 of a saturated solution of bi. Sodium carbonate, then twice with 20 cm of a saturated solution of sodium ssoride, dried over magnesium sulphate, filtered and evaporated to dryness under reduced pressure (20 mm Hg) and 30 ° C . The residue is dissolved in 2 cm of ethyladetate, filtered in the presence of vegetable black, diluted with 15 cm of isopropyl oxide and filtered. Sediment
(0.550 g) predstsshl an in ocHoi prefecture syn isomer mixture, E 2 beyz1EddriLoksikarbonil-2-methoxyimino-7- (2-tpitilamino-4-tiazolil) atsehamidor -6-Oxo-3- (2-toziloksivinil) -5 -thia-1-azabicyclo (4.2.0) -2-octene, in which the NMR spectrum (350 MHz, CBC1e, VLm.d 3.37 and 3.49 (AB j 19 Hz, 2H, -S- CH cephem); 5.07 (d, j 4, Hb 6); 5.9 (dd, j 4 and 9, Hb7), and the isomer syn E 2-benzhydryloxycarbonyl-7-2-methoxyimino- (2-tritylamino -4-thiazolyl) acetamido-8-oxo-3- (2-tosyloxyvinyl) -5-thia-1-azabicyclo (4,2,6) -3-octene, in which the NMR spectrum (350 MHz C1Cl2, ohm. D.S: 5.07 (S, 1H, H in 2), 5.32 (d, j 4, Hb 6), 5.68 (dd, j 4 and 9, H in 7), 6.19 ( S, 1H, H in 4V.
2-Benzhydryloxycarbonyl-7-2-methoxy-dano- (2-tritylamino-4-thiazolyl) acetamido-8-oxo-3- (2-oxoethyl) -5-thia-1-azabicyclo (4; 2,0) -2 -Okten can be obtained as follows.
A solution of 8.06 g of isomer syn 2-benzhydryloxycarbonyl-7-2-methoxyimino- (2-tritylamino-4-tyazolyl) acetamido} -3-methyl-8-oxr-5-thia-1-azabicyclo (4,2,0 ) -2-octene in 160 cm of anhydrous N, N-dimethylformamide is heated to. 2.26 g are added. bise dimethylamino-tert-butoxymethane and maintain at 5 minutes. The reaction mixture is diluted with 645 cm of glacial ethyl acetate and washed four times with 250 cm of distilled water, then 100 cm of a saturated aqueous solution of sodium chloride. The organic solution is dried over magnesium sulfate and filtered. After evaporation to dryness under reduced pressure (20 mm Hg) and 30 ° C, 8.1 g of brown mass is obtained, the IR and NMR spectra of which show that it consists mainly of the isomer E (syn) 2-benzhydryloxycarbonyl 7- 2-methoxyimino- (2-tritylamino-4-thiazolyl) -acetamido1-3- (2-dimethylaminovinyl) -8-oxo-5-thia-1-azabicyclo (4,2, O) -2-octene.
R 0.18; chromatography on silica gel with eluent diclohexane-ethyl acetate 50-50 (by volume).
IR spectrum (solution in CHBHH): 17b5 (carbonyl / S-lactam) and 1610 cm (enamine double bond).
NMR spectrum (350 MHz, COClS, sLm.d.): 2.87 (S, 6H: (CH3) oN-); 2.98 and 3.15 (AB, j 14 Hz, 2H, -ZCHN.7-cefem); 4.08 (S, 3 NOCHs): 5.12 (d, j 4, W, H in 6); 5.51 (dd, j 4 and 8, 1H, H at 7); 6.42 and .6.54 (AB, j 14, 2H, H vinyl Trans); 6.83 (S, 1H, H cycle thiazole); 6.94 (S, 1H, -СООСН (CfeHj)); 7.01 (S broad, 1H, (CbH5) 3CNH); 7.10-7.50 (1 5H, aromatic J-j 7.63 (d, j 8, III, -CONH-). 7.2 g of the obtained mass is dissolved in 900 cm of ethyl acetate and stirred with 120 cm 1 n. aqueous solution of hydrochloric acid for 1 h at 25 The organic solution is decanted, washed with 60 cm of saturated sodium chloride solution, then dried over magnesium sulphate and filtered. The solvent is evaporated under reduced pressure (20 mm Hg) and 309С. 6.3 g of a yellowish mass are obtained, the IR and NMR spectra of which show that it consists mainly of the isomer of the syn 2-benzhydryloxycarbonyl-7-2-methoxyimino-2- (2-trityl ino-4-thiazalyl) acetamido-8-oxo-3- (2-oxostil) -5-thia-1-azabicyclo (4.2, O) -2-octene, Rf 0.35; chromatography On silica gel with eluent cyclohexane-ethyl acetate 50-50 (by volume). IR spectrum (KBr tablets): 1780 (fj-lactam carbonyl); 1720 (conjugate ester carbonyl) and 1680 cm (carbonyl amide). NMR spectrum (350 MHz, SOS1, c / m, d.): 3.26 and 3.5-7 (AB, j 19 Hz, 2H: -CCH 2. cepham); 3.51 and 3.67 (AB, J -14 Hz, 2H: —CH7CHO); 4.08 (S, DZ: MOSNz); 5.08 (d, j 4 Hz, 1H: H in 6); 5.97 (dd, j 4 And 9 Hz, 1H H at 7); 6.73 (S, H, thiazole cycle); 6.83 (d, j 9 Hz,); 6.85 (S, 1H: -COOCH (C-H5) 2); 6.99 (S broad, 1H, (SbH5) zSMN-); 7.20-7.45 (15H, aromatic); 9.57 (S, 1H-CH 2-Benzhydryloxycarbonyl-7-12-methoxy-scinno-2-tritylamino-4-thiazyl) atech-3-methyl-8-oxo-5-thia-1-azabicyclo (4.2 , 0) -2-octene, the syn isomer, can be prepared as follows. To a solution of 3.15 g of 7-amino-2-benzhydryloxycarbonyl-3-meth l-8-oxo-5-thia-1-azabicyclo (4 , 2.0) -2-octene, B. 31.5 cm of methylene chloride was added in one step a solution of 7.2 g of anhydride of 2- (2-tritylamino-4-thiazolyl) -2-methoxyIMOIMOACINIC acid (isomer syn) in 22, 5 cm of methylene chloride. The temperature rises from 8 to C. Leave under stirring for 1 hour and 15 minutes, while the temperature increases to 20 ° C, then washed with 10 cm of 0.5N hydrochloric acid, 10 cm of distilled water and 20 cm of a saturated solution of sodium bicarbonate. The precipitate is filtered off and the organic phase is washed twice more with 20 cm of distilled water, dried over magnesium sulfate, filtered, and you are evaporated to dryness under reduced pressure (20 mm Hg) and 40 ° C .. The residue is chromatographed on a column (diameter 3 cm, height 33 cm) containing 125 g of silica gel, and eluted with ethyl acetate-cyclohexane 1.2 and 1 l, respectively 20-80 and 40-60 (by volume), selection Fractions of scum 50 cm. Fractions 31-44 are evaporated and 2.8 g of 2-benzhydryloxycarbonyl-2-G2-methoxyimino- (2-tritylamino-4-thiazolyl) acetamido-3-methyl-8-oxo-5-thia-1-azabicyclo (4, 2,0) -2-octene, the syn isomer, in the form of a solid, pale yellow substance. Example 8. To cooled in a nitrogen atmosphere to a solution of 5 g of 2-benzhydryloxycarbonyl-7-tert.-butoxycarbonylamino-3- (2-oxoethyl) -8-oxo-5-thia-1-azabicyclo (4.2, O) -2 -octene in 50 cm of methylene chloride was added 1.4 cm of triethylamine and a solution of 1.5 g of ethoxymalonyl chloride in 10 cm of methylene chloride was added dropwise over 10 minutes. Stir for 1 hour at -30 ° C, dilute with 50 cm of methylene chloride, wash three times with 50 cm of a saturated solution of sodium bicarbonate and three times with 50 cm of water, evaporate over sodium sulfate, filter and evaporate to dryness at 20 ° C and 20 mm pressure Hg (2.7 kPa). The residue is dissolved in 5 cm of ethyl acetate, a solution of 50 cm of diisopropyl oxide is added and the supernatant is decanted. The resins are dissolved in 5 cm of methylene chloride and the solvent is distilled off at 20 ° C and a pressure of 20 mm Hg. (2.7 kPa) .. 2.4 g of a pale yellow mass are obtained, consisting mainly of 2-benzhydryloxycarbonyl-7-tert.-butoxycarbonylamino-3- (2-ethoxymalonyl-oxyvinyl) -8-Oxo-5-thia- 1-azabicyclo (4,2,0) -2-octene, form E. JQ-spectrum (KBr.): 3380, 1785, 1720, 1635, 1510, 1500, 1455, 1395, 1370, 1160, 955, 760, 750 and 700 cm. NMR spectrum (350 MHz, CDCla, in.d., j in Hz): 1.29 (t, j 7, ЗН, -OCHiCH, -) 1.48 (S, 9Н, -С (С1 (з) e); .5.46 (S, 2H, -COOCH-iCO-); 4.23 (q, j 7, 2H, -OCHrj-); 5.02 (d, j 4, 1H, And 6) ; 5.22 (d, j 9, 1H, -CONJi); 5.64 (dd, j 4 and 9, 1I, HB 7); 6.95 (S, 1H, -COOCHO; 7.05 and 7 , 60 (2d, 3 - 12, 2H ,.). Example 9. To a cooled to -15 ° C solution of 2.4 g of 2-benzhydryloxycarbonyl-3- (2-oxoethyl) -8-oxo-7- (2-tritylamine- 4-thiazolyl) -2-vinyloxyiminoacetamido-5-thia-1-azabicyclo (4, 2.0) -2-octene, isomer syn, 30 cm of methylene chloride was added 0.65 g of p-toluenesulfonyl chloride, then dropwise in For 10 minutes, a solution of 0.44 cm of triethylamine in 5 cm of methylene chloride. Stir for 30 mic at -15. C. and allowed to stand for 1 hour to raise the temperature to 20 ° C. Then the mixture was diluted with 50 cm
methylene chloride, washed three times with 50 cm of a saturated sodium bicarbonate solution, three times with 50 cm of water, dried over sodium sulfate, filtered and evaporated to dryness under a pressure of 20 mm Hg. (2.7 kPa) and 30 ° C.
The residue is dissolved in 5 cm of ethyl acetate, 50 cm of diisopropyl oxide are added, stirred for 10 minutes, filtered and, after drying, 1.6 g of a beige color powder consisting mainly of 2-benzhydride, rhyloxycarbonyl-8-oxo-3-are obtained. (2-gtosyloxyvinyl) (2-tritylamino-4-thia zolyl) -2-vinyloxyiminoacetamido-5-thia-1-aaabicyclo (4.2.0) -2- and 3-octenes, a mixture of forms E and Z
IR spectrum (KBG): 1790, 1725.1690, 1640, 1525, 1495, 1450, 1195, 1180, 1075, 1005, 950, .755 and 705 cmL
NMR spectrum (350 MHz, CDCl., D. j in Hz): 2.45 (S, 3N, -CH,); 3.40 and 3.55 (2d, j ia, 2H, -SCHo-): 4.27 (dd, j 2 and 6, 1H,; C.,); .. 4.77 (dd, j 2 and 16, 1H,); 5.09 (d, j 4, IH, H in 6); 5.94 (dd, j 4 and 9, IH, H at 7); 6.81 (S, IH, H thiazole); 6.91 (S, IH, -СООСНС); 7.07 (dd, 3 6 and 16, IH,); 7.74 (d, j 8, 2H, H sulfonyl group).
2 Benzhydryloxycarbonyl-3- (2-oxoethyl) -8-OKCO-7- (2-tritylamino-4-thiazolyl) -2-vinyloxyiminoacegamido-5-thia-1-azabicyclo (4,2,0) -2-octene, isomer syn, can be obtained in the following way.
A solution of 2.5 g of 2-benzhydryloxy-carbonyl-3- (2-dimethylaminovinyl) -8-oxo-7- (2-tritylamino-4-thiazolyl) -2-vinyloxyiminoacetamido-5-tya is stirred at 25 ° C for 1 h. -1-azabicyclo (4,2,0) -2-octene, isomer syn, form E, in 70 cm of ethyl acetate in the presence of 50 cm 1 n. hydrochloric acid. The organic phase is decanted, washed twice with 50. cm of a half-saturated sodium bicarbonate solution and 50 cm of a half-saturated sodium chloride solution, dried over sodium sulfate, filtered and evaporated to dryness under a pressure of 20 mm Hg.
(2.7 kPa) and. 2.4 g of a brown mass are obtained, consisting essentially of 2-benzhydryloxycarbonyl-3- (2-oxoethyl) -8-oxo-7- (2-tritylamino-4-thiazolyl) -2-vinyloxyiminoacetamido-5-thia-1 azabicyclo (4,2,0) -fe-octene, isomer syn.
IR spectrum (KBG): 1785, 1725, 1685, 1640, 1530, 1495, 1000, 950, 755 and 700 cm-1.
NMR spectrum (350 MHz, PCS1.3, etc. j in Hz); 3.26 and 3.58 (2d, j 18, 2H, -SCH7-); 3.53 and 3.69. (2d; j 18 2H, -CHi); 4.28 (dd, j 2 and .6,1H,
°; c j; 4.78 (dd, j 2 and 17, IH, J
); 5.12 (d, j 4, IH, H in 6)
6.0 (dd, j 4 and 9, IH, H at 7); 6.8 (S, IH, H thiazole); 6.90 (S, IH,
-COOHC); 7-, 08 (dd, j 6 and 17.1H,
—CH.CH,); 9.55 (S, W, -CHO).
2-Benzhydryloxycarbonyl-3- (2-dimella1 M1Novinyl) -8-oxo-7- (2-tritylamino-4-thiazolyl) -2-vinyloxyimino-5-thia-1-azabicycle (4,2,0) -2-octene The syn isomer, Form E, can be obtained as follows.
To a solution of 2.5 g of 2-benzhydryloxycarbonyl-3-methyl-8-oxo-7g (2-tritylMino-4-thiazolyl) -. 2-vinyloxyaminoacetamido-5-thia-1-azabicyclo (4,) -2-octene, the isomer syn, 40 cm dimethylformamide is added at 0.7 cm tert-butoxy-bis-dimethylaminomethane under nitrogen and stirred for 10 minutes while the mixture is poured onto 250 cm of ethyl acetate and 250 cm of ice water. It is decanted, washed three times with 150 cm of water and 150 cm of water, saturated with sodium chloride, dried over sodium sulfate, filtered and evaporated to dryness under a pressure of 20 mm Hg. (2.7 kPa) at. Poluchak1T 2.5 g of brown mass, mainly consisting of 2-benzhydryl9xycarbonyl-3- (2-dimethylaminovinyl) -8-oxo-7- (2-tritylamino-4-thiazolyl) -2-vinyloxyiminoacetamido-5- thia-1-azabicyclo (4,2,0) -2-octene, isomer syn, form E
IR spectrum (KBG): 1770.1670, 1635 1610, 1530, 1495, 1450, 1000, 945, 755 and 700 cm-
NMR spectrum (350 MHz, COCl3, ppm, j in Hz): 2.90 (S, 6H, -N (CH3) 2); 4.25 (dd, j 2 and 6, 1H,);
4.73 (dd, j 2 and 14, 1H,);
5.18 (d, j 4, IH, H in 6); 5.60 (dd, j 4 and 9, IH, H at 7); 6.53 and 6.75 (2d, j 16, 2H,); 6.88
(S, IH, -COOSNO; 7,10. (Dd, j 6 and 14, NOCM).
2-Benzhydryloxycarbonyl-3-methyl-8-OKCO-7- (2-tritylamino-4-thiazolyl-2-vinyloxy-amino-acetamido-5-thia-1-azabicyclo (4, 2,0) -2-octene, isomer syn, obtained by condensation of 2- (2-tritylamino-4-thiazolyl) -2-vinyloxyiminoacetic acid, an isomer of syn, (4.6 g) with benzhydryl ester 7-aminodetic acetoxycephalosporoic acid (3.8 g) in the presence of N, N-dicyclohexylcarbodiimide (2 , 3 g) and 0.05 g of 4-dimethylaminopyridine in 40 s of methylene chloride at 5–20 s for 4 h. After chromatography on silica gel (200 g) with methylene chloride, 5 g of the desired product are obtained in the form of a yellow mass.
IR spectrum (KBr): 3400, 1785, 1725 1690, 1640, 1525, 1495, 1450, 1040, 1000, 940, 755 and 700, cm-
NMR spectrum (350 MHz, CDC1 ,, ppm} in Hz): 2.12 (S, 3H, -CHj); 3.22 and 3.49 (2d, j 18, 2H, -CH, -); 4.25
(dd, j 2 and 6, 1H, CfCC); 4.76
(dd, j 2 and I, 1H,., „); 5.08
td, j 4, 1H, H in 6); 5.92 (dd, j 4 and 9, 1H, H at 7); 6.83 (S, 1H, H thiazole); (S, 1H, -СООСНС); 7.0 (S, 1H, -YN-C (C ", H5) h).
Example 10. in cooled to a solution of 180.56 g of 2-benzhydryloxycar6onyl-7-tert. -Butyroxycarbonylamino-8-oxo-3- (2-tosyloxyvinyl) -5-thia-1-azabicyclo (4.2.2) -2i H-octene- (a mixture of Her Z forms) in 1.4 methylene chloride is added dropwise a solution of 55.22 g of 85% m-chloroperbenzoic acid in 600 cm of methylene chloride over 2 hours. The mixture is squeezed with 1.5 l of 5% a solution of sodium bicarbonate and twice with 1.5 l of water, dried over sodium sulfate and I1 are evaporated under reduced pressure (20 mm Hg) to a volume of 300 cm. This solution is chromatographed on a column of 3 kg of silica gel MegsK (0.05 -0.2 mm), column diameter 9.2 cm, height 145 cm. Elute with cyclohexane-ethyl acetate mixtures in succession 15 l (80-20 by volume) and 32 l (70-30 by volume) and collect fractions of 600 cm. Fractions 27 and 28 are collected and evaporated to dryness, yielding 5.56 g 2 benzhydryloxycarbonyl-7-tert.-butoxycarbonylamino-8-oxo-5-oxide-3- (2-tooyloxyvinyl) -5-thia-1-azabicyclo (4,2,0) -2-octene, form Z,
NC spectrum (CMBrj): 3420, 1800, 1720, 1505, 1380, 1370, 1195, 1180, 1050, 1010 and 730 cm
NMR spectrum (350 MHz, CDC1j, etc. j in HZ): 1.49 (S, 98, -C (CH}) j); 2.44 (S, 3N, -ClI); 3.56 and 4.04 (2d, j 19, 2H, -SCIt2-); 4.44 (d, j 4,5, HI, H in 6); 5.73 (d, j 9, 1H, -CONH-); 5.81 (dd, j 4,5 and 9,
W, 1M, H in 7); 6.42 (d. J:; 1H,
-CH CH-050 -); 6.46 (d, j 7, 1H, 1H-OS05-); 6.89 (s, 1H, -COOCH); 7.77 (d, j 9, 2П, M in the ortho position of the tosil).
In fractions 29-34, 26 g of a mixture of forms Z and E are obtained. In fractions 35-58, 43 g of Formula E are obtained.
NC spectrum (CUBrjj: 3420, 1800, 1720, 1505, 1380, 1370, 1195, 1180, 1075, 935 and 745
NMR spectrum (350 MHz, COClS, ppm j Hz); 1.48 (S, 9H, (CH}) jC-); 2.46 (S, 3H, -SI); 3.16 and 3.81 (2d, j 18, 2H, -YACNg-); 4.4b (d, j 4,5, in, II in 6); 5.73 td, j 9, 1I,
-CpNHS; 5.8 (dd, j 9 and 4.5,: H, H in 7); 6.83 (d; j 15, 1H, -CH-CH-OSOj-); 6.83 (S, 1H, COOCHC); 7.08 (d, J 13, 1H, “CH-OSOj-); 7.73 (d, j 9, 2H, H in the ortho position of the tosyl).
2-Benzhydryloxycarbonyl-7-tert. -butoxycarbonylamino-8-oxo-3- (2-tosyloxyvinyl) -5-thia-1-azabicyclo (4.2; 0) -2- and 3-octene (forms E and X) can be obtained by the procedure described in example 2,
Example 11. A solution of 10 g of 2-B "zgidryloxycarbonyl-8-oxo-3- (2-oxo-ethyl) -7-tritylamino-5-thia-1-azabicyclo (4,2,0) -2-octene and 3 , 14 g of p-toluensulfonyl chloride in 80 cm of tetrahydrofuran is cooled to -10 ° C, then treated with 2.1 cm of triethylamine. The reaction mixture was stirred for 2.5 hours at 1020 ° C and diluted with 500 cm of ethyl acetate. This solution is washed successively twice with 150 cm of distilled water, then with 200 cm of a saturated solution of sodium chloride, decanted and dried over sulfur. Fatom magnesium. The residue obtained is evaporated to dryness at a pressure of 30 mm Hg. (4 kPa) and 30 ° C, then filtered through a column of silica gel (0.067-0.2 mm), 40 cm high, 4 cm in diameter, eluted with a mixture of cyclohexane-ethyl acetate (1/1 by volume) and 125 cm fractions collected. Fractions 2-7 are combined and evaporated at a pressure of 30 mm Hg. (4 kPa) and, 9 g of an orange mass, mainly consisting of 2-benzhydryloxycarbonyl-8-oxo-3- (2-tosyloxyvinyl) -2-tritylamino-thia-1-aa-dicyclo (4.2, 0) -2-octene (a mixture of forms E and Z 2/1). This product is dissolved in 60 cm of dry methylene chloride. After cooling to -10 ° C, a solution of 2.25 g of 85% m-chloroperbenzoic acid in 25 cm of dry methylene chloride is added over 5 minutes. After holding the reaction mixture for 30 minutes, the filtrate and the filtrate are washed with 150 cm of a saturated solution of sodium bicarbonate and 100 cm of a saturated solution of sodium chloride. The solvent is evaporated at a pressure of 60 mm Hg (8 kPa) at 4 ° C and the residue is chromatographed on a column (height 40 cm, diameter 6 cm) with silica gel (0.040, 06 h), eluting with 4.5 l of a mixture of cyclohexane and ethyl acetate (25 / 75 by volume) at a pressure of 0.5 bar, and 120 cm fractions are taken. The combined fractions 21-34 are evaporated to dryness at a pressure of 30 mm Hg. (4 kPa) and 40 ° C and get 3.15 g of 2-benzhydryloxycarbonyl-8-oxo-5-oxide-3- (2-tosyloxyvinyl-7-tritylamino-5-thia-1-z "Cu1 1klo (4, 2,0) 2-octene (a mixture of forms E and Z 70/30) in the form of a solid paste.
PC spectrum (SNVgz): 3340, 1790, 1720, 1375, 1190, 1070, 1050 and 550 s
NMR spectrum of E isomer (350 MHz, ATPh3, .d., j Hz): 2.42 (S, 3N, CH3 -); 2.77 and 3.45 (2d, j 18, 2H, -SOCH2-); 3.50 (d, j 12, 1H, NH); 3.52, (d, j 4, 1H, AND g 6); 4.84 dd, j 4 and 12j 1И, Н in 7) -; 6.75 and 6.90 (2d, j 12, 2H, -CH CH-07); 6.88 (S, 1H,); 7.2-7.60 (aromatic).
NMR spectrum of Z isomer (350 MHz, CCC1e, sLm.d., j Hz): 2.4-2 (S, 3N, -SNe); 3.02 and 3.75 (2d, j 18, -SOCH2-3; 3.49 (d, j 4, 1H, H in 6); 3.50 (d, j 12, 1H, NH); 4, 84 (dd, j 4 and 12, 1H, H in 7); 6.23 6.31 (2d, j 7, 2H, -CH CH-0-); 6.85 (S, 1H,); 7, 2-7.60 (aromatic).
A solution of 23.5 g of 2-benzhydryloxycarbonyl-3- (2-dimethylaminovinyl) -8-; -oxo-7-tritylamino-5-thia-1-azabicyclo (4.2.2) -2-octene (form E) in 500 cm of ethyl acetate is stirred for 90 minutes at 25 ° C with 250 cm of 1N. saline acid. The organic phase is decanted, washed three times with 250 cm of distilled water, 100 cm of saturated sodium bicarbonate solution and 250 cm of half-saturated chloride solution, sodium, then dried over sodium sulfate and evaporated to dryness under reduced pressure (40 mm Hg) and 40 ° C. 21 g of 2-benzhydryloxycarbonyl-8-oxo-3- (2 oxoethyl) -7-tritylamino-5-thia-1-azabicyclo (4.2.2) -2-octene are obtained in the form of an orange mass.
NMR spectrum (350 MHz, CDClj, Yam.d., j-Hz): 2.99 (S, .j 9, 1H, O NH); 3.07 and 3.33 (2d, j 18, 2H, -SCH-i-) 3.50 (AB, j 14, 2H, -CHOCHO); 4.30 (d, j 4, 1H, H in 6); 4.75 (dd, j 4 and 9, W, H in 7); 6.82 (S, 1H, -COgSN (CHH5) g); 7.20-7.60 (broad, 25H, aromatic); 9.46 (S, 1H, -CHO).
To a solution of 21.8 g of a mixture of 2-benzhydryl-Sicarbonyl-3-methyl-8-oxo-7-tritylag 4 and no-5-thia-1-azabicyclo (4.2, -2-octene (40%) and its isomer 3-octene) (60%) in 120 cm of dry N, N-dimethylformamide, heated to 80 ° C in a nitrogen atmosphere, 10.8 cm. Of butoxy-bis-dimethylaminomethane A. the mixture is poured into 500 cm of ethyl acetate. Add 250 cm of distilled water, stir, decant the organic phase, wash it three times with 250 cm of distilled water, dry over magnesium sulfate and evaporate under reduced pressure (. 40, mm Hg) and. Investigate the residue by thin-layer method
chromatography shows the presence of unchanged starting product. It is again dissolved in 100 cm of anhydrous N, N-dimethylformamide, the solution is heated to a nitrogen atmosphere and kept at. for 5 minutes at this temperature after the addition of b cm tert-butoxy-bis-dimethylaminomethane. The reaction mixture is then diluted with 500 cm of ethyl acetate and treated as indicated. 24 g of an orange mass consisting mainly of 2-benzhydryloxycarbonyl-3- (2-dimethylaminovinyl) -8-oxo-7-tritylamino-5-thia-1-azabicyclo (4.2.2) -2-octene ( form E).
IR spectrum (CHBrs): 3320, 2800, 1760, 1610, 1445, 760, 705 and 1680 cm
NMR spectrum (CBCI3, 350 MHz, ppm, j Hz): 2.84 (S, 6H, - (CHj)); 2.95 and 3.12 (2d, j 16, W, -SCHo-); 3.36 (d, j 10, 1H, -NH-); 3.98 (d, j 2, 1H, H in 6); 4.41 (.dd, j and 10, W, H in 7); 6.46 and 6.72 (2d, j 14, 2H,.); 6.82 (S, III, -CH () 2.); 7.2-7; b (broad, 25N aromatic).
A mixture of 2-benzhydryloxycarbonyl-3-methyl-8-oxo-7-tritylamino-5-thia-1-azabicyclo (4.2.2) -2-octene (40%) and its isomer 3-octene (60%) can life is obtained as follows.
Within 15 minutes, a solution of 12.3 g of diphenyldiazomotane in 200 cm of acetonitrile is added to a suspension of 28.8 g of a mixture of 2-carboxy-3-methyl-8-oxo-7-trimethylamino-5-thia-1-azabicyclo (4.2 , 0) -2-octene and its isomer 3-octene in 500 cm of acetonitrile, then the reaction mixture is stirred for 2 hours at 25 ° C. The solvent is evaporated under reduced pressure (40 mm Hg) at 30 ° C and the oily residue is redissolved in 500 cm of ethyl acetate. The solution is washed successively with 1N hydrochloric acid (until decolorization), then three times with 100 cm of a saturated sodium bicarbonate solution, 100 cm of water and 100 cm of a saturated solution of sodium chloride, then dried and evaporated to dryness, to obtain 35.4 g of a mixture of 2-benzhydryloxycarbonyl -3-methyl-8-oxo-7-tritylamino-5-thia-1-azabicyclo (4.2.0) -2-octene and its isomer 3-octene as a cream-colored mass.
IR spectrum (SNVge): 3340, 1765, 1730, 1620, 1590, 1490, 1445, 745 and 700 cm
NMR spectrum (CDCl1, 350 MHz, sLm.d. j Hz ;:1.73 (S, -CHe, 3-octene); 2.04 (S, -CH3, 2-octene); 3.05 and 3 , 30 (2d, AB, j 8,, 2-octene); 4.20 (2d, j 4, H to 6, 2-octene and 3-octene); 4.60 (230, j 4 and 10, H in 7, 2-octene and 3-octene); 4.80 (S, P in 2 3-octene); 5.75 (S, broad, H in 4 ,, 2-octene); 6.78 (S, COaQUCfefls),, 3-octene); 6.89 (s,),. 2 - octane); .7,2-7, .50 Saromatic). 2-Carboxy-3-methyl-8-oxo-7-tritylamino-5-thia-1-azabicyclo (4.2, O) -2-octene (.40%) and its isomer 3-octene (BOH) can be obtained as follows. I To suspension 42.8 g of 7 amino-2-car | boxy-3-methyl-8-oxo-5-thia-1-azadicyclo (4,2,0) -2-octene in 250 cm without aqueous N, N -dimethylformamide was added 55, 6 cm of triethylamine, after cooling, a solution of 55.8 g of chloroform and 250 cm of chloroform was added to the mixture over 2 hours. 1 l, tJ b / Ikxll "vl / K yUfWlbtlCt The reaction mixture is stirred for 24 hours at, then" poured into 400 cm 1 and. hydrochloric acid. After filtering, the organic phase is separated, evaporated to half volume under reduced pressure (40 mmHg and 40 ° C and dissolved in 400 cm of ethyl acetate. The aqueous phase is extracted with 400 cm of ethyl acetate and the organic phases are combined, washed twice 250 times 1N hydrochloric acid, then: extracted four times with 500 cm of; .. 1 of a saturated sodium bicarbonate solution. The combined aqueous phases are dissolved in 300 cm of ethyl acetate, the acid is acidified to pH 3 with 12N hydrochloric acid and extracted two times with ethyl acetate 500. The organic solutions are washed with 250 cm sat. sodium chloride solution, combined, dried over sodium sulfate and evaporated to dryness under reduced pressure (40 mm Hg. OT. and the residue is compacted with 250 cm of isopropyl oxide. The solid is drained, washed with 100 cm of isopropyl oxide and dried. A yield of 22.2 is obtained. g of a mixture of carboxy-3-methyl-B-oxo-tritylamino-5-thia-1-azabicyclo (4,2,0) -2-octene and its 3-octene isomer as a solid paste. IR spectrum (. SNBGs): 3320, 3300, 2400,1765,1730,1625,1595,1490,1450, 750 and 710 cm - NMR spectrum (CDClj, 350 MHz, cL ppm) j Hz): 1.84 (S, Psp, 3-octene); 2.16 (S, -CH3, 2-octene); 3.10 and 3.40 (2d, j 10, SCH, -, 2-octene); 4.2 (2d, j 4, Nvb, 2-octene and 3-octene) 4.6 (Zdd, j 4 and 10, H in 7, 2-octene and 3-octene); 4.73 (s, H, 2, 3-octene); 5.77 (s, broad, H in 4, 3-octene); 7.2-7.5 (aromatic). Example 12. To a solution of 2.5 g of 2-benzhydryloxycarbonyl-2-2-methoxyimino (2-tritylamino-4-thiazo-lyl) acetamido3-3-methyl-8-oxo-5-thia-1-az bicyclic o (4, 2 , 0) -2-octene, the syn isomer, in 50 cm of dimethylformamide heated to 80 ° C, 0.91 g of bis (dimethylamine) ethoximuthane is added. The solution becomes brown-green. It is left for 20 minutes at, then rapidly cooled, poured onto 200 cm of ethyl La-acetate and washed three times with 80 cm of water and once with 50 cm of saturated sodium chloride solution. The ethyl acetate phase contains in solution the intermediate 2-benzhydryloxycarbonyl-3- (2-dimethylamino-7-8g-oxo-7-2-methoxyimino- (2-tritylamino, -4-thiazolyl) acetamidoZ-5-thia-1-azabicyclo C4, 2, intermediate 0) -2-octene, which can be applied directly to the next step. This solution is stirred at 37.5 cm 1N for 1 h - - - 3 s. hydrochloric acid. The aqueous phase is removed, the organic phase is washed with 20 cm of a saturated solution of sodium bicarbonate, then 20 cm of a saturated solution of sodium. The organic phase is dried over magnesium sulphate, filtered in the presence of vegetable black, and then evaporated to dryness under reduced pressure (20 mm Hg) and 40 ° C. The residue is dissolved in 10 cm lumbar "l .ifc.-t-. ffrw - tf-h th mt pyridine. O is added to the solution, cooled to an ice-bath, in 7 g of tosyl chloride, and the reaction mixture is allowed to warm to 20 ° C. After 1.5 hours, the mixture is poured onto 200 cm of ice water. The precipitate formed is filtered off, washed twice with 20 cm of water, then dissolved in 50 cm of ethyl acetate. This solution is washed with 20 cm of a saturated solution of sodium bicarbonate, 20 cm of a saturated solution of sodium chloride, dried over magnesium sulfate, filtered, in the presence of vegetable black, and evaporated to dryness under reduced pressure (20 mm Hg) and 40 ° C. The residue that contains 2-6enegidryloxycarbonyl-7 2-methoxyimino- (2-tritylamino-4-thiazolyl) acetamido-8-oxo-3- (2-tosyloxyvinyl) -5-thia-1-azabicyclo (4,2,0) -2-octene, (isomer: syn, mixture of forms E and Z, dissolved in 13 cm of methylene chloride and the resulting solution cooled to an ice-methanol bath. A solution of 0.226 g of 85% m-chloroperbenzoic is added to it within 15 minutes acid in 10 cm of methylene chloride. The reaction mixture is left for 20 min at (-10) -5 s, then washed twice with 20 cm of a saturated solution of sodium bicarbonate, dried over magnesium sulfate, filtered into Plant soot and evaporated to dryness under reduced pressure (20 mm Hg) and the residue is chromatographed on a column (1.7 cm in diameter, 21 cm in height) containing 26 g of silica gel. Eluted with ethyl acetate-cyclohexane 120; 240; 200 and 120 cm, respectively
20-80, 30-70, 40-60 (by volume), and
fractions of the eluate of 20 cm are taken. You (parry the fractions -17-34 and separate 0.88 g of 2-benzhydryloxycarbonyl-7-C2-methoxyimino- (2-tritylamino-4-thiazolyl) acetamido} -8-oxo-5-oxide 3-C2-tosyloxyvinyl) -5 thia-1-azabicyclo (4,2,0) -2-octene, isomer syn, a mixture of forms S and Z.
Example 13. To an osp to one another, as low as -5 ° C, a solution of 14.3 g2-benzhydryloxycaroyl-7- (tert-butoxycarbo-, nyl-0, oC-phenylglycinamino) -8-oxo-3- (2-tosyloxyvinyl) - 5-thia-1-azadicyclo (4,2,0) -2-octenes (or 3-octenes) (a mixture of forms E and Z) in 120 cmmethylene chloride is added with stirring dropwise over 30 minutes a solution of 3.66 g m-chloroperbenzoic acid in 30 cm of methylene chloride. Then it is stirred for 30 minutes at 0 ° C, then 250 cm of a 2% sodium bicarbonate solution are added twice and 250 times of distilled water three times, dried over sodium sulfate, filtered and evaporated to dryness under reduced pressure (20 mm Hg). Art.) and.
The residue (15 g) is fixed on 50 g of MegK silica gel (0.05–0.2 mm), and the powder is placed on a column with 250 g of Siline gel MegsK (0.05–0.2 mm), you-Column 30 cm, diameter 4.5 cm, with a mixture of cyclohexane ethyl acetate 80-20 (by volume). Elute successively 1 l of the same mixture and 2 l of a mixture of cyclohexane-ethyl acetate 60-40 (by volume), selecting fractions of 200 cm
Fractions 8–12 evaporated. Dry under reduced pressure. 8.9 g of 2-benzhydryloxycarbonyl-7- (tert-butoxycarbonyl-B, c.-phenylglycylamino) -8-oxo-5-oxide-3- (2-tosyloxyvinyl) -5-thia-1-azabicyclo (4, 2,0) -2-octene (mixture of forms E and Z).
NMR spectrum (350 MHz, SOSCHsHm.d., j Hz):
Form E: 1.48 (S, 9H, -C (CH3) h); 2.45 (S, 3H, -CHj); 3.49 and 4.34 (2d, j 19, 2H, -SCH2-); 4.93 (d, j 4, 1H, H in 6) 5.37 (d, j 8,
SNSNH5); 5.97 (dd, j 4 and 9, 1I, H B. 7); 6.72 (d, j 12,. 1H, -СЬЬ CHOSO -); 6.91 (S, 1H, -СООСНС); 8.38 (d, j 8, 1H, -CONH-); 7.83 (d, j 8, 2H, H in the ortho-position of toz1 | la);
form Z: 2.40 (S, 3N, -CH,); 5.62 and 3.85 (2d, j 19, ZH, -SCH, -); 4.98 (d, j 4, H and 6.); 5.87 (dd, j 4 and 9, H at 7); 6.14 (d, j 6, 1H, -CH CHSO-); 6.64 (d, j 6, 1M, CHOSOQ.-).
2-Benzhydryloxycarbonyl-7- (tert.-butoxycarbonyl-0, C1-phenylglycylamino-8-oxo-3- (2-tosyl-xyxinyl) -5-thia-1-azabicyclo (4.2.2) -2- or 3- octene
(a mixture of forms E and Z) obtained by the method described in example 3.
Example 14. 42 g of 2-benehydryloxycarbonyl-7-tert.-butoxycarbonylamino-3- (2-dimethylaminovinyl) 5-8-oxo-5-thia-1-azabicyclo (4.2, .0) -2octen (form .E ), obtained by the method described in example 1, is subjected to hydrolysis in a mixture of 770 cm of tetrahydrofuran, 391 cm of distilled water and 39.1 cm of pure formic acid according to the method described in example 1. Get 39.1 g of mass of brown-orange color, which is dissolved in 385 cm of pyridine. To the solution cooled to, is added dropwise over 15 6.04 cm-acetyl chloride. The reaction mixture is stirred for 30 minutes at, then for
Q 2.5 hours at a temperature of from -10 to
20 ° C, then poured into 3 liters of ice-water. The precipitate is dried, washed twice with 1 liter of distilled water and dissolved in 1050 cm.
5 methylene chloride. The organic solution is washed with 1 liter of distilled water and. twice 200 cm 1 n. hydrochloric acid, then dried over magnesium sulphate and filtered. The solution is partially evaporated under reduced pressure: Lenin (20 mm Hg) and 30 ° C to a residual volume of 700 cm. Cool the solution to 12.8 g of m-chloroperboenoic acid in 380 cm of anhydrous methylene chloride . The reaction mixture is stirred for 40 minutes at 0 ° C, then washed twice with 200 cm of a saturated solution of sodium bicarbonate and 250 cm of distilled water. After the solution was dried over magnesium sulfate and filtered, the solvent was evaporated under reduced pressure (20 mm Hg) and 30 ° C. 41.3 g of a chestnut-colored mass are obtained, which are fixed to 200 g of MerK gellic (0.05-0.2 mm) and placed on a 5 cm column filled with 400 g of MerK gel (O; 05-0, 2 mm) in cyclohexane ethyl acetate; 70-30 mixture (by volume). 1.7 l of this mixture is eluted and fractions of 300 cm are collected. Fractions 21-29 are evaporated to dryness, the residue (13.2 g) is triturated with 100 cm of isopropyl oxide,
its solid is dehydrated and recrystallized from 50 cm of a mixture of cyclohexane-ethyl acetate 70-30 (by volume). 7.8 g of 3- (2-acetoxyvinyl) -2-benzhydryloxycarbonyl-7-tert are obtained. butoxycarbonylamino-8-oxo-5-oxide-5-thia-1-azabicyclo (4.2.0) -2-octene as white crystals (mp. 210c). .
R chromatography on silica gel, eluent: cyclohexane ethyl acetate
5 50-50 (by volume). NMR-cheKTp (350 MHz, CDClj, δ j Hz): 1.48 (S, 9H, (CH3) eS-); 2.1 (S, 3N,); 3.24 and 3.96 (2d, j 19, 2H, -S / 0 / CH2-); 4.53 (d, j 4, 1H, H in 6); 5.72 (dd, j 4 9, 1H, H at 7); 5.74 (d, j 9, 1H, NH); 6.94 (S, 1H, -CODCH); 7.30 (d j 13, 1H, -CH CH-OCO-); 7.60 (d, j 13, 1H, -CH CH-OCO--). Then, 7.5 g of a mixture of 3- (2-acetoxyvinyl) -2-benehydryl .oxycarbonyl-7-tert.-butyroxycarbonylamino-8-oxo-5-oxide-1-azabicyclo (4.2, 0) -2-octenes ((I oph "i E and Z). NMR spectrum (350 MHz, CDClj ,.d j Hz) of the Z isomer: 2.14 (S, 3N, CH 3 SNR 3.41 and 4 , 30 (2d, j ii 21, 2H, -SOCH. 6.95 (d, j 10, 1H, -CH CHOCO-); 7.58 (d, j 10, 1H, -CH CHOCO-). Example 15 To a cooled to a solution of 1.65 g of 2-benzhydryloxycarbonyl-7-tert.-butoxycarbonylamino-3- (2-ethoxymalonyl-oxyvinyl) -8-oxo-5-thia-1-azadicyclo (4.2.2) -2- octene, form E, in 8 CNT methylene chloride is added dropwise (with stirring for 10 minutes, facTBOp 0.63 g of 85% m-chloro denzoic acid in 8 cm of methylene chloride. Stir for 1 hour at -10 to -15 ° C, dissolve the mixture in 50 cm of methylene chloride, wash twice with 50 cm of sodium bicarbonate solution and 50 cm of saturated sodium chloride solution, and dry over sodium sulfate , filtered and evaporated to dryness at 20 ° C and a pressure of 20 mm Hg. The residue is chromatographed on a column of Merck silica gel (0.04-0.06), column diameter 1.5 cm, height 15 cm. Elute 0.5 l of the mixture methylene chloride ethyl acetate 95-5 (by volume) at a pressure of 40 kPa and take fractions of 20 cm. Fractions 5-10 vol. Aryvay to dryness at 20 ° C and a pressure of 20 mm Hg and get 0.8 g of 2-benzhydrnloxy-g carbonyl-7-tert.-butoxycarbonylamino-3- (2-ethoxymalonyloxyvinyl) -8-oxo-5-oxide 5 -thia-1-azadicyclo (4.2, {-2-octene, form E, in the form of a yellow powder. IR spectra (KBr): 3420, 1795, 1725, 1640, 1500, 1460, 1395, 1370, 1160, 1050, 940, 760, 750 and 700. . NMR spectrum (350 MHz, COClS, ppm, J HzG1.29 (t, j 7, ЗН, -СНгСНэ): 1.48 (S, 9Н, -С (СНэ) з); 3.24 and 3.95 (2d, j 18, 2H,); 3.45 (S, 2 -OSOCHN-); 4.23 (q, j 7, 2H, -OCH 4.55 (d, j 4, IH, H 6); 5.76 (d, j 9, IH, -CONH-); 5.83 (dd, j 4 and E; W, H to 7); 6.98 (S, IH, -COOCHN 7, 61 (d, j 11, F,). Example 16. To a cooled d solution of 1.6 g of 2-benzhydryloxy 1carbonyl-8-oxo-3- (2-tosyloxyvinyl) -7- (2-tritylamino-4-thiazolyl) -2: Vinyl-aminosilane-acetamido-5-thia-1-azabicyclo (4,2,0) -2- and 3-octenes, syn isomer, mixture of forms E and Z, in 5 cm of methylene chloride is added dropwise over 10 minutes a solution of 0.33 g of 85% m-chloroperbenzoic acid in 7 cm of methylene chloride. stirred in For 1 hour, 30 cm of methylene chloride was stripped, washed twice with 50 cm of a saturated solution of sodium bicarbonate and 50 cm of a half-saturated solution of sodium chloride, dried over sodium sulfate, filtered and evaporated to dryness under a pressure of 20 mm Hg (2.7 kPa) and 30 ° C. The residue is chromatographed on a column with 20 g of MegK silica gel (0.06-0.2), a column diameter of 1 cm, a height of 10 cm. 500 cm of methylene chloride are eluted, 1 l of a mixture of methylene chloride ethyl acetate 97-3 ( ) and 1.5 liters of a mixture of 95-5 (by volume), collecting fractions of 25 cm. Fractions 14-24 are evaporated to dryness under a pressure of 20 mm Hg. (27 kPa) and 20C. Get 0.45 g of 2-benzhydryloxycarbonyl-8-oxo-5-oxide-3- (2-tosyloxyvinyl) -7- t (2-tritylamino-4-thiazyl) -2-vinyloxyiminoacetamido3-5-thia-1-azabicyclo ( 4.2.0) -2-octene, syn isomer, Form E. IR spectrum (KBr): 1800, 1725, 1690, 1635, 1520, 1495, 1450, 1195, 1180, 1070; 1050, 1000, 945, 740 and 700 cm NMR spectrum (350 MHz, COClS, ppm, j Hz): 2.45 (S, 3N, -CH); 3.19 and 3.77 (2d, j 18, 2H,); 4.27 (dd, j 2 and 6, 1H, n .n. (D, j 4, 1H, H in 6); 4.76 (dd. 13, 1H,)); 6.20 (dd. J 2 and j 4 and 9, IH, H at 7); 6.80 (S, IH, H thiazole); 6.90 (S, IH, -СООСНС); 6.92. and 7.10 (2d, j 12, IH,); 7.05 (dd, j 6 and 13, IH, NOCH); 7.73 (d, j 8, 2H, H in the ortho-position of the -OSOf - group). Example 17. To a solution of 6.1 g of 2-benzhydryloxycarbonyl-7-tert.-butoxycarbonylamino-8-oxo-3- (2-tosyloxyvinyl) -5-thia-1-azabicyclo (4,2,0) -2-octene Form E, 75 cm of acetonitrile is added dropwise over 25 minutes at 3.49 g of p-toluenesulfonic acid hydrate to 25 cm 3 of acetonitrile. Stir for 45 minutes at 35 ° C and pour the mixture into 500 cm of a saturated sodium bicarbonate solution. After contacting for 30 minutes with stirring, it is extracted with 500 cm of ethyl acetate, the organic phase is washed with 100 cm of WATER, dried over sodium sulfate, sieved and evaporated to dryness at a pressure of 20 mm Hg. Art. This gives 4.7 g of 7-amino-2-benzhydryloxycarbonyl-8-oxo-3 C2-tosyloxyvinyl) -5-thia 1-azabicyclo (4.2.2) -2-octene, form E, as a brown mass,
R 18; chromatography on silica gel, eluent cyclohexane-ethyl acetate 5 50-50 (by volume) ..
Example 18. Stirred at 20 ° C for 16 h of a solution of 4.06 g of 2-benehydryloxycarbonyl-7-tert.-butoxycarboxylamino-8-oxo-5-oxide-10 -3-C2-TOZYLOXYVINIL) -5-thia-1 -azabicyclo C, 2.0) -2-octene, a mixture of forms E and Z, (obtained as described in example 10, in 150 cm of acechonitrile with 2.28 g of p-toluenesulfonic monohydrate, 15 lots. Evaporated under reduced pressure (20 mm Hg) and 20 ° C to a volume of 10 cm, diluted with 150 cm of ethyl acetate, washed with 100 cm of 2% sodium bicarbonate solution, then 20 twice with 150 cm of a saturated solution of sodium chloride, dried over sodium sulfate and evaporated dry under reduced pressure (20 mm Hg) and 20 ° C. Obtain 3.5 g of 7-amino-2-25-benzhydryloxycarbonyl-87 OXO-5-oxide-3- (2-tosyloxyvinyl-5-thia-1 - azabicyclo (4,2,0) -2-octene, mixture of fractions E and 1, in the form of a crude solid "brown". Q
IR spectra (KBr): 3430, 3360, 1780, 1725, 1370, 1170, 1180, 1070, 745, and 700 cm. . .
NMR spectrum (350 MHz, CDClj, tf ppm, j Hz); 2.43 (S, 3N, -CH3); 3.12 and 3.75 (2d ,, j 18, g, -SCH-i-); 4.36 (d, j 4, 1H, H in 6); 4, -74 (d, j 4, 1H, H in 7); 6.87 (d, -j 12, 1H, -CH CH-OSOi-); 6.90 (S, III, -COOCHO; 6.99 (d, j-12, 1H, -CH-OSOr, -); 7.40 and 7.71 (2d, j 9, 40 -CfcH4-).
Example 19. A solution of 54.3 g of 2-benzhydryloxycarbonyl-7-tert.-butoxycarbonylamino-8-oxo-5-oxide-45 -3- (2-tosyloxyvinyl) -5-thia is stirred at 35 ° C for 2 hours. 1-azadicyclo (4,2,0) -2-octene, form E, prepared as described in example 10, and 30.4 g of p-toluenesulfonic acid hydrate in 1.4 l of acetonitrile. Evaporate to dryness at 30 ° C and a pressure of .20 mm Hg. (2.7 kPa), dissolved in 1 liter of ethyl acetate, washed with two 500 cg of half-saturated sodium bicarbonate solution and two times with 500 cm of a half-saturated solution of sodium law, dried over sodium sulfate and evaporated to dryness under a pressure of 20 mm Hg ( 2.7 kPa) and 20 ° C. The residue is triturated in 200 cm of ether. This gives 28.13 g of 7-amino-2-benzhydryloxycarbonyl-8-oxo-5-rxid-3- (2-tosyloxyvinyl) -5-thia-1-azabicyclo (4.2.2) -2 octene, form in, in the form of a light brown powder .65
Rf 0.32, chromatography on silica gel with eluant methylene chloride-methanol 85-15 (by volume).
Example 20. To a solution of 81.45 2-benzhydryloxycarbonyl-7-tert.-bytoxycarbonylamino-8-oxo-5-oxyd-3- (2-thioyl-oxivinyl-5-thia-l-azabicyclo (4.2.0) -2 -ooctene, form Z, in 1.3 liters of acetonitrile is added over 25 minutes at 35 ° C while stirring a solution of 45.65 g of p-toluenesulfonic acid hydrate in .300 Cm of acetonitrile. Stir at 40 ° C for 40 minutes and pour mixture into a solution of 40.3 g of bicarbonate on: three in 7 l of water Stir for 30 minutes at 20 ° C, filter the obtained yellow solid and air dry To obtain 64 g of 7-amino-2-benzhydryloxycarbonyl-8-oxo -5-oxide-3- (2-t Ozyloxyvinyl) -5-thia-1-azabicyclo 4,2,0 -2-octene, form Z.
IR spectra (KBr): 3420, 1780, 1730 1600, 1495, 1455, 1380, 1195, 1180 and 1005 cm-
Example 21. Stir for 16 hours with a mixture of 1.65 g of 3- (2-acetoxyvinyl) -2-benzhydryloxycarbonyl-7-tert.-butoxycarbonylamino-8-oxo-5-thia-1-azabicyclo (4.2.0 ) -2-octene, form E, (obtained as described in Example 5), 1.14 g of p-toluenesulfonic acid monohydrate and 50 cm of acetonitrile. The mixture is dissolved in 50 cm of a 5% sodium bicarbonate solution, extracted with 50 cm of ethyl acetate, the organic phase is separated and washed twice with 20 cm of saturated sodium chloride solution, dried over sodium sulfate, then evaporated to dryness under reduced pressure ( 20 mm Hg) and 20 ° C. Obtain 1.26 g of 3- (2-acetoxyvinyl) -7-amino-2-benzhydryloxycarbonyl-8-oxo-5-thia-1-azabicyclo (4,2,0) -2-octene, form E, in the form of crude red oil.
R 0.62; chromatography on sinjiKarene, solvent ethyl acetate.

权利要求:
Claims (3)
[1]
Example 22. 3 g of 2-benzhydryloxycarbonyl-7- 2-methoxyimino-2- (2-tritylamino-4-thiazolyl) acetamido-8-oxo-5-oxide-3- (2-tosyloxyvinyl) -5-thia-1- azabicyclo (4,2,0) -2-octene, isomer syn, form E, dissolved in 30 cm of methylene chloride, 1.2 cm of N, N-dimethylacetamide are added. The solution is placed under nitrogen, cooled to -10 ° C and treated with 0.9 g of phosphorus trichloride. The reaction mixture is stirred for 90 minutes at -10 to -5, then diluted with 250 cm of ethyl acetate and washed with 150 cm of a saturated aqueous solution of sodium bicarbonate and twice with 100 cm of a saturated solution of sodium chloride. After drying over sodium sulfate and filtering, the or | solution is evaporated to dryness under reduced pressure (20 mm Hg, Art.) And 30 ° C. The residue is dissolved in 20 cm of methylene chloride and the solution is chromatographed on a column (height 25 cm, diameter 5 cm) containing 240 g of silica gel (0.04-0.063 Eluted with 2 l of a mixture of cyclohexane-ethyl acetate 60-40 (by volume) and taken fractions 100 cm. Fractions 8-13 are evaporated to dryness under reduced pressure (20 mm Hg) and 30 ° C. Obtain 1.7 g of 2-benzhydryloxycarbonyl-7-I2-methoxyimino-2- (2-tritylamino-4- thiazolyl) acetamido-3- (2-rosyloxivinyl) -8-oxo-5-thia-1-azadicyclo (4.2.0) -2-octene, isomer Sin, form E.Y. 0.52; chromatography on silica gel, eluent cyclohexane-ethyl acetate 50-50 (by volume). IR spectrum (C Vgz): 3400, 1790, 1725, 1685, 1520, 1375, 1190, 1180, 1075, 1050, 755 and 740 cm. NMR spectrum (350 MHz, CDClaX ppm j Hz): 2.42 (S, 3N and 5.42 (AB, j 19, 2H, -SCHo-); 4.07 (S, 3H, -OSNz); 5.03 (d, j 4, 1H, H in 6); 5.87 (dd, j 4 and 9, 1H H in 7); 6.71 (S, 1H, H in 5 thiazole) 6.87 (S, 1H, -CO. CHS); 6 , 87 (d, 1 10, 1H, -CH CH-OSO -); 7.0 (S, broad, 1H, -NH-thiazole); 7.78 (d, j 9, Ifl, -CONH-). Example 23. To cooled to a solution of 0.58 g of 2-benzhydryoxycarbonyl-8-oxo-5-oxide-7- (2-tieylacetamido) -3- (2-tosyloxyvinyl) -5-thia-1-: aabicyclo ( 4, 2.0) -2-okTen, form Z, 10 cm of methylene chloride and 0.328 cm of dimethylacetamide, 0.144 cm of phosphorus trichloride is added and stirred for 50 minutes at the same Dissolve at 150 cm temperature. And c ivuitiz ciA 17. JT Cl H. X. T. c.z. ha ha of ethyl ethyl acetate, washed twice with 80 ml of 2% sodium bicarbonate solution and twice with 80 cm half saturated. sodium chloride solution, dried, sodium sulfate, and evaporated to dryness under reduced pressure (20 Mm. and the residue is dissolved in 3.5 cm of a mixture of cyclohexane-ethyl acetate 80-20 (by volume) and chromatographed on hCOLO C. Kv J1 CrlJTHKoX At the end of the first stage of the process, the diameter of the column is 2.5 s and the height is 20 cm, 200 cm of the previous mixture are eluted. The first fraction 50 cm 3 is removed, the next fraction 150 cm is evaporated to dryness under reduced pressure (20 mm Hg) and 2bC. Obtain 0.42 g of 2-benzhydryloxycarbonyl-8-oxo-7- (2-thienylacetamido) -3- (2-tosyloxyvinyl) -5-thia-.1-azabicyclo (4,2,0) -2-octene, form Z as a cream colored mass. 58 Rf 0.72 silica gel chromatography solvent cyclohexane-ethyl acetate. 1-4 (by volume). Test Example 24. According to the method described in Example 22, but starting from 0.78 g of Form E by 2-benzhydryloxycarbonyl-8-oxo-5-oxide-7- (2-thienylacetales to) -3- ( 2-tosyloxivinyl) -5-thia-1-azabicyclo (4.2.2) -2-octene is obtained after filtration through silica gel 0.60 F of 2-benzhydhydroxycarbonyl-8-oxo-7- (2-thienylacetamido) - 3- (2-tosyloxyvinyl) -5-thia-1-azabicyclo (4.2.0) -2-octene (Form E) as a cream. Rf 0.70; chromatography on silica gel; cyclohexane ethyl acetate 1-4 solvent (by volume). Example 25. Restore (as described in example 23) 7.1 g. 2-benzhydryloxycarbnyl-7-tert.-butoxycarbonylamino-8-oxo-5-oxide-3T - (2-tosyloxyvinyl) -5-thia-1-azabicyclo (4,2,0) -2-octene, form E, dissolved 75 cm of methylene chloride and 4.62 cm of dimethylacetamide, 2.03 cm of phosphorus trichloride. After chromatography on silica gel with eluent cyclohexane-ethyl acetate 50-50 (by volume), 6.1 g of 2-benzhydryloxycarbonyl-7-tert.-butoxycarbonyl7 HO-8-OXO-3- (2-tosyloxyvinyl) -5-thia are obtained: - 1-azabicyclo (4,2,0) -2-octene, form E. IR spectrum (SNVHG): 3425, 1780, 1720, 1505, 1370, 1190, 1180, 1075 and 760 cm-L. NMR spectrum (350 MHz, COClS, ∆d, j Hz): 1.50 (S, 9H, –C (CH3))); 2.42 (S, 3N, -CH); 3.35 and 3.42 (2d, j 18, 2H,); 4.92 (d, j 4, 1H, H in 6); 5.59 (dd, j 5 and 9, W, H in 7); 6.84 (d, j 12, 1H, -CH-CHS-); 6.88 (S, 1H, -СООСНС); 6.90 (d, j 12, 1H, CHS). Example 26. 1.5 g of 2-benzhydryloxycarbonyl-7-2-methoxyimino-2- (2-tritylamino-4-thiazolyl) acetamido-8-oxo-3- (2-tosyloxyvinyl) -5-thia-1-azabicyclo ( 4,2,0) -2-octene, isomer Sin, form E, solution i .., -, h -1-cha in a mixture of 30 cm of formic acid and 10 cm of distilled water. The solution is heated to 50 ° C for 30 minutes. After cooling, the precipitate is filtered off and the filtrate is evaporated. A Jh A to dryness under reduced pressure (U mm Hg) and. The residue is triturated with 50 cm of diethyl. The solid product is separated by filtration, washed twice with 25 cm of ethyl ether, then dried under reduced pressure (5 mm Hg). 6.75 g of 7-G2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamio-, 2-carboxy-8-oxo-3- (2-tosylxivinyl) -5-thia-1-azabicyclo (4, 2.01-2-octene, syn isomer, Form E, in the form of a solvate with formic acid R 0.57; chromatography on silica gel with eluant ethyl acetate-acetone lead-acetic acid 50-20-10-10 (by volume). IR Spectrum (kVg): 3400, 3340, 3000 2820, 2200, 1775, 1720, 1670, 1630, 1370, 1190, 1165, and 1070 cm-. NMR spectrum (350 MHz / DMSO dfc, δ j Hz): 2.42 IS , 3H, -CH tosyl); 3.55 and 3.78 (AB, j 19, 2H,) 3.83 (S, 3N, -OSNg); 5.14 (d, j 4, 1H, H in 6); 5.75 (dd, j 4 and 9, Sh N at 7); 6.65 Id, 1H, -CH CH-PSO, 2-) J fS AND H in 5 thiazole) t, 18 (S, broad, -Nti); 9.58, fd .. j 9, 1H, -CONH-). 2-Benzhydryloxycarbonyl-7- 2-methoxyimino-2- (2-tritylamino-4-thiazolyl) acetamido-8-oxo-3- (2-tosyloxyvinyl) -5-thia-1-azadicyclo C4, 2.0) - 2- octene, the syn isomer, form E, can be obtained according to the procedure described in Example 22. Example 27. A mixture of 0.35 g of (2-amino-4-thiazolIl) -2-methoxy imino acetamido - 2-benzhydryloxycarbonyl-8-oxo-3-C2-tosyloxy-vinyl-5-thia-1-azadicyclo (4,2,0) -2-octene isomer syn, Form E, 10 cm of acid and 3 cm of water. Then add 8 cm of water, filter and evaporate to dryness at 30 ° C and 0.05 mm Hg. (0,007 kPa). Dissolve twice in 20 cm of ethanol, exuding each time to dryness, at pressures of 20 mm Hg. (2.7 kPa). The resulting solid is triturated with 20 cm of diethyl ether. After filtration and drying, 0.12 (2-amino-4-thiazolyl) -2-methoxy-imino-adamido -2-carboxy-8-oxo-3 - (2-tosyloxyvinyl) -5-thia-1-azabicyclo (4,2 , 0) -2-octene, syn isomer, form E, in the form of a yellow powder. IR spectrum (KBr): 3360, 3200, 3100, 2000, 1-770, 1670, 1630, 1530, 1370, 1190, 1175, 1070, 1045, 925 and 810 cm-. NMR spectrum (350 MHz, DMSO de, "ppm, s Hz) 2.45 (S, 3N, -CHj); 3.58 and 3.80 (2d, j 18, 28, -SCH- -); 3,88 (S, ЗН, -ОСНз); 5.18 (d, j 4 -1H, H in 6); 5.78 (dd, j 4 and 9, 1H H at 7); 6, -68 and 7.20 (2d, j 12, 2H); 6.74 (S, 1H, H thiazole); (S, 2H, -NH); 7.51 and 7, 88 (2Y, j 8, 4H, tosyl group); 9.58 (d -j 9, 1H, -CONH-). Example 28. A mixture of 0.494 g of 2-benzhydryloxycarbonyl-7- 2-methoxyimino-2- (2-tritylamino-4-thiazolyl) adamide-8-oxo-3- (2-tosyloxyvinyl) - 5-thia-1-azabicyclo (4,2,0) -2-octene, isomer syn, form E, 20 cm5 acetone and 10 mg of p-toluenesulfonic acid hydrate. Evaporated to dryness at a pressure of 20 mm Hg. and 20 ° C, dissolved in 30 cm of ethyl acetate and 20 cm of a 5% sodium bicarbonate solution are decanted, the organic phase is dried over sodium sulfate, filtered and evaporated to dryness. with a pressure of 20 mm Hg. and 20 ° C. The residue is chromatographed on a column of 50 g of Merck silica gel (0.06-0.2). The column diameter is 3 cm, height is 27 cm. Elute 0.4 L of ethyl acetate and collect fractions of 20 cm. Fractions 8-10 are a mixture of the starting material and the desired product, fractions 11–17 are evaporated to dryness under a pressure of 20 mm Hg. and 20 ° c. I get 0.150 g of (2-amino-4-thiazolyl) -2 - methoxyiminoacetamido1-2-benzhydryloxycarbonyl-8-oxo-3- (2-tosyloxyvinyl) -5-thia-1-azadicyclo (4, 2, and J -2 α-octene, syn isomer, Form E, in the form of a cream-colored solid IR spectrum (SNF): 3480, 3390, 3340, 3210, 1780, 1725, 1680, 1620, 1600, 1530, 1495, 1455, 1445, 1360 , 1190, 1180, 1075, 1050, 925, 810 and 760 cm. NMR spectrum (350 MHz, DMSO db, d, j Hz): 2, -43 (S, 3N, -CHj); 3, 61 and 3.85 (2d, j 18, 2H, -SCHn3, 86 (S, 3N, -OSNz); 5.22 (d, j 4, 1H, H in b); 5.85 (dd, j 4 and -9, 1H H in 7); 6.54 and 7.38 (2d, j 12, 2C,); 6.75 (S, 1H, P thiazole); 6.88 (S, 1H, -СООСНС) ; 7.20 (S, 2H, -NHg); 7.50 and 7.84 (2d, j 8, 4H, tosyl group); 9.62 (d, j 9, 1H, -CONH-). Example 29 Put in a con act for 30 min at 4 ° С 0.42; 2-benzhydryloxycarbonyl-8-oxo-7- (2-thienylacetamido) -3- (2-tosyloxy-vinyl) -5-thia-1-azabicyclo (4,2 , 0) -2-octene, form Z, and 10 cm of trifluoroacetic acid, evaporated to dryness under reduced pressure (20 mm Hg and 20 ° C. the residue is dissolved in 150 cc of 1% sodium bicarbonate solution and washed with 150 cm of ethyl acetate. The aqueous phase is brought into contact with 150 cm of ethyl acetate and acidified with stirring with 1N hydrochloric acid solution in order to bring the pH to approximately
[2]
2. Decant, wash the ethyl acetate phase with 100 cm of a saturated solution of sodium chloride, dry over sodium sulfate and evaporate to dryness under reduced pressure (20 mm Hg and 20 ° C. Triturate the residue with 20 cm of diethyl ether and obtain after filtration and drying 90 mg of 2-carboxy-8-OXO-7- (2-thienylacetamido) -3- (2-tosyloxyvinyl) -5-thia-1-azabicyclo (4,2,0) -2-octene, form Z, as cream colored powder. IR spectrum (KBr): 3400, 2700, 2200, 1775, 1715, 1670, 1520, 1375, 1190, 1180, 815, 760 and 550. NMR spectrum (350 MHz, DMSO d, M.D. ., j Hz); 6,12 (d, j 7, -CH CHOSOo-); 6,62 (d, j 7, CHOS02-). P p and M ep 30. According to the method of example 29, but starting from 6.00 mg of 2-benz hydryloxycarbonyl-8-oxo-7- {2-thienylacetakido) -3- (2-tosyloxyvinyl) -5 | -thia-1-azabicyclo (4,2,0) -2-octaHai Form E, receive 70 mg of 2-carboxy-8-oxo-7- (2-thienyl acetacdato) (2-tosyloxyvinyl) -5-thia-1-azabicyclo (4.2.2) -2-octene, form E, in the form of cream colored powder. IR spectrum (KVg): 3380, 2700, 220 1775, 1715, 1675, 1525, 1370, 1190, 1180, 815 and 700 cm-1 NMR spectrum (350 MHz, DMSO dfe, .d., j Hz): 2.43 (S, 3H, -CHj); 5.08 (d, j 4, 1H, H in 6); 5.65 (dd, j 4 and 9, 1H, H at 7); 6.65 - (d, j 9, 1H, OBO, -); 7.17 (d, j 9, CHOSO -). 2-Benzhydryloxycarbnyl-8-oxo-7- (2-thienylacetamido) -3- (2-tosyloxyvinyl) -5-thia-1-azabicyclo (4.2.0 p2-octene (form E) can be obtained by the method described in example 24. Example 1. PRI me R 31. A solution of 0.78 g of 3- (2-acetoxyvinyl) -2-benzhydryloxycarbonyl-8-oxo-7- (2-thienylacetate amido) is stirred for 2 hours at 4 ° C. ) -5-thia-1-azabicyclo (4,2,0) -2-octene (form E) in 8 cm of trifluoroacetic acid and anisole see. Evaporate to dryness under reduced pressure (20 mm Hg) and triturate the residue with 20 cm of diethyl ether, filtered and dried, 0.48 g of crude solid is obtained. The brown color of the product is purified by dissolving it in 200 cm of diethyl ether, acidifying it to a pH of 2 with 1 and a solution of hydrochloric acid and extracting three times with 15 cm of ethyl acetate .. The organic phase is separated and dried over sodium sulfate, then evaporated to dryness under reduced pressure (20 mM Hg) I. 0.18 g of 3- (2-acetoxyvinyl) -2-carboxy-8-oxo-7- (2-thienylacetamido) -5-thia-1-azabicyclo ( 4.2.0 -2 -2-octene, form E, in the form of a cream-colored powder .. IR spectrum (KVg): 3320 1775, 1760 1670, 1640, 1530, 1370, 1200, and 700 cm. NMR spectrum ( 350 MHz, CDClj, / ppm j Hz): 2.18 (S, 3N, —ССНз); 3.65 and 3.82 (2d, j 18, 2H, -SCHa-); 5.12 (d, j 4, 1I, H in 6); 5.66 (dd, j 4 and 9. 1H, H at 7); 6.33 (d, j «4, H in 5 thiophene); 6-, 81 (d, j 13, 1H, -CH-CH-0-); 6.94 (mt, 2H, H in 3 and 4 thiophene); 7.68 (d, j 13, 1H, CH-0-); 9.12 (d, j 9, 1H, -CONH-). The starting material was obtained as described in Example 25. The products described in the following examples can be used to prepare the products according to the invention. Example 32 Starting from 66 g of 2-benehydryloxycarbonyl-7- (D-ct-tert.-butoxycarbonylaminophenylacetamido) -3- (2-dimethylamino-novinyl) -8-oxo-5-thia-1-azabicyclo (4.2, 0) -2-octene, form E, according to the procedure described in i in example 4, 57.9 g of brown mass are obtained, the values of which are identical to those of 2-benzhydryloxycarbonyl-7- (P-oC-tert.-butoxycarbonylaminophenylacetamido) - 8-oxo-3- (2-oxostil) -5-thia-1-azabicyclo (4,2,0) -2-octene / obtained in example
[3]
3.. Example 33. Starting from 1 g of 3- (2-dimethylaminovinyl) -2- (4-nitrobenzyloxycarbonyl) -8-oxo-7-phenoxy-acetamido-5-thia-1-azabicyclo (4.2.2) -2-octene, Form E, crude, according to the procedure described in Example 1, gives 0.74 g of an orange mass, consisting essentially of 2- (4g-nitrobenzyloxycarbonyl) -8-oxo-3- (2-ococoethyl) -7-phenoxyacetate; 5-thia-l-azabicyclo (4,) - 2-octene. IR spectrum (SNVhz): 3400 (-YNI-ON enol form); 2730 (aldehyde C-H); 1780 (carbonyl (4-lactam); 1720 (conjugate ester and aldehyde carbonyls); 1690 (carbonyl amide); 1650 (enol carbon-carbon double bonds); 1520 and 1345 (-Ce,). 3 - ( 2 - Dimeti lamine no NILE) - 2- (4-nitrobenzyloxycarbonyl) t8-oxo-7-phenoxyacetamido-5-thia-1-azabicyclo (4,2,0) -2-octene, form E, crude, can be prepared as follows: A solution of 17 g of 3-methyl-2- (4-nitrobenzylox-1-carbonyl) -8-oxo-7-phenoxy-acetamido-5-thia-1-gasadicyclo (4.2.0) -2-octene in 100 sg4 anhydrous N , Ndimethylformamide is heated to 80 ° C in a dry, nitrogen atmosphere, then forgotten to 10.8 cg l bis-dimethylamino-tert-butoxymethane for 1 min at 80 ° C. After that, the reaction mixture is diluted with 400 cm of ethyl acetate and 250 cm of stilted ode.The organic phase is decanted, washed twice with 250 cm of distilled water, then 250 cm of saturated aqueous Atri chloride solution, dried and filtered. The resulting residue after evaporation of the solution under reduced pressure (20 mm Hg) and 30 ° C was again dissolved in 50 cm of methylene chloride and the solution was drunk dropwise in 1600 cm of isopropyl oxide. The resulting precipitate is drained, washed four times with 100 cm of isopropyl oxide and dried under reduced pressure (10 mm Hg) and 25 °; 8.6 g of porous ocher color are obtained, the IR and NMR spectra of which indicate that it consists mainly of E- (2-dimethylaminovinyl) -2- (4-nitrobenzyloxycarbonyl) -8-oxo-7-phenoxyacetamido-5 -thia-1-aza6icyclo (4,2,0) -2-octene, form E. R 0,3; chromatography on silica gel with eluent cyclohexane-ethyl acetate 40-60 (by volume). Example 34. 1d. 2-benzhydryloxycarbonyl-7-benzoylamino-3 - (2-dimethylaminovinil) -8-oxo-5-thia -1-azabicyclo C4,2,0) -2-octene, forms E, dissolved at 10 cm pure formic acid . The resulting solution was poured into a mixture of 100 cm of acetate and 100 cm of distilled water. The organic phase is decanted and washed successively with 100 cm of distilled water, 100 cm; a saturated aqueous solution of sodium chloride, twice 50 cm of a saturated aqueous solution of sodium bicarbonate | ) and and 100 cm of a saturated aqueous solution of sodium chloride. After drying over maggate sulphate, the solution is filtered and evaporated to dryness under reduced pressure. 0.9 g of an orange mass is obtained, consisting essentially of 2-benzhydryloxycarbonyl-7-benzonamino-8-oxo-3- (2-oxoethyl) -5-thia-1-azabicyclo (4.2.0 -2- octene. Rf 0.37; chromatography on silica gel with cyclohexane-istidelated salt 50-50 (by volume). IR spectrum (KBG disks): 2720 (CH aldehyde); 1770 (carbonyl / l-lactam). 2-BenzhydrSh1Oxycarbonyl -7-benzo-ylamino-3- (2-dimethyl ovinyl) -8-oxo-5-thia-1-azadicyclo (4,2, O) -octene, form E, can be obtained as follows: To a solution of 24 g 2 -benzhydryl-1-carbonyl-7-benzoylamino-3-methyl-, 8-ca bb-5-thia-1-azadicyclo (4,2,0) -2-octene 100 g of anhydrous dimethylformamide was added under dry nitrogen to 10 g of bis-dimethylamino-tpeT. -butoxymethane. The reaction cider was stirred at 25 ° C for 23 hours, then poured into a mixture of 300 cm of ethyl acetate and 700 cm of a saturated aqueous solution of sodium chloride The aqueous phase is decanted and extracted with 250 cm of ethyl acetate. The organic phases are combined, washed with 250 cm of a 1N aqueous solution of hydrochloric acid, 500 cm of distilled water and 300 cm of a saturated aqueous solution of sodium chloride,; It is dried over magnesium sulphate in the presence of vegetable black and filtered. The solvent is evaporated under reduced pressure (20 mm Hg) and 30 ° C. The residue is dissolved in 200 cm of methylene chloride and fixed onto 50 g of silica gel. The resulting powder is placed in a column (height 60 cm, diameter 5 cm) containing 415 g of silica gel in a mixture of cyclohexane-ethyl acetate 95-5 (by volume). 5 l of a mixture of cyclohexane-ethyl acetate 95-5 (by volume), then 5 l of a mixture of cyclohexane-ethyl acetate 90-10 (by volume), then 5 l of cyclohexane-ethyl acetate 80-20 (by volume) and 7.5 l of a mixture of cycloheissane are eluted - ethyl acetate 70-30 (by volume) to remove impurities, then 8 l of a mixture of cyclohexane-ethyl acetate 60-40 (by volume), which is collected and evaporated to dryness. Get 10.4 g of 2-benzhydryloxycarbonyl-7-benzoyl: amino-3- (2-dimethylaminovinyl) -8-oxo-5-thia-1-azabicyclo (4,2,0) -2-octene, form E, as a yellow solid. Rf 0.24; chromatography on silica gel with cyclohexane-ethyl acetate 50-50 (by volume). IR Spectrum (CHSS); 2800, 1760, 1740, 1660 and 1605 cm NMR spectrum (60 MHz, CDClj, sLm.d 2.85 (S, 6H, (eH3)); 5.1 (d, j 4 Hz, 1H, H in 6 ); 5.65 (ddj j 9 and 4 Hz, 1H, H in 7); 6.8 (S, 1H, -CH (C (, H5) 7); 7.05-8.2 (massive, aromatic and -CONH-). UV spectrum (, C 1.9-10-5m, .P 1 cm), s, 392 nm; 1 6000. The invention The method of obtaining 3-oxivinylcephalosporin derivatives of the formula RlT9H- (| .JCH CH -0-Cs o where R is hydrogen, trityl, tert.-butoxycarbonyl, a radical of the formula Rj-CH-where R is phenyl or 2-thienyl; hydrogen or an amino group protected by a tert-butoxyncarbonyl, or a formul radical of DT1 1e R-hydrogen or tritis; R, - m or vinyl; RJ - hydrogen or benegi Rj - oyl, meel, acetyl, or it is mapoyl; n O or 1; piktirna line means a double bond in position 2 or 3 of the cephalosporin ring, as a mixture of isomers or individual isomers, characterized in that the compound of the formula. (V K has the indicated values other than hydrogen, and provided that the free syn-groups are wrinkled and n has the indicated values, they are reacted with a compound of the formula Yaz - C1, OH) where R} has the indicated values, in a solvent in the basic medium during the tetrature from room to - Soyas and if necessary when and p 1, the obtained 3-hydroxy-d is converted by reduction to sulfide or, when p o, the resulting sulfide is converted by oxidation to S-oxide and, if necessary, the desired product, where RI is benzhydryl, is converted to the target product, where hydrogen and / or, if necessary, remove the R or Rf, group, covering the amino group, and isolate the target product as a mixture of isomers or divide it into individual isomers. Sources of information taken into account in the examination 1. US patent 4001225, cl. 260-243 C, published. 1977.

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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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FR7913097A|FR2457297B1|1979-05-23|1979-05-23|

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