Process for producing derivatives of 2-penem-3-carboxylic acid, or its susbtitutedderivatives, or it

专利摘要:

公开号:SU925252A3
申请号:SU792720750
申请日:1979-02-01
公开日:1982-04-30
发明作者:Гостелли Жак；Эрнест Иван；Ланг Марк；Бэрнс Вудворт Роберт
申请人:Циба-Гейги Аг (Инофирма)；
IPC主号:

专利说明:

These compounds possess the properties of antibiotics and are used in the manufacture of pharmacological agents 11. The purpose of the invention is to obtain new compounds that expand the arsenal of effects on a living organism. The goal is achieved based on a known reaction method for the preparation of 2-penem-3-carboxylic acid derivatives of the formula I Ea H oJ-N-JL o where RO is the lowest-kil, hydroxy- (low) alkyl, where the hydroxy group can be protected by a group such as, for example, a p-nitrobenzyloxycarbonyl group, a phenyl (lower) alkyl, phenyl or phenoxy (lower) alkanoyloxy radical; R, is a hydrogen atom, lower alkyl. amino (lower) alkyl, acylamino (lower) alkyl, lower alkylthio, amino (lower) alkylthio or acylamino (lower) alkylthio radical, where the amino group may be protected by a protective group, such as, for example tert-bucket sicarbonyl or p-nitrobenzyloxycarbonyl, in the form of free acid, or in the form of its protected derivatives, such as acetonyl or p-nitrobenzyl ester, or in the form of its salts, such as the sodium salt, which means that the ylidene compound of the formula II where RO. and RI is as defined above, the functional groups in these residues are preferably in protected form and R is a radical forming together with the carbonyl moiety, -C (0) is a protected carbonyl group; Z is oxygen or sulfur; X means either triza-displaced phrsonio group, or twice 1 esterified phosphono group with ester, cyclized by heating to 30160 С in an inert solvent, if necessary, protecting oxy, amino from carboxyl-protecting groups and, if necessary, If necessary, the resulting free compound is converted to salt. In the starting material of formula II, the functional groups are usually in protected form, and the amino group, for example, also in the form of a nitro or azido group. In the starting material of formula II, the radical R means a hydroxy group that is esterified to ether and forms, with the group C (0), easily split, especially under mild conditions, a carboxyl group that has been esterified to ester, and, if necessary, functional groups in the carboxyl-protecting group, Rj may be protected. The group is in particular lower alkoxy, for example, methoxy or tert -butoxy, lower alkenyloxy, in particular 2- (lower) alkenyloxy, for example allyloxy, or .2-halogen (lower) alkoxy, for example 2.2, 2-trichloroethoxy, 2-bromoethoxy, or 2-iodoethoxy; 2- (lower) alkylsulfonyl (lower) alkoxy, for example 2-methylsufonylethoxy, or substituted if necessary, such as containing lower alkoxy, for example methoxy, or nitro, 1-phenyl (lower) alkoxy, such as benzyloxy, - methoxybenzyloxy, 5 nitrobenzyloxy, diphenylmethoxy or, dimethoxydiphenylmethoxy, - (methacylphenyloxy, acetonyloxy, 2-cyanoethoxy, 2-trimethylsilyl ethoxy, 2- (dibutylmethylsilyl) -ethoxy, or 2-triphenylsilyloxytoxy) -hydroxyroxyroxyroxyroxyroxyroxyroxyroxyroxyroxyroxyroxyroxyroxyroxy. alkylsilyloxy, n An example is trimethylsilyloxy or one of the above hydroxy groups that are esterified to ether and which are cleaved under physiological conditions, most preferably R2 is p-nitrobenoylloxy. Group X in the starting material of formula II is one of the phosphonio or phosphonogroup used in the Wittig condensation reaction, in particular triaryl-, for example, triphenyl 792 bodyside carboxyl groups, either together or selectively. In a compound of formula I containing a free carboxyl group, such a group can be converted into protected by a carboxyl group. In this way, esters are obtained. In a compound of formula I with a carboxyl group that has been esterified to an ester, this group can be converted to another carboxyl group that has been esterified to an ester. In the process, free functional groups, such as free amino compounds, for example, by acylation, three types of titration or silicating, free hydroxy groups and mercapto groups, for example, by esterifying to simple or ester, including silicon, are temporarily protected and can be released after the reaction. separately or together. ; The proposed compounds can be used, for example, for the preparation of pharmaceutical preparations containing an active amount of an active principle together or in a mixture with inorganic or organic, solid or liquid preparations used for (pharmaceutical purposes, which are suitable for enteral and parenteral use. Pharmaceutical preparations that may contain other pharmacological valuable substances are prepared, for example, using traditional methods of mixing, granulating, drafted and, dissolving or lyophilizing, and contain from about 0.1 to 100, in particular from about 1 to 50% of the active principle, and lyophilized preparations up to 100 active principle. The organic radicals mentioned contain (unless the term “lower” is not specifically stated) to 7, preferably up to carbon atoms. P RI meper 1. Preparation of 4-acetyp thio-3-methyl-2-oxo-azethyl / cine (racemic cis and trans-compound); 38 mg solution (3.0b mmol) -acetoxy -Z-methyl-azetidin-2-one (racemic mixture of cis and transisomer in a ratio of 3: 1, melting point 53-65 ° C) 1.13 ml of water and 0.27 ml of acetone are mixed at room temperature under a nitrogen atmosphere dropwise with a solution of 0.33 ml of thioacetic acid in t, 5 ml of 1 N sodium hydroxide solution and stirred at this temperature for 3 hours. The reaction mixture is exhaustively extracted with methylene chloride. The combined organic phases are dried over sodium sulfate and evaporated in vacuo. The residue is chromatographed on silica gel with a mixture of toluene / ethyl acetate (: 1–3: 1) and semi °, first a pure trans compound, then a mixture of cis and trans isomers, and then a pure cis compound. DX (xfio gram obtained by the method of thin layer chromatography on silica gel) Rf 0.31 (cis isomer); 0.3b (transisomer) (toluene / ethyl acetate 2: 3); IR spectrum (W2SE2): absorption bands at 2.95; 5.6; 5.87; 8.65; 8.85; 10.5 microns. NMR spectrum (in CDCEj / IOOMc; in parts per million): cis compound: 6.2, 1H, wide (DjO substitution); 5.4 $, 1H, d (J 5., 5. Hz); 3.5-3.3, 1H t; 2, +, 3N, S; 1.3, ZN, d; trans-compound 6.5, 1H, wide (substitution); , 93; 1H, d (J 2.5 Hz1; 3.03, 4, 1H t; 2.4 ZN, S; 1, 2, ZN d. Example 2. Preparation of 2- p-nitrobenzyl ester 2 (A-acetylthio-3- methyl 2-oxo-1-azetidinyl) -2-hydroxyacetic acid (racemic CIC-, transmix) .At room temperature, 129 mg (S, 81 mmol) -acetylthio-3-methyl-2-oxo-azetidine (racemic cis- , transsmix) is mixed with a solution of 500 mg of 2-ethoxy-2-hydroxyacetic acid para-nitrobenzyl ester mixed with 10 ml of toluene and 2.5 ml of dimethylformamide. After adding freshly dried molecular sieves, the mixture is stirred under nitrogen for 2 hours at 50 ° C. Molecules p The sieves are filtered, washed with toluene, and the filtrate and the washing are co-evaporated under vacuum.The residue is dried under high vacuum and chromatographed on silica gel with a mixture of toluene-ethyl acetate in a ratio of 9: 1 to 8: 2. After eluting unreacted para-nitrobenzyl ether 2 is ethoxy -2-hydroxyacetic acid elute a mixture of cis-trans-isomers with the following physicochemical properties: DC: R 0.38 (toluene - ethyl acetate 2: 3); IR (CHjCF): absorption bands at 2.85; 5.62; 5.7; 5, -9; .6,2; 6.55; 7, and 8.25 microns. Example 3. Preparation of 2- (4-acetylthio-3-methyl-2-oxo-1-azetidinyl) -2-triphenyl-phosphoranylidene-acetic acid para-nit robenzyl ester (racemic cis-transmix). a) A solution of 225 mg of 2- (4-acetylthio-3-methyl-2-oxo-1-azetidinyl) -2-hydroxyacetic acid para-nitrobenzene ovate (racemic cis-transmix) in 5 ml of absolute dioxane is added to the mixed within 30 minutes to a solution of 1 g of the base of Hunig in 2.5 ml of absolute dioxane. After adding a solution of 0.175 ml of thionyl chloride in 1.5 ml of absolute dioxane, the reaction mixture is stirred for 100 minutes at room temperature and under nitrogen atmosphere. The Hönib base is filtered, washed with dioxane and the filtrate evaporated in vacuo. DX crude 2- (+ -acetylthiotrimethyl-2-oxo-1 -azetidinyl) -2-chloro-acetic acid p-nitrobenzyl ester (racemic cis - transme): Rf 0.62 (toluene-ethyl acetate 2: 3). b) The resulting 2 - (- acetylthio-3-methyb-2-OXO-1 -azetidinyl -2-chloroacetic acid crude p-nitrobenzyl ester is dissolved in 12 ml of absolute dioxane, mixed with 1 g of Hunigas base, mixed for 30 minutes and then mixed with 312 mg of triphenylphosphine and stirred for 15 hours at 50 ° under nitrogen. Polybase Hönig is filtered off, washed with dioxane and the filtrate and the washing liquid are evaporated together in vacuo. The residue is chromatographed on silica gel with a mixture of toluene - ethyl acetate and a cis transmix with the following physical chemical properties: DC: R 0.28 (toluene - ethyl acetate 2: 3); IR spectrum () of the absorption band at 5.67; 5.9; 6.15; 6.55; 6.95; 7,; 9 , 0, and 9.25 µm Example: Preparation of 2,6-dimethyl-2-penem-3-carboxylic paranitrobenzyl ester (racemic cis-methyl mixture). 118 mg solution of 2- (α-acetylthio-3-methyl para-nitrobenzyl ester -2-oxo-1-azetidinyl) -2-triphenylphosphorus anilidene acetic acid (racemic cis-transmix) in 50 ml of absolute toluene was mixed with a catalytic amount of para-hydroxyquinone and stirred under nitrogen for 8 hours at 90 °. The solvent is evaporated in vacuo and the residue is chromatographed on silica gel with 19: 1 toluene ethyl acetate. A cis-transmixture (1 :) is obtained in the form of a yellowish oil with the following physicochemical properties of LH: Rf 0.59 (toluene ethyl acetate 2: 3); IR (CHjO): absorption bands at 5.6; 5.35; 6.3 6.55; 7; 7.6; 8.3; 9.5 microns; NMR spectrum (in CDCfj / lOO MS; in parts per million); 8, 2; 2H, 7.75-7.76, 2H, t; 5.7-5.2, ЗН, t; ““ .3B, 1H, t; 2, k, 2 .. ЗН, 2 S; 1.6–1, C, 3N, 2 d. Example 5. Preparation of 2,6-dimethyl-2-penem-2-carboxylic acid (racemic cis-transmix). A solution of mg (0.1 mmol) of 2,6-dimethyl-2-penem-3-carboxylic paranitrobenzyl ester (racemic cis-transmix I :) in 3 ml of absolute ethyl acetate is mixed with 2 ml of a 0.2 M aqueous solution of sodium bicarbonate and 100 mg of a 10% palladium catalyst and stirred at normal pressure for 0 min in a hydrogen atmosphere. The hydrated mixture is filtered from the catalyst through diatomaceous earth, further washed with a 0.2 M sodium hydrogen carbonate solution and several times with ethyl acetate. The aqueous phase is washed with methylene chloride, acidified with an aqueous solution of citric acid and exhaustively extracted with methylene chloride. The combined organic phases (dried over sodium sulfate, filtered, evaporated in vacuo and dried in high vacuum. The resulting compound (cis-transm, approximately 1 :) has the following physicochemical properties: JH: Rf 0.28 (toluene ethyl acetate - acetic acid 60: tO: 5); IR spectrum () absorption bands at 3.5, 5.6, 5.95, 6.3 microns; NMR spectrum (DMSO d 6/100 Me; in parts per million): 5.65 , 1H, q; 3.3-3.9, 2H, m (j-HjO); 2.28, 3N, S, T. pl. 119. PRM and MER 6. Preparation of sodium salt 2, 6-dimethyl-2-penem-3-carboxylic acid (racemic cis-transmix). Solution 50 mg of 2,6-dimethyl-2-penem-3-carboxylic acids in an equivalent amount of an aqueous solution of sodium bicarbonate are evaporated in vacuo and dried in high vacuum Example 7. Preparation of 4-acetylthio-3-methyl-2-oxo-azetidine (racemic cis-trans compound). A solution of 2 g of α-acetoxy-3- methyl azetidin-2-one (racemic mixture of cis and trans isomers in a ratio of 3: 1; melting point 53-65 °) e 5.16 ml of water and 1.25 ml of acetone are mixed at room temperature under nitrogen atmosphere and dropwise with a solution of 1.5 ml of thioacetic acid 8 20.5 ml of 1N sodium hydroxide solution and stirred at this temperature 3 hours. The reaction mixture is exhaustively extracted with methylene chloride. The combined organic phases over sodium sulfate are evaporated in vacuo. The residue is chromatographed on 150 g of silica gel with 9: 1 toluene-ethyl acetate and a substantially pure trans-isomer of the compound is obtained with the following physicochemical properties of DC: 0.38 (toluene-ethyl acetate 2: 3V, IR spectrum ( 01.062): absorption bands at 2.95, 5.6, 5.87, 7.37, 7.5, 8.6, 8, 82 microns, NMR spectrum (CDCEj / lOO Me; in parts per million): 6.55 , 1H, ha (substitution of LH);, 9, 1H, d, J) 2 Hz, 3.35-3.05, 1H, t; 2, 38, ЗН, Sl, i, ЗН, d, J 7 Hz. The following describes the selection of a mixture of cis and trans isomers. Example 8. Preparation of (2 - (- acetylthio-3-methyl-2-oxo-1-azetidinyl) -2-hydroxyacetic acid (paranitrobenzyl ester) (racemic trans-compound). At room temperature 1, 35 g (8, + 9 mmol) - acetylthio-3-methyl-2-oxo-azetidine (racemic trans-compound) is mixed with a solution of 5 g of 2-ethoxy-2-hydroxyacetic acid para-nitrobenzyl ester in a mixture of 100 ml of toluene and 25 ml of dimethylformamide After adding freshly dried molecular sieve, the mixture is mixed stirred under nitrogen for 15 h | gtri "at ambient temperature and then for 2 h at 50 °. M the molecular sieves are filtered off, washed with toluene and the filtrate and the washings are evaporated together in vacuo, the residue is dried under high vacuum and chromatographed on 100 g of silica gel with toluene-ethyl acetate 9: 1. After elution of unreacted para-nitro benzyl ether 2-9 toxic acetic acid is eluted with the following physicochemical properties: DC: Rf 0.33 (toluene - ethyl acetate 2: 3); IR spectrum (CHjCtz): absorption bands at 2.85, 5.6, 5.7, 5, 87, 6.2, 6.52, 7, k, 8.28, 9-9.2 microns. Example 9. Preparation of 2- (-acetylthio-Z-methyl-2-oxo-1-azetidinyl) -2-triphenylphosphoranylidene-acetic acid para-nitrobenzyl ester (racemic trans-compound) i a) A solution of 3 g of 2- (4-para-nitrobenzyl ester) acetylthio-3-methyl-2-oxo-1-azetidinyl) -2-hydroxyacetic acid (racemic trans-compound) in 75 ml of absolute dioxane. 13.5 g of Hunig's base in 35 g of absolute dioxane are added to a solution that has already been stirred for 30 minutes. After adding solution 2, ml of thionyl chloride in 22, ml of absolute dioxane, the reaction mixture is stirred for 100 minutes at room temperature and under nitrogen atmosphere. Hyunig's polyacid is filtered off, washed with dioxane and the filtrate evaporated in vacuo. DX crude para-nitrobenzyl ester 2 - (- (- acetylthio-3-methyl-2-OKco-l-azetidinyl) 2-chloroacetic acid (racemic trans-compound): R 0.59 (toluene ethyl acetate 2: 3). b) The resulting 2 - (- acetyl-thio-3-methyl-2-OXO-1-azetidinyl) -2-chloroacetic acid crude p-nitrobenzyl ester is dissolved in 175 ml of absolute dioxane, mixed with 13.5 g of Hunigas base; then mixed with 2 mg of triphenylphosphine and stirred for 15 hours at 50 ° under nitrogen atmosphere. The base of the Hunig is filtered off, washed with dioxane and the filtrate and the washings are evaporated together in vacuo. The residue is chromatographed on silica gel with a mixture of toluene ethyl acetate and a trans compound is obtained with the following physicochemical properties: DC: R 0.2 (toluene ethyl acetate 2: 3); IR spectrum (absorption bands at 5.67, 5.9, 6.15, 6.55, 7, 9.0 microns. Example 10. Preparation of 2,6-dimethyl-2-penem-3-carbonyl para-nitrobenzyl ester acids (racemic trans-compound). A 3-mg (4-acetylthio-3-methyl-2-oxo-1-azetidinyl) -3-triphenylphosphoranylidene-acetic acid 2-(4-acetylthio-3-methyl-2-oxo-1-azetidinyl) para-nitrobenzyl ester solution is mixed with catalytic amount of para-hydroxyquinone and stirred under nitrogen for
 h at 90. The solvent is evaporated in vacuo and the residue is chromatographed on 20 g of silica gel with a mixture of 19: 1 toluene ethyl acetate. A trans compound is obtained in the form of yellowish crystals with a melting point of 141-1 3 and the following physicochemical properties: DC: K 0.6 (toluene-ethyl acetate 2: 3); IR spectrum () - absorption bands at 3 ,, 5.77 5.82, 6.27, 6.55, 7 ,, 7.6, 8.3, 9.22 microns; NMR spectrum (in CBC s / OO MS; in parts per million): - 8.25-8.15, 2H, w; 7.65-7.56, 2H, t; 5.55-5.12, 3N, m + d (J 1.5 Hz); 3 9-3,6, 1H, m 2.36, ЗН, S; 1.5, 3N, d.
Example P. Preparation of 2,6-dimethyl-2-penem-3-carboxylic acid (racemic trans-compound).
A solution of mg (0.2 mmol) of 2,3-Dimethyl-2-penem-3-carboxylic acid paraiitrobenzyl ester (racemic trans-compound) in 5 ml of absolute ethyl acetate is mixed with 3 ml of a 0.2 N aqueous solution of sodium hydrogen carbonate and 150 mg of palladium catalyst and stirred under normal pressure for 50 minutes in a hydrogen atmosphere. The hydrogenated mixture is filtered from the catalyst through diatomaceous earth, further washed with a 0.2 N sodium hydrogen carbonate solution and several times with ethyl acetate. The aqueous phase is washed with methylene chloride, acidified with an aqueous solution of citric acid and exhaustively extracted with methylene chloride. The combined organic phases are dried over sodium sulfate, filtered, evaporated in vacuo and dried in high vacuum. The compound obtained has the following physicochemical properties: melting point 119 ° (decomposition); HH:
Rf is 0.3 (toluene-ethyl acetate-acetic acid); IR (potassium bromide): absorption bands at 3.3-3.5, 5.62, 6.0, 6.35, 6.95, 7, $ 5, 7.85 µm; NMR spectrum (DMSO dg / lOO Me; a ppm): 5.38, 1I, d, (J 1.5 Hz); 3.7, TN t; H., tH, m (substitution); 2.2, ZN, S; , ZN, d.
Example 12. Preparation of α-acetylthio-3-isopropyl-2-oxo-azetidine (racemic trans compound).
A solution of 750 mg (mmol) h-acetoxy-3-isopropyl-azetidin-2-one (racemic mixture of cis and trans isomer in a ratio of 1: 3) in 3.6 ml of water and 0.9 ml of acetone are mixed at room temperature under nitrogen dropwise with a solution of 0.52 ml of thioacetic acid in 7 ml of 1 N sodium hydroxide solution and stirred at this temperature for 75 minutes. The reaction mixture is exhaustively extracted with methylene chloride. The combined organic phases are dried over sodium sulfate and evaporated in vacuo. The residue is chromatographed on 40 g of silica gel with a mixture of toluene - ethyl acetate. and get a transconnection. DH: Rf O, (toluene ethyl acetate 2: 3); IR spectrum (Q: 2Cfz} absorption bands at 2.95, 3.37, 5.62, 5.87, 8.8 µm. NMR spectrum (in Me; in ppm): 6.35, 1H m ( substitution DjO); 5.01, 1n, d (J 2.5 Hz; 3.0, 1H, t; 2, -37, 3N, S; 2.1, 1H, t; 1.05, 3N t.
The starting material is prepared as follows.
a) A mixture of 172.28 g (216.5 ml;
2 mol) of isovaleric acid aldehyde, goiter g (283 ml) of acetic anhydride and 2k g of fresh potassium acetate are boiled for 17 hours under reflux. The cooled mixture is washed with sodium carbonate solution until the organic phase is neutral. After washing with water and drying over magnesium sulfate, the resulting oil is distilled. H-methyl-1-butenyl acetate is obtained (cystranssmix 1 :) with a boiling point of 135-1 0 ° / 7 bO mm Hg.
b) A solution of 12.8 g (0.1 mol) of 3-methyl-1-butenyl acetate (cis-transmix Ilii) in 40 ml of absolute methylene chloride is mixed at room temperature and under nitrogen atmosphere with a solution of 8.72 ml of N-chlorosulfonyl isocyanate in 10 ml of absolute methylene chloride. After kh, the reaction mixture is slowly poured onto a mixture of 10 ml of water, g of ice, 24 g of sodium bicarbonate and 8.3 g of sodium sulfite, the temperature being maintained between 0 and 5 in necessary cases. After about 30 minutes, the organic phase gives a neutral reaction, after which it is separated. The aqueous phase is extracted with methylene chloride. The organic phases are combined, dried over sodium sulfate and evaporated in
silica gel with a mixture of toluene - ethyladetate, and a cis-transmix-acetoxy-3-isopropyl-azetidin-2-one is obtained in a ratio of about 1: 3.  DH: Rf 0.3 (toluene - ethyl acetate 2: 3); IR spectrum (in methylene chloride): absorption bands at 2. 95, 3.37, 5.6, 5.72, 7.32, 8.1.  9.7, 10.2 microns; NMR spectrum (deuterochloroforne 100 MS; in parts per million 6.75, 1H, m (substitution); 5.85 d, J 4, H Hz (cis) and 5.6, d, J 1.5 Hz ( trans-), 1H; 3.03, 1H, t; 2.1, 3N, 2 S 2.3-1.8 - 1H, t; 1.1, 6H, t.  Example 13  Preparation of 2- (4-acetylthio-3-isopropyl-2-oxo-1-azetidinyl) -2-hydroxyacetic acid nitrobenzyl ester vapor (racemic transcompound).  At room temperature, a solution of B1b mg (3.3 mmol) -acetylthio-3-isopropyl-2-oxo-azetidine (racemic trans-compound) in 8 ml of toluene and 10.5 ml of dimethylformamide is mixed with 1.9 g of para-nitrobenzyl ether 2- ethoxy-2-hydroxy-acetic acid.  After adding freshly dried molecular sieve, the mixture is stirred in a nitrogen atmosphere for 15 hours at room temperature and then for 2 hours at 50 °.  The molecular sieves are filtered, washed with toluene, and the filtrate and the washing liquid are evaporated together.  vacuum.  The residue is dried under high vacuum and chromatographed on 60 g of silica gel with toluene-ethyl acetate 9: 1.  Both are slightly contaminated with unreacted para-nitrobenzyl ester of 2-ethoxy-2-hydroxyacetic acid trans-isomer with the following physicochemical properties: DC: Rf 0, and 0.37 (toluene - ethyl acetate 2: 3); Infrared Spectrum (WSS): absorption bands at 5.62, 5.68.6.55, 7 ,.  Example I.  Preparation of 2- (4-acetylthio-3-isopropyl-2-oxo-1-azetidinyl) -2-triphenylphosphoranylidene-acetic acid para-nitrobenzyl ester (racemic trans-compound).  a) A solution of 1.175 g of 2 - (- acetylthio-3-isopropyl-2-oKCO-l-azetidinyl) -2-hydroxyacetic acid para-nitrobenzyl ester (racemic trans-compound) in 21 ml of absolute dicoxane is added to the mixture already stirred for 30 minutes a solution of 3.8 g of the base of Junig in 10 ml of absolute absolute of a solution of 0.67 ml of thionyl chloride in 6.3 ml of absolute dioxane, the reaction mixture is stirred for 90 min at room temperature and under nitrogen atmosphere.  The base of the Hunig is filtered off, washed with dioxane and the filtrate evaporated in vacuo.  The crude 2- (A-acetylthio-3-iso1propyl-2-oxo-1-azetidinyl) -2-chloroacetic acid crude para-nitro benzyl ester (racemic trans-compound) can be used without further purification in the next step. .  b) The crude 2- (t-acetylthio-3-isopropyl-2-OXO-1-azetidinyl) -2-chloroacetic acid crude p-nitrobenzyl ester is dissolved in 50 ml of absotropic dioxane, mixed with 3.8 g of Hunigos base, mixed for 30 minutes, then mixed with 1.18 g of triphenylphosphine and stirred for 15 hours at 50 under oTa atmosphere.  The polybase of Hunig is filtered off, washed with dioxane, and the filtrate and the washing liquid are evaporated together in vacuo.  The residue is chromatographed on 60 g of silica gel with a mixture of ethyl acetate 7: 3 and the title compound is obtained with the following physicochemical properties: DC: Rf 0.25 (toluene ethyl acetate 2: 3); IR spectrum (ffljCE): absorption bands at 5.7, 5.9, 6.17, 6.55, 7.2, 9.05 microns.   Example 15  Preparation of 2-methyl-6-isopropyl-2-penem-3-carboxylic acid para-nitrobenzyl ester (racemic trans-compound).  A solution of 660 mg of para-nitrobenzyl ester of 2 - (- acetylthio-3-isopropyl-2-OXO-1-azetidinyl) -2-triphenylphosphoraninyl indenene acetic acid (racemic trans-compound) in 300 ml of absolute toluene is mixed with a catalytic amount of para-hydroxyquinone and stirred. nitrogen for kQ h at 90 °.  The solvent is evaporated in vacuo and the residue is chromatographed on.  30 g of silica gel with a mixture of toluene - ethyl acetate 19: 1.  After crystallization from a mixture of diethyl ether / methylene chloride, a trans compound is obtained in the form of colorless crystals with the following physicochemical properties: melting point 138-139 DX Rf 0.59 (toluene – ethyl acetate 2: 3); IR (SIGSR): extrusion bands at 5.57, 5.82, 6.27, 6.55, 7 ,, 7.6 NMR spectrum (in deuterochloroform 100 Ms; in ppm): 8, 3-8. 2, 2H, t; 7.5-7 ,, 2H, t; 5.75-5.1, ЗН, t; 3.6-3.5, 1H, dd, J 8 and 1.5 Hz; 2.35, SN S; 1.07, 6H, t.  Example 16  Preparation of 2-methyl-6-isopropyl-2-penem-carboxylic acid (racemic trans-compound).  A solution of 100 mg of 2-methyl-6-isopropyl-2-penem-3-carboxylic acid para-nitrobenzyl ester (racemic trans-compound) in 7. l of absolute ethyl acetate is mixed with 4 ml of 0. 2 N aqueous solution of Nitri bicarbonate and 50 mg of a palladium catalyst and stirred under normal pressure for 30 minutes in a hydrogen atmosphere.  The hydrogenated mixture is filtered from the catalyst through diatomaceous earth, further washed with a 0.2 N sodium hydro carbonate solution and several times with ethyl acetate.  The aqueous phase is washed with methylene chloride, acidified with an aqueous solution of citric acid and exhaustively extracted with methylene chloride.  The combined organic phases are dried over sodium sulfate, filtered, evaporated in vacuo and dried in high vacuum.  The compound obtained has the following physicochemical properties: melting point BUT (decomposition); JH: Rf 0.37 (toluene - ethyl acetate - acetic acid); IR (potassium bromide): absorption bands at 3.5, 5.62.  6.0, 6.35, 6.9, 7.52, 7.8, 8.0 microns; NMR spectrum (DMSMCO de / 100 MS; in parts per million): 5.52, W, d, J 1.5 Hz; 3.56, 1H, + 2 HjO, dd, J 1.5 and 7.5 Hz, 2.26, 3N, S, 2.0, 1H, t; 1-0.9, 6H, t.  Example 17  Preparation of C-acetylthio-3-benzyl-2-oxo-azetidine (racemic trans-compound).  A solution of 2.19 g (10 mmol) ac-3-3 phenyl acetidin-2-one racemic mixture of cis and trans isomer in a ratio of 9:13) in 10 ml of dioxane is mixed at room temperature under a nitrogen atmosphere, dropwise with solution 0, 76 g (10 mmol) of thioacetic acid in 10 ml of 1 N sodium hydroxide solution and stirred at this temperature for 3 hours.  The reaction mixture is exhaustively extracted with methylene chloride.  The combined organic phases are dried over sodium sulfate and evaporated in vacuo.  The residue is chromatographed on silica gel with a mixture of toluene and ethyl acetate 9: 1 and a mixture is obtained in a ratio of 2:10.   recrystallization from methylene chloride / hexane gives a trans compound with a melting point, DC: Rf 0.52 (toluene - ethyl acetate 1: 1); IR spectrum ().  absorption bands at 2.95, 5.65, 5.95, 7.0, 8.8, 10.5 µm.  NMR spectrum (deuterium chloroform / / 100 MS; in parts per million): 7.2, 5H, m 6.60; 1H, b; , 99, W, d, J 2 Hz; 3 ,, 1Н, dq, JB V Hz; Jc 6 Hz, JD 2 Hz; 3.18, 1H, q, J 15 Hz, Jc 6 Hz; 3.00, 1H, Jf, H5 Hz, JB 8 Hz; 2.30, ZN, S.  The starting material is prepared as follows.  a) A mixture of 25 g (0.186 mol) of 3-phenyl-propionaldegnd, 50 ml of acetone hydride and 50 ml of pyridine is stirred for 15 hours at 100 and then evaporated in a vacuum created by a water-jet pump.  The residue is dissolved in methylene chloride, washed with 5% sodium hydrogen carbonate aqueous solution and citric acid solution, dried over sodium sulfate and the solvent is removed in vacuo.  The residue is distilled in vacuo.  A 3-phenyl-1-propenyl acetate (cis-transm 1: 1) with a boiling point of 61-65 ° / / 1 mm Hg is obtained. Art.  b) A mixture of 17.6 g (1.1 mol) of 3 Phenyl-1-propenyl acetate (cis-transm 1: 1) and 14.15 g (1.10 mmol) of N-chlorosulfonyl isocyanate prepared at O is stirred for 6 hours at 10-15 °.  The reaction mixture is diluted with 100 ml of cold methylene chloride and slowly poured onto the mixture 10 ml of water, 45 g of ice, 2 g of sodium bicarbonate and 17 g of sodium sulfite.  After filtration, the organic phase is separated.  The aqueous phase is extracted with methylene chloride.  The organic phases are combined, dried over sodium sulfate and evaporated in vacuo.  The residue is chromatographed on. silica gel with a mixture of toluene - ethyl acetate in a ratio of from 9: 1 to 8: 2 and receive a mixture of cis-trans-isomers-acetoxy-3-benzyl-azetidin-2-one in a ratio of 9:13.  JH:  R 0.5 (toluene - ethyl acetate 1: 1) i IR spectrum (in methylene chloride): absorption bands at 2.95, 5.6, 5.75, 7.35, 1992 8.15, 8.65, 9 , 6, 10.25 microns; NMR spectrum (deuterochloroform / 100 MS; in parts per million); 2, OTs, S and 2.08, S, 3N; 2.95-3.15, 2H, m 3.35-3.8, 1H, t 5.50 0.6, H, d J 2 Hz (trans-); 5.86 0, k, H, d, J i Hz (cis-); other signals at 6.80-7 ,.  Example 18 Preparation of 2- (4-acetylthio-benzyl-2-oxo-1-acetidinyl -2-hydroxyacetic acid para-nitrobenzyl ester (racemic trans-compound), At room temperature, a solution of 0.73 g (3.1 mmol) of 4-acetylthio -3-benzyl-3-oxo-azetidine (racemic trans-compound) in 50 ml of toluene and 20 ml of dimethylformamide is mixed with 2 g of 2-ethoxy-2-hydroxyacetic acid 2-para-nitrobenzyl ester.  After adding freshly dried molecular sieves. the mixture is stirred under nitrogen atmosphere overnight at room temperature and then for 2 hours at 50.  The molecular sieves are filtered, washed with toluene, and the filtrate and the washing liquid are evaporated in vacuo.  The residue is dried in.  high vacuum and chromatographic on silica gel with a mixture of toluene - ethyl acetate in the ratio from 9: 1 to.  Pol1 (| both are slightly contaminated with unreacted para-nitrobenzyl ester of 2-ethoxy-2-hydroxyacetic acid isomer with the following physicochemical properties: DC: Rf 0.57 (toluene ethyl acetate 1: 1); IR spectrum (methylene chloride): bands absorption at 2.85, 5.60, 5.70, 6.00, 6.20, 6.55, 7.0, 8.25, 9.00, 11.75 µm.  Example 19  Receiving a pair: 2- (-acetylthio-3-benzyl-2-oxo-1-azetidinyl) -2-triphenylphosphoranylidene acetic acid nitrobenzyl ester, (racemic trans-compound).  ) A solution of 1.5 g of 2- (4-acetylthio-3-benzyl-2-oxo-1-acetidinyl -2-hydroxyacetic acid para-nitrobenzyl ester (racemic trans-compound) in 20 ml of dry dioxane is mixed with 6 g of Hunyg base.  After adding dropwise a solution of 1.5 ml of thionyl chloride in 10 ml of dioxane, the reaction mixture is stirred for 60 minutes at room temperature in a polyunication of Hyunig under a nitrogen atmosphere, washed with dioxane, filtered, and the filtrate is evaporated in vacuo.  The resulting crude p-nitrobenzyl 220 ester of 2- (4-acetylthio-3-benzyl-2-oxo-1-azetidinyl) -2-chloroacetic acid (racemic transcompound) can be introduced to the next stage without further purification.  b) 2- (A-acetylthio-3-isopropyl-2-oxo-1-azetidinyl) -2-chloroacetic acid-derived para-nitrobenzyl ester is dissolved in 20 ml of dry dioxane, mixed with 6 g of Hunigas base, mixed for 30 minutes, then mixed with 1.5 g of triphenylphosphine and stirred overnight at 50 under a nitrogen atmosphere.  The base of the Hunig is filtered off, washed with dioxane and the filtrate and the washing liquid together are evaporated in vacuo.  The residue is chromatographed on silica gel with a mixture of toluene and ethyl acetate in a ratio of from 9: 1 to 1: 1 and the title compound trans compound is obtained with the following physicochemical properties: DC: Rf 0.50 (toluene ethyl acetate 1: 1); IR (methylene chloride): absorption bands at 5.7, 5.9, 6.2, 6.55, 7.00, 7, L2, 9.05, I, 75 microns.  Example 20  Preparation of 2-methyl-6-benzyl-2-penem-3-carboxylic acid para-nitrobenzyl ester (racemic trans-compound).  A solution of 0.90 g (1.3 mmol) of 2 - (+ - acetylthio-3-benzyl-2-oxo-1-azetidinyl) -2-triphenyl-phosphoranylidene acetic acid (racemic trans-compound) 2-(+ -acetylthio-3-benzyl-2-oxo-1-azetidinyl) ether in 50 ml of dry toluene mixed with a catalytic amount of para-hydroxyquinone and stirred under nitrogen for 2 days at 90 °.  The solvent is evaporated in vacuo and the residue is chromatographed on silica gel with 9: 1 toluene-ethyl acetate.  After crystallization from a mixture of methylene chloride / diethyl ether, a trans compound is obtained with the following physicochemical properties: melting point 182-183 °; DC: R 0.85 (toluene - ethyl acetate 1: 1); IR spectrum (methylene chloride absorption bands at 5.60, 5.85, 6.30, 6.55, 7 ,.  7.6-8.25, 8.55, 9.25, 11.70 microns; NMR spectrum (in deuterium chloroform / 100 MS; in parts per million): 2.36, 3N, S 3.12; 1H, dd, JA l Hz, JB 9 Hz; 3.3, 1H, dd, JA Ak Hz, Jc 6 Hz; , 03, 1H, dq, Jg 9 Hz, Jc 6 Hz, J 2 Hz; 5 ,, F, d, JD 2 Hz; five. 25, 1H.  d, J and Hz; 5, + 5, 1H; d, J 14 Hz; 7.30, 5H, t; 7.66, 2H, d, J 9 Hz; 8.27, 2H, d, J 9 Hz.  Example 21  Preparation of 2-methyl-6-benzyl-2-penem-3-carboxylic acid (racemic trans compound).  A solution of 200 mg of 2-methyl-6-benzyl-2-penem-3-carboxylic acid para-nitrobenzyl ester (racemic trans compound) in 12 ml of absolute ethyl acetate is mixed with 8 ml of a 0.2M aqueous solution of sodium bicarbonate and lOO mg of palladium-carbon catalyst and stirred at normal pressure for 60 minutes under a hydrogen atmosphere.  The hydrogenated mixture is filtered from the catalyst through diatomaceous earth.  The aqueous phase is separated, acidified with an aqueous solution of citric acid and exhaustively extracted with methylene chloride.  The combined organic phases are dried over sodium sulfate, filtered, evaporated in vacuo and dried in a high vacuum.  The compound obtained has the following physicochemical properties: DC: Rf 0.31 (toluene ethyl acetate - acetic acid by ratio); IR spectrum (potassium bromide): absorption bands at 3.20-i, 30, wide; 5.65, 6.0, 6.35, 6.9, 7.5, 7.9, 8.2 microns.  Example 22 Preparation of U-ethylthio-thiocarbonylthio-Z-isopropyl-2-oxoazetidine (racemic trans compound).  A solution of 195 mg (1.1 mmol) of tox-3 isopropyl-azetidin-2-one (rocemic mixture of cis and trans isomer in a ratio of 1: 3) in 1 ml of water and 0.2 ml of acetone are mixed at room temperature under nitrogen atmosphere. drops with a solution of 230 mg of potassium ethyl tritiocarbonate in 1.5 ml of water and stirred at this temperature for 120 minutes.  The reaction mixture is exhaustively extracted with methylene chloride.  The combined organic phases are dried over sodium sulfate and evaporated in vacuo.  The residue is chromatographed on 12 g of silica gel with a mixture of toluene - ethyl acetate 9: and a trans compound is obtained.  Melting point 65-66, DH: K 0.5 (toluene | Ethyl acetate 2: 3); IR (methylene chloride): absorption bands at 2.95, 3.37, 5.62.  9.25 microns; NMR spectrum (in deuterium chloroform / 100 MS; in parts per million); 6, b5, 1H, m (substitution of DgO); 5 ,, 1Н, d (J 2.5 Hz); 3.39, 2H, q; 3.05, 1H, m; 2, t5, IHm; 1.38 MH; t; 1.1, 6H, m.   Example 23  Getting paranitrobenzyl ester.  2 - (- ethylthiocarbonylthio-3 isopropyl-2-oxo-1-azetidinyl) -2-hydroxyacetic acid (racemic trans-compound).  At room temperature, a solution of 137 mg (0.55 mmol) of A-ethylthiocarbonylthio-3-isopropyl-2-oxo-azetidine (racemic trans compound) in 8 ml of toluene and 2 ml of dimethylformamide is mixed with 311 mg of para-nitrobenzyl 2-ethoxy ether -2-hydroxyacetic acid.  After adding freshly dried molecular sieve, the mixture is stirred under nitrogen for 15 hours at room temperature and then for 2 hours at 50.  The molecular sieve is filtered off, washed with toluene, and the filtrate and the washing liquid are evaporated together in vacuo.  The residue is dried under high vacuum and chromatographed on 80 g of silica gel with a mixture of toluene, ethyl acetate 9: 1 Both trans-isomers, slightly contaminated with unreacted p-nitrobenzyl ether of 2-ethoxy-2-hydroxyacetic acid, are obtained with the following physicochemical properties: DX: R 0 4 (toluene ethyl acetate 2: 3); IR spectrum (methyl chloride): absorption bands at 5.62, 5.7, 6.55, 7, 2, 8.2, 9.2 µm.  Example 24  Preparation of 2- (4-ethylthiothio-carbonylthio-3-isopropyl-2-oxo-1-azetidinyl) -2-triphenylphosphoranylidene-acetic acid para-nitrobenzyl ester (racemic trans-compound).  A solution of bob mg of 2- (4-ethylthio-thiocarbonylthio-3-isopropyl-2-oxo-1-azetidinyl) -2-hydroxyacetic acid para-nitrobenzyl ester (racemic trans-compound) in 6 ml of absolute tetrahydrofuran is cooled to -15, at While stirring, it is mixed with 0.1b ml (2.23 mmol) of thionyl chloride and then slowly with a solution of 0.31 ml of triethylamine in 0.3 ml of absolute tetrahydrofuran.  The reaction mixture is stirred for 1 h at 0, mixed with 30 ml of cold methylene chloride and washed with 2 N hydrochloric acid.  The organic phase is washed with water until neutral, dried with sulfate and evaporated in vacuo.  The crude 2- (4-ethylthiothiocarbonylthio-3-isopropy-2-OXO-1-azetidinyl) -2-chloro-acetic acid crude p-nitrobenzyl ester is dissolved in 1.5 ml of dry tetrahydrofuran, mixed with 0.71 g of triphenylphosphine and stirred in atmosphere nitrogen at room temperature overnight.  The reaction mixture is diluted with methylene chloride, washed successively with a saturated aqueous solution of sodium bicarbonate and water, dried over sodium sulfate and evaporated in vacuo.  The residue after chromatography on silica gel with a mixture of toluene and ethyl acetate.  is the desired compound.  DH: Rf 0.5 (toluene - ethyl acetate 2: 3); IR spectrum (methylene chloride): absorption bands at 3 ,:, 6.15 6. 55, 7. 5, 9.05, 9.25 microns.  Example 25  Preparation of 2-ethylthio-6-isopropyl-2-penem-3-carboxylic acid para-nitroxybenzyl ester (racemic trans-compound), Solution 600 mg (0.855 mmol) of para-nitrobenzyl 2-ester (-ethylthiothiocarbonylthio-3-isopropyl-2-oxo-1-azetidine) A) -2-triphenylphosphoranylidene acetic acid (racemic trans-compound) in 250 ml of absolute ortho-xylene is mixed with a catalytic amount of para-hydroxyquinone and stirred under nitrogen atmosphere for tS hours under reflux.  The solvent is evaporated in vacuo and the residue is chromatographed on 35 g of silica gel with a 19: 1 toluene-ethyl acetate mixture.  After crystallization from a mixture of diethyl ether-methylene chloride, trans-co-coupling is obtained in the form of colorless crystals.  HH: Rf 0.62.  (toluene - ethyl acetate 2: 3); IR (methylene chloride): absorption bands at 5.57, 5.9, 6.55, 7 ,, 7.52 µm.  Example 26  Preparation of 2-ethyl thio-6-isopropyl-2-penem-3-carboxylic acid (racemic trans compound).  A solution of 100 mg of 2-ethylthio-6-isopropyl-2-penem-3-carboxylic acid para-nitrobenzyl ester (racemic trans-compound) in 6 ml of ethyl acetate is mixed with k ml of 0.2 N aqueous sodium hydrogen carbonate solution and 150 mg of 10 palladium catalyst and stirred at normal pressure for 240 minutes in a hydrogen atmosphere.  The hydrogenated mixture is filtered from the catalyst through diatomaceous earth, further washed with 0.2 N sodium bicarbonate solution and several times with ethyl acetate.  The aqueous phase is washed with methylene chloride, acidified with an aqueous solution of citric acid and exhaustively extracted with methylene chloride.  The combined organic phases are dried over sodium sulfate, filtered, evaporated. under vacuum, and dried under high vacuum.  The compound obtained has the following physicochemical properties: DC: R 0.35 (toluene - ethyl acetate - acetic acid); IR (potassium bromide): absorption bands at 3.5, 5.62, 6.0, 6.75, 6.9, 7. 52.  7.9, 8.15, 8.9 microns.  Example 27  Preparation of 6-diazo penicillanic acid methyl ester.  Get similar to the known method.  1.01 g of crude 6-beta (N-nitroso) phenoxy-acetamido-penicillanic acid methyl ester is dissolved at room temperature in 75 ml of absolute chloroform, and after adding 200 ml of a saturated aqueous solution of sodium bicarbonate, it is stirred for 9 hours at a temperature between 10 and 20 °.  The chloroform solution is separated, washed with water and dried over sodium sulfate.  After evaporation of the solvent in vacuo at room temperature, the crude diazo compound is obtained as an oil.  It can be used without further purification for the subsequent reaction.  IR spectrum (in methylene chloride): characteristic absorption bands at 3, 80, 5.55, 5.70, 6.23.  6.50, 6.68, 7.75, 8.22, 8.85, 10.6, 11.42 microns.  Example 28  Preparation of 6-alpha-methoxypenicillanic acid methyl ester.  A solution of 2 g of 6-diazo-penicillanic acid crude methyl ester in 15 ml of absolute methylene chloride is mixed with 5 ml of methanol and a few drops of a 30% aqueous perchloric acid solution and stirred for 15 minutes at room temperature.  The reaction mixture is diluted with 30 ml of methylene chloride, washed successively with an aqueous solution of bicarbo 1 Naga sodium, water and sodium chloride solution, dried over sodium sulfate and evaporated in vacuo.  The residue is chromatographed on silica gel with a mixture of toluene - ethyl acetate in the ratio E: 1 and: and a slightly polluted compound is obtained.  IR spectrum (in methylene chloride): characteristic bands at 3.0, 5. 63, 5. 70, 6.90, 7.30, 7.68, 8.25, 8 ,, 8. 90.  9.15, 9.70, 9.86 microns.  P p i.  meper 29.  Preparation of 6-alpha-methoxy-penicillanic acid 1-oxide of methyl ester.  A solution of +73 mg of methyl ester 6 alpha-methoxypenicillanic acid in 10 ml of methylene chloride is cooled to 0, mixed with 33 mg of meta-chloroperbenzoic acid, and the resulting suspension is stirred for another 1 hour at this temperature.  The reaction mixture is diluted with 50 ml of methylene chloride, washed twice with an aqueous solution of sodium bicarbonate and water, and dried over sodium sulfate.  The solvent is evaporated in vacuo and the residue is chromatographed on silica gel.  Using a mixture of toluene - ethyl acetate in a ratio of: 1, the compound is recovered as a white powder.  The analytical sample is recrystallized from methylene chloride-diethyl ether - pentane, and it has the following physicochemical properties: melting point Lr +281 + 1 °; IR (methylene chloride): characteristic absorption bands at 3.0, 5.58, 5. 70, 6.85, 6.97, 7.75, 8.20, 8.90, 9.5 microns.  Example 30  Preparation of methyl 2 (3 S, 4, K) -4- (benzthiazol-2-yldithio) -3-methoxy-2-oxo-azetidin-1-yl-3-methyleneo-methyl acid.  A solution of 307 mg of α-methoxypenicillanic acid 1-oxide of methyl ester 6 is dissolved in 10 ml of toluene, mixed with 196.57 mg of 2-mercaptobenz thiazole and heated for 90 minutes under reflux.  The solvent is distilled off in vacuo and the residue is chromatographed on silica gel.  When eluted with a mixture of toluene - ethyl acetate, the compound is obtained in a colorless oil wire.  IR spectrum (in methylene chloride, the characteristic bands at, 5, b2g, 5.72, 6.68, 6.85, 7.02, 7. 25  7.50, 8.10, 8.20, 8.60, 8.95, 9.55.  9.92, 10.92 microns.  Example 31 — Preparation of 2-G (3S, 4R) -4- (benzthiazol-2-yldithio) -3-methoxy-2-oxo-azetidin-1-yl-3-methylcrotonic acid methyl ester.  A solution of 2 mg methyl ester of 2-G (3S, kI) -4- (benziazol-2-yldithio) -3-methoxy-2-oxo-azetidin-1-yl-3-methylene butyric acid in 25 ml of methylene chloride is mixed with 0. 1 ml of triethylamine and stirred at room temperature for 100 minutes.  The reaction mixture was diluted with methylene chloride, washed twice with an aqueous solution of citric acid and water, dried over sodium sulfate, and the solvent was removed in vacuo.  The residue is purified by chromatography on silica gel with a mixture of toluene and ethyl acetate in a ratio of 9: 1 and: 1 to obtain the compound as an oil.  IR spectrum (in methylene chloride): characteristic absorption bands at 3 ,, 5.63, 5.78, 6.85, 7.03, 7.23, 7.32, 7.0, 8.15, 8.87 , 9.00, 9.25, 9.92 microns.  P m and mep 32.  Preparation of 2- (3S, tK) -4-acetylthio-3-methoxy-2-oxoazetidin-1-yl 3-methylcrotonic acid methyl ester.  A solution of 372 mg of methyl 2 (3 S, t K) (benziazol-2-yl-dithio) -3-methoxy-2-oxoazetidin-1-yl-3-methylcrotonic acid in 10 ml of dimethylformamide is cooled to -20, mixed with 10 ml of a solution of 2 g of sodium borohydride in 200 ml of dimethylformamide and stirred at the same temperature for 30 minutes.  The reaction mixture is mixed with 5 ml of freshly distilled acetyl bromide and further stirred at 0 for O min. After adding 150 ml of benzene, the reaction mixture is washed successively with sodium bicarbonate solution and water, dried over sodium sulfate and evaporated in vacuo.  After chromatography on silica gel with toluene-ethyl acetate 9: 1, the residue affords the compound as a slightly yellowish oil.  IR spectrum (in methylene chloride) with characteristic absorption bands at 3. tO.  5.63, 5.77, 5.83.  6.10, 6.95, 7.20, 7.30, 7. 70, 8.12, 8.90, 9.20, 9.90, 10.20, 10.50, 11.83 microns.  Example 33- Preparation of 2- (3S, kH) -A-acetyl-: thio-3 methoxy-2-oxoazetidin-1-yl -2-oxoacetic acid methyl ester.  Through a cooled to -30 solution of 87 mg (0.31 mmol) of methyl 2 f (3 S, K) -4-acetyl-3-methoxy-2-oxo-azethidin-1-yl-3-methylprotonic acid methyl ester in 5 ml of ethyl acetate skip 3 equivalents of ozone.  The reaction mixture is diluted with 30 ml of methylene chloride and shaken with an aqueous solution of sodium bisulfite for 2 minutes.  The organic phase is separated, washed with a saturated solution of sodium chloride, dried over sodium sulfate and evaporated in vacuo.  IR spectrum of the obtained oily compound (in methylene chloride): characteristic bands at the Z. R.  , 5.67, 5. 82, 6.97.  7.33, 8.10, 8.92, 9.88, 10 microns.  .  .  The product without further purification can be introduced to the next stage.   Example H.  Preparation of (3 S, 4 K) - -acetylthio-3-methoxy-2-oxo-azetidine.  A solution of 71.20 mg of methyl 2 (3S, kK) -4-acetylthio-3-methoxy-2-oxoazetidin-1 -yl -2-oxoacetic acid (crude product) in 10 np of 1% aqueous methanol solution sewn overnight at room temperature. The reaction mixture is diluted with methylene chloride, washed with water, dried over sodium sulfate and evaporated in vacuo.  The residue is chromatographed on silica gel with a mixture of toluene and ethyl acetate 9: 1 to obtain the compound, IR spectrum (in methylene chloride): characteristic absorption bands at 2.95, 3, 5.60, 5.88, 7.00, 7.37, 7.52, 8.25, 8.70, 8.85, 10.5, 12.15 microns.  Example 35  Preparation of 2- (3 S, 4 R) -A-acetylthio-3-methoxy-2-oxo-azeticin-V or -2-hydroxyacetic acid para-nitrobenzyl ester.  A solution of mg (3 S, 4 K) - - acetic thio-3-methoxy-2-oxo-azetidine in a mixture of 8 ml of toluene and 2 ml of dimethylformamide is mixed with 7T mg of p-nitrobenzyl 2-ethoxy-2-hydroxyacetic acid and H g molecular sieve A was stirred at room temperature overnight.  The molecular sieves are filtered off and the filtrate is evaporated in vacuo.  The residue is chromatographed on silica gel, and a compound contaminated with a small amount of glyoxylate is obtained by elution with a mixture of toluene-ethyl acetate in a ratio of 9: 1 and 4: 1.  Example 36  Preparation of 2- (3S, 4R) -4-acetylthio-3-methoxy-2-oxoazetidin-1 -yl -2-triphene-JJ-forcophenylidenene-acetic acid 2- (3S, 4R) ester, a) Suspension of 2 g of Hyunig base in 8 ml of dioxane is mixed for 30 min at room temperature; peratura, mixed with 832 mg of 2- (3S, kR) -4-acetylthio-3 methoxy-2-oxo-azetidin-1-yl -2-oxyacetic acid para-1-nitrobenzyl ester, dissolved in 12 ml of dioxane, and then slowly with a solution of 0.5 ml of thionichloride in 10 ml of dioxane.  The mixture was stirred for 2 hours at room temperature, filtered from the Hunigue base and the filtrate was evaporated in vacuo.  The residue is purified by chromatography on silica gel with 1: 1 toluene-acetate to give 2- (3 S, K) -acetylthio-3-methoxy-2-oxoazetidin-1-yl -2-chloroacetic para-nitroxyethyl ester. acids in crude form, b) A solution of 833 mg of 2- (3S, 4I) -acetylthio-3-methoxy-2-oxoazetidin-1-yl -2-chloroacetic acid para-nitrobenzyl ester in 50 ml of Vioxia mixed with V12 mg triphenylphosphine and 3 g of the Hunig base, and stirred overnight at 50 ° C., The Hyunig poly base was removed by filtration, and the filtrate was evaporated in vacuo.  The residue is chromatographed on silica gel with a mixture of toluene and ethyl acetate in the ratio of 9: 1, 1 and 1: 1, and the title compound is obtained.  IR spectrum (in methylene chloride): characteristic absorption bands at 3, 5.67, 5.85, 6.15, 6.55, 6.97, 7M.  8.0, 9.03 microns.  Example 37  Preparation of (5 R, 6 S) -2-methyl-6-methoxy-2-penem-3 carboxylic acid para-nitrobenzyl ester.  A solution of mg of 2- (3S, 4R) -acetylthio-3 methoxy-2-oxoazetidin-1-yl -2-triphenylphosphoranilylidene acetic acid para-nitrobenzyl ester of 2- (3S, 4R) and 100 ml of absolute toluene is mixed with a catalytic amount of hydroquinone and stirred for 32 hours. at 90 in nitrogen atmosphere.  Toluene is- evaporated in vacuo and the residue chromatographed on silica gel with a mixture of 19: 1 toluene ethyl acetate.  The compound is obtained as a white solid.  IR spectrum (in methylene chloride): characteristic absorption bands at 3, 0, 5. 55.  6.30, 6.55, 7.03, 7.60, 8.20, 8. C2.  8.60, 8.90, 9.20, 9.60, 11.7 microns; NMR spectrum (deuterochloroform / 100 MS; in parts per million): 8.22, 2H, d, J 8 Hz; 7.6, 2H d, J V Hz; 1H, d, 7 2 Hz; five. 35, 2H, AB; , 91, 1H, d, J 2 Hz; 3.57, ZN.  S; 2.37, ZN, S.
Example 38: Preparation of (5 R, 6 5) -2-methyl-b-methoxy-2-penem-3 carboxylic acid.
A solution of 3 mg of para-nitrobenzyl ester (5 R, 6 5) -2- | 1-ethyl-6-methoxy-2-penem-3-carboxylic acid in a mixture of 2 ml of ethyl acetate and 2 ml of 2 M sodium bicarbonate solution is mixed with 75 mg of palladium-carbon catalyst and hydrogenated at atmospheric pressure for 1.5 h at room temperature. The hydrogenated mixture is filtered through diatomaceous earth, the filter residue is washed with 1 ml of 2 M aqueous solution of sodium bicarbonate and ethyl acetate. The aqueous phase is separated from the filtrate, acidified with a 0.1 M aqueous citric acid solution and extracted several times with megylene chloride. The combined methylene chloride extracts are dried over sodium sulfate and evaporated in vacuo. IR spectrum (in methylene chloride) of the obtained crude compound: characteristic absorption bands at 3, 5.57, 5.80, 5.95,. 6.30, 7.00, 8.20, 9.90 microns.
Example 39- Preparation of alpha-phenoxy-acetoxypenicillanic acid methyl ester 6.
Solution 7, g (20.3 mmol) of 6-beta-(N-nitro-zo) -phenoxy-acetamido-penicillanic acid methyl ester 6 (crude product) is stirred in 100 ml of benzene for 3 hours at 50 under nitrogen atmosphere. The solvent is evaporated in vacuo and the residue is chromatographed on silica gel with toluene-ethyl acetate 9; 1. G puffed oily npd duct is recrystallized from diethyl ether-hexane to obtain a compound with a melting point of 71 °; oCi5. 11 t 1 ° (SNSC); IR spectra (in methylene chloride): characteristic, absorption bands at 3, 5.6, 5, 6.25, 6.69, 7.17, 8.26, 8.55, 9.05, 9.18 microns.
Example jO. Obtaining 1-oxide of methyl ester 6 alpha-phenoxy-acetoxypenicillanic acid.
A solution of t, t6-r (3.18 mmol) of methyl ester 6 alpha-phenoxyacetoxy-penicillanic acid in 30 ml of absolute methylene chloride is mixed in O in portions with 1 g (1 equivalent) of a 50% solution of meta-chloroperbenzoic acid. After the addition is complete, the reaction mixture is stirred for 30 minutes at about 0, then diluted with methylene chloride, washed successively with aqueous pacTBODOM sodium bicarbonate, water and sodium chloride solution and dried over sodium sulfate. After evaporation of the solvent, the precipitate is chromatographed on silica gel with toluene-ethyl acetate. The compound is obtained as foam AX: Rf 0.24 (toluene - ethyl acetate 1: IR spectrum (in methylene chloride): characteristic absorption bands at 3.33, 3.1. 5.57., 5.72,, 6.27 6.72, 7.0, 8.25, 8.6, 9.21, 9.46 microns
PRI and MER ti. Preparation of 2- (3S, R) -4-benzthiazol-2-yl-dithio) -3-phenoxyacetate-2-oxyazoethoxy-2-oxy-azethidin-1-yl-3-methylene butyl ester methyl ester.
A solution of 1.01 g (2.65 mmol) of alpha-phenoxy-acetoxy-penicillanic acid 1-oxide methyl ester 6 is dissolved in 30 mm of toluene, mixed with mg, b5 mmol) of 2-mercapto-benzthiazole and heated for 60 minutes under nitrogen at reflux. The solvent is distilled off in vacuo and the residue is chromatographed with iHa silica e. B. When eluted with a mixture of toluene-ethyl acetate 19: 1, the compound was obtained as a pale yellow oil. IR spectrum (in methylene chloride): characteristic bands at 3 ,, 5.62, 5.75, 6.27, 6.71, 6.89, 7.05, 7.30, 7, “5, 7.68 , 8.15, 8.55, 9.15, 9.35, 9.95 microns. HH: Rf 0.63 (toluene - ethyl acetate 1: 1).
An example of k2. Preparation of 2- (3S, R) -4- (benzthiazol-2-yl-dithio) -3-phenoxyacetoxy-2-octoosetidin-1 -yl-3-methylcrotonic acid methyl ester.
A solution of 1.28 g (2.41 mmol) of 2- (3 S, K) - - {benzthiazol-2-yl-dithio) -3 methyl ester of phenoxyacetoxy-2-oxoazetidine -yl-3-methylene butyric acid in 30 ml methylene chloride is mixed with 0 ml of triethylamine and. stirred at room temperature for 30 minutes. The reaction mixture is diluted with 50 ml of methylene chloride, washed successively with a 2 N hydrochloric acid solution, water and a solution of sodium chloride, dried over sodium sulfate and the solvent is removed in vacuo. The residue is purified by chromatography on silica gel with a 19: 1 toluene-ethyl acetate mixture to give the compound as a pale yellow oil. IR spectrum (in methylene chloride): characteristic absorption bands at H., 5.69. 3.82, 5.90. 6.28, 6.73, 6.90, 7.06, 7.28, 7.38, 7.75. 8.20, 8.60, 9.27. 9.96 microns; HH: Rf 0.61 (toluene - ethyl acetate 1: 1). An example. Preparation of 2- (3S, AKZ-A-acetylthio3-phenoxyacetoxy-2-oxoazetidin-1-yl -3-methyl-crotonic acid methyl ester. A solution of 687 ml (1.29 mmol) of 2-f3S methyl ester R) -U- (benzthiazol-2-yl-dithio) -3-phenoxyacetoxy-2-oxoazetidin-1-yl-3-methylcrotonic acid in k ml of dimethylformamide is added to a solution of 7b mg (2 mmol) of borohydride cooled to -20 sodium in 10 ml of dimethylformamide and stirred at the same temperature for 10 minutes; The reaction mixture is mixed with 7 ml of freshly distilled acetyl bromide and stirred further at 0 ° for Q min. After adding 400 ml of benzene, the reaction mixture was sequentially washed with an aqueous solution of sodium bicarbonate, water and saline solution, dried over sodium sulfate and evaporated in vacuo. After chromatography on silica gel with a mixture of toluene ethyl acetate 19: 1, the residue gives the compound in the form of an oil, which is subjected to further purification on silica gel plates with a mixture of toluene – ethyl acetate 1: 1. The compound is obtained as an oily product; IR spectrum (in methylene chloride): characteristic absorption bands at 3., 5.63. 5.83, 6.27, 6.70, 7.00. 7.25. 7.35. 8.15 8.58, 8.93. 9.20 microns; HH: Rf 0.54 (toluene - ethyl acetate 1: 1).
Example 4. Obtaining 2- (3S, 4R) -a-acetylthio-3-phenoxyacetoxy-2-oxoazetidin-1-yl -2-oxo-acetic acid methyl ester.
Through cooled to -20 ° solution of 170 mg (0.42 mmol) of methyl ester 9
methylene chloride, washed successively with water and saturated sodium chloride solution. dried over sodium sulfate and evaporated in vacuo. The residue is chromatographed on silica gel with toluene-ethyl acetate 1: 1 to give the compound. IR spectrum (in methylene chloride): characteristic bands at 2.95, 3.45. 5.55. 5.60, 5.88, 6.25. 6.68, 8.33, 8.85 microns. HH: Rf 0.36 (toluene - ethyl acetate 1: 1).
Example 46. Preparation of p-nitrobenzyl ester 2 S. 4 R) -4-acetylthio-3-phenoxyacetoxy-2-oxo-azetidin-1-yl -2-hydroxyacetic acid
A solution of 283 mg of (35, 4 T) -4-acetylthio-3 methoxy-2-oxo-azetidine in demolition of 8 ml of toluene and 2 ml of dimethylformamide is mixed with 760 mg of 2-ethoxy-2-hydroxyacetic acid 2-ethoxy-2-hydroxyacetate sieve A4 and stir at room temperature overnight. The molecular sieves are filtered off and the filtrate is evaporated in vacuo. The residue is chromatographed on silica gel, whereupon the mixture is eluated with a mixture of toluene and ethyl acetic acid in a ratio of 4: 1 semi232 | 2- (3 S, CZ-α-acetylthio-3-phenoxyacetoxy-2-oxo-azetidine-1 -yl-3-me "Tilcrotonic acid in 5 ml of ethyl acetate is passed 4 equivalents of ozone. The reaction mixture is diluted with 5 ml of ethyl acetate and vigorously shaken with an aqueous solution of sodium bisulfite. The organic phase is separated, washed with water and saturated sodium chloride, dried over sodium sulfate and evaporated vacuum: the infrared spectrum of the resulting oil of the com pound compound (in methylene chloride): characteristic bands at 3.38, 5, L8, 5.63, 5.70, 5.83, 6.27, 6.70, 7.00, 7M, 8.07, 8.25. 8.63, 8.95 μm. The obtained product can be introduced into the next stage without further purification. Example 45. Preparation (3 S, t Yu-4-acetylthio-3-phenoxy-acetoxy-2-oxoazetidine. Solution 129 mg (mmol) methyl ester (3 S, k K) -2 - (+ - acetylthio-3-phenoxyacetoxy-2-oxoazetidin-1-yl -2-oxoacetic acid (crude product) in 10 ml of an aqueous solution of methanol is stirred for h at room temperature . The reaction mixture is diluted with 50 ml of the compound contaminated with a small amount of glyoxylate. Example kj. Preparation of 2- (3S, R-α-acetylthio-3-phenoxyacetoxy-2-oxoazetidin-1-yl -2-triphenylphosphorium and ldenoacetic acid para-nitrobenzyl ester. A) A suspension of 2 g of Hyagrin in 3 ml of dioxane is stirred for 30 minutes at at room temperature, mixed with 962 mg of 2- (3 S, 4 R) -acetyl-thio-3-phenoxy-acetoxy-2-oxo-azetidine-1-Il-2-hydroxyacetic acid 2-(3 S, 4 R) para-nitrobenzyl ester dissolved in 10 ml of dioxane and then slowly with a solution of 0.38 ml of thionyl chloride in 8 ml of dioxane. The mixture is stirred for 2 hours at room temperature, filtered from a Hunigue base, and the filtrate is evaporated in vacuo. The residue is purified by chromatography on silica gel with a mixture of toluene and ethyl acetate 1: 1 to obtain 2- (3S, C, R) -α-acetylthio-3-methoxy-2-oxo-azetidyl-1-yl-2-chloro-acetic acid acid para-nitrochloride in crude the form. b) A solution of 9bO mg of 2-W S para-nitrobenzyl ester, k R) -4-aue ethylthio-3-phenoxyacetoxy-2-oxoazetidin-1-yl -2-chloroacetic acid in tO ml of dioxane is mixed with 786 mg of three phenylphosphine and 3 g of the Hongyu baseline and stirred overnight at 50 ° under nitrogen atmosphere. The polyfine Hunig is removed by filtration and the filtrate is evaporated in vacuo. The residue is chromatographed on silica gel with toluene-ethyl acetate 9: 1 to give a compound. IR spectrum (in methylene chloride): characteristic absorption bands at 5.7, 5.9, 6.17, 6.55, 7, 5 microns. An example. Preparation of (5R, b S) -2-methyl-6-phenoxy-acetoxy-2-stub-3- para-nitro-benzyl ester arboxylic acid. A solution of 285 mg of 2-S, ijR) -acetylthio-3-phenoxyacetoxy-2-oxo-azetidin-1-yl -2-triphenylphosphoranylideneacetic acid para-nitrobenzyl ester, 2-S, ijR) is mixed with a catalytic amount of hydroquinone and stirred for 35- at 90 ° under nitrogen, the toluene is evaporated in vacuo and the residue is chromatographed on silica gel with a 19: 1 toluene-ethyl acetate mixture. The compound is obtained as an oil. IR spectrum (in methylene chloride): characteristic absorption bands at 5.55, 6.30, 6.55, 7.2 microns. Example E Preparation of (5 R, 6 5) -2-methyl-6-phenoxy-acetoxy-2-penem-3-carboxylic acid, Solution 15 mg of (5 R, 6 5) -2-methyl-6-phenoxy-pao-nitrobenzyl ester -acetoxy-2-penem-3-carboxylic acid in a mixture of 2 ml of ethyl acetate and 2 ml of 2M sodium bicarbonate solution is mixed with 75 mg of a 10% palladium-carbon catalyst and hydrogenated at atmospheric pressure for 1.5 hours at room temperature. The hydrogenated mixture is filtered through diatomaceous earth, the filter residue is washed with 1 ml of 2M aqueous sodium bicarbonate solution and methyl acetate. From the filtrate | The aqueous phase is separated, acidified with a 0.1 M aqueous solution of citric acid and extracted several times with methylene chloride. The combined methylene chloride extracts over the sulf: sodium tom and evaporated in vacuo. The IR spectrum (in ethanol) of the resulting crude compound: characteristic absorption band at 5.6 µm; UV spectrum (in ethanol): L max 305 nm. Example 50. Preparation of 6-alpha-methoxypenicillanic acid 1-oxide 2,2,2-trichloroethyl ester. A solution of 2 g of alpha-methoxypenicillanic acid 2,2,2-trichloroethyl ester 6 in 100 ml of methylene chloride and 0.3 ml of acetone is cooled to, mixed for 5 minutes with 1 ml of kO% solution of peracetic acid and stirred for 15 minutes at same temperature. After this, the reaction mixture is mixed with 15 ml of a 0.1 N sodium thiosulfate solution. The organic solution is separated and washed twice with ice water. After drying over sodium sulfate, the solvent is evaporated in vacuo and the residue is recrystallized from ether-petroleum ether. The compound obtained has the following physicochemical properties: melting point 127-128; IR spectrum (in methylene chloride): characteristic absorption bands at H, 5.58, 8.33. 8 ,, 8,70, 9. “8 microns. Example 51. Preparation of 2,2 f (3 S, R) -4- (bizthiazol-2-yl-dithio) -3-methoxy-2-oxr-azetidin-1-yl-3- 2,2-2,2-trichloroethyl ester methylenebutyric acid.
A solution of 3 g of alpha-methoxy-penicillanic acid 1-oxide of 2,2,2-trichloroethyl ester 6 in O ml of absolute toluene is mixed with 1.39 g of 2-mercaptobenzthiazol and heated for 11 11 5 minutes under nitrogen atmosphere under reflux. The solvent is removed in vacuo and the compound is obtained in a yellowish oil, the IR spectrum (in methylene chloride): characteristic absorption bands at 3.39, 5t60, 5.65, 6.85, 8.20, 8.62, 8.97, 9.85, 9.95 microns.
The resulting product can be introduced without further purification to the next stage.
Example 52 Preparation of 2- (3 S, 4 K) -4- (Benzthiazol-2-yl-dithio) -3 methoxy-2-oxo-azetidin-1-yl-3-methyl 2,2,2-trichloroethyl ester of 2- (3 S, 4 K) - 20 crotonic acid.
A solution, 17 g of 2, 2-3 S, I-4- (benzthiazol-2-yl-dithio) -3-methoxy-2-oxo-ozetidine 1-yl-3-methyleneo-acid-2-2,2-trichloroethyl ester 5 times in 75 ml of absolute methylene chloride is mixed at 0 ° with 0.78 ml of triethylamine and stirred at this temperature for 15 minutes. The reaction mixture is washed successively with a 4 N solution of phosphoric acid, a saturated aqueous solution of sodium bicarbonate and brine, and dried over sodium sulfate. The solvent is evaporated and the residue is purified by chromatography on silica gel with toluene and a mixture of toluene and ethyl acetate 19: 1- The compound is obtained in the form of an oil; IR spectrum (methylene chloride): characteristic absorption bands at 3.39, 5.62, 5.76, 40 6.85, 7.0i, 7.25, 6.85, 9.01, 9, 9.85, 9 , 95 microns.
Example 53. Preparation of 2,2 (3S, k, R) -α-acetylthio-3-methoxy-2-oxo-asetyl-45-din-3-methyl-3-methylcrotonic acid
A solution of 3.26 g of 2,2,2-trichloroethyl ester of 2- (3 S, I) -benzthiazol-2-yl-dithio} -3-methoxy-2-oxoazetidin-1-yl-3-methylcrotonic acid in Zb , 3 ml of acetic anhydride and 12, ml of acetic acid are cooled to -15 ° and mixed with g of triphenylphosphine. After 75 minutes of stirring under nitrogen at the same temperature, 24.8 ml of pyridine is added to the mixture. After further 3 hours of stirring at 0 °, the reaction mixture is evaporated under reduced pressure and the resulting residue is purified by chromatography on silica gel with toluene and a mixture of toluene and ethyl acetate 19: 1; IR spectrum (in methylene chloride): characteristic absorption bands at 3.0, 5.63, 5.77, 5.80, 6.13, 7.25, 7.35, 8.26, 9 °, 0, 9 , 52, 11.90 μm. Example 5. Preparation of 2- (3 S, R) -acetylthio-3-methoxy-2-oxo-azethidin-1-yl -2-oxo-acetic acid 2,2- 2-trichloroethyl ester.
Through cooled to -30 ° solution 8, g of 2- (3S, 4K) -4-acetylthio-3-methoxy-2-oxoazetidin-1-yl-3-methylcrotonic acid 2,2,2-trichloroethyl ester in 7b5 ml methyl acetate miss 3 equivalents of ozone. After being treated with ozone, the reaction mixture was left to stand for 15 minutes at the same temperature and thereafter, the excess ozone was removed with a stream of nitrogen. The reaction mixture was washed at 0 ° with an aqueous solution of sodium bisulfite and then with brine. After separation, the combined organic phases are extracted 4 more times with methyl acetate. The combined methyl ether solutions are dried over sodium sulfate and evaporated in vacuo, the IR spectrum of the oily compound obtained (in methylene chloride): characteristic absorption bands at 3.39, 5.8, 5.63, 6.09, 6.9 7.25 , 7.38, 7.6, 8.23, 8.93, 9.90, 11.83 microns.
Example 55. Obtaining (3 S, tR) - -acetylthio-Z-methoxy-2-oxoazetidine,
a) A solution of 1.52 g of 2,2- (3S, 4K) -4-acetylthio-3-methoxy-2-oxo-azetidin-1-yl -2-oxo-acetic acid 2,2--trichloroethyl ester of 2- (3 S, 4 K) in crude 290 ml of methanol, kQ ml of methyl acetate and 5.9 ml of water are heated for
20 minutes under nitrogen at reflux. The solvent is evaporated in vacuo. After chromatography on silica gel with a mixture of toluene and ethyl acetate 3: 1, the desired compound is obtained. IR spectrum (in methylene chloride): characteristic absorption bands at 2.95, EVL, 5.60, 5.88, 7.37, 7.52, 8.25, 8.70, 8.85, 10.5, 12.12 µm.
The same compound can be obtained as follows.
b) A solution of 40 mg (3 S, k of Yu-4-acetoxy-3 methoxy-2-oxo-azetidine (see below) in 1.5 ml of phosphate buffer (pH 7) and 0.1 ml of dioxane 37925 are mixed with 1, 5 equivalents of an aqueous solution of sodium thioacetate and stirred at room temperature for 30 minutes. The reaction mixture is extracted with methylene chloride and the separated organic solution is then dried over sodium sulfate. The solvent is evaporated in vacuo and the residue is purified by chromatography on silica gel with toluene / ethyl acetate 3: 1. The IR spectrum of the compound thus obtained ( methylene chloride) is identical to the spectrum of the product obtained according to option a, EXAMPLE 56. Preparation of p-nitratesbenzyl ester 2- (3 S, k R) - -acetylthio-3-methoxy-2-oxoazetidin-1-yl -2-oxyacetic Acids. A solution of 350 mg (3 S, U-h-acetylthio-3-methoxy-2-oxoazetidine in a mixture of 2i ml of absolute toluene and 6 ml of absolute dimethylformamide is mixed with 1.15 g of p-nitrobenzyl ether 2-ethoxy-2-hydroxyacetic acid and g molecular sieves A4 and stirred at room temperature under a nitrogen atmosphere overnight. The molecular sieves are filtered off and the filtrate is evaporated in vacuo. The residue is chromatographed on silica gel, and elution with toluene and a toluene-ethyl acetate 19: 1 mixture gives the compound. IR spectrum (in methylene chloride): characteristic absorption bands at 2.86, 3.39, 5; 60, 5.68, 5.88, 6.21, 6.56, 7, 8.26, 9.01, 11 , 76 microns. Example 57. Preparation of para-nitrobenzyl ester of 2 - {(3 S, "R) -4-acetylthio-3-methoxy-2-oxoazetidine -1-yl -2-chloroacetic acid ester. A solution of 0.6 g of 2-G (3S, 4R) -4-acetylthio-3-methoxy-2-oxoazetidin-1-yl1 -2-oxyacetic acid 2-G para-nitrobenzyl ester in 7 ml of dry tetrahydrofuran is cooled to -15 ° and mixed with 0.19 ml of thionyl chloride. Thereafter, at the same temperature, 0.37 ml of triethylamine in O, ml of dry tetrahydrofuran is added dropwise. The reaction mixture is stirred for one hour at 0 °, diluted with cold methylene chloride and washed with ice-cold 2. hydrochloric acid solution. After repeated extraction by shaking with water, the methylene chloride solution is dried over sodium sulfate and evaporated. IR38 spectrum (in methylene chloride): characteristic absorption bands at H., 5.59, 5.65, 5.88 6.21, 6.55. W., 8.23, 8.55, 9.05, 10.5, 11, 76 μm, Example 58. Preparation of 2- (3 S, 4 R) -4-acetylthio-3-methoxy-2- p-nitroxybenzyl ester oxoazetidin-1-yl -2-triphenylphosphoranylideneacetate. A solution of 0.63 g of 2- f (3 S, i I) - | -acetylthio-3 methoxy-2-oxoazetidin-1-yl -2-chloroacetic acid para-nitrobenzyl ester in 1.8 ml of dry tetrahydrofur ana is mixed with 0 , 8 g of triphenylphosphine and stirred overnight in a nitrogen atmosphere at room temperature. The mixture was diluted with methylene chloride and washed with cold saturated sodium bicarbonate aqueous solution. Additional rinsing with water, drying over sodium sulfate and evaporation in vacuo gives a crude compound, which is purified by chromatography on silica gel with a mixture of toluene and ethyl acetate in a ratio of 19: 1. up to 3: 1. IR spectrum (in methylene chloride): characteristic absorption bands at 3.0, 5, B7, 5, ° 0, 6.20, 6.58, 7, "6, 9.05 µm. Example 59. Preparation of (5 R, 6 S) -2-methyl-6-methoxy-2-penem-3-carboxylic paranitrobenzyl ester. A solution of 7 mg of 2- (3S, 4H) -1'-acetylthio-3-methoxy-2-oxoazetidin-1-yl -2-triphenylphosphoranylidene-acetic acid para-nitrobenzyl ester of 2- (3S, 4H) in 30 ml of absolute toluene is mixed with a catalytic amount of 3.5 - ditert. -butyl-oxytoluene and heated for 3 hours under nitrogen at reflux. Toluene is evaporated in vacuo and the residue is chromatographed on silica gel using a mixture of toluene and ethyl acetate 19. The compound is obtained in solid form. IR spectrum (in methylene chloride): characteristic absorption bands at H, 5.60, 5.85, 6.63, 6.58, 7, 7.60, 8.23, 9.26 11.76 microns. Example 60. Preparation of 3 ethyl- (2-acetylaminoethylthio-thiocarbonylthio1-2-pxoazetidine (racemic cis-trans-compound.en.e.) a). A solution of 0.78 g (5 mmol) of 4-acetoxy-3 ethyl- azetidin-2-one (racemic mixture of cis and trans isomers in a ratio of 6: ()) in 2 ml of dioxane /} is added dropwise under nitrogen to a solution of 1.175 g of potassium 2-acetylamino, ethyl) tritiocarbonate in 20 ml of pre-cooled phosphate buffer (pU 7) and stirred for 60 minutes. The reaction mixture is centrifuged, the clear solution from the top is decanted, and the oily residue The organic phase is dried over sodium sulfate and evaporated in vacuo. The residue is triturated once with diethyl ether and in this form is further processed: DC: Rf 0.16 (ethyl acetate); IR spectrum (in methylene chloride): bands absorption at 2.92, 2.97, 5.63, 5.97, 6.62, 9.35 and 12.3 microns Both raw materials can be obtained as follows: b) To the mixed solution .3.5 g (0.302 mol) of 1-butenyl acetate in 35 ml of dry methylene chloride, at -10, 2.7 g (26.3 ml; 0,302 mol) N-chlorosulfonyl isocyanate. After another 4 hours of stirring at 0, the reaction mixture is diluted with 50 ml of pre-cooled methylene chloride and 32 ml of water, kk g of ice, 113 g of sodium bicarbonate and 38.2 g of anhydrous sodium sulfite are added dropwise to the hydrolized mixture. During hydrolysis, the temperature due to external cooling is maintained at an O level. If the organic phase no longer gives an acidic reaction, the reaction mixture is diluted with 100 ml of diethyl ether and filtered through celite. The organic phase is separated, the aqueous phase is extracted three times with 00 ml of diethyl ether, the organic phases are combined, dried and evaporated in vacuo. The residue is chromatographed on silica gel with a 2: 1 mixture of toluene - ethyl acetate and a racemic mixture of cis and trans-4-acetoxy-3-ethylazetidin-2-one is obtained in the ratio b: as an oil. IR (methylene chloride): absorption bands at 2.9, 5.60, 5.75, 7.35, 8.06 and 8.85 µm. c) A solution of 1.708 g (1.35 mmol) of 2-acetylaminoethyl mercaptan in 2 ml of absolute ethanol is added dropwise over 0.5 hour with stirring and cooling to 10–15 ° to a solution of 0.80 g M, 35 mmol) of potassium hydroxide in 5 ml of absolute ethanol. In the next 30 minutes, a solution of 1.09 g (1 +, 35 mmol) of carbon disulphide in 3 ml of absolute ethanol is added, and the temperature is maintained at a level of 10-15. The reaction mixture is further stirred by stirring for 3 hours at room temperature and cooled for 20 minutes in an ice bath. The yellow crystalline precipitate is filtered off, washed once with absolute ethanol, and (2-acetyl-aminoethyl) potassium trithiarcharbonate is obtained with a melting point of 171-17. IR spectrum (potassium bromide): absorption bands at 2.95, 6.18, 6.50, 7.00, 7.32, 7, + 3, 7.79, 8.33, 9.09 and 11, 83 microns. Example 61. Preparation of 2-3-ethyl-2-acetylaminoethylthio-thiocarbonylthio -2-oxo-1-azetidinyl -2-hydroxyacetic paranitrobenzyl ester of racemic cystrans-compound. At room temperature a solution of 3.30 g (11 mmol) 3 -ethyl-4- (2-acetylaminoethylthio-thiocarb6-n-thio-2-oxoazetidine (racemic cis-trans compound) in 120 ml of toluene and 32 ml of dimethylformamide is mixed with, 2.0 g (16.5 mmol) of 2-ethoxy-2-p-nitrobenzyl ester of 2-ethoxy-2- hydroxy acetic acid. After adding freshly dried molecular sieve, the mixture is stirred under nitrogen for 3 hours at room temperature. Molecular sieves are filtered, washed with 20 ml of toluene and the filtrate and the washings are evaporated together in vacuo, the residue is dried under high vacuum and then triturated with diethyl ether to remove unreacted 2-ethoxy-2-nitroxybenyl ester 2-ethoxy-2- hydroxyacetic acid. A compound is obtained with the following physicochemical properties: DC: R 0.16 (ethyl acetate); IR spectrum (methylene chloride): absorption bands at 2.86, 2.92, 3.03, 5.65, 5.71, 5.97, 6.58, 7.1 and 8.37 microns. Example 62. Preparation of 2- {(3 ethyl- - (2-a-Cetilamine ethyl-thio-thiocarbonylthio) -2-OXO-1-azetidinyl -2-triphenylphosphoranylidene-acetic acid paranitrobenzyl ester (racemic cis-trans compound). Solution 5.52 g (11 mmol) 2- | 3-ethyl- - (2-acetylaminoethylthi-thiocarbonylthio) -2-oxo-1 -azetidinyl 1 -2-hydroxyacetic acid 2- | 3-ethyl- (2-acetylaminoethylthio-thiocarbonylthio) para-nitrobenzyl ester (racemic cis-trans-soyne, decomposition) is cooled to -15, mixed under stirring with 1, 02 ml (And mmol of thionyl chloride and then slowly with 1.95 ml (k mmol) of triethylamine. Reaction The mixture is stirred for 20 minutes at O, mixed with 150 ml of methylene chloride and washed with ice-cold 1 N hydrochloric acid solution, the organic phase is dried with sodium sulfate and evaporated in vacuo. The resulting 2- 3-ethyl-p-nitrobenzyl ether | - (2-acetylaminoethylthiothiocarbonylthio) -2-oxo-1-azetidinyl-1-3-chloroacetic acid is dissolved in 3 ml of dry tetrahydrofuran, mixed with 6 g of triphenylphosphine and stirred for 2 hours at room temperature. The reaction mixture is diluted with 200 ml of methylene chloride, washed with a saturated aqueous solution of sodium bicarbonate, dried over sodium sulfate and evaporated in vacuo. The residue is obtained after chromatography on silica gel with ethyl acetate Compound AX: R 0.19 (ethyl acetate); IR (methylene chloride): absorption bands at 2.93, 5.70, 5.97. 6.17, 6.58, 6.99. 7.00, 8.07. 8.33 and 9.39 microns. Example 63. Preparation of 2- (2-acetylaminoethylthio) -6-ethyl-2-penem-3-carboxylic acid paranitrobenzyl ester (racemic cis and trans compounds). A solution of 1.75 g (2.3 mmol) of 2- 3-ethyl-3- (2-acetylaminoethylthio-thiocarbonylthio) -2-oxo-1-azetidinyl -2-triphenyl phosphoranylidene-acetic acid paranitrobenzyl ester; ) in 1500 ml of dry ortho-xylene is mixed with a catalytic amount of hydroquinone and stirred under nitrogen for 7 hours under reflux. The solvent is evaporated in vacuo and chromatographed on silica gel with ethyl acetate. A mixture of cis and trans isomers of the compound is obtained. By a combination of preparative thin layer chromatography (on methyl silica isobutyl ketonon) and. column chromatography (on silica gel with ethyl acetate) can be obtained cis- and trans-compound. Cis-compound: placenta temperature (after crystallization from methylene chloride / diethyl ether mixture); JH: K 0.62 (methyl isobutyl ketone); IR (methylene chloride): absorption bands at 2.93. 5.62, 5.98, 6.60, 7.6, 7.57. 8, and 9.09 microns. Trans compound: melting point 132-133 (after crystallization from methylene chloride / diethyl ether); HH: K 0.56 (methylisobutyl ketone); IR spectrum {(methylene chloride); absorption bands at 2.92, 5.62, 5.96. 6.58, 7 ,. 7.58, 8.40, and 9.01 microns. Example 6. Preparation of 2- (2-acetylaminoethylthio) -6-ethyl-2-penem-3-carboxylic acid (racemic cis and trans compounds). a) A solution of 100 mg (0.22 mmol) of 2- (2-acetylaminoethylthio) -6-ethyl-2-penem-3-carboxylic acid para-nitrobenzyl ester (racemic cis-compound) in 6 ml of absolute ethyl acetate is mixed with k ml 0.2% aqueous solution of sodium bicarbonate and 200 mg of a 10% palladium catalyst and stirred under normal pressure for 60 minutes in a hydrogen atmosphere. The hydrogenated mixture is filtered from the catalyst through diatomaceous earth. The aqueous phase is separated, washed with diethyl ether and acidified with an aqueous solution of citric acid and exhaustively extracted with methylene chloride. The combined methylene chloride phases are dried over sodium sulfate, filtered, evaporated in vacuo and dried in high vacuum. The resulting cis compound has the following physicochemical properties: melting point 153 (methylene chloride / diethyl ether); IR spectrum (potassium bromide): absorption bands at H.OUB, 3.22, 3.39. 3., 3.50, 3.77. .08, 5.67. 6.06, 6.21, 6.35. 6.75. 7.0., 7.69, 7.93. 8.27 9.01. 9.62 and I, 38 microns. b) Similarly, starting from 100 mg of 2- (2-acetylaminoethylthio) -6-these -2-penem-3-carboxylic acid para-nitrobenzyl ester (racemic trans-compound), a trans compound is obtained. IR (potassium bromide): absorption bands at 3.01, 3.39. H., 5.68, 6.10, 6.85. 7.75, 8.16. 8.7 and 8.93 microns. Example 65 Preparation of 3-ethyl- - ("-para-nitrobenzyl-oxycarbonyl-aminobutyrylthio) -2-oxoazetidine (racemic cis-trans compound in the ratio 1 :)
A pre-cooled solution of 3.2 g (20 mmol) of Z-ethyl-acetoxyazetidin-2-one (racemic cystrans-compound in the ratio of b :) in 50 ml of dioxane is mixed dropwise with a solution prepared in cold of 7.95 g (26, 7 mmol) k para-nitrobenzyloxycarbonylamino-thiobutyric acid in 26.7 ml of 1 N sodium hydroxide solution and stirred at room temperature for 2 hours. The reaction mixture was exhaustively extracted with methylene chloride. The combined organic phases are dried over sodium sulfate and evaporated in vacuo. The residue is chromatographed on silica gel with a mixture of toluene - ethyl acetate in a ratio of 9: 1,: 1 and 1: 1, and a compound with the following physicochemical properties is obtained: flX: Rf 0.10 (toluene ethyl acetate 1: 1); IR spectrum (methylene chloride): absorption bands at 2 81, 2.92, 5.66, 5.81, 5.9, 6.58, 7.52, and 8.20 µm.
The thiocarboxylic acid used as the starting material is obtained as follows.
a) A solution of 10.30 g (0.1 mmol) of 4-aminobutyric acid is mixed in 300 ml of 1 N sodium hydroxide solution in an ice bath, dropwise A for 20 minutes with a solution of 25.87 g
(0.12 mmol) para-nitrobenzyl chloroformate in 100 ml of dry dioxane. The reaction mixture is stirred for 3 hours at room temperature, washed with ethyl acetate and acidified with a 2 N hydrochloric acid solution. The precipitated β-para-nitrobenzyloxycarbonylaminobutyric acid is filtered off and recrystallized from ethyl acetate. Melting point 1A5-Y6 °.
b) To a cooled to -10 solution of 2.82 g (10 mmol) of 4-para-nitrobenzenexycarbonylaminobutyric acid
2.2 g (20 mmol) of triethylamine and a solution of 1.4 ml (10 mmol) of isobutyl chloroformate in 20 ml of dry methylene chloride are added dropwise in 50 ml of dry methylene chloride. The reaction mixture is stirred for one hour and then an intensive hydrogen flow is passed through it for 2 hours. After acidification with 2N sulfuric acid solution, the organic phase is separated, dried and evaporated in vacuo. The resulting 4-para-nitrobenzyloxycarbonylamino acid on acid
It can be further processed without further purification.
PRI me R 66. Preparation of 2-Zethyl-C-para-parabrobenzyloxycarbonylaminobutyrylthio) -2-oxo-1-azetidinyl -2-hydroxyacetic acid paranitrobenzyl ester.
At room temperature, 6.50 g (16.45 mmol) of 3-ethyl-4- (4-para-nitrobenzyloxycarbonylaminobutyrylthio) -2-oxoazetidine (racemic cis-, trans-compound) and 8.41 g of para-nitrobenzyl ether 2- ethoxy-2-hydroxyacetic acid is dissolved in 1O of toluene and 40 ml of dimethylformamide. After about 15 g of freshly dried molecular sieve has been added, the mixture is stirred under nitrogen for 3 hours at room temperature. The molecular sieves are filtered and washed with dimethylformamide / toluene (1: 4). the filtrate is evaporated in vacuo, dried under high vacuum and the residue is infused with diethyl ether to remove unreacted 2-ethoxy-2-hydroxyacetic acid p-nitrobenzyl ester. The crude compound has the following physicochemical properties: flX: Rf 0.1 (toluene ethyl acetate 1: 1); IR (methylene chloride): absorption bands at 2.83, 2.90, 5.67, 5.73, 5.80, 5.99, 6.58, 7.52, 8.26 and 9.52 microns .
Example 67. Preparation of 2-3-ethyl-4- (4-para-nitrobenzyloxycarbonylaminobutyrylthio) -2-oxo-1-azetidinyl -2-triphenylphosphoranylidene-acetic acid para-nitrobenzyl ester of 2-3-ethyl-4- (4-para-nitrobenzyloxycarbonylaminobutyrylthio) (racemic cis-trans compound).
a) To a mixture of 10.40 g (17.2 mmol) of 2- 3-ethyl-4- (4-para-nitrobenzyloxycarbonylaminobutyrylthio) -2-oxo-1-azetidinyl -2-oxyacetic acid para-nitrobenzyl ester in 40 ml dioxane at -15 was added dropwise successively 3.06 ml (42 mmol) of thionyl chloride and 5.85 ml (42 mmol) of triethylamine. Reactionary
the mixture is stirred for 20 minutes at 0 and under nitrogen atmosphere, diluted with 200 ml of methylene chloride and washed with a cooled 1 N hydrochloric acid solution. The organic phase is dried and evaporated in vacuo.
b) The crude para-nitrobene 2-3-ethyl-4- (4-para-nitrobenzyloxycarbonylaminobutyrylthio) -2-oxo-1-azetidinyl -2-chloroacetic acid methyl ester obtained is dissolved in a minimum amount of tetrahydrofuran, mixed with 9 g of triphenylphosphine and stirred overnight at room temperature under an azit atmosphere. The reaction mixture is diluted with 250 ml of methylene chloride; yes, it is washed with a saturated aqueous solution of sodium hydrogencarbonate, dried and evaporated in vacuo. The residue is chromatographed on silica gel with a mixture of toluene and ethyl acetate 1: 1 to obtain a compound with the following physicochemical properties: DC: E 0.05 (toluene / ethyl acetate 1: 1); IR (methylene chloride): absorption bands at 2.90. 5.73. 5.80. 5.9. 6.58, 7.52. 8.20 and 9.35 microns. .
Example 68. Preparation of 6-ethyl-2- (3-para-nitrobenzyl oxycarbonylaminopropyl) -2-penem-3-carboxylic paranitrobenzyl ester (racemic cis-trans-compound)
Solution 5, “O g (6.36 mmo) of 2-Z-ethyl- - (p-nitrobenzyloxycarbonylaminobutyryl-thio) -2-oxo-1-azetidinyl -2-triphenylphosphoranylidene-acetic acid para-nitrobenzyl ester of 2-3-ethyl- - (p-nitrobenzyloxycarbonylaminobutyryl-thio) ) in 1500 ml of dry toluene is mixed with a catalytic amount of hydroquinone and stirred under nitrogen for 20 hours at 100. The solvent is evaporated in vacuo and the residue is chromatographed on silica gel with toluene-ethyl acetate:. A mixture of cis and trans isomers of the compound is obtained in a ratio of 1:10 with the following physicochemical properties: flX: R 0.22 (toluene - ethyl acetate 1: 1); IR spectrum (methylene chloride): absorption bands at 2.90, 5.62, 5.81, 5.85. 6.58. 7.52. 7.87 and 8.20 microns. Upon repeated chromatography, the cis and trans compounds are obtained in pure form.
Example 69. Preparation of 6-ethyl-2- (3-aminopropyl) -2-penem-3-carboxylic acid (racemic cis-trans-compound).
A solution of 2 g (mmol) of 6-ethyl-2- (3 para-nitrobenzyloxycarbonylaminopropyl) -2-penem-3-carboxylic acid para-nitrobenzyl ester (racemic cis-trans-compound) in 600 ml of dioxane, 330 ml of ethanol and 600 ml of water mixed with 2 g of disodium hydrogen phosphate and g of a 10% palladium catalyst and stirred at normal pressure for one hour in a hydrogen atmosphere. The hydrogenated mixture is filtered from the catalyst through diatomaceous earth. The filtrate is washed with 3 ml of 1500 ml of ethyl acetate and lyophilized. The lyophilized product is chromatographed twice on silylated silica gel (ANTEK-CEL, UP-C thin-layer plates) with a mixture of water - acetoneTryl 9. 1 and a compound (cis-trans about 1:10) is obtained with the following physicochemical DH (ANTEC-CEL) , UP-C, 2): Rf 0.55 (water - acetonitrile 9: 1); IR spectrum (potassium bromide) absorption bands at 2.9 t, 3.39. 5.68, b ,. 7.33. 7.81, 8.93. 12.82 and 1.28 microns.
 From the pure cis or trans compound obtained in the preliminary stage, the pure cis and trans compounds mentioned in the title can be obtained.
Example 70. Getting beta. beta, beta-trichloroethyl ester of 2-CP S. "S) and (3 S. I) -4-acetoxy-3-methoxy-2-oxo-azetidin-1-yl 3-methylene butyl acid.
200 mg of 1-oxide beta. Beta, betatrichloroethyl ether (6 8) -6-methoxypenicillanic acid are mixed in 13 ml of absolute benzene with O, and ml of glacial acetic acid and 0.35 ml of trimethylphosphite and heated for 7 hours with reverse a fridge. The solvent is evaporated in vacuo and the residue is purified by chromatography on silica gel with a mixture of toluene and ethyl acetate in a ratio of 19: 1 and 9: 1
The connection can thus be divided. IR (methylene chloride): characteristic absorption bands for the (3 S, f R) -isomer (trans compound): 3., 5.62. 5.68. 7.25 e 7.35. 8.26, 9.01. 10.93. 11.83 microns; for the (3 S, i S) isomer (cis compound): 3., 5.61, 5.7, 7.25. 7.35, 8.21, 9.61, 10.93 microns.
The ratio of cis-compounds to trans-compounds is about 1: 1.
Example 71. Preparation of beta-, beta-, beta-trichloroethype ester 2- (3 S, L) - and (3 S, K) -acetoxy-3-methoxy-2-oxo-azetidin-1-yl-1-3-methylcrotic acid
A solution of 0.93 g of beta, beta, beta-trichloroethyl ether 2-1 (3 S, 4 S) and (3 S, 4 I) - -acetoxy-3-methoxy-2-oxoazetidin-1-yl) -3 methylene oil Acidic acid in 60 ml of absolute methylene chloride is cooled to 0 ° and stirred for 10 minutes with 0.33 ml of triethylamine.  The reaction mixture is washed, then successively with k N phosphoric acid solution, saturated sodium bicarbonate aqueous solution and water, dried over sodium sulfate.  The solvent is evaporated in vacuo and the residue is purified by chromatography on a silica gel.  IR spectrum (in methylene chloride): characteristic absorption bands at 3, 5.50, 5.73, 6.13, 7.19, 7.33, 8.26, 9.09, 9.57, 10.6 , 10.87, 12.19 microns.  Example 72  Preparation of beta-, beta-beta-trichloroethyl ester of 2- (3 S, k S) - and (3 S, 4 K) -4-acetoxy-3 methoxy-2-oxo-azetidin-1-yl -2-oxoacetic acid .  Through a solution of 0.91 g of beta-, beta-beta-trichloroethyl ether 2- (3 S, t S) - and (3 S, R) -4-acetoxy-3-methoxy-2-oxoazetidine, cooled to -30 ° 1-yl-α-methylcrotonic acid in 130 ml of methyl acetic ester is passed 3 equivalents of ooozoic acid.  After ozone treatment, the cigiecb is left to stand for 15 minutes at the same temperature, and after that, excess ozone is removed by a stream of nitrogen.  The reaction mixture is washed at 0 with an aqueous solution of sulphite on ri and then with brine.  The combined aqueous solutions are reextracted three times with methyl ester of acetic acid.  The combined organic extracts are dried over sodium sulfate and evaporated in vacuo.  IR spectrum in methylene chloride): characteristic absorption bands at 3.1, 5.6, 5.68, 5. 81, 7.27, 7.43, 8.23, 8.40, 9.5, 9.90 microns.  Example 73  Preparation of (3 S, 4 S) - and (3 S, 4 R) -4-acetoxy-3-methoxy-2-oxy-osetidine.  A solution of 120 mg of beta-beta-beta-trichloroethyl ester 2 (3 S, 4 S) and (3 S, 4 K) -4-acetoxy-3-methoxy-2-oxoazetidin-1 -yl -2-oxoacetic acid in 25 ml of methanol, 3.5 ml of methyl acetic ester and 0.5 ml of water are heated for 20 minutes under reflux.  The solvent is evaporated in vacuo and the residue is obtained after chromatography on silica gel with a toluene / ethyl acetate mixture of 9: 1 pure (3 S, k) -acetoxy-3-methoxy-2-oxoazetidine.  IR spectrum (in methylene chloride): characteristic bands absorbed at 2.9b, 3 ,, 5.57, 5.73, 7.30, 8.23, 8.70, 8.35, E, 62, 10, 0 10.20 microns.  Upon further elution, pure (3 S, k S) - -acetoxy-3-methoxy-2-oxo-azetidine; IR spectrum (in methylene chloride): characteristic absorption bands at 2.9, 3 ,, 5,56, 5,73, 7,35, 7Л9, 0 9,52 microns.  Example 7  Preparation of (3 S, K) -4- (2-para-nitrobenzyloxycarbon. Il-aminoethylthio-thiocoabonylthio) -3-methoxy-2-oxo-azetidine.  A solution of 150 mg (1 mmol) of (3 S, 4 S) -acetoxy-3-methoxy-2-oxo-azetidine in 3 ml of phosphate buffer with OH and 0.2 ml of dioxane are mixed at room temperature under nitrogen atmosphere with drops of a solution of 422 mg of 2-para-nitrobenzyloxycarbonylaminoethyl-3-tritiocarbonate potassium in 1 ml of water and stirred at the same temperature for 30 minutes.  The reaction mixture is exhaustively extracted with methylene chloride.  The combined organic phases are dried over sodium sulfate and evaporated under vacuum.  The residue is chromatographed on silica gel to give a compound with the following IR spectrum (in methylene chloride): characteristic absorption bands at 2.95, 5.62, 5.78, 6.21, 6.5b, 7.41, 8.26, 9 , 25 microns.  Example 75  Preparation of 2- (3 S, 4 K) -4- (2-para-nitrobenzyloxycarbonylaminoethyl-thiocarbonylthio) -3-methoxy-2-OXO-1-azetidinyl -2-hydroxyacetic acid para-nitrobenzyl ester.  Analogously to example 23, 646 mg (1.5 mmol) (3 S, 4 I) -4- (2-para-nitrobenzyloxycarbonylaminoethylthio-thiocarbonylthio) -3-methoxy-2-oxoazetidine in 22 ml of absolute toluene and 5.5 ml of absolute dimethylformamide is reacted with 848 mg of 2-ethoxy-2-hydroxyux p-nitrobenzyl ester; and with hydrochloric acid in the presence of freshly dried molecular sieves.  After separation of the reaction mixture and chromatography on silica gel, a compound is obtained.  IR spectrum (in methylene chloride): characteristic absorption bands Poi 5.62, 5.7, 6.56, 7. one.  8.26 microns  Example 76.  Preparation of 2- (3 S, R) p-nitrobenzyl ester (2-para-nitrobenzyloxycarbonylaminoethylthio-thiocarboiyylthio) -3-labels of c-2-oxo-1-azetidinyl -2-triphenylphosphoranylideneacetic acid.  Analogously to example 24, a solution of mg of para-nitrobenzyl ester of 2- (3 S, C K) -4- (2-para-nitrobenzyloxycarbonylaminoethylthio-thiocarbonylthio) -3-methoxy-2-oxo-1-azethynyl -2-hydroxyacetic acid, 5 ml of | Absolute tetrahydrofuran is mixed with 0.12 ml of thionyl chloride and 0.23 m of triethylamine in 0.23 ml of absolute tetrahydrofuran.  After completion of the reaction and separation of the reaction mixture, the crude para-nitrobenzyl ester of 2- (3 S, k K) (2-para-nitrobene zyloxycarbonylaminoethylthio-thiocarbonylthio) -Z-methoxy-2-oxo-1-azetidini obtained as an intermediate product -2-Chloroacetic acid in 1.15 ml of absolute tetrahydrofuran is mixed with 0.5 g of triphenylphosphine.  After: separating the reaction mixture and chromatography on silica gel, the compound is obtained.  IR spectrum (in methyl chloride): characteristic absorption bands at 3.4, 5.7, 5.78, 6.15, 6.55, 7. +5, 8.26 microns.  Example 77.  Preparation of (6S, 5R) 2- (2-para-nitrobenzyloxycarbonylaminoethylthio) -6-methoxy-2-penem-3-carboxylic para-nitrobenzyl ester.  Analogously to example 25, a solution of para-nitrobenzyl ester 2 1 (3 S, 4 K) -4- (2-para-nitrobenzyl oxycarbonylaminoethylthio-thiocarbonyl-thio) -3 methoxy-2-oxo-1-azetidinyl-2-triphenylphosphorienylidene acetic acid is mixed in 165 ml of absolute ortho-xylene with a reverse cooler.  After separation of the reaction mixture and chromatography on silica gel with a mixture of toluene and ethyl acetate in the ratio from 19: 1 to 9: 1, the compound is obtained.  IR (methylene chloride absorption bands at 5.57, 5.78, 5.9, 6.55, 7.45 and 8.26 µm.  Example 78  Preparation of (6 S, 5 K) -2-C2-aminoethylthio) -6-methoxy-2-penem-3-carboxylic acid.  Analogously to Example B9, a solution of 295 mg of para-nitrobenzyl ether (6 S, 5 K) -2-G2-para-nitrobenzyloxycarbonylamino-ethylthio) -6-methoxy-2-penem-Zcarboxylic acid in 85 ml of dioxane, 47 ml of ethanol and 85 ml of water are treated with 286 mg of disodium hydrogen phosphate and 570 mg of a 10% palladium-carbon catalyst in a hydrogen atmosphere at normal pressure.  After completion of the reaction and separation of the reaction mixture, the following compound is obtained with the following IR spectrum (bromide potassium): absorption bands at 2.8-4.16 5.68, 6.41 and 8.26 microns.  Example 79  Preparation of (3 S, 4 R) -4- (4-para-nitrobenzyloxycarbonyl-aminobutythyl, o) -3-methoxy-2-oxo azetidine.  As in Example 55 b), 159 mg of (3 S, 4 5) -4-acetoxy-3-methoxy-2-oxoazetidine in 6 ml of phosphate buffer with a pH of 7 and 0.4 ml of dioxane are mixed with an aqueous solution of 480 mg of sodium salt 4 -para-nitrobenzyloxycarbonylaminothiobutyric acid.  After separation of the reaction mixture and chromatography on a silica gel, a compound with the following IR spectrum (methylene chloride) is obtained: characteristic absorption bands at 2.95, 5.6, 5.78, 5.87, 6.56, 7.41 and 8.26 um  Example 80  Preparation of 2- (3S, 4R) -4- (4-para-nitrobenzyloxycarbonylaminobutyryl-thio) -3-methoxy-2-oxo-1-azetidinyl -2-hydroxyacetic acid para-nitrobenzyl ester.  Analogously to Example 23, 400 mg of (3 S, 4 I) -4- (4-para-nitrobenzyloxycarbonylaminobutyrylthio} -3-methoxy-2-oxo-azetidine) in 15 ml of absolute toluene and 3.7 ml of absolute dimethylformamide are reacted with 5b5 mg of para- 2-ethoxy-2-hydroxyacetic acid nitrobenzyl ester in the presence of freshly dried molecular sieves.  After separation of the reaction mixture and chromatography on silica gel, a compound with the following IR spectrum (methylene chloride) is obtained: characteristic absorption bands at 5.6, 5. 7, 5.78, 5.87, 6.56, 7.41 and 8.26 microns.  Example 81  Preparation of 2- (3S, 4R) -4- (4-para-nitrobenzyloxycarbonylaminobutyrylthio) -3 para-nitrobenzyl ester of methoxy-2-oxo-1 -azetidinyl -2-triphenylphosphoranylidene-acetic acid.  Analogously to example 24, a solution of 606 mg of 2- (3 S, -4 K) -4-para-nitrobenzyloxycarbonylaminobutyrylthio) -3-methoxy-2-OXO-1-azetidinyl -2-hydroxyacetic acid para-nitrobenzyl ester in 4.3 ml absolute tetragi of furan is mixed with 0.12 ml of thionyl chloride and then with 0.23 ml of triethypy per 0.23 ml of absolute tetrahydrofuran.  After completion of the reaction and chilling of the reaction mixture, the resulting crude 2- (3S, k K) crude para-nitrobenzyl ester (4-para-nitrobenzyl sycarbonylaminobutyrylthio) -3 methoxy -2-OXO-1-azetidinyl -2-chloroacetic acid in 1, 15 ml of absolute tetrahydrofuran is mixed with 0 g of trifluorin nfosphine.  After separation of the reaction mixture and chromatography on silica gel, a compound with the following IR spectrum (methylene chloride) is obtained; characteristic absorption bands at 5.7, 5.78, 5.9, 6.15, 6.55, 7.5, and 8.26 microns.  Example 82  Preparation of (6S, 5R) -2- (3-para-nitrobenzyloxycarbonylaminopropyl) -6-methoxy-2-penem-3 carboxylic acid para-nitrobenzyl ester.  Analogously to example 68, a solution of COO mg of 2- (3S, kK) -4 - (- p-nitrobenzyl-pxycarbonylaminobutyryl-thio-3-methoxy -2-OXO-1-azetidinyl -2-trifenol-amphosphoranylidene-acetic acid mixtures of pao-nitrobenzyl ester of 2- (3 S, k K)) in 1 ml of absolute toluene under reflux.  After separation of the reaction mixture and chromatogram (L on silica gel with toluene-ethyl acetate in a ratio of from 13: to 9: 1, the compound is obtained.  IR spectra (methylene chloride): characteristic absorption bands at 5.57, 5.78, 5.85, 6.55, 7, t5 and 8.26 microns.  Example 83  Preparation of (6S, 5I) -2- (3-aminopropyl) -6-methoxy-2-penem-3-carboxylic acid.  , And to Example 69, a solution of 572 mg of (6S, 5K) -2- (3-para-nitrobenzyloxycarbonylaminopropyl) -6-methoxy-2-penem-3-carboxylic acid para-nitrobenzyl ester (6S, 5 K) in 2 ml of ethyl acetate with 16 ml 0.2 n. sodium bicarbonate solution and 600 mg of palladium-carbon catalyst are stirred under a hydrogen atmosphere.  After completion of the reaction and separation of the reaction mixture, a compound with the following IR spectrum (potassium bromide) is obtained: absorption bands at 2.75, 15; 5.67; 6 42 and 8.25 microns.  An example.  Production of beta, beta, beta-trichloroethyl ether 2f (3 S, C R) - and (3 S, 4 K) - chloro-5-methoxy-2-oxo-azetidin-1-yl-1-3-methylcrotonic acid.  612 mg of beta, beta, beta-trichloroethyl ether (6 8) -6-methoxy-penicillanic acid are mixed in 9 ml of absolute methylene chloride at -80 dropwise with 3.25 ml of a 1.1 M solution containing active chlorine in tetrachloride carbon.  After stirring for two hours at -80 °, the reaction mixture is brought to room temperature over one hour.  The solvent is evaporated in vacuo and the residue is chromatographed on silica gel.  The compound has the following IR spectrum (in methylene chloride):  characteristic absorption bands for H, 5.60, 5.76, 6.15, 7.22, 7.35, 8.33, 9.09, 9.52, and 12.20 µm.  In the resulting mixture, the ratio (3 S, 4 S) is the compound to (3 S, 4 R).  The compound is 1:10.  Example 85, Getting beta. beta, beta-trichloroethyl ester -2- (3 S, S) - and (3 S, i I) - + -chloro-3-methoxy-2-oxo-azetidin-1-yl -2-oxo-acetic acid.  Through a solution of 210 mg of beta, beta, beta-trichloroethyl ether 2- (3 S, 4 S) - and (3 S, k R) - + - chloro-3 methoxy-2-oxoazetidin-1-, cooled to -35 ° C Il-3-methylcrotonic acid in 30 ml of methyl ester of acetic acid miss 2 equivalents of ozone.  After treatment with ozone, the mixture is left to stand for 15 minutes at the same temperature and thereafter, excess ozone is removed by a stream of nitrogen.  The reaction mixture is washed at 0 ° 1: 2; with a saturated aqueous solution of sodium bisulfite and then with brine.  The combined aqueous solutions were further extracted 3 more times with acetic acid methyl ester.  The organic extracts are dried over sodium sulfate and evaporated in vacuo.  The crude compound has the following IR spectrum (in methylene chloride); characteristic absorption bands at 3. one.  5.6, 5. 65, 5.80, 7.6.  8.23, 8, A7, 8.89, 9.57, 9.95, and 11.90 microns.  Example 86  Preparation of (3 S, k S) - and (3 S, t K) -4-chloro-3-methoxy-2-oxo-azetidine.  A solution of 339 mg of beta, beta, betatrichloroethyl ether 2- (3 S, S) and / 3 S, 4 K) - chloro-3-methoxy-2-oxo539 azetidin-1 -yl -2-oxoacetic acid and 197 mg 2 , α-dinitrophenylhydrazine in O ml of tetrahydrofuran is heated for 30 minutes under reflux.  The solvent is scorched and the residue is chromatographed on silica gel.  The compound has the following IR spectrum (methylene chloride): characteristic absorption bands at 2.9, 5.56, 8.26 and 9.09 µm.  Example 87.  Preparation of (3 S, C R) (-para-nitrobenzyloxycarbonylaminobutyrylthio) -3-methoxy-2-oxo azetidine.  A solution of 135 mg (3 S, 4 K) -1-chloro-3-methoxy-2-oxo-azetidine in 6 ml of phosphate buffer with a pH of 7 and 0.4 ml of dioxane are mixed in the presence of 150 mg of sodium iodide dropwise with a solution 350 mg of sodium salt of para-nitrobenzyloxycarbonylaminothiobutyric acid in ml of water.  After 30 minutes of stirring at room temperature, the mixture is thoroughly extracted with methylene chloride.  After separating and drying the organic phase over sodium sulfate, the solvent is evaporated in vacuo and the residue is chromatographed on silica gel.  The compound has the following IR spectrum (methylene chloride): absorption bands at 2.95, 5. 6, 5.78, 5.87, 6.56, 7 ,. 1 and 8.26 microns.  Example B8.  Preparation of threo-trans-6-1-p-nit robenyloxycarbonyloxyethyl | -penemin-3-carboxylic acid acetonyl ester.  A solution of 1.9b g (2.5 mmol) of 2- {threo-trans-3- (1-P-nitrobenzyloxycarbonyloxyethyl) acetonyl ester (cis-β-carbomethoxy-vinyl mecapto) -2-oxo-1-azetidinyl -2-triphenylphosphoranylideneacetic acid in fO ml of methylene chloride is added to 1.25 ml of trifluoroacetic acid at -20 ° C and the mixture is introduced stream 0 into Oj (0.33 mmol per minute) for 15 minutes at the same temperature.  Then, excess nitrogen is removed by the addition of nitrogen, 2 ml of dimethyl sulfide is added at JC, stirred for 10 min, diluted with 50 ml of ice-cold porous methylene, washed twice with portions of 25 ml of 10% potassium bicarbonate solution, dried the organic phase is sodium sulfate, evaporated in a vacuum rotary evaporator, the solid residue is dried under high vacuum for 2 minutes and dissolved in 60 ml of methylene chloride (freshly filtered with aloxide).  Then the solution is heated under reflux for 90 minutes under a nitrogen atmosphere, after cooling it is evaporated in a vacuum rotary evaporator and the residue is chromatographed on 25 g of Merck - 510; a mixture of toluene - ethyl acetate 3: 1 as a solvent.  After evaporation of the appropriate fractions, a pure amorphous compound is obtained.  Rf 0.55 (EtOAc); Their spectrum (CHjCIj).  absorption bands at | 1795, 1750, 1720, 1530.1350 cm NMR spectrum (in acetone-d / IOO MS, in parts per million): 8 ,, 4H, dd; 7.6.  1H, S; 5.95.  1H, d, J 2.5 Hz; 5.3, 2H, S; 5.4-5.1, 1H, m; “, 8, 2H, S; "4.2, VH, dd, J 6 Hz, J 2.5 Hz: 2.1, 3N, S; 1.5, 3N, d, and 6.5 Hz.  Example 89  Receipt. erythro-trans-6- (1-p-nitrobenzyloxycarbonyl-hydroxyethyl) -peneme-3-carboxylic acid acetonyl ester.  According to the described method, the above compound is obtained, starting from the erythro-transgene compound.  T.  square  15 "-15HP, Rf 0.55 (EtOAc).  Infrared spectrum (W2S12): absorption bands at 1795,, 1720, 1530, 1350 NMR spectrum (in acetone - d / 100 Me, in ppm): 8,, 6,, dd; 7.6, 1I, S; 5.8, 1H, d, J 2.5 Hz; 5.35, 2H, S; 5.25, 1H, dd, J 6.5, J 3.5 Hz; 3.80, 2H, S; 3.8, 1H, m; 2.1, 3N, S; 1.5, 3N, d, J 6.5 Hz.  , Example 90.  Prism of threo-trans-6- (1-hydroxyethyl) 3-carboxylic acid acetonyl ester.  A solution of 0.936 g (2 mmol) of threo-trans-6- (1-p-nitrobenzyloxycarbonyloxyethyl) acetyl ester with an 80 3-carboxylic acid foam in 80 mp of a mixture consisting of equal parts of acetonitrile and ethanol is hydrogenated over 800 mg 10 Pd / C catalyst at room temperature for 2.5 hours  The mixture is filtered, the filtrate is evaporated and the residue is chromatographed on kQ g MerkSiOj with toluene-ethyl acetate 2: 1 as a solvent.  The appropriate fractions are isolated from solvent c.  a vacuum rotary evaporator and the residue is crystallized by the addition of ether / methylene chloride. . .  Rf O, (EtOAc); T.  square  115-1164 IR spectrum (CHjCta): 3850, 1790, 1725 1720, 1560, 1175 cm; NMR spectrum (in acetone d / 100 Me (in ppm parts 7.6, 1H, S; 5.85; 1H, d, J 2 Hz; +, 8, 1H, S; k, k, 1H, m; , -, 0, 1 Н, S; 3.85, 1Н, d, J 7 Hz; J 2 Hz; 2.15, ЗН, S; 1,3, ЗН, d, J 6,5 Hz.  Example 91  Getting acetyl. erythro-trans-6- (1-hydroxyethyl) -penem-3-carboxylic acid ester.  According to the described method, this compound is obtained from the Aris-trans-trans compound.  Rf 0.4 (EtOAc), T.  square  120121, 5 ° C; IR spectrum (WGSR); absorption bands at 2580, 1790, 1725, 156 1175 NMR spectrum (in d / 100 acetone in ppm): 7.55, 1H, d, D 1 Hz; 5.8, 1H, d, J 2 Hz; A, 8, 2H, S; 4, -, 0, 1H, S; i, 4-4,2, 1H, m; i, 0, 1H, m; 2.15, 3N S; 1.35, 3N, d, J 6.5 Hz.  , Example 92.  Production of threo-trans-6- (1-hydroxyethyl) -penem-3-carboxylic acid.  To a solution, 0.271 g (1 mmol) of threo-trans-6- (1-ox-ethyl) acetonyl ester 3-carboxylic acid acetonyl ester in 40 ml of acetonitrile and 10 ml of water are added dropwise 10 ml of 0.1N.  NaOH solution in a nitrogen atmosphere at 0 ° C for 15 minutes.  The mixture is stirred with 6 g of swollen weakly acidic cation exchanger IV (Merck) for 5 minutes at a temperature of OC, filtered and evaporated in vacuo to a volume of -20 ml and chromatographed on 10 tiles of antegel-dodecyltrichlorosilane-DS with water size 20 X, 20 cm.  Elution with a mixture of acetonitrile - H20 (3: 1) and lyophilization of the filtrate gave a pure compound in the form of a solid, amorphous substance.  Rf Oh, (, tile; antegel-dodecyltrichlorosilane-DS).  IR-c Lektr- (KVg) 1750; NMR spectrum (in DjO / lOO Me in parts per million): 7.2 1H, S; 5.95, 1I, d, and 2 Hz; I, k5, 1H, m; 4.15, 1H, dd, U 6 Hz; J 2 Hz; 1.48, 3N, d, and 6.5 Hz.  Example 93  Preparation of erythro-trans-6- (1-hydroxyethyl) -penem-3-carboxylic acid.  According to example 88, the compound of emit from the starting erythro-trans-compound.  This is a solid, amorphous substance.  Rf 0.4 (H20, tiles andegel dodecyltrichlorosilane-DS).  IR spectrum TKBg): 1750 cm-; NMR spectrum (V / 100 MS, in ppm): 7.3, 1H, S; 5.9, 1H, d, J- 2 Hz, 4.4, 1H, m; 4.2, 1H, dd, J 4 Hz; J 2 Hz; 1.52.  ZN, d, J 6.5 Hz.  Example 94 oPreparation of (5 R, 65) -6- (2-hydroxyprop-2-yl) p-nitrobenzyl ester by 3-carboxylic acid.  A solution of 0.49 g (0.69 mmol) of 2- (3 S, 4 R) -3- (2-hydroxyprop-2-yl) p-nitrobenzyl ester 4- (trans-D-carboethoxyvinyl mercapto) -2-oxo- 1-azetidinyl -2-triphenylphosphoranylideneacetic acid in 60 ml of methylene chloride was added to 3.0b ml of trifluoroacetic acid at -20 ° C and stream 0 was introduced into this mixture at Oj at the same temperature.  Then, excess 0 is removed by introducing nitrogen, 3.06 ml of dimethyl sulfide is added, stirred for 15 minutes at room temperature, diluted with 20 ml of ice-cold methylene chloride, washed twice with portions of 20 ml of an aqueous solution of sodium bicarbonate, then 20 ml of brine, the organic phase is dried with sodium sulfate, evaporated in a vacuum with a rotary evaporator, the solid residue is evaporated under high vacuum and dissolved in 60 ml of toluene (freshly filtered with aloxide).  Then the solution is heated for 90 minutes at 60 °, evaporated after cooling in a vacuum rotary evaporator, and the residue is chromatographed on 6 g of MepK-Si02 with a mixture of toluene - ethyl acetate (51) as a solvent.  After evaporation of suitable fractions, the above-mentioned compound is obtained in pure amorphous form.  Rf 0.49 (ethyl acetate 1: 1 ether); IR spectrum (CH2CE2) - absorption bands at 3570, 1790, 1720, 1530, 1330, 1210 cm-, NMR spectrum (in CDClI) / 100 Me, in parts per million): 8.37, 5, 4H, dd ; 7.33, VH, S; 5.8, 1H, d / J 2 Hz, 5.35, 2H, m; 4.3, 1H, m; 3.85, 1H, dd J 2 Hz; J 6 Hz; 2.05, LN, broad; 1.38, ZN, d / J 6 Hz /.  V Example 95.  Obtaining (5 R, 6 5) -6- (2-oceaniprop-2-i) -penem-3-carboxylic acid (sodium salt).  A solution of 0.18 g of p-nit | eobenzyl ester (5 R, 6 S) -6-, 2-hydroxyprop-2-yl with a foam of 3-carboxylic acid in a mixture of 15 ml of ethyl acetate and 15 ml of a 0.41 th aqueous solution Sodium bicarbonate 579252 / is added to 0.15 g of catalyst over a 10% palladium-carbon mixture and hydrogenated at atmospheric pressure for 50 minutes at room temperature.  The hydrogenated mixture is filtered through diatomaceous earth and the residue on the filter is washed with water.  The aqueous phase is separated from the filtrate, washed with ethyl acetate, concentrated under high vacuum, and chromatographed with water on 6 tiles of antegel-dodecyltrichlorosilane-DS, measuring 20 x 20 cm.  Elution with a mixture of acetonitrile (H20) and lyophilization of the filtrate gave the compound as a pure amorphous solid.  K 0.37 (HjO plate antegel -, dodecyltrichlorosilane-DS).  IR spectrum (KBG); 1755, 1590, 1555 cm; NMR-, spectrum (in DnO / lOO Me s parts per million): 7, CHO, 1H, S; 6.12, 1H, d / / J 2 Hz / ;. “, 32, 1H, d / J 3 Hz /, 1.7, 3N, S; 1.66, ZN, S.  Example 9b.  Preparation of (5 R, 6 S) -6- (1 R) -1-hydroxyethyl penem-3-carboxylic acid p-nitrobenzyl ester.  A solution of 0.17 g (0.21 mmol) of p- nitrobenzyl ester of 2- (3 S, R) -4- (1 R) -l-hydroxyethyl - - trans - (- karzo-boethyl oxivinyl mercapto) -2-OXO- 1-azetidinyl -2-triphenylphosphoranylideneacetic acid in 18 ml of methylene chloride is added to 0.93 ml of trifluoroacetic acid at -20 ° C and an ozone-oxygen mixture is introduced into this mixture jj at the same temperature.  Excessive Oj is then removed by introducing nitrogen.  After adding 0.93 ml of dimethyl sulfide, the mixture is stirred for one hour at a condensed temperature, diluted with 20 ml of ice-cold methylene chloride, washed 15 times with 10 ml of 10% aqueous sodium bicarbonate solution and then with brine.  Organic 45
the phase is dried with sodium sulfate and evaporated in a vacuum rotary evaporator. The solid residue is dried under high vacuum and dissolved in 20 ml of toluene (freshly filtered aloxide). The solution is heated for 3 hours under nitrogen, after cooling it is evaporated in a vacuum rotary evaporator and the residue is chromatographed on 16 g of MepK-SiOj with toluene-ethyl acetate P as the solvent. After evaporation of the appropriate fractions, the compound is obtained in an amorphous form of Chibt. 5 20 25
characteristic absorption bands at 2.95; 5.66; 6.29; LU SN DS: R 0, 5 (UPS, 2 plits, solvent: HgQ)

权利要求:
Claims (3)
[1]
The claims of the invention. 1. A method of obtaining derivatives of 2penem-3-carboxylic acid of the formula I
.. "TL
° -Ey4
where RO.- lower alkyl, hydroxy (lower) alkyl, where the hydroxy group may be 258 Rf 0.59 (ethyl acetate - a simple ether 1/1); IR (CHjCtj): absorption bands at 3550, 1790, 1720, 1525, 1530, 1320, 1200 CM. NMR spectrum (in D O / IOO Me in parts per million): 8.3-7.5, ““ H, dd; 7.3, 1H, S; 5.85, 1H, d CJ 2 Hz); 5.33, 2H, m; 3.85 1H, d (J 2 Hz), Example 97. Preparation of (5 R. 6 S) -6-f (1 I) -1-hydroxyethyl 1-penem-3-carboxylic acid (sodium hydroxide salt). A solution of 3 mg of p-nitrobenzyl ester (5 R, 6 S) I) -1-hydroxyethyl foam 3-carbonic acid in a mixture of 1 y ethyl acetate and 4 ml of 0% sodium bicarbonate aqueous solution is added mixtures based on palladium-carbon and hydrogenated for 0 min at atmospheric pressure at room temperature. Processing and chromatography were carried out according to Example 96 and the compound was obtained in a pure, amorphous, solid form. Rf 0, (plate antegel-dodecyltrichlorosilane-DS): IR spectrum (KVg); 1760 cm; NMR spectrum (in BCA / SO of MS in parts per million); 7.25, 1H, S; 5.96, 1H, d / a 2 Hzji, 45, 1H, m; 1.15, 1H, dd / J 6 Hz, J 2 Hz; 1.5, 3N, d / J 6 Hz. PRI me R 98. Obtaining the sodium salt of (5 R, 6 5) -6-hydroxymethyl-3-carboxylic acid. By catalytic hydrogenation of (5 R, 6 S) -6-hydroxymethyl-penem-3-carboxylic acid pnitrobenzyl ester, which can be obtained according to Example 9b, in tetrahydrofuran (water with 10% palladium-based catalyst) of carbon, filtering, evaporating the solvent, taking tium residue in an aqueous solution of sodium bicarbonate and freeze-drying to obtain the compound UV spectrum (H.jO): Aa 30 m (-fJjOO); IR spectrum (Nujol): protected by a protective group such as, for example, p-nitrobenzyloxycarbonyl, phenyl (lower) alkyl, phenyl or phenoxy (lower) alkanoyl iradizhal; and RI is a hydrogen atom, lower alkyl, amino (lower) alkyl, acylamino (lower alkyl, lower alkylthio-amino (lower) alkylthio or acylamino (lower) alkylthio radical, where the amino group can be protected by a protecting group such such as tert, butoxycarbonyl or p-nitrobenzyloxy carbonyl, as a free acid or as its protected derivatives, such as an acetonyl or p-nitrobenzyl ester, or as its salts, such as a sodium salt, characterized in that Formulas II where Ra and R have meanings, the functional groups in these residues are preferably in protected form, the C (0) R2 residue is a carboxyl group protected in esterified form, Z is oxygen or sulfur and X is a trisubstituted phosphonio group. OR is twice esterified into an ester phosphono group. together with the cation, is subjected to cyclization by heating to 30-160 s in an inert solvent, if necessary, protecting the oxy-, amino- and carboxyl-protecting groups, and, if necessary, freely obtained The compound is salified.
[2]
2. A method according to claim 1, characterized in that a compound of formula II is used, wherein the C (0) -R radical is a carboxyl group esterified to ester that is cleavable in a neutral or alkaline medium or under physiological conditions.
[3]
3. Method according to paragraphs. 1 and 2, characterized in that a compound of the formula II is used, where the radical R is a p-nitrobenzyloxy group. k. The method according to paragraphs. .1-3, about tl and chuyuschie and the fact that they use a compound of formula II, where the radical X denotes a triaryl or tri (isis) alkylphosphonic group. 5. Method according to paragraphs. I-, characterized in that a compound of the formula II is used, wherein the X® radical is a triphenylphosphonio group. 6. A method according to claim 1-5, characterized in that a (4 R) -connection of formula II is used. Sources of information taken into account during the examination 1. Published for Germany No. 2655298 Cl. C 07 D 99/58, published 1977.

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同族专利:

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NO158679C|1988-10-19|

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DK160099C|1991-06-24|

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ES477336A1|1979-07-01|

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EP0003960B1|1983-06-29|

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DK43279A|1979-08-03|

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JPH045677B2|1992-02-03|

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ZA79433B|1980-02-27|

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GB2013674A|1979-08-15|

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NO790332L|1979-08-03|

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DK160099B|1991-01-28|

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IE790191L|1979-08-02|

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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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CH114078|1978-02-02|

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