SU818486A3 - Method of preparing 7-alpha-methoxy-7-beta-(4-substituted methylene-1,3-dithioethan-2-ylcarbox-amido)-3-(1-methyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acids - Google Patents

Description

methyl} -3-cephem-4-carboxylic acid of formula

OSH

-N

Hjus

X

ABOUT

Cun yes

exposure to 4-reaction with methylvn-1, 3-dithiethan-2-carboxylic acid of the formula

t ")

Cun

I

where R and R have the above values, 1O1,

or with its functional derivative in organic esx 1 solvent at a temperature of from -5 ° C to room.

The compounds of formulas (I) and {ItI) can react directly with each other in the presence of a condensing agent / such an N, N -dicyclohexylcgfbodiimide / such, or it is possible to introduce protective groups into R and R according to their properties and ft, and also use the compound of formula (II) after the introduction of protective groups in the 4 position. when R and / or ft of the compound FO1H11ula (I1) is a carboxy group, as well as the carboxy group of the compound of Formula (HI) in position 4 is preliminarily 3a The 2 compounds of formula (111) or the amino group at position 7 of the compounds of formula (II) are converted into a reactive method (& 1e derivatives. Preferred examples of reactive carboxylic acid derivatives are, Hanptotep halide anhydride, mixed acid anhydride, active ester, act an explicit amide, acid anhydride or acid azide.

The compounds of formula (III) are new compounds and are prepared by the reactions of 2,2-disamoceno ethylene-1,1-dithio a

SH

tw)

# 5H and PP-have the aforementioned zenogenacetic acid or its

forcolyl alkyl ester

X.

SN-SOOY, (V)

X - ggshogen atom

 a hydrogen atom or a lower alkyl group.

and then, if the compound of formula (V) is a lower alkyl ester, it is converted to an acid or to a reactive acid derivative.

The reaction of compounds (II) and J (I, I) or their reactive derivatives is usually carried out in an inert solvent, and in order to avoid the epimerization of the methoxy group in the 7ct position during the reaction, before it is preferable to conduct the reaction at a low temperature, temperatures below.

The resulting compounds can thus be converted to a compound of formula (I) by removing the protective group or 5 groups.

The proposed compounds exhibit high antibacterial activity, in particular, against gram-negative bacteria.

0 Compounds of the form w (I) can be converted to their pharmaceutically acceptable non-toxic effective salts, which include alkali metal salts, such as sodium 1 or potassium 5 salts (for example, using sodium or potassium 2-methylhexanoate) 1mon, or a salt of an organic amine, or a salt with novocaine or ethanolamine.

The proposed compounds can be orally, rectally or by injection subcutaneously, intravenously or intravenously.

Injecting a suitably prepared sterile solution or suspension containing an effective, but non-toxic, amount of the cephalosporin compound provided is a preferred application. Doses of the cephalosporin compound are usually 250-3000 mg per day 0 for an adult and can vary depending on the conditions of the disease, age, weight and condition of the patient.

The proposed method is illustrated by the following 5 examples. Example.

OSV9

noos

% - dx

9 o

X COOK

A. in 15 ml of methylene chloride, solution of 0.340 g of (tert-butoxycarbonyl) ethylidene -1, 3-dithiethane-2-carboxylic acid and 0.206 g of pyridine are dissolved and 0.284 g are added with stirring in an ice-water bath. phosphorus penteshloride. The reaction lasts about 1 hour at a temperature below. After cooling the reaction mixture, 0.690 g of a solution of 7-L-amino-Leto1-CI-3- (1-methylt 65 tetrazol-5-ylthiomethyl) -3-cephem-4-carboxylic acid bezhydryl ether 7 solution is added dropwise to the drop in 10 ml methylene chloride, then 1.6 ml of pyridine is added dropwise, and the reaction in the mixture takes about 1 hour at a temperature of from -30 to -4 (JS. After the completion of the reactions, 10 mp 5 n is added dropwise to the reaction mixture. hydrochloric acid at a temperature below 0 ° C and the reaction product is extracted with methylene chloride. The extract is washed with a saturated aqueous solution of chloride-1 atri f atom over anhydrous calcium chloride and methylene chloride is distilled to give 1/1 g. The residue is subjected to chromatography on a silica gel column, then 0.490 g (yield 47%) of caramel-like benzhydryl ether 7) -tl- (tert-butane hydroxycarbonyl) atilenide 3 is obtained. 1, 3-dithioethan-2-yl} -carboxamido-methoxy-3- (1-methyltetrazol-3-yltisz methyl) -l-cefem-4-carboxylic acid using a mixture of ethyl acetate and n-hexane in a volume ratio of Isl in as eluent. Nuclear Magnetic Resonance Spectrum (D4-OMSO) (f (ppm) 1.44 (9H, tert-butyl); 1.56 (3N, 1:11 6 ") 6.92 {1H, -SI (СННз) ); 9.68 (1H, -CONH-) B. In 25 ml of anisole, 0.44 t of the product obtained in step A is dissolved, and while cooling the solution below in an ice-water bath, 7.5 ml are added to it trifluoroacetic acid is added dropwise. The reaction is continued for about 1 hour at 5-10 ° C, anisole and excess trifluoroacetic acid are distilled off under reduced pressure, and the residue is powdered by adding ether to it. After extraction of the powder by filtration, it is well spilled with ether and 0.271 g (yield, 86.7%) of light yellow powder (1-carboxyethylidene) -1,3-dithietan-2-yl3 carboxamido-7ow-methoxy-3- ( 1-methyltetrazol-5-ylthiomethyl) -D-cephem-4-carboxylic acid. Nuclear magnetic resonance spectrum (DJ, -DHS O) sG (ppm); “); 3.41 1.56 (ЗН, ЗН f --.-. Q GH / j; 3.93 (ЗН,); t СН 5.13 (2Н, Н of Cj and 9.57 (1Н, -CONH- Infrared Spectrum (KBG): 1870 cm Example 1 (Reference). In a three-necked flask (100 ml), 40 ml of dimethoxyethane and 10 ml of tetrahydrofuran are placed, both of which are recovered by distillation. The mixture is cooled below -70 ° C on a dry icy acetone bath, 1 ml of n-isopropylcyclohexyl1 min and 3.43 ml of 15% n-butyl n-hexane solution are added in a stream of nitrogen. Then, after adding 0.65 g of tert-butyl propionate, the reaction takes about 30 min at a temperature below -700 s with stirring .B reaction mixture to 0.332 ml of carbon disulfide at a temperature of from -75 to -73 ° C in approximately 30 minutes is dropwise. The reaction is then carried out for about 10 minutes at a temperature below -70 ° C and then a solution of 3.4 ivi 15% is added dropwise to the reaction mixture. n-butyl lithium n-hexane at a temperature below -70 ° C for 30 minutes. After about 15 minutes at a temperature below, sodium diiodoacetate, prepared in advance by the reaction of 0.24 g of 50% sodium hydrogen chloride and 1, is added to the reaction mixture, 56 g of diiodoacetic acid in 10 ml of dimethoxyethane while cooling with ice, the mixture is stirred all night at room temperature. The solvent is distilled off from the reaction mixture under reduced pressure and, after adding cold ether to the residue and acidifying the residue with 1N hydrochloric acid, the product is extracted with ether. The ether extract is washed well with a saturated aqueous solution of chloro-. sodium hydroxide, dried over anhydrous sodium sulfate, and then ether is distilled off to obtain 1.42 g of a brown oily product. The product is subjected to silica gel column chromatography to obtain 0.5 g of oily 4-fl- (tet-buto (2carboic; -ethylidene) -1, 3-dithia-A-2-carboxylic acid, using a mixture of chloroform, methanol, and formic acid in volume balance and 35: 5: 2 as eluent.) 1 deris-magnetic re-ionic spectrum (0 (, -DNS O) tfOP): 1.42 (9H, tert-butyl); -OOC-s 1.53 (Zy,); CH. 5.14 (IH, Infrared Spectrum, 2970 (tert-butyl) ;, 2520-2650 (-COOH); 1640-1740 (-COO-tert-butyl, -COOH 1360, 1250 and 840 (tert-butyl) P p and meper 2.. ™ A. In 6 ml of tetrahydrofuran is dissolved 0.7 g of 7 p -amino-7og-methoxy-3- (1-methyl tetrazol-5-yl) thiomethyl-D-cephem-4-carboxylate benzhydride of 4-g (tert-butoxycarbonyl) (methoxy) methylene) -1,3-di-diethane-2-carboxylic acid and 0.3 g of N, N-dicyclohec silcarbodiimide upon cooling The mixture is stirred at ambient temperature for 2 hours. The undissolved substances are filtered off and the filtrate is concentrated. and reduced davlen. The residue is subjected to column chromatography to obtain 0.36 g of 7 | L- (4- (tert-butoxycarbonyl) (methoxy) -m Tylen-1, 3-dithietan-2-yl} carboxy: am-7 -methoxy-3- (1-methyltetrazol-5g-yl) thiomethyl-cephem-4-carboxyl acid benzhydryl ether using a mixture of benzene and ethyl acetate in a volume ratio of 85: 1 as eluent. :: Nuclear Magnetic Resonance Spectrum ( CDCE) 1.50 (9H, t-butyl); 3.59 1 IPI Su and 3.64 (ZN 3.82 (ZN, 4.38 (2H, -CHj-S or C ,,); 4.77 (1H, CH-)):: 5.07 (1H , H or C (,); 6.92 (1H, CI () 2); 7.2-7.5 (YUN, -CH (Cj, H5 ij) B.) In 7 ml of anisole, dissolve 0.23 g of the product obtained in step A and while cooling the solution to temperatures from -5 to 5.1 ml of trifluoroacetic acid is gradually added, followed by stirring for about 30 minutes at 0-8 C. The reaction mixture is concentrated under reduced pressure and added to the residue. the ether and the resulting light brown powder are removed by filtration. The powder is washed well with ether and dried under reduced pressure. nii to obtain 0.12 g of 7p) -Y4- (carboxy) (1 yutoxy) methylene3-1, 3-dithietan-2-yl} carboxamido-7z-methoxy-3- (1-methyltetrazol-5-yl) thiomethyl- nd cepheme-4-carboxylic acid. Nuclear magnetic resonance spectrum (D-DMS O) rf (pjam); 3.42 (3N, OCH ,, CT,); -OOC 3.55 (3N); 3, 85 (3N, 5.16 (2H, H ofC, and 9.59 (1H, -CONH-)) Example 2 (filling) (CH, L СООС 3 b of the compound Mix 4.5 g tert-butyl methoxyacetate and 10 ml tetrahydrofuran to (equal to a solution of lithium dinzopropylamine, obtained by adding 18.2 ml of 15% n-butyl lithium hexane solution to a mixture of 3 g of diieopropylamine and 20 MP of tetrahydrofuran at temperatures -40 to -TSRs and after the addition of O, 9 ml of carbon disulfide at a temperature below the resulting mixture was stirred for about 20 NMH at the same temperature. After adding the resulting diisopropipamine lithium solution (1/2 of the specified amount) and carbon disulfide (half of the specified amount) to the reaction mixture, TfaMnepaType approximately -40 to -7 ° C to cause the reaction of lithium diisopropylamine (1/4 of the specified amount) and carbon disulfide (1/4 of the indicated amount) is added to the mixture to induce the reaction, and then 9 g of sodium diiodoacetate are added to the reaction mixture, followed by raising the temperature and stirring for about 1 hour at 0-5 seconds and then about 1 hour at room temperature. erature. The resulting reaction mixture is concentrated under reduced pressure and after the addition of 20 MP of 10% hydrochloric acid, a predissuing residue is extracted with 100 ml of benzene. The extract is washed with water and concentrated under reduced pressure. The resulting residue was subjected to chromatography on a silica gel column to obtain 5.6 g of 4- (tert-butoxycarbonyl) (methoxy) methylene -1, 3-dithi-ethane-2-carboxylic acid using a mixture of chloroform and ethanol in a volume ratio of 10 : 2-5 as eluent. Nuclear Magnetic Resonance Spectrum (SOSTS) cf (ppm): 1.52 (9B, (CH4) COOC-) j 3.67 (3N, CHjO-); 4.88 (1H, t (8.64 (IH, -COOH), PR-memer 3. USC) HOOCv 5chi JI3 / CH.BV ek A. When treated with 0.8 g of benzhydryl ether L- amino-7o-methoxy-3- (1-methyltetrazol-5-yl) thiomethyl-D-cephem-4-carboxylic acid and 0.8 g of 4- (benzoyl) (tert-butoxycarbonyl) -methylene -1, 3-dithiethane -2-carboxylic acid, as in Example 2A, I obtain 0.35 g of benzhydryl ester 7P) 4- (benzoyl) -tert-butoxycarboyl methylene -1,3-dithietan-2-yl carboxes up to -7csy-mutoxy-3 - (1-methyl-tetrazol-5-yl) yew-cephem-4-carboxylic acid. Nuclear Magnetic Resonance Spectrum (SOSTS) G (ppm, 2 (9H, t-butyl); 3.60 (3N, --- OCH); 3.82 (3N, N); CHj 4.39 (2H, - CHj-C,); 5.00 (IHl 5.09 (IHJ o7 6.92 (1I, -CH (); 7.2-7.6 (1SH, and an aromatic ring); 7.77 (1H, - CONH-) B. When processing 0.23 g of the product obtained in stage A as in Example 2 B, 0.13 g of 71H- (4-C (Seenzoyl (carboxy) methylene-3-1,3-dithietan-2-yl carboxamido -7O4-methoxy-3- (1-methyltetrazol-5-Sh1) thiomethyl-L1-cepheme-4-carboxylic acid. The nuclear-magnetic resonance spectrum (0, -OM50) abc (, 9 3,46 (ZN, OCH, ); 3.95 (3N,) 5 4.32 (2H, -CHj-Cj); 5.19 (1H, H from Cj,); 5.41 (1H, 7.48 (5H, CjjHj-OC- ); 9.72 (1H, -CONH-) Example 3 (referential). (CH5) CEPC, s 0.24 g of sodium hydride (50% in oil) and 0.6 ml of carbon disulfide are added to a mixture of 2.2 g of tert-butyl benzonyl acetate and 20 ml of tert-butanol in a mixture of 15-20 ° C, followed by stirring for about 40 minutes and then add 0.24 g of sodium hydride (50% in oil) to the mixture, followed by stirring for about 1 hour. To the resulting reaction mixture, add 1.52 g of sodium dichloratedetate: followed by stirring for about 4 hours at room temperature temperature The reaction mixture was concentrated under reduced pressure, and after adding 30 ml of 1 N hydrochloric acid to the residue, the product was extracted with 30 ml of benzene. The extract is washed with water, dried and concentrated under reduced pressure. Adding a mixture of benzene and n-hexane in a volume ratio of PG to the resulting residue gives 0.9 g of yellowish crystals of 4-1 benoyl) (three% butoxycarbonyl) methylene -, 3-dithiethan-2-carboxylic acid. Example4. CsC CHCONH V A. In 10 MP of anhydrous tetrahydrofuran, 0.3 g of 4-merc-butoxycarbonyl) (methylthio) methylene -1,3-ditietan-2-carboxylic acid, 0.2 g of N, N-dicyclohexbylcarbodiimine, and 0 are dissolved. , 5 g of 71L-a-1No-7o-methoxy-3- (1-methyltetrazol-5-yl) -thiomethyl-cepheme-4-carboxylic benzhydryl ether. Then the solution is stirred for 1 h at room temperature. The solvent is distilled off under reduced pressure. The resulting residue was converted into x-ray chromatography on a column of silica gel to obtain 0.3 7p - {- 4- (tert-butoxycarbonyl) - (methylthio) methylene} -1,3-diethiethan-2-yl-carboxamnzo-7c benhehydryl ester -methoxy-3- (1-methyltetra-5-yl} thiomethyl- {4-cephem-4-carboxylic acid using a mixture of benzene and ethyl acetate in a volume ratio of 9: 1 as eluent. Nuclear Magnetic Reverse Spectrum (SOC) ( G (rrP1) 1.52 (9H, tert-butyl); 2.22 (ZN, CH, jS-); 3.78 (5H, --OCHN and-CH - from C,); 3.82 (ZN ,); -CH 4.24 (2H,, C, j); S. 4.72 (IH, 5.08 (IH, H from Cj,); 6.92 (IH, -CH (Cj, Hg) , j); 7.35 (lOH, -CH (C4, H5),); 7.80 (IH, -CONH-) B. In 1.5 ml 0.3 g of the product obtained in Stage A is dissolved in nizol, and while stirring the solution, 5 ml of trifluoroacetic acid are added dropwise with stirring at temperatures from -5 to -3С, followed by stirring for about 1 hour at the PegMlation mixture is evaporated to dry under reduced pressure and ether is added to the residue.The precipitate is removed by filtration, washed well with ether, and dried over phosphorus pentoxide under reduced pressure to obtain 0.17 g of 7- (carboxy) (methylthio) methylene -1, 3- dithioethan-2-yl} -carbox amide-7L-methoxy-3- (1-methidtetrazol-5-yl) thiomethyl-A-cefem-4-k rbonoE th to isloty. Nuclear Magnetic Resonance Spectrum (D -ONSO) cP (ppni) :); 1.16 (AH, 3.43 (AH, HOS.);

CH-);

5.16 (1H,

A. When processing. 0.15 g of 4-f (trit-butoxycarbonyl) - (methylthio) -methylene1-1, 3-dithi-ethan-2-carboxylic acid, 0.1 g of Y.M-dicyclohexylcarbsdimimide and 0.26 g of 7- | -7c-methoxy-3- (1-mintyl tetraeol-5-yl) thiomethyl-benzhydryl ester-4-carboxylic acid ester, as in Example 4d, gives 0.14 g benzhydryl ester 7 (i-.49, 65 { 1H, - SONH-) Example 4 (reference), (CHj) jCOOC S Y CJ) CNSOH 5x CfijS-S in 14 ml of tetrahydrofuran are suspended in 0.96 g of sodium hydride (50% in oil). After adding dropwise a mixture of 20 ml of tert-butano a and 15 ml of anhydrous tetrahydrofuran to the suspension, the mixture is stirred at room temperature for 10 minutes. A mixture of 1.62 g of tert-butyl methylthioacetate and 5 ml of anhydrous tetrahydrofuran is then added to the mixture and, after 30 minutes, 0.6 ml of carbon disulfide is added to the mixture at the same temperature, followed by stirring for about 50 minutes. Then, 3.34 g of sodium diiodoacetate is added to the mixture at a lower temperature, and the induced reaction lasts about 50 minutes while cooling ldsl. The solvent is distilled off under reduced pressure, the resulting residue is dissolved in 50 ml of ice water and the solution is washed with ether twice. The resulting aqueous layer is recovered, the pH is adjusted to 2 with 10% hydrochloric acid, dried over anhydrous magnesium sulfate, and then the ether is distilled off under reduced pressure. The residue is subjected to silica gel column chromatography to obtain 1.3 g of an oil 4- | (tert-butoxycarbonyl) (methylthio) methylene -1, 3-dithi-ethane-2-carboxylic acid, using a mixture of chloroform, methanol and formic acid as the eluent . Nuclear magnetic resonance spectrum (soy C) with Ya (ppm) 1.52 (9H, (CH ,,) ,, СООС-); 2.22 (3N, CH ,, S-); S 4.74 (1H C 9.12 (1H, -COOH) Example 5 / - (tert-butoxycarbonyl} - (ethyltylene D-1, 3-dithietan-2-yl carbo to) -7L- methoxy-3- (1-methyltetra-5- and l) thiomethyl-d-cefem-4-carboxy acid. nuclear magnetic resonance spectrum (SOSC) (ppm) i 1.22 (3N, CHo CHjS-); 1, 52 {9H, t-butyl); 2.68 (2H, CH-bCH-zS-); (5H, -CH, - or C, j, and 3.82 (3N, - OCH); 4.38 (2H, -CHA or Cj); 4.70 (1H, 5.08 (1I, AND Cj Groups); 6.92 (1H, -CH (СНН5),); 7.32 (UN, -CH (C5H5),); 7.79 (1H, -CONH-) B. When processing a mixture of 0.14 duct obtained in stage A, anisole and 5 ml of trifluoroacetic lots, as in Example 4, I get 0.07 g ( carboxy) - (ethyltylene -1, 3-dithioethan-2-yl} carbo-7sg, -methox and-3- (1-methyltet, resolving -thiomethyl-y1-cephem-4-carboxylicity. Nuclear-magnetic resonance spectrum (Oj, -DMSO) d {ppgr); l, 14 (3N, GH,); 2, 62 (2H, CH, jCaj, S-); 3.43 (ZN, - OCH); 3.61 (2H, -CH, - C-group); 3.94 (ZN,) 4.28 (2H, groups C,) 5.08 (1H, And groups Cj,); 5.14 (IH, .Х 9.64 (1H, -CONH-) Recommendations for p1I1mmer 5.

When treating 3.4 g of tert-butyl ethyl thioadetate, as in Reference Example 4, 4.05 g of oily 4 tert-butoxycarbonyl) - (ethylthio) mv CHj 4.20 (2H, group C ,,,) are obtained; ilene} -, 3-ditietan-2-carboxylic acid.  I am an epho-magnetic resonant spectrum (SOSTS) (I {pp.): 1.42 (3N, SNC, CH55-); 1.52 (9H, (СН „,) ,, SOOS. -); 2.68 (2H, CHn, CH4S-): &.  4.76 (1H, C 9.52 (1H, -COOH)) Example 6.  . i; COOCH2 400 mg of 4- (bis) methoxycarbonyl (methylene) -1, 3-dithiethan-2-carboxylic acid is dissolved in 5 ml of methylene chloride.  After adding 180 ml of pyridine and then 290 mg of phosphorus pentachloride with ice-cooling, the mixture is stirred for about 3 min.  The solution is brought to a solution obtained by dissolving 500 mg of benzhydryl ester of 7 | L-amino-Lz-methoxy-3- (1-methyltetrazol-5-yl) tis ethyl-L-cepheme-4-carbonic acid in 10 ml of methylene chloride and cooling the solution to temperatures from -2 p to, and then the mixture is stirred for about 1 hour at the same temperature.  The reaction mixture is washed well with 10 ml of water, 5 ml of dilute hydrochloric acid and 5 ml of water, then dried over anhydrous magnesium sulfate and distilled under reduced pressure.  The residue is subjected to chromatography on a column of silica gel, obtained with m, 450 mg of benzhydryl ether. bis: (methoxycarbonyl) methylene -1, 3-dithietan-2-yl -carboxginido-7a-methoxy-3- (1-methyltetrazol-5-yl) thiomethyl | -cephem-4-carboxylic acid, using a mixture of chloroform and ethyl acetate in a volume ratio of 6: 1 as eluent.  Nuclear magnetic resonance spectrum (CDC l) d (ppm): 3.58 (5H, - group C, and -CH group C. ); 3.80 (6H, -СООСН ,,); N - N AND AND 3.83 (3N); 4.84 (IH, 5.07 (IH, H of the Cj group,); 6, 93 (IH, —CH () ,.  ); 7.36- (YUN, H of the phenyl of the -CH group (),) In a mixture of 4 ml of trifluoroacetic acid and 1 ml of anisole, 400 m of (methoxycar6onyl) methylene} -1, 3-dithiethan-2g-yl car6amo-amido-70-methoxy is dissolved -3- (1-methyl-tetrazol-5 yl) thiomethyl-β-cephem-4-caroic acid benagryl ester and the solution was stirred for about 1 hour while cooling with ice.  The reaction mixture is evaporated, dried dry and the residue is mixed with ether.  The product is recovered by filtration, washed well with ether, dried overnight over phosphorus pentoxide under reduced pressure, and 200 mg of 71B-14-bis (methoxycarbonyl methylene} -1, 3-dithietan-2-yl-carboxamido-7l-methoxy- 3- (1-methyltetrazol-5-yl) thiomethyl-cephaem-4-carb nova acid. , Nuclear magnetic resonance spectrum (0 -OMSO) cf (ppm); 3.44 (ZN, CHN, 0 - Su groups); 3.70 (6H, - COOCHj); 3.93 (3N, N - N}; / X / NN 4.29 2H, - C-group,); 5.08 (1H1. 5, „„ groups 5.16 (IHJ S 6 (reference).  Example of cG snohsn oosB 10 MP of anhydrous tetrahydrofur is suspended on 2.1 g of disodium; o 2,2-bis (methoxycarbonyl) ethIen-l, l-dithiolate. After adding 2.2 dibromoacetate of sodium to the suspensions, the mixture is stirred for about 2 hours at room temperature.  The solvent is distilled off from the reaction mixture under a lower pressure, and the residue is dissolved in 5 ml of water, the pH of the solution is adjusted to 3.5-4.0 with dilute hydrochloric acid and extracted with ethyl acetate.  The exhist is dried over anhydrous sodium sulfate and the solvent is distilled off under reduced pressure.  The residue is mixed with ether and filtered to obtain 1.5 g of 4-tbis (methoxycarbonyl) methylene -1, 3-dithiethan-2-carboxylic acid.  Nuclear magnetic resonance spectrum (D-DMSO) cf (pp); SNO, OOS 3.70 v6H, 5.20 (1H,. C Example 7.  . ° ° . c c: HCONHl S - J-14h. SNG5L. xYa a.  500 mg is dissolved in 5 ml of methyl chloride; 4-bis (tert-butoxycarbonyl) methylene-1, 3-dithiethan-2-yl carboxylic acid.  After adding 226 mg of pyridine and then 360 mg of phosphorus pentachloride to the solution under ice cooling, the mixture is stirred for about 30 minutes, added to the solution obtained by dissolving 500 mg of 7 | L-amino-7O1-methoxy-3- (1-methyltetrazol-5- yl) -thiomethyl-y-cepheme-4-carboxylate benzhydryl ether in 10 MP of methylene chloride and cooled to a temperature of -20 to, and the mixture is stirred for about 1 hour at the same temperature.  The reaction mixture is washed well with 10 ml of water, 5 ml of dilute hydrochloric acid and 5 ml of water, dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure.  The residue is subjected to silica gel column chromatography using a mixture of chloroform and ethyl acetate in a 6: 1 volume ratio as eluent to give 300 mg of benzhydryl ester 7 | L-H4-bis (tert-butoxycarbonyl) methylene -1, 3-dithiethan-2- yl carboxalo7o-methoxy- (1-methyltetrazol-5-yl) thiomethyl-cephem-4-carboxylic acid.  Nuclear Magnetic Resonance Spectrum (COGI. J,) sYa (rrt): 1.50 (18H, t -); 3.60 (5H, SNgO - of С and -CHjof С,); 3.86 (zn, fi); / 4 / N N I CH 4.40 (2H, of Cj); 4.82 (IH, C4-);.  5.10 (. IH, H of Cfc); 6.94 (IH, -CH (),); 7.38 (lOH, H phenyl from the group -CH (Ce, Hs)) B.  in a mixture of 4 MP of trifluoroacetic acid and 0.5 ml of anisole, 200 mg of tert-6-oxy-6-nig are dissolved. -methylene -1,3-dithiethan-2-yl-carb samido-7o (-methoxy-3- (1-methyltetrazo-5-yl) thiomethyl-cephem-4-carboxylic acid oenehydryl ether.  Rust the thief is stirred for about 1 hour while cooling with ice.  The solvent is then distilled off under reduced pressure, and ether is added to the resulting residue to form a precipitate which is recovered from the filtrate.  After washing with ether, 100 ml of 7 | L- 4 dicarboxymethylene -1, 3-dithietan-2 yl-carboxamido-7e-methoxy-3- (1-methyltetrazol-5-yl) thiomethyl-4-cefem-4-carboxylic acid are obtained.  Nuclear magnetic resonance spectrum (Df, -DMSO) d 3.44 (3N, - C-j groups); 3.64 (2H, C, J 3.93 (3N ,.   4.30 V2H, -CH, j-S- from Q); . , 16 (IH,) from s, and N-CH6Xg--. , 24 En / Example 7 (reference).  (CHj) 3COOC. five.  cxo (CH) j SOOS Analogously to reference example 6, using two-sodium 2,2-bic (tr bytoxycarbonyl) ethylene-l, 1-dithiolate, get 4- (bis) tert-butoxycarbon - (methylene), 3-dithiethane-2-carbonones acid.  Nuclear Magnetic Resonance Spectrum (D, -DMSO) cG (1.46 (9H, fCH) jCOOC-); S 5.18 (1H, C CH-) Example 8.  H,) cHCOHH-f - Y DL / - L.  SOOISCKj A.  In 12 ml of tetrahydrofuran dissolved 370 ml of 7 | L-amino-1-methoxy-3- (l-methyltetrazol-5-yl) thiomethyl-cephem-4-carboxymethyl benzhydryl ether g 150 mg of N-, N-dicyclohexylcarbodiimide and 150 ml of 4-t (Kap6aMoyl) (cyan) -methylene} -, 3- dithiethane-2-carboxylic acid, stirred for 2 hours at room temperature.  The precipitate formed is filtered off and the solvent is distilled off from the filtrate under reduced pressure.  The residue is subjected to silica gel column chromatography using a mixture of chloroform and isopropanol in a volume ratio of 9s1 as eluent, to give 190 mg of benzhydryl ester 7 {L-4-carbamoyl) (cyan) -methylene -1,3-dithiethane-2-yl -carboxamides-7L-methoxy-3- (1-methyltetrazol-5-yl) thiomethyl-cefem-4-carboxylic acid.  Nuclear magnetic resonance spectrum (h: OC I-g,) cf (ppm): 3.55 (3N, 2HCH-jO, and Cj; 3.83 (3N, CH. - N 4.32 (2H, group Ct,); 5.08 (1H, / 5.20 (1n, s / snso-); 6.92 (1H,); 7.30 (YUN, (), CH-) B.  160 mg of the product obtained in Step A is dissolved in 10 ml of methylene chloride.  After addition of 0.5 anisole, the mixture is cooled to -2 ° C.  After adding dropwise 25 ml of trifluoroacetic acid to the mixture at a temperature of from -20 to -10 ° C, the mixture is stirred for about 1 hour at a temperature of from -10 to Cf :.  The solvent is distilled off under reduced pressure.  After adding 16 ml of efir to the residue that has formed, the mixture is poached for about 20 minutes.  The mixture is then filtered under reduced pressure, and the resulting precipitate is well washed with ether and dried under reduced pressure to obtain 80 mg of 4 Icarbamoyl) (cyan) methylene -1,3-dithi-ethan-2-yl-carboxamide-7ot-Metoxy-3- (1- methyltetrazol-5-yl) thiomethyl-cef-4-carboxylic acid.  Nuclear Magnetic Resonance Spectrum (& j, -OMSO) (f (ppm); 3.44 (3N, CHO, 0-); 3.84 (2H, -CH, groups C, j); 3.95 ( ZN, CHj-N; 4.32 (2H, -CH of Co,); 5.17 (1H, H of Group C); 5.51 (iH, s; CHCO-) 8 (reference).  Example NC, ssooCsn) 4.8 g of disodium 2-carbamoyl-2-cyano-ethylene-1,1-dimercaptide is dissolved in 50 ml of dimethyl sulfoxide.  After the addition of g of tert-butyl dibromadetate to the solution, the mixture is stirred for about 48 hours at room temperature.  The solvent is distilled off from the resulting reaction mixture under reduced pressure and the product is extracted with ethyl acetate.  The extract is washed with water, with an aqueous solution of sodium chloride, dried over anhydrous x: ultraphosphate, and the solvent is distilled off under reduced pressure.  The residue is chromatographed on a column of silica gel. and 0.8 g of tert-butyl-4-rcarbamoyl) (cyan) methylene -1, 3-dithiethane-2-carboxylate are obtained using a mixture of chloroform and ethyl acetate in a volume ratio of 7: 1 as eluent.  Nuclear magnetic resonance spectrum (D (, - DMSO) cf (ppm): 1.47 (9H, (СНт,) ,, СОрС-) ;.  S 5.42 (IH, H, / Example 9 (reference).  LIFE; To 0.4 g of tert-butyl 4- (carbamoyl) (cyan) methylene 3-3, 3-dithi-ethan-2-carboxyl silat, obtained in Example 7, add 2 ml of anisole and 8 ml of trifluoroacetic acid and a mixture of 1 Sew about 1 h at room temperature.  The solvent is distilled off under reduced pressure and the residue is mixed with 10 ml of ether, followed by stirring for about 1 hour.  The resulting precipitate is recovered by filtration, washed with ether and dried under reduced pressure to give 0/15 g of 4- (carbamoyl) (cyan) methylene -1 3-dithi-ethane-2-carboxylic acid.  PRI m, er 9.  „C) CC (g) CHCONH A. 0.43 g of 7p-amino-7O4-methoxy-3- (1-methyltetrazol-5-yl) thiomethyl-cephem-4-carboxylate benzhydryl ester is dissolved in 12 ml of methylene chloride.  After cooling the solution to -40 ° C, 0.65 g of pyridine is added.  Then, a solution obtained by dissolving 0.2 g of 4- (dicyanomethylene) -1, 3-dithiethan-2-carboxylic acid, 18 ml of methylene chloride, is added dropwise to this mixture at a temperature of from -40 to -250 ° C, adding 21 g of phosphorus pentachloride and stirring the mixture for about 25 minutes at room temperature, then the mixture is stirred for about 1 hour at -30 to -20 ° C.  After completion of the reaction, 60 ml of chloroform is added to the reaction mixture and it is washed with 1% hydrochloric acid, water and saturated aqueous solution of sodium chloride.  The resulting organic layer is recovered and dried over anhydrous magnesium sulphate.  The solvent is distilled off under reduced pressure, and the residue is subjected to silica gel column chromatography to obtain 0.37 g of benzhydryl ether (dicyanomethylene) -, 3-dithiethan-2-yl-carboxamido-7c-methoxy-3- (1-methyltetrazol-5- or) thiomethyl - & - cepheme-4-carboxylic acid using a mixture of chloroform and isopropanol in an o6bef "iOM ratio of 40: 1 as eluent.  Nuclear Magnetic Resonance Spectrum (SOSTS) {PP) 3.54 (5H, -CH, -C2IOCCH group); 3.86 (3N, N); I CH 4.30 (2H, -CHjS - group C); 5.06 (2H, H groups C- and; CH-); 6.90 (1H, -CHVC Hg)); 7.30 (UN, -C ()) B. 0.37 g of the product obtained in Step A is dissolved in 10 MP of methylene chloride.  After adding 0.5 ml of anisole to the solution, the mixture is cooled to -200c.  Then it is added dropwise with 2 ml of trifluoroacetic acid at a temperature of from -20 dO, and the resulting mixture is stirred for about 30 minutes at a temperature of from -10 to. The solvent is distilled off under reduced pressure, and the residue is added with 20 ml of ether, followed by stirring about 30 min  The mixture is filtered off under reduced pressure and the resulting precipitate is washed well with ether and dried under reduced pressure to give 0.21 g of 7 | & C4- (dicyanmethylene) -G, 3-dithietan-2-yl} -carboxamido-7o-methoxy- 3- (1-methyltetrazol-5-yl) methyl-6g cefem-4-carboxylic acid Nuclear Magnetic Resonance Spectrum (Oj, -DMSO) cr (ppm) 3.44 (3N, - OCH,); 3.64 {2H, -CH, j, - groups Cj (j); 3.74 (3N, N); /.  W 4, 30 (2H.   - group C); 5.18 (1H, H of group C); 6.62 (1H, CH-) S / Example 10 (reference).  CHCOOC (CH ,,) to 15 ml of methylene chloride was added 0.28 g of tert-butyl 4-carbamoyl (cy- methylene -1,3-dithiethyl and 2-carboxylate obtained in Reference Example 7.  After adding 0.33 g of pyridine and 0.43 g of phosphorus pentachloride, the mixture is stirred for about 30 minutes at room temperature.  Then, 30 ml of chloroform was added to the reaction mixture, and the mixture was washed with 1N. sulfuric acid with a 5% aqueous solution of sodium carbonate and then with a saturated solution of sodium chloride.  The mixture is dried over without aqueous sodium sulfate, and the solvent is distilled off under reduced pressure. The resulting residue is subjected to silica gel column chromatography to obtain 0.23 g of tert-butylH4-di cyanomethyl y-, 3-dithizane-2-carboxate using chloroform as a mercapt.  Nuclear Magnetic Resonance Spectrum (CDCl) cG (ppm); 1.54 (9H, -СООС (СН,) ,,; S 5.02 (1н, - с ::: СН-) Example 11 {reference).  taken to o, 23 g of tert-butyl 4-dicyanine tylen-1,3-ditizane-2-carboxylate, obtained in Reference Example 9, 9 ml of anisole and 6 ml of trifluoroacetic acid are added and the mixture is stirred for about 3 hours at room temperature.  The solvent was distilled off under reduced pressure, and 10 ml of hexane was mixed with the obtained residue, stirring for about 10 minutes.  The solvent is removed by decantation.  Then with the residue thus obtained, do the same procedure twice.  The residue is then dried under reduced pressure to obtain 0.18 g of 4-dicyanomethylene-1, 3-dithi-ethane-2-carboxylic acid.  Example 10  : tf HOOCCH-C) CHCONH V A.  0.714 g of 4- (tert-butoxycarbonylmethylene) -, 3-dithiethane-2-carboxylic acid is dissolved in 20 MP of methylene chloride.  Then, 0.454 g of pyridine was added to the solution, followed by cooling to a temperature below 5 ° C, after which 0.630 g was added to the mixture.  phosphorus pentachloride.  The induced reaction lasts about 1 hour at a temperature below.  The resulting reaction mixture. the solution obtained by dissolving 1.5 g of benzhydryl ester 71B-amino-7-methoxy-3- (1-methyltetrazol-5-yl) -tyometry lth - is added dropwise to it at a temperature of about -500 ° C. cephem-4-carboxylic acid in 15 ml of methylene chloride.  Then 3 ml of pyridine are added and the reaction is continued for about 1 hour at a temperature of from -30 to -35 ° C.  After completion of the reaction, 20 ml of hydrochloric acid are added to the reaction mixture at a temperature below.  The resulting methylene chloride layer is removed and the aqueous layer is extracted with 20 ml of methylene chloride.  The extract was combined with a layer of methylene chloride and the mixture was washed twice with 20 ml of a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and then the solvent was distilled off to obtain 1.89 g of a brown residue.  The residue is subjected to silica gel column chromatography to obtain 0.308 g of benzhydryl ester 7rg 4-rheth-butoxycarbonylmethylene-1,3-dithiztan-2-yl-3-carboxamido-Tec-me to-3- (1-methyltetrazol-5-yl) -thiomethyl-y -cephem-4-carboxylic acid, using a mixture of ethyl acetate and n-hexane in a 2: 1 volume ratio as the eluent.  Nuclear magnetic resonance spectrum (0 -OM50) (I (rrgt1)) 1.40 (9H, tert-butyl); 3,44 (ЗН, - OCH); 3.88 (3N, V-); I 5.23 (IH, n groups C); 5.33 (3N, -Cf CH-); 5 5.84 (1H, -CH 6.88 (1H, -CH (Cj, H5),); 9.66 (1H, -CONH-) B.)  0.3 g of the product obtained in step A is dissolved in 1.7 ml of anisole.  After the solution is cooled, a solution of 5.1 ml of trifluoroacetic acid is added dropwise to the temperature below, at a temperature below Ooc.  After the reaction lasts about 30 minutes at 0-5 ° C and then at about 30 minutes.  After completion of the reaction, anisole and trifluoroacetic acid are distilled off under reduced pressure and the residue is crushed by adding ether.  The powder is well rinsed with ether and dried to obtain 0.1584 g of a pale yellow powder (carboxymethylene) -1,3-dithium ethan-2-yl carbox of dado-7ct-moct-3- (1-methyltetrazol-5-yl ) thiomethyl-cephem-4-carboxylic acid.  Nuclear Magnetic Resonance Spectrum (MS O) cf (RRS); 3.43 (ZN, - OSNE); 3.94 (3N, 5, 17 (1H, H of group C); S.  5.33 (1H, f CH-); -Sx / 5.84 (1H, -CH); 9.63 (1H, -CONH-) Example 12 (reference).  A mixture of 80 ml of dimethoxyethane and 20 tetrahydrofuran, recovered by distillation, is cooled to a temperature below in a stream of nitrogen and after adding 2 ml of N-isopropyl cyclohexylamine and 6.88 ml of a 15% solution of n-butyllithium n-hexane is added dropwise 1.16 g of tert-butyl acetate to the mixture, after which the reaction is continued for about 30 minutes at a lower temperature and 0.664 ml of carbon disulfide is added to the reaction mixture for about 30 minutes at a lower temperature.  The reaction mixture has a light yellow color.  After the evoked reaction lasts about 30 minutes at a temperature below -70 ° C, 6.8 ml of a 15% n-hexane solution of n-hexane is added dropwise to the reaction mixture over 15 minutes at a temperature below -72 ° C, whereupon the reaction is continued for about 20 minutes at a temperature below -70 ° C.  A solution containing crystals of sodium diiodoacetate, prepared from 0.48 g of 50% sodium hydride and 3.12 g of diiodooacetic acid in 15 ml of dimethoxyethane, is then added to the reaction mixture.  The temperature of the reaction mixture is allowed to rise to room temperature and the reaction continues to overnight.  The solvent was distilled off and the resulting dark brown oily substance was extracted by adding 50 ml of cold ether and 20 ml of HCl.  The aqueous layer is further extracted with the addition of 30 ml of cold ether and the extracts are combined.  The mixture was washed twice with 30 ml of a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and then the ether was distilled off to obtain 3 g of a brown oily product.  The product is subjected to silica gel column chromatography to obtain 0.564 g of 4- (tert-butoxycarbonylmethylene) -1, 3-dithi-ethane-2-carboxylic acid, using a mixture of chloroform, methanol and formic acid in a volume ratio of 95: 5: 2 as eluent.  Nuclear magnetic resonance spectrum (0 (, - OI50) cG (ppm), 1.45 (9H, tert-butyl); 5.03 (17.     CH-); X 5 / 5,69 (1H, -CH-C Example. C-, CHCONнW A, 6 -. t.  About 1 COOHti A.  0.32 g of 7 (b-amino-7L-methoxy-3- (1-methyltetrazol-5-yl) thiomethyl-b1-cepheme-4-carboxylate benzhydride ester) is dissolved in 8 ml of methylene chloride.  After cooling the solution to -30 ° C, 48 g of pyridine was added to it.   dropwise to the solution D is added at a temperature of m -40 to -3 (GS solution obtained by dissolving 0.37 g. 4- (tert-butoxyarbonyl) (methylsulfonyl) -methylene1, 3-dithiethane-2-carboxylic acid 8 MP of methylene chloride and the addition of 0.25 g of phosphorus pentachloride and 18 g of pyridine.  After stirring the mixture for about 1 hour at a temperature of from 30 to -20 ° C, ml of chloroform is added and the mixture is washed with 1% SALTIC acid, water and then saturated sodium chloride solution, and dried over anhydrous magnesium sulphate.  The solvent is distilled under reduced pressure and the residue is subjected to chromatography on a column of silica gel to give 0.25 g of 7-p) 4-ret-butoxycarbonyl- (methyl sulfonyl) methylene -1, 3-dithi-ethan-2-yl carboxamide-7og- -methoxy-3- (1-methyltetraool-5-yl) -thiomethyl-l-cepheme -4-carboxylate benzhydryl ether using a mixture of chloroform and isopropanol in a 40: 1 ratio by volume as eluent.  Nuclear magnetic resonance spectrum (COC1) cG (ppm): 1.54 (9H, tert-butyl); 3.58 (ZN, OCH); 3.18 (3N, CH5S02); 3.84 (3N, V); 4D6 (2H, -CH, Cj groups); 5.07 (1H, H of group C); 5.31 an, CH); S 6.91 (1H, -CtKCe H).  ); 7.30 (YUN, -CH () g) c.  0.2 g of the product obtained in step A is added to 2.5 MP anisole.  The solution is cooled to -20 ° C and 10 ml of trifluoroacetic acid are then added dropwise to the mixture at a temperature of from -20 to, after which the mixture is stirred for about 20 minutes at the same temperature and then cool.  40 min at  The solvent is distilled off under reduced pressure, the residue is mixed with 30 ml of ether and the mixture is stirred for about 20 minutes.  The reaction mixture is filtered under reduced pressure and the resultant precipitate is washed well with efflux and dried under reduced pressure to obtain 0.08 g of (methylsulfonyl) -methylene-1,3-dithietan-2-yl carboxamide-7c-methoxy-3- carboxylic acid. (1-methyltetrazol-5-yl) thiomethyl-D-cefem-4-carboxylic acid.  Nuclear Magnetic Resonance Spectrum (0 (, - OMSO) d (pprn); 3.20 (ZN, CKj, SO); 3.45 (ZN, - OCH, j); 3.62 (2H, -CH groups C ); 3.94 (3H, V); 4.30 (2H, -CHS. - GI groups); 5.13 {1H,) H groups with - CH-) 5.17 (. lH, j Example 13 (reference).  (CH-).  COOCv.    g.  CH 2 CO 2 CH 3 SOi, 65 ml of tert-butanol, dissolved 2.05 g of tert-butyl methylsulfonyl acetate.  After adding 1.32 g of tert.  . potassium-butylate, the mixture is stirred for about 5 minutes.  Then, 0.91 g of carbon disulfide is added dropwise to the mixture and stirred for about 5 minutes, and then 1.32 g of tert-butyl " potassium is added and the mixture is stirred for about 1 h.  Then, 3.8 g of diiodoacetic acid and 1.32 g of potassium t-butylate are added to the mixture and the resulting mixture is stirred overnight.  The solvent is distilled off from the resulting reaction mixture under reduced pressure.  The resulting residue is mixed with water, the pH is adjusted to 2 with 10% hydrochloric acid and extracted with ethyl acetate.  The extract is washed with water, a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure.  The residue was subjected to silica gel column chromatography to obtain 1.7 g of 4- (tert-butoxy arbonyl) (methylsulphonyl) methylene -1, 3-dithi-ethane-2-carboxylic acid, using a 50: 1 mixture of chloroform and methanol as eluent.  Nuclear Magnetic Resonance Spectrum (COST), ((ppm): 1.52 (9H, (SNp,) COOC-); 3.20 (3N, CHjSOj-) Example 12.  Hl.  SGNsonn, 5 (OY A.  In 1.5 Mji of methylene chloride, 0.6 g of 4- (4-tert-byproduct-oi-tert-byproxycarbonylbenzylidene) -l, 3-dithiethan-2-carboxylic acid is dissolved.  After adding 0.2 ml of pyridine and 0.285 g of phosphorus pentachloride under ice cooling, the mixture is stirred for about 7 minutes.  The solution is added to the solution obtained by dissolving 0.5 g of benzhydryl ester 7 | L-amino-Te-methoxy-3- (1-methyltetrazol-5-yl) thiomethyl-D-cephem-4-carboxylic acid in 15 ml of methylene chloride, cooling to a temperature of -30 to and adding there

0.45 ml of pyridine, the mixture is stirred for about 20 minutes at the same temperature.

The reaction mixture is mixed with 60 ml of chloroform, pressed with 30 ml of water, 30 ml of 1% 2% hydrochloric acid and hall & liter of 30 ml of water, dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. The residue is subjected to silica gel column chromatography to obtain 0.4 g of benzhydryl ether 7 / L-4- (4-tert-butoxy-o {-t-butoxycarbonylbenzylodene) -1, 3-dithiethan-2-yl carboxamido-7X methoxy-3- (1-methyl-tetrazol-5-yl) thiomethyl-D-cephem-4-carboxylic acid, using a mixture of benzene and ethyl acetate in a volume ratio of 11: 2 as eluent.

Nuclear magnetic resonance spectrum (SOSTS) (I (rrgg ():

(.. „).

1.47 (9H, J

3.60 (5H, BHCO, and CHjjr groups C);

3.83 (3N, N};

sn,

- / gh

4.8-3 1H,

 V, -1,

s5, 08 (1H, H of group C); 6.92 (1H, -CHCC Hj));

NN

6.94 (2H, P Q

7.15 (2HJ „- N

B. In a mixture of 10 ml of trifluoroacetic acid and 2 ml of anisole, the product is dissolved, obtained in stage A, while cooling with ice. The mixture is stirred for about 30 minutes at. The solvent was distilled off under reduced pressure, and 40 ml of ether was added to the residue to form a precipitate. The precipitate is recovered by filtration and washing with water to form 0.2 g of 7p-U4- (o-carbox-4-hydroxybenzylidene) -l, 3-dithietan-2-yl carboxamide-7A-methoxy-3- {1-methyltetra-el-5 -il) thiomethyl- & - cephem-4-carboxylic acid.

Nuclear magnetic resonance spectrum (l., - DMSO) (f (ppm);

3.42 (ЗН, - OCH);

3.94 (3N, N); I SNT

/

s - ch-)

(2H, H group 1.

(2NL -)

(2Hjn n

Example 14 (reference).

/

snsoon

.X

2.5 g of tert-butyl 4-tert-butoxyphenyl acetate and 25 ml of anhydrous tetrahydrofuran are added to 8.6 g MP of a 15% aqueous solution of tert-butanol potassium tert-butylate and 25 ml of anhydrous tetrahydrofuran with stirring at room temperature. After stirring for about 2-3 hours, 0.6 ml of carbon disulfide is added dropwise to the mixture and then stirred for about 10 minutes. Thereafter, 8.6 ml of a 15% potassium solution of tert-butanol tert-butylate is added to the mixture and stirred for about 5 minutes. Next, 8.6 ml of a 15% potassium tert-butanol tert-butylate solution was added to the mixture, and then 1.22 g of dichloroacetic acid was added dropwise to the mixture at a temperature of about and stirred for about 40 minutes at room temperature.

After adding dichloroacetic acid to the reaction mixture until then. Until the mixture becomes slightly alkaline, the solvent is distilled off under reduced pressure and the mixture is mixed with ice water and washed with ether. Then 0.5 ml of 3N hydrochloric acid is added to the mixture and the product is extracted with ether. To the extract is then added 0.5 ml of 3N. hydrochloric acid. The product is extracted with ether and the procedure is repeated. Each extracted fraction obtained is detected by chromatography on a thin layer of silica gel, the fractions containing the product are combined and dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure to obtain 1.3 g of 4- (4-tert-butoxy-o-tert-butoxycarbonylbenzylidene) -1, 3-dithiethan-2-carboxylic acid.

Nuclear Magnetic Resonance Spectrum (D-DMSO) (ppm)

135 (9H, -) (cNCSC-);

1.48 (9H,

 Jс

CH-);

4.85 (1H, C

H H 6.93 (2H, 1 J:

7.15 (2Hj

Example 13

, ,five,

) cHCONH

- A. 0.5 g of 4- (o-tert-butoxycarbonylbenzylidene) -1,3-dithiethan-2-carboxylic acid is dissolved in 15 MP of methylene chloride. After adding 0.1 MP of pyridine and 0.285 g of n-phosphorus during the cooling with ice, the mixture is stirred for about 20 minutes. Then, when processing the reaction mixture, as in Example 12 D, use a mixture of benzene and ethyl acetate in a volume ratio of 9: 2; Approximately 0.4 g of 7p-P4- (o6-tert-butoxycarbonylbenelideide) ester) -1,3-dithioethane an-2-yl1 kerbock amido-7 ° C - methoxy-3- ( 1-methyltetrazol-5-yl) thiomethyl-cephem-4-carboxylic acid. Nuclear magnetic resonance spectrum VCDC 1) cG (ppm): 1.46 (9H, tert-butyl); 3.58 (5H, OSNl and-CH, - Ca group); 3.80 OH, V); 4.85 UH, 5.08 (1H, H groups Cjj); 6.93 (1H, -CH ()); about 7.34 (15H, () jCH-) B. By treating 0.4 g of the product obtained in Step A, as in Example 12 B, about 0.2 g (o1-carboxybenzylide 9d) -1,3-dithietane - 2-yl) carboxamido-7o of methoxy-3 1- (methyltetrazol-5-yl) -thiomethyl-cefvm-4-carboxylic acid, Nuclear - magnetic resonance spectrum (0 -OMSO) (): 3.41 (ZN OSI;); 3.92 (3N, V); k. S 5; GROUPS С,) 7.28 (5Н,) Example 15 (reference). to 15.6 g of a 15% potassium solution of tert-butanol t-butylate, 4 g of t-butyl phenyl acetate and then 1.6 g of carbon disulfide are added with stirring at room temperature. After stirring the mixture for about 15 minutes, 20 ml of anhydrous tetrahydrofuran are added to the mixture and then 31.2 g of a 15% solution of potassium t-butanol tert-butylate are added. Then, 2.7 g of dichloroacetic acid is added dropwise to the mixture at 30 -40 ° C, followed by stirring for about 30 minutes at the same temperature to complete the reaction. After adding dichloroacetic acid to the reaction mixture until it becomes slightly alkaline, the solvent is distilled off under reduced pressure and the residue is mixed with ice-water with the subsequent npoNUBaHHeM ether. Then 0.5 ml of 3N hydrochloric acid is added to the mixture and the product is extracted with ether. To the extract was added 0.5 ml of 3N. hydrochloric acid. The product is extracted with ether and the procedure is repeated. The composition of each extract fraction is determined by chromatography on a thin layer of silica gel, and the fractions containing the desired product are combined and dried over anhydrous magnesium sulfate. The solvent is then distilled off under reduced pressure to obtain about 1 g of 4 - ((- tert-butoxycarbonylbenzyl iden) -1, 3-dithi-ethan-2-carboxylic acid. Nuclear Magnetic Resonance Spectrum (0 (, - OMSO) cf (1 , 40 l9H, (СН ,,) ,, СООС-); 5.17 (1H, - С (СН-); S About 7.30 (5H, Example 14), and N, "- CrS iJHCONH CHjsA ( HJC), j NCO--, NSA. In 15 ml of methylene chloride, 500 mg of 4- (tert-butoxycarbonyl-M, N-dimethylcarbamoylmethylene) -1, 3-dithiethane-2-carboxylic acid are dissolved. After adding 0.19 ml of pyridine and then 163 ml of phosphorus chloride while cooling with ice, the mixture is stirred for about 5 minutes. The solution is added to a solution obtained by dissolving 500 mg of 7p-amino-7oC with methoxy-3- (1-methyltetrazol-5-yl) thiomethyl, cephaem-4-carboxylic acid in 15 ml of methylene chloride and adding 0.3 ml of pyridine to the solution is cooled to -ZEP and the mixture is stirred for about 30 minutes at the same temperature. To the reaction mixture is added about 60 ml of chloroform. The mixture is finished with about 3Q ml of water, about 30 mp of 1-2% hydrochloric acid and then three times with 30 ml of water, and dried over anhydrous magnesium sulphate. The solvent is distilled off under reduced pressure and the residue is subjected to silica gel column chromatography to give 200 mg of benehydryl ether (tert-butoxycarbonyl-N, m-dimethylcarbamoylmethylene) -1,3-dithiethan-2-yl-carboxamido-7a-methoxy- 3- (1-methi tetrazol-5-yl) thiomethyl-D-cepheme-4-carboxylic acid, using a mixture of benzene and ethyl acetate in a volume ratio of 3: 2 as eluent. Nuclear Magnetic Resonance (CCEL) cG (ppm): 1.48 (9H, t-C H9-); 2.96 (6H (CH) 2 NCO-); 3.60 (5H, CHjO and -CHD group C,) - M 3.84 (3N, CH, - NI); с :: ссо-); 4.93 (1H, 5.06 (1H, H of the Cfc group); 6.90 (1H, -CH (CH)) B.) in a mixture of 10 MP trifluoroacetic acid and ml of anisole, dissolve the product obtained in Step A, while cooling with ice, and the mixture is stirred for about 30 minutes at. The solvent is distilled off under reduced pressure and the precipitate formed is collected by filtration and washed with ether to obtain 100 mg of 7p-f (4-carboxy-N, N-dimethylcarbamoylthylene) -1,3-dithietan-2-yl-carboxamido, -7оO-methoxy-3- (1-methyltetrazol-5-yl-tibmethyl-D-cefem-4-carboxylic acid. Nuclear Magnetic Resonance Spectrum (0, - OM50) SG (ppm); 2.87 (6H, (СН ",), 2, NCO -); 3,43 (3N,); 3,94 (3N, CH - N 5.16 (1H, cC groups c, and 5.25 (1H Pr and me 16) (reference), (cn) : coax C C cc J snsoon / CH

By treating tert-butyl dimethylcarbamoylacetate, as in reference, at CHi, at least 15, 4- (tert-butoxycarbonyl Idimethyl arbamoyl) methylene-1,3-dithiethan-2-carboxylic acid is obtained.  Nuclear Magnetic Resonance Spectrum UOCIj) f (ppm): 1.50 (9H, (CH3COOC-); 3.02 (6H, N -); 4.97 {1H, c (f CH-) S Example 15.  Nw - --- CHjS-Au  Mr. A.  0.87 g of 4- (acetyl) - (tert-butoxycarbonyl) methylene-1,2-dithiethan-2-carboxylic acid is dissolved in 15 ML of methylene chloride.  After adding 0.474 g of pyridine and then 0.624 g of p-phosphorus chloride, the mixture is stirred for about 30 minutes.  The solution is added to a solution obtained by dissolving 0.6 g of benzhydryl zirther 71b-amino-7c6-methoxy-3- (1-methyltetraZOL-5-IL) thiomethyl-ce-cephem-4-carboxylic acid in 20 MP of methylene chloride with cooling solution before adding 1 ml of pyridine, and the mixture is stirred for about 1 hour at the same temperature.  To the reaction mixture are added 10 ml of water, 1 ml of hydrochloric acid and 80 MP of chloroform.  The resulting chloroform layer is separated, washed thoroughly with 1% hydrochloric acid to completely separate the pyridine, then with water, dried over anhydrous sodium sulphate and the solvent is distilled off at a lower pressure.  The resulting residue was subjected to silica gel column chromatography to give O, 55 g of (acetyl) (tert-butoxycarbonyl) methylene benzhydryl ether (methyloxy -1, 3-dithiethan-2-yl) carboxamide-7os methoxy-3- (l-methyltetrazol-5- yl) thiomethyl-cepheme-carboxylic acid, using a mixture of benzene and ethyl acetate in a volume ratio of 10: 2 as eluent.  Nuclear Magnetic Resonance Spectrum (CDC) j,) cf (ppni); 1.53 (9H, t-butyl); 2.45 (3N,); 3.56 (5H, OCHE, I-CH ,. groups of 3.82 (3N, 4. 37 (2H, - groups Cj); 4.94 (IH, - fCH-); S / 5.09 (IH, H groups C); 6.94- (IH, -CH ()); 7.20-7.50 (Yun, -CH (SatNd) 2) c. In a mixture of 12 MP trifluoroacetic acid and 3 ml of anisole, 0.55 g of the product obtained in stage A is dissolved at a temperature.  The mixture is stirred for about 20 minutes at 15 s.  The solvent is distilled off under reduced pressure, 20 ml of ether are added to the residue, the precipitate is removed by filtration and washed with ether to obtain 0.33 g of (acetyl) carboxymethylene -1, 3-dithiethan-2-yl} carboxamido-7-6-methoxy-3 - (tyltetrazol-5-yl) thiomethyl-cephem-4-carboxylic acid.  Nuclear Magnetic Resonance Spectrum (0, -DMSO) cf (ppm): 2. 38 (KN,. CHjOC-); 3,43 (ЗН, - OCH); / 3.94 (3N, N); Cft 4.32 (2H, -CH, - groups i.  5.16 (IH, groups c, and 5.30 (IH Example 17 (reference)).  (CH) COOC xoxion 4.8 g of sodium hydride (50% in oil) is added to 150 ml of tert-butanol.  Then, 15.8 g of tert-butyl acetoacetate is gradually added to the mixture.  After adding 7.6 g of carbon disulfide while cooling with ice, the mixture is stirred for about 18 hours at room temperature, after which 4.8 g of sodium hydride (50 in oil) is added gradually with cooling with ice and after stirring the mixture for about 2 hours. at room temperature, 16.7 g of potassium dichloroacetate are added to Nei and stirred for about 2 hours.  The resulting reaction mixture is concentrated under reduced pressure.  The residue is mixed with 300 ml of ethyl acetate and 200 ml of ice water and the pH is adjusted to 3-4 with 1N. hydrochloric acid.  After forming the organic layer, it is washed with an aqueous solution of sodium chloride and extracted with a saturated aqueous solution of sodium hydrogen carbonate.  (CH) Sodium bicarbonate extract is rotted with 50 ml of ethyl acetate; pH is adjusted to 3-4 1 n. hydrochloric acid and extracted with 200 ml of ethyl acetate.  The ethyl acetate extract is washed with a native solution of sodium chloride, dried over anhydrous sodium sulfate and then concentrated.  The residue is rolled through 50 ml of a mixture of petroleum e (1p and ether in a volume ratio of 10: 1 and dissolved in 5 ml of ether.  Then 50 ml of petroleum ether are gradually added to the solution and the crystals precipitated as a result of this are removed by means of a filtrate to obtain 10 g of 4- (gshechetil) tert-α-butoxycarbonyl) methylene}, 3-dithiethan-2-carboxylic acid.  Nuclear magnetic resonance, spectrum (soy), j) cC pprri): 1.53 (9H, CH) s COOC-); 2.49 (3N, CHi, OC-); .   , 94 (1H, СГГ Example 16.  ) with with "" - 4-- -N, COOHCH, A.  1.1 g of 4- (tert-butoxycarbonyl) (5-meth, ylthio-1,3,4-thiadiazol-2-yl) methylene-1, 3-dithi-ethane-2-carboxylic acid is dissolved in 20 MP of methylene chloride.  After adding 0.462 g of pyridine and 6.606 g of phosphorus pentachloride while cooling with ice, the mixture is stirred with about 30 of them.  The solution is added to a solution obtained by dissolving 0.9 g of 7) L-amino-7 ° C-methoxy-3- (1-methyltetrazol-5-yl) thiomethyl-L-cepheme-4-carboxylic benzhydryl ether in 30 ml of methylene chloride, cooling the solution to temperature) and adding 0.75 ml of pyridine to it, and the mixture is stirred for about 1 hour at room temperature.  The reaction mixture is mixed with 10 ml of water and 40 ml of chloroform.  The chloroform layer formed was thoroughly washed with 1% hydrochloric acid to completely release pyridine, then with water, dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure.  The residue is subjected to chromatography on a silica gel column, yielding 0. 2 g of (tertbutoxycarbonyl) benzhydryl ether (5-methylthio-1,3,4-thiaadiaol-2-yl) methylene-1, 3-dithioethan-2-yl carboxamido-7OO-methoxy-3- (1-methyltetrazol-5-yl) thiomethyl-L-cephem-4-carboxylic acid, using a mixture of benzene and ethyl acetate in a volume ratio of 10: 2 as eluent.  Nuclear Magnetic Resonance (CDCloj) 0 (ppni) spectrum.  1.58 (9H, t-butyl); 2.72 (ЗН,); , 3.58 (ЗН, - OCHj); 3.80 (3N, N); I 4.36 (2H, -CHjjS - group C); 5.03 (iHl nb b bH of Cd and C / CI-) 5.09 (IHJ -S / (5.90 (IH, -CH (Cj, H5) 2); 7.10-7.50 (UN -CH () 2) c.  In a mixture of 8 ml of trifluoroacetic acid and 2 ml of anisole, 0.2 g of the product obtained in Step A was dissolved at -5 ° C and stirred for about 1 hour at 17-18 ° C.  The solvent is distilled off under reduced pressure, 20 ml of ether are added to the residue, the precipitate formed is removed by filtration and washed with ether to obtain 0.05 g of 7 | L-4- (carbroxy) -5 methyl-1-o; 3, 4- thiadiazol-2-yl) 1iethylene -1,3-dithioethane 2-yl} -carboxam to-7-methoxy-3- (1-methyltetrazol-5-yl) thiomethyl-cefem-4-carboxylic. acid.  Nuclear Magnetic Resonance Spectrum (D5-OMSO) cP (ppm): 2.75 (3N, CH1S-); 3.45 (ЗН, ОСНз); / L 3.94 (3N, N); I 4.30 (2H, -CH, jS — Cd groups); O 5.19 (IH, -) 5.35 (1H,) Example 18 (reference).  (sn,) zsoos. , s C C (In the case of CNSAH N-N / XS It IK in 100 ml of tert-butanol a solution of 1.58 g of cobalt potassium.  After the addition of 10 g of tert-butyl 5-methyl tyr-1, 3,4-thiadiazole-2-acetate, the mixture is stirred for about 20 minutes.  After this, 3.25 carbon disulfide is added dropwise to the mixture over 10 hours. After stirring the mixture for about 1 hour, 1.55 g of potassium t-butylate are gradually added to the mixture and stirred for about 20 minutes, after which 6 are added. 83 g of dichloroacetic potassium and stirred for about 18 hours.  The reaction mixture is concentrated under reduced pressure.  The residue is mixed with 33 ml of ethyl acetate and 200 ml of ice water, the pH of the mixture is adjusted to 3-4 1N. hydrochloric acid and the resulting organic layer are made with an aqueous solution of sodium chloride and then extracted with 1000 MP of a saturated aqueous solution of sodium hydrogencarbonate.  The sodium bicarbonate extract is washed with 100 ml of ethyl acetate, the pH is adjusted to 34 5 and.  hydrochloric acid and then extracted with 200 ml of ethyl acetate.  The ethyl acetate extract is washed with an aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and concentrated.  The residue was subjected to silica gel column chromatography to obtain 1 g of 4- (tert-butyxycarbonyl) (5-methylthio-1,. 3,4-t1 adiazral-2-yl) methylen-1, 3-dithi-ethan-2-carboxylic acid using chloroform and then a mixture of chloroform and methanol in a 50: 1 volume ratio as eluent.  Nuclear magnetic resonance spectrum (CDCIj) / (Ppw): 1.59 (9H, 1СН ,,), СООС-); 2.79 (3N, CHjS-); 4.99 (1H, C CHF-) S Example 17, °°) c. cOcHCO. H-U. V I UNIFI A.  0.2 ri 4-Pbenzhydryloxycarbonyl) (sulfamoyl) methylene2-1, 3-dithiethane-2-carboxylic acid, 0.25 g of benzhydryl ester 7 (L-amino-7o-methoxy-3- ( 1-methyltetrazol-5-yl) thiomethyl-L-cefem-4-carboxylic acid, and 0.1 g of N, N-dicyclohexyl carbodiimide.  Then the solution is stirred overnight at room temperature.  The undissolved substances are filtered off and the solvent is distilled off from the filtrate under reduced pressure.  The residue is subjected to chromatography on a silica gel column to yield a bin. 0.095 g of 7p- (4- (benzhydryloxycarbonyl) (sulfamoyl) methylene-1,3-dithietan-2-yl carboxamido-7o-methoxy-3- (1-methyltetrazol-5-yl) -thiomethyl-L-cephem- 4-carboxylic acid, using a mixture of chloroform and isopropanol in a volume ratio of 1 as eluent.  AT.  0.095 g of the product obtained in Step A is dissolved in 10 ml of methylene chloride.  After adding 0.5 ml of anisole, the mixture is cooled to -20 ° C. Then 2 ml of trifluoroacetic acid are added dropwise to the mixture at -20 before and after stirring for about 30 minutes at the same temperature, the resulting mixture is stirred for about 1 hour at.  The solvent is distilled off from the reaction mixture under reduced pressure, and 1 ml of ether is added to the residue with stirring for about 15 minutes.  The reaction mixture is then filtered under reduced pressure, and the precipitate formed is washed well and dried under reduced pressure to give 0.034 g of carboxy (sulfamoyl) methylene 1-1,3-dithiethane.  -2-yl carboxamido-7o-methoxy-3- (1-methyltetrazol-5-yl) -thiomethyl-L-cefem-4-carboxylic. acid.  Nuclear magnetic resonance spectrum (D (, - OMSO) cf (ppm) 3.42 (3N, - OCH); 3.94 (3N,); I СНо, 4.30 (2H, -СН, - Croupgal Cn) ;, 12 (1H,) /, 17 (1n,), s, and / ch9, 66 (1H, -NHCO-) Example 1E (reference).  NHjSO, () csox. To 1.12 g of benzhydryl sulfamoyl acetate is added 30 ml of anhydrous, tetrahydrofuran and 20 ml of tert-butanol. After cooling the mixture, 0.177 g of sodium hydride (50% in oil) is added to it and stirred for about 15 min.  To the mixture is added. 0.3 g of carbon disulfide.  The mixture is stirred for about 30 minutes at a temperature of from -10 to -50s.  Then, 0.354 g of sodium hydride (50% in oil and 0.5 g of diiodoacetic acid) are added to it.  After stirring the mixture for about 20 minutes at a temperature from 10 ° C to 0 ° C, the mixture is stirred overnight at room temperature. The solvent is distilled off from the reaction mixture under reduced pressure and after the pH is adjusted to 2 pL. Adding ice water and 5% hydrochloric acid to it, extract the reaction mixture with ethyl acetate.  The extract was washed twice with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure.  The residue was subjected to silica gel column chromatography to obtain 0.2 g of 4-Pbenzhydryloxycarbonyl) (sulfamoyl) methyl, 3-dithi-ethane-2-carboxylic acid, using a 10: 1 mixture of chloroform and methanol as eluent.  Nuclear Magnetic Resonance Spectrum (C OS C) cG (pp #) 4.66 (1H, C C CH-) S 6.96 (1H, (Cft Hg) 5 СЙ-); 7.33 (YUN, (Ct, H5) 2CH-) EXAMPLE 18.  OCH HCONH-WVG9. (g /.  J iy4-CH sA. H coo A.  800 mg of 4-Ct-butoxycarbonyl) (3-pyridine) methylene -1,3-dithiethan-2-carboxylic acid is dissolved in 40 ml of methylene chloride.  After adding 0.3 ml of pyridine and then 440 mg of phosphorus pentachloride while cooling with ice, the mixture is stirred for about 15 minutes. The solution is added to the solution obtained by dissolving 0.8 g of 7 | L-amino-7-methoxy-3- (1-methyltetrazol-5 -yl) thiomethyl- & -cepheme-4-carboxylic acid in 25 ml of methylene chloride and adding 0.7 ml of pyridine at, then the resulting mixture is stirred for about 20 minutes at the same temperature.  Thereafter, 200 vai, chloroform is added to the reaction mixture, the mixture is washed twice with 150 ml of an aqueous solution of 1.3% acetic acid and then twice with 100 ml of water, dried over anhydrous magnesium sulfate.  The solvent is distilled off under reduced pressure and the precipitate formed is subjected to chromatography on a column with Silica gel, yielding 400 mg of (tert-butoxycarbonyl) - (3-pyridyl) methylene} -1,3-dithietan-2-yl carboxamido-7G-methoxy-3 - (1-ketiltetrazol-5-yl) thiomethyl-b, fem-4-k arbonic acid, using a mixture of benzene and ethyl acetate in a volume ratio of 2: 1 as eluent.  Spectrum of nucleotide resonance (COCI) cP (Ppm): 1.47 (9H,); 3.59 (5H, CH ,,, - groups Cj); 3.83 (3N, N —CKj,): -); 4.91 (IH, 5.08. (1H, H - groups Cf,}; 6.93 (IH, -CH (CgH) 2);.  850 (IH.  Q (); 8.53 (IH, jfY) B.  In a mixture of 15 ml of trfluoroacetic acid and 3 ml of anisole, 400 mg of the compound obtained in step A are dissolved under ice cooling and stirred for 10 to 150 ° C for 40 min.  The solvent was distilled off under reduced pressure, and 50 ml of ether was added to the residue to obtain a precipitate, which was removed by filtration and final heating with ether.  The residue is chromatographed on a column of silica gel to obtain about 100 mg of 4- (carbox-3-pyridyl) methylene-1,3-dithi-ethan-2-carboxamido-7os-methoxy-3- (1-methyl-tetra-el-5 -yl) thiomethyl th-cefem-4-carboxylic acid, using a mixture of chloroform, methanol and formic acid in a volume ratio of 50: 7 as eluent.  The nuclear magnetic resonance spectrum of (D –OMSO) d (ppm) t is about 3.41 (Z. H, CH O-); 3.93 (ЗН,); 5.15 (1H, / S (1H,) X 7.39 (1H, -UU); 11 Cg) 7.67 (1H 8.44 (2H ifT) l. Example 20 (referential).  1 (COOC By treating tert-butyl 3-pyridyl acetate, as in the recommendation of Example 15, 4- (tert-butoxycarboni (3-pyridyl) -methylene-1 3-ditiztan-2-carboxylic acid is obtained).  Nuclear magnetic resonance spectrum (O, -DMSO) (G (ppm); 1.42 (9H, (CH, j). jCOOC-); 5.22 (1H, C i :: CH-); 7.40 {1NL 7.66 (1ND 8.45 (2Hj Example 19.  0ОСНз Лс сС нсомн: W A. In 55-ML anhydrous. tetrahydrofuran dissolved 0.22 g of 4- (acetyl) (carbamoyl) methylene -1,3-ditiztan-2carboxylic acid, 0.496 g of 7p -amino-7a-methoxy-3- (1-methyltetrazol-5-yl) thiomethyl benzhydride ester - y cephem-4-carboxylic acid and 0.194 g of N, N-dicyclohexylcarbodiimide.  The solution is stirred for about 2 hours at room temperature.  The insoluble materials are filtered off and the filtrate is concentrated under reduced pressure.  The resulting residue is subjected to chromatography 4 1I in a column of silica gel to give O, 35 g of benzhydryl zirph 7jB-i 4-L (acetyl) (carbamoyl) methylene -1,3-ditiztan-2 -yl carboxamido-7c. - methoxy-3- (1-methyltetrazol-5-yl) tisichetil- & 2-cepheme-4-carboxylic acid, using first a mixture of chloroform and ethyl acetate in a volume ratio of 1: 1 and then a mixture of chloroform and ethyl acetate in a volume ratio of 1: 3 as eluent.  B. In a mixture of 8 ml of trifluoroacetic acid and 2 ml of anisole are dissolved.  0.35 g of the product obtained in. Step Af at and then stirred for about 30 minutes at.  The resulting reaction mixture is concentrated and the residue is mixed with ether and then stirred for about 30 minutes.  The precipitate is recovered by filtration and washed with ether to give 0.09 g of 7p- {4- (acetyl) (carbamoyl) methylene3 -1, 3-dithietan-2-yl-carboxamido-7a-methoxy-3- (1-methyltetrazol-5 -yl) tyomethyl-L-cephem-4-carboxylic acid.  Nuclear magnetic resonance spectrum (-OM50) sG {; rrgg) O II 2.32 (3N,); 3, 42 (SN, SNZO - group C); 3.93 (3N, / h „xM 4.30 (2H, -CHgS — Cj groups); 5.17 (IHl groups C, and, 5.2 € (IHJ 6.  s Example 21 (reference).  snsoon A.  5.7 ° g of kggs tert-butylate are dissolved in 50 ml of tert-butanol and 50 ml of anhydrous tetrahydrofuran are added to the solution.  Then, after dissolving 2.6 g of acetacetamide in it, the solution obtained by dissolving 1.96 g of carbon disulfide in 5 ml of anhydrous tetrahydrofuran is added dropwise to the solution while cooling with ice.  To the resulting reaction mixture, 100 ml of anhydrous tetrahydrofuran are added and stirred for about 1.5 hours at room temperature.  Then, a suspension prepared by the reaction of 8 g of diiodoacetic acid and 1.23 g of sodium hydride (50% in oil) in 100 ml of anhydrous tetrahydrofuran was added to the mixture while cooling with ice and the mixture was stirred for about 2.5 hours at room temperature.  The resulting reaction mixture is concentrated and the residue is mixed with 50 ml of 1N.  SALTIC Acid and extracted with 100 ml of ethyl. etata.  The extract is washed with 50 ml of an aqueous solution of sodium chloride and the resulting organic layer is extracted with 100 ml of oat (a valuable aqueous solution of sodium hydrogen carbonate, the pH of the extract is adjusted to 2-3 with concentrated hydrochloric acid and then extracted with 100 ml of ethyl acetate.  The extract is washed with 50 m of an aqueous solution of sodium chloride, dried over anhydrous magnesium sulphate and concentrated.  The resulting residue is dissolved in 30 ml of methylene chloride and after the addition of 5 g of diphenyldiazomethane while cooling with ice, the mixture is stirred for about 2 hours at room temperature.  The reaction mixture is concentrated and the resulting residue is subjected to chromatography on a silica gel column to give 0.6 g of 4- (acetyl) (carbamoyl) methylene -1,3-dithi-ethan-2-carboxyl benzhydryl ether, first using chloroform, and then chloroform and methanol in the object ratio of 10: 2 as a quality.  The spectrum of a nuclear magnetic resonance with a (C OS "1,) I (rrp); 2.32 (3N,); -S 4.99 (1H,:; CH-) j 6.97 (1H, -COOCH () 2); 7.2-7.4 (JUN, -COOCH (),) V.  In a mixture of 8 ml of trifluoroacetic acid and 2 ml of anisole, 0.6 g of the product obtained in stage A is dissolved, and the temperature of the reaction mixture is heated to within 20 minutes with and.  The reaction mixture is then concentrated, and 10 ml of a mixture of ether and petropeic ether are added to the residue in a 1: 1 volume ratio to form a precipitate, which is removed by filtration to give 0.2 g of Cacetyl) (carbamoyl) methylene -1,3-dithietane-2- carboxylic acid.  Nuclear magnetic resonance spectrum (D, -OMSO) f (PPP); 2.31 (3N,); 5.20 (1H, Example 20.  ;. Ir. ).  -.  Jl. , s4L 11 III I cooit A.  610 mg of 4- (1-tert-butoxycarbonylpropylidene) -1, 3-dithiethane-2-carboxylic acid are dissolved in 15 MP of tetrahydrofuran and after adding 1.05 g of benzhydroyl ester 7 | L-amino-7c1. -methoxy-3- (1-methyltetrazol-5-yl) thiomethyl-cephem-4-carboxylic acid and 0.5 g of N, N-dicyclohexylcarbodiimide, the mixture is stirred for about 2 hours at room temperature for reaction.  After completion of the reaction, the separated N, N-dicyclohexyl urea is filtered off and the solvent is distilled off from the feedtorate under reduced pressure to form a caramel-like residue.  The resulting residue is dissolved in 50 ml of ethyl acetate and the solution is washed with 30 ml of 1N.  hydrochloric acid and then with water and dried over anhydrous magnesium sulphate.  The solvent is distilled off under reduced pressure to obtain 450 g of a brown caramel-like residue.  The residue is chromatographed. in a column with 30 g of silica gel and the product is washed first with benzene and then with a mixture of benzene and ethyl acetate in a volume ratio of 95: 5 and a mixture of benzene and ethyl acetate in a volume ratio of 90: 10i fractions containing the desired product are combined to give about 10 mg of benzhydryl ether T / bC -d-TpeT-butoxycarboxypropylidene) -1,3-dithietan-2-yl 3-carboxamido-7 (X-methoxy-3- (1-methyltetrazol-5-yl) -thiomethyl-A-cephem-4-kfbioic acid.

Spectrum of nuclear magnetic resonance (С DC Ц) сГ (рр№)

1.62 (ЗН, CHj ,, t);

2.08 (9H, (CH) ,, C-);

2.66 (2H, .dif- / q)}

4.22 (ЗН, -СОН, S);

4.44 (3N, N-, CH); .

5.40 and 5.47 (H groups (CH-) 7.54 (1H, -CHCCbHs));

. 7.8-8.2 (UN, () J); 8.30 (1H, -NH-CO-)

B, in 1.1 ml of anisole, 200 mg of the caramel-like product obtained in stage A is dissolved, and the solution is cooled to a temperature in an ice-cold bath. To the solution is added dropwise m3.3 ml of trifluoroacetic acid at a temperature below and then the mixture is stirred for about 1 hour at which to cause a reaction. Then, anisole and excess trifluoroacetic acid are distilled off under reduced pressure at a temperature below room temperature and the residue is mixed with 10 ml of water and extracted with a mixture of n-butanol and ethyl acetate in a 1: 1 volume ratio. The organic layer is collected, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. The residue is triturated with 10 ml of ether to give 54 mg of 7) (l carboxypropylidene) -, 3-dithietvn-2-yl carboxamido-7: y-methoxy-3- (1-methyltetrazol-5-yl) thiomethyl-L - cephem-4-carboxylic acid.

Spectrum of nuclear magnetic resonances (Df, -DHSO) cf {ppm).

/ 0.96 (3N, -CHj. T):

2., 00 (2H, q);

3.41 (3N, -0-CH ,,, S);

3.92 (3H, N — CHj, S);

5.10 and 5.16 (H groups C, and /);

NC /

9.60 (1H, -NHCO-) Example 22 (reference).

snsoon

 with

A mixture of 120 ml of dimethoxyethanol and 30 ml of tetrahydrofuran is cooled to -74 ° C on a dry ice-acetone bath, and then 4.0 ml of N-isopropylcyclohexylamine and 13.72 ml are added to the mixture.

15% n-butyllithium n-hexane solution, during which the temperature rises from -73 to. After adding 3.17 g of tert-butyl butylate and reacting from -74 to -75 ° C for about 30 minutes to a mixture, 0.664 ml of carbon disulfide is added dropwise to the mixture over 10 minutes and the reaction is continued for about 20 minutes at the same temperature, then 6.86 ml of 15% n-butyl lithium and n-hexane solution are added dropwise to the reaction mixture for 10 minutes and the induced reaction lasts about 30 minutes. After this, 0.332 ml of carbon disulfide is added to the reaction mixture over 10 minutes and the reaction is continued for about 10 minutes. Next, 3.43 ml of a 15% n-butyl lithium solution of n-hexane is added dropwise to the reaction mixture at a temperature below for 13 minutes and then the reaction is continued for about 20 minutes at a temperature of from -74 to -73 ° C. Then, 0.166 MP of carbon disulfide is added to the reaction mixture at about 6 minutes and the reaction is continued for about 25 minutes. Then, diiodoacetat, obtained by the reaction of 0.84 g of 50% sodium hydride and 5.46 g of diiodoacetic acid in 25 ml of dimethoxyethane, is added to the reaction mixture. The reaction lasts about 30 minutes at O-sPCj and then overnight at room temperature. The solvent was distilled off under reduced pressure from the reaction mixture, and the residue was extracted with 50 ml of cold ether and 40 ml of 1N. hydrochloric acid. The resulting ether layer was extracted twice with 20 ml of a saturated aqueous solution of sodium bicarbonate. The aqueous extracts are combined and the pH is adjusted to 1N. hydrochloric acid, extracted twice with 30 ml and 20 ml of ether, respectively. The extracts are combined and washed with water, dry and dry over anhydrous sodium sulphate and then the ether is distilled off to obtain 1.08 g of an oily product. The oily product is subjected to chromatography on a silica gel column and the fractions containing the desired product are combined using a mixture of chloroform and methanol in a volume ratio of | 10: 1 to give 630 mg of a brown oily 4- (1-carboxyproduct-Li) -1.3 dithiethane-2-carboxylic acid.

Nuclear Magnetic Resonance Spectrum. (CoC) cP (ppm);

1.24 (3N, -CHj t); 1.47, (9H, (CH3) sC-. S); 2.01 (2H, -CHP-, q);

: /

; sn-, S)

4.87 (1H, "

Claims (1)

sX. Example 21. HOOCCH N.-Sv Hnrir. I I, .. Jl tl N / "" v / vii A. In 10 MP of tetrahydrofuran, 350 mg of C4-1,2-bis (tert-butoxy carbonate) ethylidene-1,3-diti, ethane-2carboxylic acid are dissolved. After adding 0.5 g of 7 | b-amino-7sz-methoxy-3- (1-methyl-tetrazol-5-yl) thiomethyl-l-cefemg 4carboxylic benzhydryl ether and 218 mg of N, N-dicyclohexylcar bdimimide, the reaction takes place about 2 hours at room temperature. After filtering off the precipitated N, H-dicyclohexylurea, the solvent is distilled off from the filtrate and the residue is subjected to chromatography on a slurry column and the fractions containing the product are combined, first using benzene and then a mixture of benzene and ethyl acetate in a 9: 1 volume ratio as eluent, and get 120 m benzhydryl ether 1,: 2-bis (tert-butoxycarbonyl) -ethylidene -1,3-dithioethan-2-yl} carboxamido-7o-labels Si-3- (1-methyltetrazol-5-yl) thiomethyl- l-cephem-4-carboxylic acid. Nuclear Magnetic Resonance Spectrum (SOSTS) cf (rrtp); 1.42-1.48 (18H, (CH), jC-); 2.58 (2H, -CH-a); 3.59 (3H, -OCHj); 3.80 (3N, N-CH); 4.36 (2H, -CH, j - groups Cj, q); 4.87 and 5.09 (H of group C and 6.92 (H, -CH (),); 7.2-7.6 (YUN, -C () B. 115 mg of the product is dissolved in 1 MP anisole obtained in step A. After cooling the solution to a temperature below 10 ° C in an ice-water bath, 3 ml of trifluoroacetic acid are added dropwise to the solution at a temperature below. After stirring the mixture for about 1 hour at 5-1 C acids and anisole are distilled out from the reaction mixture under reduced pressure and at a temperature not less than 10 ml of ether to give 73.7 mg of (1,2-dicarboxyethylidene) -1,3-dithioethan-2-yl 3 carboxamide o- W-methoxy-3- (1-methyltetrazol-5-yl) thiometyl-L-cepheme-4-kgh of the bovine acid Spectrum of a nuclear magnetic reeon with a (0 (, - OI50) cG (ppm) -. iH, 3 , 94 (3H, :: N-CH.J); 4.30 (2, H, -СИ, - groups Cj); 5.16 and 5.20 (H groups C - (CH-); °° s "Overlaps the peak of DMSP -OCH overlaps with the peak of water. Example 23 (Reference). {CH) 5СООС С СНС Dispath (CH j) COOCH2C To a mixture of 80 ml of diethylene glycol dimethyl ether: and 20 ml of tetrahydrofuran are added to 1.54 ml of diisopropylamine and the mixture is cooled. to -74c in a dry ice-acetone bath. Then, 6.86 ml of a 15% n-butyllithium solution of n-hexane is added to the mixture and the reaction takes place at TeivjnepaType from -72 to -74-s. 2.3 g of tert-butyl succinate are added to the reaction mixture and the reaction is then carried out at -74 ° C for about 30 minutes. Then, 0.33 ml of carbon disulfide is added to the reaction mixture dropwise over about 15 minutes and the reaction is continued for about 15 minutes at. In addition, 3.43 ml of a 15% n-hexane solution of n-hexane is added dropwise to the reaction mixture at -7lc for 20 minutes, and the reaction is continued for about 20 minutes at the same temperature. Then, to the reaction mixture, 0.166 ml of carbon disulfide is added dropwise over 13 minutes at -72 ° C and the reaction is carried out for about 17 minutes at the same temperature. In addition, hcl is added dropwise to the reaction mixture over 10 minutes) and at a temperature below -71 ° C 1715 ml of a 15% n-butyl lithium solution of n-hexane. Finally, 0.083 MP of carbon disulfide is added dropwise to the reaction mixture for 10 minutes and the reaction is continued for about 20 minutes at a temperature of from -7 to. Also, sodium diiodoacetate suspension, prepared in advance from 432 mg of 50% sodium hydride and 2.8 g of diiodoacetic acid in 20 MP diethylene glycol dimethyl ether, is added dropwise to the reaction mixture obtained in the described reaction, during which system temperature rises from -74 to 64s. The temperature is then increased and, after carrying out the reaction for 1 hour at 0-5 ° C, the mixture is stirred overnight at room temperature to continue the reaction. Thereafter, the solvent is distilled off under reduced pressure to obtain a brown precipitate. The residue is mixed with 50 ml of ether and 20 MP with cold 10% sulfuric acid and extracted with ether. The resulting ether layer is extracted twice with 50 ml of a saturated sodium hydrogen carbonate solution. The resulting aqueous layer is extracted with 50 ml of 10% sulfuric acid and extruded with 50 MP and 30 ml of ether. The ether extracts were combined and I permuted twice with 30 ml of: saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and the ether was distilled off to obtain 1.83 g of an oily product. The oily product was subjected to chromatography on a column of silica gel, using 70 g of silica gel. Chloroform was used as eluent, then a mixture of chlorofor and methanol in a volume ratio of 50: 1 and the fractions containing the product were collected to give 700 ml of 4-C1, 2-bis- (tert-butoxycarbonyl) -1, 3-dithiethane-2-carbonoic acid Nuclear magnetic resonance spectrum (SOSC) cf (pph); 1.22 (18H, 2 X (CH5) C-); 2.58 (2H, -CHj-); 4.91 {IH, Mace. Spectrum m / e: 362 M. P p and m e p 22. S with. :: () dHCOMM- | f- - 5 TI, NHOC A. To a solution obtained by dissolving 500 mg of 7fb-aMHHO-7oC-MeTOKCH-3- {1-methi-tetrazol-5-yl) thiomethyl-benzhydryl ester | 51 -cepheme-4-carboxylic acid in 35 ml of tetrahydrofuran, 500 ml of 4- {tert-b / tocarboxylic) (N-methylcarbamoyl) methylene -1,3-dithioet-2-carboxylic acid and 400 ml of N-drop is added dropwise to the mixture , N-dicyclohexylcarbodiimide and the mixture is stirred for about 3/5 h at room temperature. The solvent was distilled off from the reaction mixture under reduced pressure, and the resulting residue was subjected to chromatography on a silica gel column to obtain 300 mg of (carboxy) - (M-methylcarbamoyl) methylene -1,3-dithietan-2-yl carboxamido -7O1-methoxy benzhydryl ester -3- (1-methyltetrazol-5-yl thiomethyl-β-cefem-4-carboxylic acid using a mixture of chloroform and ethyl acetate in a volume ratio of 4: 1 as eluent. Nuclear magnetic resonance spectrum (C DC 1) cG ( ppt, 1.52 (9H, tC, Hg-); 2.83 (ZN, Ctix, NHCO-); 3.60 (5H, CH O-and-CH-pears Cg); 3.84 (ZN, C , HN. I): about 4.82 (IH, 5.08 (IH, H group Cj,); 6.93 (IH, -CNSS Nd) ,;) B. In a mixture of 10 ml of trifluoroacetic acid and 2 ml of anisole, 300 mg of the product obtained in stage A is dissolved under ice-cooling. The solution is stirred for about 1 h at. Solvent it is removed from the reaction mixture under reduced pressure, and the residue is mixed with ether, followed by stirring. The resulting precipitate is taken up with P01 "| filtration and washed with ether to obtain 170 mg of 7j2) (carbox) (- methylcarbamoyl) methylene -1,3-dithiethane -2-yl1 -carboxamido-7 (X is methoxy-3- (1-methyltetraZOL-5-IL) -thiomethyl-l-cefem-4-carboxylic acid. Nuclear Magnetic Resonance Spectrum (O -ONSOcflppm). 2.68 (3N, CHa, NHCO-); 3.42 (ЗН,); N N3 .94ZH, CHL-N:; I); - about 5.12 (2H, H groups C and C, CH-) - S Example 24 (reference). CH-NHOC (СН) ССООС To 3 ml of a 15% solution of tert-butanol of potassium t-butylate are added 540 mg of tert-butyl-M-methyl diphosphoric acid and 12 ml of anhydrous tetrahydrofuran by stirring at room temperature. After stirring the mixture for 5 minutes, 0.0935 ml of carbon disulfide is added to it in drops, followed by stirring for about 10 minutes. Then 1.5 ml of a 15% tert-butyl tert-butyl potassium solution are added to the mixture. followed by stirring for about 10 minutes, 046 ml of carbon disulfide is added dropwise and stirred for about 0 minutes, the same procedure is repeated using 0.8 ml of 15% tert-butanol ret-butyl acetate and 0.023 ml carbon disulfide ,. Then, the sodium diiodoacetate 1 suspension, prepared separately by dissolving 0.98 g of diiodoacetic acid in 7 MP anhydrous tetrahydrofuran and adding 115 g of 50% sodium pdrid to the pomany solution with cooling, is added to the described reaction mixture, followed by stirring about 1 at room temperature to terminate the reaction. After that, the solvent is distilled off under reduced pressure, 150 ml of ether and 50 ml of 0.2 N hydrochloric acid cooled to OOC are added to the product, and the product is extracted with ether, then washed two Wait 50 ml of water. The ether layer is extracted with 50 ml of 2% sodium hydrogen carbonate hydrate and the aqueous layer is neutralized to about 7.5 with pH 1 n hydrochloric acid and extracted with 100 ml ether, 0.5 MP 1 n is added to the aqueous layer. hydrochloric acid and extracted with 100 ml of ether. The procedure is repeated. Each ether extract was subjected to silica gel chromatography on a t-layer using a mixture of acetone trilon, ethyl acetate and water in a 3: 1: 1 volume ratio as eluent. Fractions containing the product were combined, the solvent was distilled off under reduced pressure to obtain 600 mg of oily 4- (tert-butoxy-carbonyl) methylcarbamoyl (methylene.) -1,3-dithiethan-2-to-arboxylic acid. The spectrum of nuclear magnetic resonance cf {ppmV. 1.52 (9H (CH, j) o, C-); 2.84 (CH ,.); 4.83 (IH, “CH-) Example 23. By the same procedure as in Example 2 Au and 2B, using 4 (tert-butoxycarbonyl). (carbamoyl) methylene -1,3-dithioethane-2-carboxylic acid and 7 (-mino-7lЗt-methoxy-3- (1-methyltetrazol-5-yl) thiomethyl-bg-cephem-4-carboxylic benzhydryl ether, are obtained ( 4- (carbamoyl) (carboxy) methyleneX-, 2-dithietan-2-yl carboxamido-7 (X methoxy-3- (1-methyltetrazol-5 yl) thiomethyl-b-cefem-4-carboxylic acid. Spectrum of nuclear magnetic resonance (0 -DMSO) cP (pprrt) i 3.40 (zn, -Cy groups); 3.61 (2H, -rCHg- groups C); N 3, 92 (3H, And 2H, xg-Chsn. .sn.n groups C, and 1H 1I, - COOH); 2H, - COMH ,,); lH, -) The invention claims for obtaining 7 oi-marks of Ci-7 (Lyne methylene-1,3-dithiethanoxamido) -3- ( 1-methyltetraiome thyl-3-cephem-4-carbonot of the formula (I) xv-Socn- | -f rso, Ms / -CK, COOH free or substituted in the form of a lower alkyl fat, a nitrile or amide carboxy group, a hydrogen atom, a lower alkyl, a lower alkoxy, carboxy (lower) alkyl, lower alkylthio, lower alkanoyl, lower alkylsulfonyl, sulfamoyl, phenyl, oxypheyl, benzoyl, free OR substituted as lower alkyl ether, nitrile, amide or N-MOHO, H-di- (lower alkyl) Smida carboxy group, pyridyl 2-methylthio-1,3,4-thiadiazolyl-5, characterized in that 7 | 4-amino-7sl-methoxy-3- (1-methylte Rasoli-5-iltiomvtil) -3-cephem-4-carboxylic acid of formula (I) I g. Cooperated with 4-notice-1, 3-dithi-ethan-2-car18 slots of formula (III) where R and R have the above values, or its functional derivative, of an organic solvent at a temperature from -500 to room temperature. Priority on the basis of July 28, 1997, with R being a free or substituted carboxy group in the form of a nitrile; R is free or substituted as amide or N-MOHO or N, m-dy (lower acyl) amide of carboxy group 02. 02.78; for K, free or substituted nitrite of carboxy group; R is a hydrogen atom, lower alkyl, lower alkoxy, lower alkylthio, lower alkanoyl, lower alkylsulfonyl, sulfamoyl, nitrile, phenyl, hydroxyphenyl, benzoyl, pyridyl, or 2-methyl-1,3,4-thiadiazolyl-5. Sources of information, taken into account in the examination 1. Patent ША 3932396, кл. 260-243 C, published. 1976.