SU833162A3 - Method of preparing 1-oxadethiacephalosporins - Google Patents

Abstract

PURPOSE:1-Oxadithiacephem cpds. I [ A is amino or protected amino; E is H or methoxy; Y is II(COB is carboxy or protected carboxy; X is H or nucleophile; Z is leaving gp.); the dotted line is alpha or beta-bond], e.g. 7alpha-benzamido3-methyl-1-dithia-1-oxa-3-cephem-4-carboxylic acid benzylester.

Description

  . . :. . . This invention relates to the synthesis of new derivatives of 1-oxadethiacephalo. sporins which can be used as semi-products in the synthesis of biologically active compounds. A known method for the preparation of 1-6xadiethiacephalosporins of the formula Al-CH CONH-f, wherein Ar is 2- or 3-thienyl, phenyl, p-o-syfeil or p-acetoxyphenyl; OWL / and OWL - independently of. other, free or protected carboxyl group, by acylation of 7-amino-7-methoxy-1-oxadethiacephalo sporin with the corresponding arylmalonic acid or its reactive derivative. These compounds possess the biologically active properties fl. The purpose of the invention is to expand the range of intermediates for the synthesis of biologically active substances. This goal is achieved by sposbbrozo 1-oxadethiacephalosporins., Hydrogen, alkyl., Aryloxyalkyl, aralkyl or aryl; a hydrogen atom or a halogen, hydroxy, acyloxy, lower alkylthio, lower alkylsulfonyloxy or 1-methyltetrazol-5-ylthio group; a halogen atom or an hydroxy-acyloxy group; or X and Z together represent oxygen or a simple chemical bond; free or protected as an alkyl or aralkyl carboxy ester, is that the compounds l-W-CH-CC; where R, X, Z, and COOB have the indicated values, are treated with an inorganic acid or sulfonic acid, silt with a strong carboxylic acid, or Lewis kilogram, in a medium as a solvent of a hydrocarbon, or a halogenated hydrocarbon, or simple ether, or ester, or ketone, or sulfoxide, or nitrile, or alcohol, or carboxylic acid, at a temperature of from -30 to within 5 minutes to 10 hours in the case of neo (CHARITY with the subsequent removal of the group protecting the carboxyl group by treatment acid. as a mineral acid For example, hydrochloric, sulfuric, or phosphoric acid can be used; methanesulfonic acid, toluene sulfonic acid, trifluoromethanesulfonic acid or trifluoroacetic acid can be used as sulfonic acid or toluene sulfonic acid, and boron trifluoride boron, zinc chloride, st. Antimony chloride or titanium trichloride. The reaction is most often carried out within 15 minutes to 3 hours, at a temperature of 15–30 s. If necessary, the reaction can be carried out with stirring or in an inert gas such as nitrogen, argon or carbon dioxide. Typical inert solvents include as a hydrocarbon, for example hexane ,. cyclohexane, benzene or toluene, such as a halohydrocarbon, for example dichloromethane, chloroform, dichloroethane, carbon tetrachloride or chlorobenzene as an ether. For example, diethyl ether, isobutyl ether, dioxane or tetrahydrofuran, as an ester,

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an example of ethyl acetate, butyl acetate or methyl benzoate, such as a ketone, for example acetone, metal ethyl ketone or cyclohexanone, such as a sulfoxide, for example dime-; Tylsulfoxide, such as nitrile, for example acetonitrile or benzonitrile, or mixtures thereof. Solvents in which a hydroxyl group is present react with the starting materials (II), leading to the formation of by-products, but they can be used under controlled conditions of the reaction. Typical examples of such hydroxyl solvents are an alcohol, such as methanol, ethanol, T-butanol or benzyl alcohol, an acid, such as formic, acetic or propionic, or mixtures thereof. The free hydroxyl group of the oxazolinoazetidine of formula (.11) can be protected in advance by means of a hydroxyl group blocking group, which is easily removed under reaction conditions, for example formyl or tetrahydropyranyl. Preferably, 1 part of oxazolinoazetidine (II) is dissolved in a mixture of 5-10 hours of halo carbon, for example chloroform or dichloromethane, and 010 parts of ether solvent, for example ether or dioxane, mixed with 0.005-5 molar equivalent of acid, for example boron fluoride firat, toluene sulfonic acid, copper sulfate, zinc chloride or tin chloride, then the solution is kept at a temperature of 10-60 ° C for 0.5-10 hours, which leads to the formation of the corresponding compound (I), with a yield of 50-95 % The starting materials are prepared from β-epenpenicillin-1-oxides in accordance with the following sequence, reactions where R, COOB and X have the indicated meanings. Compounds (I) obtained in the cyclization reagent can be isolated from the reaction mixture by removing the used solvent, unreacted substances, by-products and similar contaminants in the course of concentration, extraction, washing, drying or similar methods. and purified by re-precipitation, chromatography, crystallization absorption or similar purification methods. The sterisomers at positions 3 or 7 are separated by careful chromatography or fractional recrystallization. If desired, stereoisomers. subjected to subsequent processing without their separation. Use of the resulting product tov. , Compounds (1) are used as starting materials for the preparation of, for example, the known bactericidal 1-children-1-oxacephalosporins as a result of administration or peregroup: the double bond in position 3 is replaced with an antibiotically preferred side chain and / or unlocked carboxyl group soob. Conventional compound cores are represented by ygens in the form of fugmul 0 ets identical to the stereochemistry of cephalosporin in position 6. The stereochemistry of COOP in the indicated composition is usually the same as that of penicillin. the presence of the R configuration, if isomers may exist, and the absence of restriction of this configuration. The experimental errors in the infrared spectra are in the range of +10 cm, and the experimental errors in the nuclear magnetic resonance spectra are within 0.2 parts per million. Challenge points are not adjusted to the created conditions. Anhydrous sodium sulfate is used to dry the solution. Example (reaction 32). Oxazolinoazetidine (P) is dissolved in a solvent and mixed with an acid, resulting in the formation of a compound containing 1-child-1-oxaceph according to the conditions shown in Table 2. 1. The physical constants of the compounds obtained are given in table. 2. Reactions 13 of table. .1 shows the experimental cyclization procedure. 1. Solution of 12.0 g of yiphenylmethyl 2- (/ 1 R, 5S / -3-phenyl-7-oxo-4-.ox-2, b-diazabicyclo (3.2.0) hept-2-en-b -yl) -2-isopropenyl acetate, 1.0 g of osmium tetroxide and 12.0 g of potassium chlorate in mixtures and 400 ml of tetrahydrofuran and 200 mp of water are stirred at 58 ° C for 3.5 hours. After cooling, the reaction mixture poured into ice water and extracted with ethyl acetate. The extract is washed with brine, 10% sodium thiosulfate aqueous solution, and then bicarbonate aqueous solution.

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1) ifJH, SjbH- or (1R, 5S) -7-OKcO-4-oxa-2, 6-diazobicyclo (3.2.0) hept-2-ene.

2) 1-children-1-oxocate.

The stereochemistry around the carbon atom 1 of the bicyclohept 2-ene system is identical to the stereochemistry of b-epipenicillin in position 6, and the stereochemistry around the carbon atom 5 of the bicyclohept-2-ene system is opposite to the stereochemistry in cephalosporin in position b.

The stereochemistry around the carbon atom of 6 systeny 1 children-1-o "sacephamic konatri, dried and evaporated, yielding 12.88 g of diphenyl methyl 2- (/ 1 R, 5S) -3-phenche-7-oxyc4-occa-2, b- diazabicyclo- (3,2,0) hept-2-en-6-yl) -3, 4-dioxy-3-methylbutyrate.

IR spectrum: 3500 br, 1770 br, 1742, 1636 CNPV

2. To a solution of 10.88 g of the prepared product in 300 ml of ether, add 0.075 ml of boron trifluoride etherate, then the mixture is stirred for 3.5 hours at room temperature under nitrogen, poured into a good solution of sodium bicarbonate and extracted with ethyl acetate . The extract is washed with brine and evaporated. The resin is washed with a mixture of dichloromethane ether, as a result of this, 15 g of a mixture of isomers at 3 rinses of diphenylmethyl 7c6-tbenzamido-3-methyl-3 | -oxy-1-children-1-oxacem-4c-oxylate are obtained. IR spectrum: 11 a; 2 3560, 3445, 1774, 1739, 1670 cm-. This mixture is subjected to chromatographic separation on a column of silica gel deactivated with a 10% solution of water. The eluate obtained by using a mixture of benzene-eth acetate. (4: 1); Recrystallized from a mixture of acetone and ether, and then from a mixture of acetone and dichloromethane to form two separate stereo sources. Cleavage of the carboxyl blocking group, Example 2. To a solution of 960 m of diphenylmethyl 7p | -benzamido-7c-methox -Cc-methyl-3 (-acetoxy-1-children-1-ox-cefam-4o -carboxylate in 4 ml of anisole added 10 ml of trifluoroacetic acid at, then the mixture is stirred for 15 minutes and evaporated under reduced pressure. A residue is formed from a mixture of ether and n-hexane, which solidifies and allows to obtain 470 mg 7 (-benzam de 7o y 6 xy-3 oO-methyl-3 acetoxy-1-deti-1-oxacem-4-carboxylic acid as a colorless powder, (70%). T, pl. 208-203 s (decomposition of An Similarly, the following free carboxylic acids are prepared from the corresponding diphenylmethyl esters: 7 | -benzamido-7 "-mets: xi-3o-oxy-Zamethyl-1-detiana-1-oxacepham-4" o G CHgSPh COOCHPf, fa) to a 512 solution mg of compound (a) in a mixture of 10 ml of benzene and 1 ml of methanol was added 0.4 g of triphenylphosphine, then the mixture was stirred for 1.5 hours at 65 ° C. The residue was pushed over the chromatographic separation on a column of 30 g of silica gel, containing 10% water, eluted with benzene, containing 20-80% acetic acid JVCHC-CH, COOCHPhn-carboxylic acid. T, mp, 100113 ° C. 7O1g-benzamido-7o methoxy-3a1-trifluoroacetoxy-3 | b-methi} 1-1-children-1-oxacepham-4c1-carboxylic acid, mp. 108-113 C; - Benzamido-7o.-methoxy-3-methyl-1-children-1-oxacepham-4-carboxylic acid, T, mp, 195.-g-198 ° C, IR spectrum: 3250, 1766, 1742, 1642. .. 7-benzamido-3 | -chloro-3 | -chloromethyl-1-children-1-oxacepham-4-6-carboxylic acid, - T, mp, 118-122c (decomposition), Example 3, K solution 1.125 g of diphenylmethyl 7c -benzamido-3-exomethylene-1 children-1-oxacepham-4e6-carboxylate in a mixture of 15 ml of dichloromethane and 3.5 ml of anisole. A drop of 625 mg of gshuminium in 20 ml of nitromethane is added in drops. This process is carried out stirring and temperature -., after that the mixture is stirred for 30 minutes at a temperature of from -10 to under nitrogen. The reaction mixture was poured into ice water containing hydrochloric acid, and extracted with ethyl acetate. The extract solution is washed with a saturated aqueous solution of sodium bicarbonate,. thereafter, the washings are acidified with concentrated hydrochloric acid and re-extracted with ethyl acetate. The organic layer is washed with water, dried and evaporated. 623 mg of 7o / -benzamido-3-exomethia flax-1-dbti-1-oxacem-4cC-carboxylic acid are obtained. Getting the original compounds. P r and m p 4, 1 ,. .. W,%. . , it is COOCHR (7 "acids, allows to obtain 202 mg of solids,.,. R. IR spectrum: -i);) 3370, 1782, 755 1685 cm--,. Spectrum NMR: 2.50-3.35 m 1H; 4.18 s H; 5, OS S 1H; 5.22 5 1H; 5.28 d (3Hz) 1H; . , 50 S MN; 6.08 d (3Hz) 1H; 6.98 s H; 7.20-8.00 m 1 5H, PRI me R 5, with a dream of COOCHPff.

1. To a solution of 4.6 g of diphenylmethyl 2- (3-benzyl-7-oxo-2,6-diaza-4-oxabicyclo (3.2.0) hept-2-en-6-yl) -3-methyl -3-butenoate in 70 ml of ethyl acetate was added 3.8 ml of 2.74 M hydrochloric acid solution in ethyl acetate and 12 ml of a 1.47 M solution of chlorine in carbon tetrachloride, then the mixture was stirred at room temperature for 15 min Then, 80 ml of a 5% aqueous solution of sodium β-thiosulfate, 3.4 g of sodium bicarbonate and 240 ml of acetone are added to the reaction mixture, and the resulting general solution is kept at room temperature for 2.5 hours. The product is isolated by 15 extraction with ethyl acetate, dried over ratri sulfate and evaporated. 3.33 g of diphenylmethyl 2- (3-benzyl-7-oxo-2, b-diazo-4-oxabicyclo (3.2.0) hept-2-en-6-yl) -20-3-chloromethyl- are obtained. Z-butenoate, so pl. 82-83 ° C.

2.This substance is dissolved in 25 ml of acetone, mixed with 3.3 g of sodium iodide and kept at room temperature for 25 hours. The reaction mixture is concentrated to remove acetone and extracted with ethyl acetate. The extract is washed with an aqueous solution of sodium thiosulfate and water, dried over sodium sulfate and evaporated. Get

3.0 g of the corresponding iodide.

3. To a solution of 1.59 g of residue obtained according to the procedure described, in a mixture of 13 ml of dimethyl sulfoxide and 3 ml of water is added

0.77 g of copper oxide, after that the mixture is stirred for 1 h at 39 ° C. The reaction mixture is filtered to remove solid particles and extracted with ethyl acetate. The extract solution is washed with water, dried over sodium sulfate and evaporated. Get

0.35 g of diphenylmethyl 2- (3-benzyl-7.-Oxo-2, b-diaza-4-oxabicyclo (3.2 Hept-2-en-6-yl) -3-hydroxymethyl-3-butenoate, mp 40-55 p.

In Tables 1 and 2, the following abbreviations are used.

Ph is phenyl;

Stetr - 1-methyl-1,2,3,4-tetrazol-5-yl;

. - p-nitrophenyl}

C, H4. - p-tolyl;

 -p-p-cyanophenyl;

C0H4. C & -. O - p-chlorophenyl;

Bu-t -.t-buti l;

OAc - acetoxy,

 between X and Z means that CH X and Z taken together represent methylene,

-O- between X and Z means that X and Z are epoxy;

A is an amino or substituted amino group in place of RCONH;

Wt is the weight of the original substance;

CH is the weight of the starting 3-exomethylene compound;

EtOAc - ethyl acetate;

THF is tetrahydrofuran;

DMF - N N-dimethylformamide;

 - concentration. Nd5O;

 - dystil ether;

 - tert-butyl hypochlorite;

eq is the equivalent;

DBN - 1,5-diazobicyclo (3,4,0) ionene-5;

(CH2) g-NH - piperidine;

-temp - reaction temperature;

r.t. - room temperature;

reflux - boiling point;

hr is the hour;

hv - lamp irradiation;

D or d. Z - the presence of a double bond in position 2 (3) or 3 (4) instead of a residual group in position 3.

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Claims (1)

1. USSR patent in application 2464302 / 23-04, cl. C 07 D 498/04, 1976,