SU727147A3 - Method of preparing cephalosporins - Google Patents

Abstract

1472870 Cephalosporin synthesis SOC FARMACEUTICI ITALIA SpA 20 May 1975 [22 May 1974] 28410/76 Divided out of 1472865 Heading C2C A process for the preparation of a cephalosporin having the general formula comprises treating a thiohydrazoazetidine of the formula wherein R is hydrogen, (C 1 -C 4 )alkyl, cyanomethyl, thienylmethyl, furylmethyl, naphthylmethyl, benzyl, phenoxymethyl, phenylisopropyl, phenoxyisopropyl, 4 - pyridyl - 4 thiomethyl or 1-tetrazolyl-methyl; R<SP>2</SP> and R<SP>3</SP> represent (C 1 -C 4 )alkyl, a mononuclear aryl or heterocyclic group, cyano, -COR<SP>4</SP>, -COOR<SP>4</SP>, -PO(OR<SP>4</SP>) 2 or -CONHR<SP>4</SP> in which R<SP>4</SP> is (C 1 -C 4 )alkyl or a mononuclear aryl or heterocyclic group; or R<SP>2</SP> and R<SP>3</SP> together represent a residue of any of the formulae Y is a residue of the formula and Z is hydrogen, bromine, iodine, hydroxyl, alkanoyloxy, alkyloxy, azido, amino, acetoxy, carbamate or an S-mononuclear nitrogen heterocyclic ring with an organic or inorganic base or an inorganic basic or weakly acid oxide at a temperature of from -100‹ to + 120‹ C. The inorganic oxide is suitably Al 2 O 3 , Fe 2 O 3 , Cr 2 O 3 or SiO 2 , and the base is suitably Na 2 CO 3 , NH 4 OH an alkali or alkaline earth metal hydroxide, an alkali metal alcoholate, an aliphatic, aromatic or heterocyclic amine, an alkylammonium base or a basic resin.

Description

The invention relates to the production of cephalosporin antibiotics, in particular to a new method for the preparation of cephalosporins of the general formula

where R ^{1 is} selected from the group consisting of alkoxy with 1-4 carbon atoms, trichloroethoxy, p-methoxybenzyloxy, p-nitrobenzyloxy, phenacylbxy and p-halo phenoxyloxy;

Ζ is a hydrogen atom or an acetoxy group.

A known method for the preparation of cephalosporins by rearrangement of penicillin 1 oxides in an inert organic solvent in the presence of a salt of a nitrogen containing base with a pKv of at least 4 and an acid [1].

The disadvantage of this method is the low efficiency of the process, due to the fact that the rearrangement of penicillinsulfoxides occurs with the formation of a mixture of various isomeric products.

The aim of the invention is to increase the efficiency of the process.

The goal is achieved by the method of producing cephalosporins of the formula (I), which consists in the fact that thiaeolinazetidinone of the General formula

where R and Ζ have the meanings indicated above, are subjected to interaction with the azo derivative of the General formula

K-C 00 R ²

II

K —COOR ³ where R ^{1 is not the} same or different and means methyl or ethyl, in acetone at room temperature in the presence of an aqueous organic acid, such as p-toluenesulfonic acid, forming 2β-hydrazothioazetidinone of the general formula NH-C00R ²

N-C00R ' ¹

where is R *, R ^? , R · ⁵ and Z have the above meanings, are reacted with an inorganic basic or weakly acid oxide, such as aluminum or silicon oxide, or with an inorganic or organic base, such as an alkali metal hydroxide or alcoholate, in a solvent such as like benzene or ethyl acetate, or tetrahydrofuran, or dimethylformamide, at a temperature of from -20 to + 80 ° C. ,

A distinctive feature of this method is the interaction of a thiazolinazetidinone of formula (II) with an azo derivative of formula (III) followed by treatment of an intermediate product of 2p-hydrazothioazetidinone of formula (IY) with an inorganic basic or weakly acid oxide or inorganic or organic base.

The process can be carried out both with isolation and without isolation of an intermediate compound of formula (IY).

Example. 1. Methyl-k-isopropenyl-Z- [2β- (Ν, Ν-dicarboxymethylhydrazothio) -p-phenoxyacetamido-4-oxoazetidin-1-yl] -acetate.

A solution of 5.0 g of methyl-L-isopropenyl-o (- [3-phenoxymethyl-1 <X, 5 (λ-7-οκοο-4-thia-2,6-diazabicyclo [3.2.0] hept-2 .-en-b-yl ^ -acetate in 200 ml of acetone containing 5 ml of dimethyl azodicarboxylate, 2.5 g of p-toluenesulfonic acid monohydrate and 2.5 ml of water, kept at room temperature for 6-8 hours. Then the solution is cooled to 0 ° C and neutralized with saturated sodium bicarbonate solution.

The precipitated sodium salt of p-toluenesulfonic acid is filtered off and the residue obtained after evaporation of the acetone at room temperature is dissolved in methylene chloride and washed with salt water. The organic layer was dried over anhydrous sodium sulfate and evaporated. The residue was chromatographed with silica and eluted with 15% benzene-ethyl acetate. 6.2 g of the expected product are obtained; so pl. 133-135 ° C.

IR (SSC): 3410 (N-H), 1775 (C = 0, β-lactam), 1735 (C = 0, ether and carbamates) 1685 cm '(C = 0, amide).

NMR spectrum (CDC? ₃ ): 1.9 4 (singlet, 3N, CH ₃ -C =); 3.68, 3.73 and 3.81 (singlets, 94, three COOCH ^); 4.56 (singlet, 2H, OCH, ₂ CO); 4.90 (singlet, 1H, N — CH — COOCH ₃ ); 5.07 and 5.16 (extended singlets, 2H, = CH _g ); 5.3-5.7 (multiplet, 2H, CH, β-lactam) and 6.9-8.0 ί (multiplet, 7H, aromatic H and ΝΗ).

Mass spectrum: M / e 510 (M ⁺ ) and 363 (main fragmentation ion) m-en-co- _e N-COOCH.

Example 2. 2,2,2-Trichloroethyl- (X-isopropenyl-α- [2p- (Ν, Ν-dicarboxymethylhydrazothio) -3 β-phenoxyacetamido-4-oxoazetidin-1-yl] -acetate

0.15 ml of water, 0.25 ml of dimethyl azodicarboxylate and 125 mg of p-toluenesulfonic acid monohydrate are added to a solution of 300 mg of 2,2,2-trichloroethyl-L-Ieopropenyl-c <- [3-phenoxymethyl-ία, 5 ° (-7- oxo-4-thia-2,6-diazabicyclo [3.2.0] hept-2-en-6-yl-acetate in 10 ml of acetone. The solution was kept at room temperature for 6 hours. Then it was neutralized with saturated sodium bicarbonate solution , methylene chloride is added to it and treated with shaking with salt water.The organic layer is dehydrated with sodium sulfate and evaporated to dryness. The residue is chromatographed using red oxide hennia and elute with a mixture of benzene and ethyl acetate (85:15 by volume). The expected product is obtained as an amorphous solid.

IR spectrum (CHECe _h ): 3400 (Ν-Η), 1770 (C = 0, p-lactam), 1740 (C = 0, ether and carbamates) and 3690 cm (C = 0, amide).

Example 3. Methyl-7-phenoxyacetamido-3-methyl-3-Cephem-4-carboxyl at.

A solution of 1.0 g of methyl <X ~ isopropenyl-cX- [2 β- (Ν, Ν-dicarboxymethylhydrazothio] -p-phenoxyacetamido-4-oxoazetidin-1-yl] -acetate (i.e., the product from example 1) 40 ml of benzene are treated with an excess of alumina in a magnetic mixer at room temperature after 60 minutes, the alumina is filtered off and the residue is crystallized from ethyl ether or chromatographed with silica, eluted with a mixture of benzene and ethyl acetate (90:10 by volume) to obtain 0.580 g target product, mp 140-141 ° C (recrystallization from ethyl ether).

Example 4. Methyl-7-phenoxyacetamido-3-methyl-3-Cephem-4-carboxy lat.

A solution of 400 mg of the product obtained in Example 1 in 30 ml of ethyl acetate was treated with excess silicon oxide in a magnetic stirrer g and heated under reflux for 48 hours. After the removal of silicon oxide, the filtrate was evaporated to dryness and the residue was crystallized or chromatographed using silica. Get 180, mg of the target product, mp. 141-142 ° C.

Example 5. Methyl-7-phenoxyacetamido-3-methyl-3-cephem-4-carboxylate. fifteen

0.8 ml of a 30% aqueous potassium hydroxide solution is added with stirring in a magnetic mixer and at room temperature to a solution of 510 mg of the product obtained according to Example 20 in 20 ml of benzene. Stirring is continued for 30 minutes, and then the organic layer is separated, washed with acidified water and dried. The residue was crystallized from 25 ethyl ether to give 310 mg of the expected product, mp. 141-142 ° C.

Example 6. 2,2,2-Trichloroethyl-7-phenoxyacetamido-3-methyl-3-cefem-4-carboxylate. -jq

A solution of 250 g of 2,2,2-trichloroethyl- (X-isopropenyl-y- [2β- (N, N-dicarboxymethylhydrazothio) -3 £ -phenoxyacetamido-4-oxoazetidin-1-yl] acetate in 150 ml of benzene is treated in magnetic the mixer at room temperature with an excess of alumina. After holding for 60 minutes, the solution was filtered and chromatographed with silica, eluting with a mixture of benzene and ethyl acetate (93: 7 by volume). ^ ”150 mg of the expected product was obtained, mp 116 - 117 ° C.

Example 7. Methyl-7-phenoxyacetamido-3-methyl-3-Cephem-4-carboxylate. 45

This example describes a process for transitioning from a compound of formula (II) to a compound of formula (I) without isolating a compound of formula (IY).

A solution of 500 mg methyl-L-isopropene-50 nyl- <X- (3-phenoxymethyl-ΙΛ, 5 ° (-7-oxo-4-thia-2,6-diazabicyclo [3.2.0] hept-2-ene -6-yl) -acetate in 25 mp acetone containing 0.5 ml of dimethyl azodicarboxylate, 250 ml of p-toluol sulfonic acid monohydrate and 0.25 ml of water, kept at room temperature for 6 hours. After cooling, the solution is neutralized with a saturated bicarbonate solution sodium and extracted with shaking with benzene and salt water.The organic layer is dried over anhydrous sodium sulfate, then the solution is filtered, the benzene and the residue are evaporated from the filtrate llizuyut from ethyl ether. 350 mg of the title compound, m.p. 140-143 ° C.

Example 8. Methyl-7-phenoxyacetamido-3-methyl-3-Cephem-4-carboxylate.

Solution 7 50 mg methyl-oC-ieopropenyl-i- {3-phenoxymethyl-1 <X, 5 (X-7 ~ oxo-4-thia-2,6-diazabicyclo [3.2.0] hept-2-ene -6-yl) -acetate in 35 ml of acetone containing 0.75 ml of dimethyl azodicarboxylate, 375 mg of p-toluenesulfonic acid monohydrate and 0.375 megapixels of water, is kept for 6 hours at room temperature. After cooling to 0 ° C., the solution was neutralized with saturated sodium bicarbonate solution, water was added and extracted with benzene. The organic layer is dried and 1.2 MP of a 30% potassium hydroxide solution is added while stirring with a magnetic stirrer and at room temperature. After holding for 30 minutes, the organic layer was separated, washed with acidified water and water, and dried over anhydrous sodium sulfate. The evaporation residue is crystallized from ethyl ether and 540 mg of the expected product is obtained, mp. 141-142 ° C.

Example 9. Methyl-7-phenoxyacetamido-3-methyl-3-cephem-4-carboxylate (see Example 3).

A solution of 1.0 g of the product obtained according to example 1 in 10 mp anhydrous tetrahydrofuran is added to a suspension of 5 equivalents of lithium methylate in 30 ml of anhydrous tetrahydrofuran at -40 ° C and the resulting mixture is stirred for 1 h. After neutralization with acetic acid the solution was warmed to room temperature, neutralized with an aqueous solution of sodium bicarbonate and extracted with ethyl acetate.

The organic layer was washed with water, dried over anhydrous sodium sulfate and the solvent was evaporated in vacuo. Methyl 7-phenoxyacetamido-3-methyl-3-Cephem-4-carboxylate is obtained, which is crystallized from diethyl ether.

Claims (1)

1. Belgian Patent No. 747119,. cl. C 07 d, pub. 1970 (proto