SU731899A3 - Method of preparing delta-3-cephalosporin esters - Google Patents

Abstract

Antibacterial alkanoyloxymethyl cephalosporin esters prepd. from 4-carboxy cpd. and alkanoyloxymethyl halide

Description

The invention relates to a method for producing new cephalosporin esters having improved antimi; a microbial spectrum of action that may find application in medicine.

A known method of producing A ³ -acylloxymethyl esters of cephalosporins by the interaction of the potassium salt of cephalosporin, sodium iodide and chloromethyl pivalate [1].

The aim of the invention is to obtain new cephalosporin derivatives with improved antimicrobial spectrum of action.

This goal is achieved by the fact that get A ³ -cephalosporin esters of the General formula

γ K

COOCHjOCORj wherein Ri - a hydrogen atom or S1_ ₄ alkanoyl; R ₂ is methyl, ethyl, isopropyl or tert-butyl, characterized in that the compound of the general formula

Yu wherein R] has the abovementioned meaning, are reacted with alkanecarboxylic acid halomethyl ether of the general formula XCH ₂ OCOR ₂ wherein R ₂ has the abovementioned meaning,

X is a chlorine or bromine atom in an inert solvent at 18-30 ° C in the presence of one equivalent part of the base per equivalent amount of a mixture of the starting compounds.

Example 1. To a solution of 4.85 g of 7 - (/) - 2 formiloxsp-2-phenylacetamido) - 3 - (1-methyl-1,2,3,4 - tetrazol-5-yltomethyl) - 3-cefem-4- carboxylic acid, 1.53 g of chloromethyl pivalate and 1.03 g of sodium bromide in

25 ml of dimethylformamide (DMF) was added dropwise a solution of 1.81 g of dicyclohexylamine in 15 ml of DMF. The reaction mixture was stirred for 12 hours at room temperature. After filtering the reaction mixture, the filtrate was added to 700 ml of ethyl acetate. The organic solution was washed successively with an aqueous saturated sodium chloride solution, an aqueous sodium bicarbonate solution, 1N. hydrochloric acid solution and water. After drying the organic solution, the solvent was distilled off under reduced pressure, and after recrystallization, pivaloyloxymethyl ether 7- (7) -2-formyloxy-2-phenylafetamido) - 3 - (1-methyl-1,2, 3,4-tetrazol-5-ylthiomethyl ) - 3-Cephem-4-carboxylic acid; t. pl. 155-156 ° C.

Calcd for C ₂ 5H ₂ 8N ₆ O ₈ S ₂ (.. 604 mol wt)%: C 49.66; H 4.67; N 13.9.

Found,%: C 49.74; H 4.69; N, 13.73.

Example 2. 2.42 g of 7- (7) -2formyloxy-2-phenylacetamido) - 3 - (1-methyl-1,2,3,4-tetrazol-5-ylthiomethyl) -3-cefem-4-carboxylic acid are dissolved acid and 1.72 ml (17.2 mmol) of bromomethyl acetate in a mixture of 50 ml of acetone and 10 ml of DMF. The mixture was stirred at room temperature and 0.595 ml, 4.2 mmol of triethylamine in 30 ml of acetone was added dropwise over 0.5 h. Upon completion of the addition, the mixture was filtered and the filtrate was evaporated in vacuo. The residue was washed with chloroform and washed successively with water, saturated sodium bicarbonate solution and saturated sodium chloride solution. The chloroform phase is dried with sodium sulfate and evaporated in vacuo to a foamy residue. The crude residue has 2 spots by thin layer chromatography (silica gel, ethyl acetate). The crude product is recrystallized from methanol to give 7- (7) -2-formyloxy-2-phenylacetamido) - 3- (1-methyl-1,2,3,4-tetrazole-5-ylthiomethyl) -3-cef- 4-carboxylic acid.

Calculated for C ₂₂ H ₂₂ N ₆ O ₈ S ₂ (mol. Weight 562),%: C 46.97; H 3.94; N, 14.94. Found,%: C 46.92; H 4.06; N, 14.74.

Claims (2)

the mixture was stirred for 12 hours at room temperature. After filtering the reaction mixture, the filtrate was added to 700 ml of ethyl acetate. The organic solution was successively washed with an aqueous saturated solution of sodium chloride, with an aqueous solution of sodium bicarbonate, 1 and. hydrochloric acid solution and water. After drying the organic solution, the solvent was distilled off under reduced pressure and after recrystallization a pivaloyloxymethyl ester of 7- (O-2-formyloxy-2-phenyl-fetamido) -1 - (1-methyl-1,2, 3,4-tetrazol-5-ylthiomethyl) was obtained. ) - Z-cephem-4-carboxylic acid; so nl 155-156 ° C. Calculated for C25H28Nb0852 (mol. Wt. 604),%: C 49.66; H 4.67; N 13.9. . Found,%: C 49.74; H 4.69; N 13.73. Example 2. Dissolve 2.42 g of 7- (D-2-formyloxy-2-phenyl acetamido) -3- (1-methyl-1, 2,3,4-tetrazol-5-ylthiomethyl) -3-cephem-4-carboxylic acid and 1.72 ml (17.2 mmol) of methyl acetate in a mixture of 50 ml of acetone and 10 ml of DMF. The mixture was stirred at room temperature and 0.595 ml, 4.2 mmol of triethylamine in 30 ml of acetone was added dropwise over 0.5 h. After the addition is complete, the mixture is filtered and the filtrate is evaporated in vacuo. The residue is washed with chloroform and washed successively with water, a saturated solution of sodium bicarbonate and a saturated solution of sodium chloride. The chloroform phase is dried with sodium sulfate and evaporated in vacuo to a foamy residue. The crude residue has 2 points by thin layer chromatography (silica gel, ethyl acetate). The crude product is recrystallized from methanol to give the acetoxymethyl ester of 7- (y-2-formyloxy-2-phenylacetamido) -3- (1-methyl-1,2,3,4-tetrazole-5-ylthiomethyl) -3-cephem-4 -carboxylic acid. Calculated for C22n22N6O8S2 (mol. Weight 562),%: C, 487; H 3.94; N 14.94. Found,%: C 46,92; H 4.06; N 14.74. The invention The method of obtaining D-cephalosporin esters of the general formula COOCH OCORj j. where Ri is a hydrogen atom or C1 4 alkanoyl; R2 is methyl, ethyl, isopropyl or tert-different in that the compound of the general formula S .. CKC01U1 0 where RI has the above values is reacted with alkanecarboxylic acid halide ester of the general formula XCH2OCOR2, where R2 has the above values, X is a chlorine or bromine atom, in an inert solvent at 18-30 ° C in the presence of one equivalent part of the base for an equivalent amount of the mixture of the starting compounds. Sources of information taken into account in the examination 1. US Patent No. 3708479, cl. 260-243, pub. 01/02/73.