SU1436882A3 - Method of producing diphenylmethyl ether of 7-benzylidene-amino-3-(3-chloro-1-propen-1-yl) - cephem-4-carboxylic acid - Google Patents

Abstract

7-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-(substituted)-iminoacetamido]-3 -[3-(quaternaryammonio)-1 - propen-1-yl]-3-cephem-4-carboxylates of the formula <IMAGE> in which R<1> and R<2> are as defined herein and <IMAGE> is a quaternary ammonio group as defined herein, and salts, solvates, hydrates and esters thereof, are potent antibacterial agents. Processes for their preparation and intermediates in such processes are described.

Description

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This invention relates to a process for the preparation of a new chemical compound, namely, 7-benzylideneamino-3- (3-H1-3-propy-1-yl) 3-cephem-4-carboxylic acid diphekylmethyl ester, which is an intermediate in the synthesis of new cephalosporic antibiotics. - new p yes.

The aim of the invention is to obtain a new intermediate for the synthesis of cephalosporin antibiotics against microorganisms resistant to the known antibiotics of the penicillin and cephalosporin series.

EXAMPLE CHP. Preparation of diphenylmethyl-7-benzylideneamino-3-f (triphenylphosphoranylidene) methyl 3-cephem-4 carboxylate.

A. Diphenylmethyl chloride 7-benz1-thienamino-3-triphenylphosphonomethyl-3-cephem-A-carboxyoxylate

To suspension diphenylmethyl 7-ami. but-3-chloromethyl-3-cephem-4-carboxylate hydrochloride (II hydrochloride) (200 g, 0.44 mol) in methylene chloride (940 ml) was added 1N. guide; sodium oxide (440 ml) at room temperature. The mixture is shaken for 10 minutes and the organic layer is separated. Magnesium sulfate (75 g) and benzaldehyde (51 g, 0.48 mol) are added to the organic layer and the mixture is allowed to stand for 3 hours. The reaction of the HjTO mixture is filtered and insoluble substances are washed with methylene chloride (200 ml). Triphenylphosphine (126 g, 0.48 mol) is added to the combined filtrate with industrial water. The mixture is concentrated to about 400 ml and left to stand for 4 days. The resulting viscous oil is diluted with ethyl acetate (1 L) and triturated to separate the desired compound as a pale yellow crystalline powder, which is collected by filtration and dried in vacuo. Yield 322 g (96%). Melting point 185-190 ° (decomp.)

IR spectrum: (, (KBG), 1780; .1720; 1630.

UV spectrum: d d (methylene chloride), them (6): 260 (24100).

B. Preparation of diphenylmethyl 7-benz-3a-1-amino-3-Htriphenylphosphoranilidene-methyl-3-cephem-4-carboxylate.

A mixture of the product from stage A (322 g, 0.42 mol) and 5 and. sodium carbonate

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(252 ml) in ethylene chloride (1.6 l) is stirred vigorously for 15 minutes at room temperature. The organic layer is separated, dried over magnesium sulfate, and concentrated to approximately 500 ml volume. The concentrate is added to acetone (1 L) with stirring to give a light yellow crystalline powder, which is collected by filtration to yield 237 g (78%) of the title compound, melting at 195-198 ° C (decomp.)

IR spectrum: d s (KBG),: 1770, 1620.

UV spectrum: А „aks (methylene chloride),; nm (P: 254 (23000); 389 (22000).

NMR spectrum 5 (CDCl1) ppm: 2.56 and 3.1b (2H, ABg), 5.00; (IH, doublet, J 4 Hz) 5 5.23 (1H, doublet, J 4 Hz); 5.47 (1H, doublet, I 22 Hz); 6.95 (1Y, singlet); 7.2-7.8 (ZONE, multiplet), 8.55 (1Y, singlet).

B. Preparation of diphenylmethyl 7-benzylideneamino-3 (triphenylphosphoranylidene) methyl 3-3 cephem-4 carboxylate.

To a solution of diphenylmethyl iodide 7-benz1-shidanamine6-3- (triphenylphosphonio) metsh13-3-cephem-4-car-, bauxilate (60 g, 70 mmol) in methylene chloride (350 ml) is added sodium hydroxide (140 ml) and Amberlite lRA-410 (OH form, 35 g) at 5 ° C. The mixture is stirred for 1 hour and filtered. The organic layer is separated, dried over magnesium sulfate, concentrated to approximately. 100 ml of volume and precipitated with ethyl acetate (500 ml). The resulting yellow solid was collected by filtration and dried in vacuo to give 48 g (94%) of the title compound, melting at 195-8 ° C (decomposition).

IR spectrum (KBg), 1770, 1620.

PRI mme R 2. Preparation of diphenylmethyl 7-benzylidene-amino-3- (3-chloro-1-propen-1-yl) -3-cephem-4-carboxylate.

To a stirred solution of the title compound of Example 1B or 1B (2.9 g, 4 mmol) in a mixture of methylene chloride (40 ml) and WATER (10 ml) was added anhydrous chloroacetaldehyde (800 mg) at room temperature. To the mixture, an additional 800 mg of chloroacetaldehyde is added in three portions over a period of 1 hour, while the pH of the mixture is maintained between 6 and 9 by the addition of 1N. sodium hydroxide.

After 15 minutes, the aqueous layer was removed and the organic layer was dried over magnesium sulfate. Evaporation of the solvent gave a red oil, which was dissolved in a mixture of ethyl acetate and isopropyl ether (1/2, 80 ml). The solution is washed in succession with a saturated aqueous sodium bicarbonate (10 ml) and water (10 ml). After drying over magnesium sulphate, removal of the solvent gives 3.3 g of a yellow oil. The oil solution in matylene chloride (50 ml) is filtered using cedicagel (12 g, W-cogel C-200) containing 1 / 1.5 M phosphate buffer (1.2 ml, pH 6.4) and the silica gel is washed with methylene chloride (so ml) the filtrate and the wash water are combined and evaporated to dryness. The residue was triturated with hexane to give 1.7 g (80%) of the title compound in the form of a yellow powder. The NMR spectrum showed that the chloropropenyl part of the molecule has a configuration. Melting point above 50 ° C (decomposition). IR spectrum, o, kc (KBr), cm-: 3400} 1775; 1720; 1630.

UV spectrum /. (Etagüp), km (5): 253 (11000); 258 (11,000); 265 (10,000); 273 (8300); 281 (7000), 290 (6300).

NMR spectrum (DMSO-dfe), ppm: 3.63 (2G, s-sinlet.2-H); 4.0 (2H, multiplet, CH, g-C1); 5.42 (2H, multiplet 6H and); 5.72 (1H, doublet J 4.5, 7-H); 6.27 (W, doublet, J 11.3-CH); 6.85 (W, singlet, CHPh) i 7.33 (YUN, multiplet, Ph2-H).

Preparation of anhydrous chloroacetaldehyde.

Calcium chloride is added to a cooled solution of 50% aqueous chloroacetaldehyde (50 ml) with stirring to separate it into two layers. The chloroacetalide-hydride layer (upper layer) is separated and diluted with chloroform (100 ml) and mixed with sulfate magnesium (20 g), heated to reflux for 5 minutes and filtered. The solvent and water are removed azeotropically (boiling point 56-64 ° C) and the residue is distilled to give anhydrous chloroacetaldenide, boiling point 70 82 s / 760 mm Hg.

IR spectrum: iax (film) 1720cm

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Claims (1)

Invention Formula A process for the preparation of 7-benzshididenamino-3- ((3-chloro-1-propen-1-yl) -3-cephem 4-carboxylic acid diphenylmethyl ester  cH Tsi-r- / N CH CH2C  coaxially (СеН5) 2 characterized in that the benzaldehyde of the formula is clear is reacted with 7-amino-3-chloromethi-1-cephem-4-carboxylic acid diphenylmethyl ester of formula H2N-T ABOUT T i - CHgCi COOCHlCeHs) in an inert organic solvent medium at room temperature, the resulting 7-benzyl-1-amino-3-chloromethyl-3-cephem-4-carboxylic acid diphenylmethyl ester of the formula 35  Vc Hr NnG 40 ° SOOCH (SbN5) ,,, subjected to interaction With triphenyl "phosphine of the formula 45 (SbN5) 5P in an inert organic solvent medium at room temperature, the resulting diphenylmethyl ester 50 7-benzylidene-3- (trnphenylphosphine, but) methyl-3-cephem-4-carboxylic acid is a chloride of the formula sg  J-CVL / IG S ° COOCHCCeHs) ,, 514368826 interact with inorganic / Sx chesky base in an inert medium. / CH-gh Jl (organic solvent at com | temperature (di-g COOCJH CeJis) 7-benzylideneamine phenylmethyl ester is reacted with 3- (triphenylphosphoranylidene) methyl-3-thaldehyde with chlorine in an inert organic cephem - 4 - carboxylic acid in solvent form at room temperature and the product is isolated.