Preparation method of 3-ethyl-4-7-aminocephalosporanic acid

Abstract

The invention discloses a preparation method of 3-ethyl-4-7-aminocephalosporanic acid. The method comprises the following steps: taking 7-(phenylacetyl) amino-3-vinyl-4-cephalosporanic acid p-methoxybenzyl ester as a raw material, taking solid superacid as a catalyst, reacting for 1 to 10 hours in mixed solvent of haloalkane, acetate and acetonitrile at the temperature of 0 to 50 DEG C, cooling a reaction solution to the room temperature, then processing to obtain faint-yellow solid and to obtain a target product, wherein solid superacid is a tin-series solid superacid modified by transitional metal; haloalkane is alkyl chloride with a carbon atomic number of 1 to 10; the acetate is CH3COOR, wherein R is alkane with a carbon atomic number of 1 to 10. By adopting a heterogeneous catalytic one-pot reaction technology and solid acid catalyst with high activity to prepare 7-(phenylacetyl) amino-3-vinyl-4-cephalosporanic acid p-methoxybenzyl ester, the technology is easy to operate, does not corrode equipment, has less waste water, waste gas and waste solid, is convenient in post-treatment and capable of reutilizing solid acid, and is an economical and practical environment-friendly technology.

Description

technical field

[0001] The present invention relates to a new method for preparing 7-amino-3-vinyl-4-cephalosporanic acid. Background technique

[0002] 7-Amino-3-vinyl-4-cephalosporanic acid (7-AVCA) is an important intermediate in the synthesis of the third-generation oral cephalosporin antibiotics Cefixime and Cefdinir. Cefixime has the characteristics of broad antibacterial spectrum, long half-life, less cross-resistance, less amount, and outstanding penetration performance; cefdinir is highly stable to β-lactamase, has broad antibacterial activity, high antibacterial activity, low toxicity, and adverse reactions Small. The patent protection of cefixime in our country ended in July 2001, and it has now expired. It is a pharmaceutical raw material urgently needed to be developed in our country; cefdinir was approved to go on the market in China in 2001. The administrative protection period ends in July 2006. Cefdinir and cefixime are cephalosporins currently recommende...

Examples

Embodiment 1

[0021] Embodiment 1: Preparation of 7-amino-3-vinyl-4-cephalosporanic acid

[0022] In a 50 ml three-necked flask, add 46 mg (0.1 mmol) of p-methoxybenzyl 7-phenylacetamido-3-vinyl-4-cephalosporanic acid, solid superacid catalyst S 2 o 8 2- / SnO 2 -Fe 2 o 3 23mg, 46mg of dichloromethane, 46mg of isoamyl acetate, 138mg of acetonitrile, react at 5°C for 5 hours, then cool the reaction solution to room temperature, add 10mg of activated carbon to the reaction solution for decolorization, filter, and concentrate the filtrate to precipitate pale yellow The solid was 18.3mg, and the yield was 81%. m.p.180~182℃, purity≥96%.

[0023] IR(KBr)cm -1 : 3158, 3010, 2890, 1800, 1615, 1540, 1060.

[0024] 1 H-NMR (D 2 O,400MHz)δ:3.52~3.67(2H,ABq,C 2 h 2 ),5.02~5.05(1H,dd,C 6 -H),5.19~5.20(1H,dd,C 7 -H), 5.34~5.37 (1H, d, Vinyl-H), 5.38~5.40 (1H, d, Vinyl-H), 6.68~6.72 (1H, dd, Vinyl-H).

Embodiment 2

[0025] Embodiment 2: Preparation of 7-amino-3-vinyl-4-cephalosporanic acid

[0026] In a 50 ml three-necked flask, add 46 mg (0.1 mmol) of p-methoxybenzyl 7-phenylacetamido-3-vinyl-4-cephalosporanic acid, solid superacid catalyst S 2 o 8 2- / SnO 2 -Fe 2 o 3 46 mg, dichloromethane 46 mg, isoamyl acetate 92 mg, acetonitrile 230 mg, react at 0°C for 10 hours, then cool the reaction solution to room temperature, add 10 mg of activated carbon to the reaction solution for decolorization, filter, and concentrate the filtrate to precipitate pale yellow Solid 18.5 mg, yield 82%. m.p.180~182℃, purity≥96%.

Embodiment 3

[0027] Embodiment 3: Preparation of 7-amino-3-vinyl-4-cephalosporanic acid

[0028] In a 50 ml three-necked flask, add 46 mg (0.1 mmol) of p-methoxybenzyl 7-phenylacetamido-3-vinyl-4-cephalosporanic acid, solid superacid catalyst SO 4 2- / SnO 2 -Fe 2 o 3 46mg, 46mg of dichloromethane, 138mg of butyl acetate, 230mg of acetonitrile, react at 0°C for 10 hours, then cool the reaction solution to room temperature, add 10mg of activated carbon to the reaction solution for decolorization, filter, and concentrate the filtrate to precipitate a light yellow solid 18.2 mg, yield 80.6%. m.p.180~182℃, purity≥96%.

technical field

[0001] The present invention relates to a new method for preparing 7-amino-3-vinyl-4-cephalosporanic acid. Background technique

[0002] 7-Amino-3-vinyl-4-cephalosporanic acid (7-AVCA) is an important intermediate in the synthesis of the third-generation oral cephalosporin antibiotics Cefixime and Cefdinir. Cefixime has the characteristics of broad antibacterial spectrum, long half-life, less cross-resistance, less amount, and outstanding penetration performance; cefdinir is highly stable to β-lactamase, has broad antibacterial activity, high antibacterial activity, low toxicity, and adverse reactions Small. The patent protection of cefixime in our country ended in July 2001, and it has now expired. It is a pharmaceutical raw material urgently needed to be developed in our country; cefdinir was approved to go on the market in China in 2001. The administrative protection period ends in July 2006. Cefdinir and cefixime are cephalosporins currently recommende...

Examples

Embodiment 1

[0021] Embodiment 1: Preparation of 7-amino-3-vinyl-4-cephalosporanic acid

[0022] In a 50 ml three-necked flask, add 46 mg (0.1 mmol) of p-methoxybenzyl 7-phenylacetamido-3-vinyl-4-cephalosporanic acid, solid superacid catalyst S 2 o 8 2- / SnO 2 -Fe 2 o 3 23mg, 46mg of dichloromethane, 46mg of isoamyl acetate, 138mg of acetonitrile, react at 5°C for 5 hours, then cool the reaction solution to room temperature, add 10mg of activated carbon to the reaction solution for decolorization, filter, and concentrate the filtrate to precipitate pale yellow The solid was 18.3mg, and the yield was 81%. m.p.180~182℃, purity≥96%.

[0023] IR(KBr)cm -1 : 3158, 3010, 2890, 1800, 1615, 1540, 1060.

[0024] 1 H-NMR (D 2 O,400MHz)δ:3.52~3.67(2H,ABq,C 2 h 2 ),5.02~5.05(1H,dd,C 6 -H),5.19~5.20(1H,dd,C 7 -H), 5.34~5.37 (1H, d, Vinyl-H), 5.38~5.40 (1H, d, Vinyl-H), 6.68~6.72 (1H, dd, Vinyl-H).

Embodiment 2

[0025] Embodiment 2: Preparation of 7-amino-3-vinyl-4-cephalosporanic acid

[0026] In a 50 ml three-necked flask, add 46 mg (0.1 mmol) of p-methoxybenzyl 7-phenylacetamido-3-vinyl-4-cephalosporanic acid, solid superacid catalyst S 2 o 8 2- / SnO 2 -Fe 2 o 3 46 mg, dichloromethane 46 mg, isoamyl acetate 92 mg, acetonitrile 230 mg, react at 0°C for 10 hours, then cool the reaction solution to room temperature, add 10 mg of activated carbon to the reaction solution for decolorization, filter, and concentrate the filtrate to precipitate pale yellow Solid 18.5 mg, yield 82%. m.p.180~182℃, purity≥96%.

Embodiment 3

[0027] Embodiment 3: Preparation of 7-amino-3-vinyl-4-cephalosporanic acid

[0028] In a 50 ml three-necked flask, add 46 mg (0.1 mmol) of p-methoxybenzyl 7-phenylacetamido-3-vinyl-4-cephalosporanic acid, solid superacid catalyst SO 4 2- / SnO 2 -Fe 2 o 3 46mg, 46mg of dichloromethane, 138mg of butyl acetate, 230mg of acetonitrile, react at 0°C for 10 hours, then cool the reaction solution to room temperature, add 10mg of activated carbon to the reaction solution for decolorization, filter, and concentrate the filtrate to precipitate a light yellow solid 18.2 mg, yield 80.6%. m.p.180~182℃, purity≥96%.