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Process for preparation of cephalosporin derivative

A manufacturing method and technology of cephalosporins are applied in the directions of medical preparations containing active ingredients, antibacterial drugs, pharmaceutical formulas, etc., and can solve the problems of complicated procedures and unfavorable industries.

Inactive Publication Date: 2012-10-10
NIPPON CHECMICAL IND CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] However, in the method of the reaction scheme (1), in order to obtain the target cephalosporin antibiotic, R in the formula 1 It is necessary to use a protected amino group, so a step of removing the amino protecting group is necessarily required, and the process becomes complicated, which is industrially disadvantageous

Method used

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  • Process for preparation of cephalosporin derivative
  • Process for preparation of cephalosporin derivative
  • Process for preparation of cephalosporin derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0129] (1) Deprotection reaction process of the 7-position amide bond

[0130] In a four-necked flask, 10.0 g of a compound represented by the following formula (10) (3.5% content of E body) was weighed, and 240 g of a 6% by weight aqueous sodium bicarbonate solution was added to prepare an aqueous sodium salt solution. 7.0 g of penicillin-G acylase (PGA-450, manufactured by Dallas Biotech Limited) was added to this aqueous solution. A 5% by weight aqueous solution of sodium carbonate at a liquid temperature of 25 to 35° C. was added to control the pH at 7.5 to 8.5, and the 7-position deprotection reaction of the sodium salt of the compound represented by the formula (10) was performed for 2 hours. After completion of the reaction, 7.0 g of a sodium salt of a compound represented by the following formula (11) containing 3.5% of the E body in terms of the E body content was contained in the aqueous solution. In addition, it contains 16.6% of phenylacetic acid in terms of pheny...

Embodiment 2

[0156] In the first step of Example 1, except that 2.8 g of CL-KP (trade name) manufactured by Ajinomoto Fine Chemicals Co., Ltd. was used as activated carbon, the carbon dioxide represented by the formula (11) was obtained in the same manner as in Example 1. Compound crystals. The iodine adsorption performance of the activated carbon is 1620mg / g, and the methylene blue adsorption performance is 280ml / g.

[0157] Next, after reacting in the same manner as in the second step of Example 1, 40 g of a 2.5% aqueous sodium bicarbonate solution was added, followed by washing with 80 g of dichloromethane twice, and the aqueous layer was concentrated. The sodium salt of the compound represented by formula (7) precipitates by concentration. Furthermore, 50 g of acetone was added and aged at 0 to 5° C. for 30 minutes, and the precipitated crystals were collected by filtration, washed with water and acetone, and dried. In addition, the various physical properties of the compound of form...

Embodiment 3

[0161] (1) Deprotection reaction process of the 7-position amide bond

[0162] Enzyme reaction was carried out under the same operation and conditions as in Example 1. After completion of the reaction, 7.0 g of the sodium salt of the compound represented by the formula (11) containing 3.5% of the E body content was contained in the aqueous solution. In addition, it contains 16.6% of phenylacetic acid in terms of phenylacetic acid content.

[0163] (2) Phenylacetic acid removal process (B process)

[0164] The enzyme (PGA-450) was filtered out from the aqueous solution obtained in the first step, the liquid temperature was kept at 10°C and adjusted to pH 4.2 with concentrated hydrochloric acid, and aged for 1 hour directly. The compound represented by the formula (1) is precipitated by this aging, and then filtered to recover the precipitate. In addition, the phenylacetic acid content of the obtained precipitate was 0.5%.

[0165] (3) The first process

[0166] 7.0 g of th...

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Abstract

Provided is a process by which an objective cephalosporin derivative having a high Z-isomer content or an alkali metal salt thereof can be prepared via simple steps with industrial advantages. A process for the preparation of a cephalosporin derivative (4a) or an alkali metal salt thereof, characterized by comprising the first step of bringing an aqueous solution of 7-amino-3-[(E / Z)-2-(4-methylthiazol-5-yl)vinyl]-3-cephem-4-carboxylic acid (1) or an alkali salt thereof into contact with an active carbon that has an iodine adsorptivity of 1200mg / g or more as determined by JIS K-1474 and a methylene blue adsorptivity of 250ml / g or more as determined thereby to prepare the carboxylic acid (1) having an enhanced content of Z-isomer (2) or an alkali metal salt thereof, and the second step of subjecting the carboxylic acid (1); which has been prepared in the first step and has an enhanced content of Z-isomer (2) to reaction with a compound (3).

Description

technical field [0001] The present invention relates to a method for producing a cephalosporin derivative and an alkali metal salt thereof in which the content of the Z body is higher than that of the E body. Background technique [0002] Known 7-[2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-[2-(4-methyl) represented by the following general formula (7) Thiazol-5-yl)vinyl]-3-cephem-4-carboxylic acid (syn-isomer, cis-isomer) is known as cefditoren ( Cefditoren) are excellent cephalosporin antibiotics. [0003] [0004] At present, the synthesis method proposal of this cefditoren has the following method: as shown in the following reaction scheme (1), through the compound shown in the following general formula (A) and the 7-amino- Production by reaction of 3-[(Z)-2-(4-methylthiazol-5-yl)vinyl]-3-cephem-4-carboxylic acid or its alkali metal salt (for example, refer to Patent Document 1) . [0005] Reaction flow (1) [0006] [0007] However, in the method of th...

Claims

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Application Information

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IPC IPC(8): C07D501/24A61K31/545A61P31/04C07D501/06
CPCC07D501/06C07D501/24A61K31/545A61P31/04
Inventor 和久井淳大原宣彦田久保洋介松本信夫
Owner NIPPON CHECMICAL IND CO LTD
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