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Process for production of 3-alkenylcephem compounds

一种制造方法、头孢烯的技术，应用在有机化学、抗细菌药等方向，能够解决回收/柱充填剂再生等负担大、不能满足需要等问题

Active Publication Date: 2007-05-16
OTSUKA CHEM CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] But, according to the method described in this document, in its embodiment 4 and embodiment 5, E body content (rate) is respectively 14% and 2%, can not satisfy the requirement
[0008] Recently, especially in the pharmaceutical manufacturing industry, separation and purification using chromatography columns has been used as an industrial method, but it can be said that it is not the most suitable method due to the heavy burden of recovery of eluents and regeneration of column packing materials.

Method used

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  • Process for production of 3-alkenylcephem compounds
  • Process for production of 3-alkenylcephem compounds
  • Process for production of 3-alkenylcephem compounds

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0051] [Operation 1] Weigh compound (3) (R 1 = benzyl, R 2=diphenylmethyl) 10g, put into a 500mL four-necked flask, add 55mL of phenol, and stir at 50-55°C for 5 hours. After adding 100 mL of ethyl acetate and 200 mL of 5% aqueous sodium bicarbonate solution to the reaction liquid, it was cooled to below 10°C. Remove the organic layer, collect the water layer, wash 3 times with ethyl acetate 150mL, obtain compound (4) (R 1 = benzyl, M = sodium) in water. 5 g of PGA-450 was added to this aqueous solution, and the reaction was carried out for 3 hours at 20 to 30° C. with a 5% sodium carbonate aqueous solution while controlling the pH in the range of 7.5 to 8.5. After the reaction, the enzyme was removed by filtration, and an aqueous solution of compound (1') (M=sodium) was obtained in a flask. In this aqueous solution, 4.77 g (yield: 84.0%) of the compound (1') corresponding to 10% E volume content existed.

[0052] [Operation 2] After cooling the aqueous solution to 10° C....

Embodiment 2

[0058] [Operation 1] Weigh compound (3) (R 1 = benzyl, R 2 = p-methoxybenzyl) 10g, put into a 500mL four-necked flask, add 60mL of cresol, and stir at 45-50°C for 10 hours. After adding 100 mL of butyl acetate and 200 mL of 5% aqueous sodium bicarbonate solution to the reaction liquid, it was cooled to below 10°C. Remove the organic layer, collect the water layer, wash 3 times with butyl acetate 150mL, obtain compound (4) (R 1 = benzyl, M = sodium) in water. PGA-450 (5 g) was added to this aqueous solution, and it reacted for 3 hours at 20-30 degreeC with 5% sodium carbonate aqueous solution, controlling pH=7.5-8.5 in the range. After the reaction, the enzyme was removed by filtration, and an aqueous solution of compound (1') (M=sodium) was obtained in a flask. In this aqueous solution, 5.29 g (yield: 86.0%) of the compound (1') corresponding to 9% E volume content existed.

[0059] [Operation 2] After cooling this aqueous solution to 10° C. or lower, 4.5 g of activated c...

Embodiment 3

[0064] [Operation 1] Weigh compound (3) (R 1 = phenoxymethyl, R 2 = p-methoxybenzyl) 10g, put into a 500mL four-necked flask, add 50mL of phenol / cresol (1 / 1) mixed solvent, and stir at 50-60°C for 4 hours. After adding 100 mL of methyl isobutyl ketone and 200 mL of 5% aqueous sodium bicarbonate solution to the reaction liquid, it was cooled to below 10°C. Remove organic layer, collect water layer, wash 3 times with methyl isobutyl ketone 150mL, obtain compound (4) (R 1 = phenoxymethyl, M = sodium) in water. PGA-450 (5 g) was added to this aqueous solution, and it reacted for 4 hours at 25-30 degreeC with 5% sodium carbonate aqueous solution, controlling pH=7.7-8.7 in the range. After the reaction, the enzyme was removed by filtration to obtain an aqueous solution of compound (1') (M=sodium). In this aqueous solution, 4.84 g (yield: 80.9%) of the compound (1') having an E body content of 15% was present.

[0065] [Operation 2] After cooling this aqueous solution to 10° C. ...

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Abstract

The invention provides a process for the production of 7-amino-3-[(E / Z)-2- (4-methylthiazol-5-yl)vinyl]-3-cephem-4-carboxylic acid of formula (1) and alkali metal salts thereof which have enhanced contents of 7-amino-3-[(Z)-2-(4-methylthiazol-5-yl)vinyl]-3- cephem-4-carboxylic acid of formula (2) and alkali metal salts thereof, characterized by adding a high-porous polymer and / or activated carbon to an aqueous solution of an alkali metal salt of 7-amino-3-[(E / Z)-2-(4-methylthiazol-5-yl)vinyl]-3-cephem -4-carboxylic acid of formula (1) to treat the solution with the high-porous polymer and / or the activated carbon.

Description

technical field [0001] The present invention relates to a method for producing 7-amino-3-[(Z)-2-(4-methylthiazol-5-yl)vinyl]-3-cephem-4-carboxylic acid and a salt thereof. Background technique [0002] Cefditoren pivoxil, an oral cephem preparation represented by formula (5), is widely used as an excellent antibacterial agent with a broad antibacterial spectrum and strong antibacterial activity. [0003] [0004] As shown by cefditoren pivox, in the cephalosporin antibiotics with alkenyl group at the 3-position, the three-dimensional structure of the alkenyl group at the 3-position is Z configuration, which shows excellent antibacterial effect on Gram-negative bacteria Part of the mechanism is attributed to this configuration. Therefore, it is very important not to make cefditoren pivox obtain the geometric isomer of E configuration to exist as a medicine antibacterial agent as much as possible. Z body content. [0005] For example, it is disclosed that the Z / E mixture...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D501/18C07D501/00
CPCC07D501/00A61P31/04C07D501/14C07D501/16C07D501/18
Inventor 西冈洋一伊藤昌弘龟山丰
Owner OTSUKA CHEM CO LTD