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Method for synthesizing intermediate of cefcapene pivoxil,

A technology of cefcapene pivoxil and synthetic method, which is applied in the direction of organic chemistry, etc., to achieve the effects of simple operation, reduced preparation cost, and reduced reaction steps

Inactive Publication Date: 2013-12-18
CHONGQING CHANGJIE MEDICINE CHEM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, after consulting the literature, there are no relevant patents and journals reporting the method of preparing formula 1 from formula 2; and there is no 7-ACA as the starting material, without the 4-carboxyl protection directly generating 7- Formula 2 is prepared by position acylation reaction, and formula 1 is prepared by 3-position deacetylation hydrolysis reaction, and the method of finally preparing cefcapene pivoxil is reported.

Method used

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  • Method for synthesizing intermediate of cefcapene pivoxil,
  • Method for synthesizing intermediate of cefcapene pivoxil,
  • Method for synthesizing intermediate of cefcapene pivoxil,

Examples

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reference example 1

[0033] Reference Example 1 7β-[(Z)-2-(2-tert-butoxycarbonylaminothiazol-4-yl)-2-butenoyl]amino-3-acetoxymethyl-3-cephem-4-carboxy Synthesis of acid (Formula 2) (refer to US4500716)

[0034] Add 142g (0.5mol) of (Z)-2-(2-tert-butoxycarbonylaminothiazol-4-yl)-2-butenoic acid and 76mL (0.55mol) of triethylamine into dichloromethane (400mL) and cool down To -50°C, 40mL (0.52mol) of methanesulfonyl chloride was added dropwise, the temperature was controlled between -50°C to -40°C, and the drop was completed, and stirred at -50°C to -40°C for 5h. Then, add 163g (0.6mol) of 7-ACA (0.6mol) and 180mL (1.3mol) of triethylamine in dichloromethane (400mL) dropwise to the reaction solution, and control the temperature between -50°C and -40°C. ℃~-40℃ for 3h. Acidify with dilute hydrochloric acid and extract with ethyl acetate. The extract was washed with brine and dilute sodium bicarbonate water, dried and concentrated to give 7β-[(Z)-2-(2-tert-butoxycarbonylaminothiazol-4-yl)-2-butenoyl...

Embodiment 1

[0035] Example 1 7β-[(Z)-2-(2-tert-butoxycarbonylaminothiazol-4-yl)-2-butenoyl]amino-3-hydroxymethyl-3-cephem-4-carboxylic acid (formula 1) synthesis

[0036] Add 20g (36.2mmol) of compound formula 2 into 100mL of purified water, lower the temperature to -15°C, adjust the pH to 8 with sodium hydroxide, and keep the reaction for 3 hours. After the reaction is completed, add 10g of tetra-n-butylammonium bisulfate, dichloromethane (50mL×2) extraction, take the dichloromethane layer, concentrate the dichloromethane to cut off the flow, add isopropyl ether to the residue, stir and crystallize, filter with suction, and dry to obtain compound formula 1 18.0g, yield 98%, content 94 %.

Embodiment 2

[0037] Example 2 7β-[(Z)-2-(2-tert-butoxycarbonylaminothiazol-4-yl)-2-butenoyl]amino-3-hydroxymethyl-3-cephem-4-carboxylic acid (formula 1) synthesis

[0038] Add 20g (36.2mmol) of compound formula 2 into 50mL of acetone and 100mL of water, cool down to -30°C, adjust the pH to 7 with sodium carbonate, and keep the reaction for 10h. After the reaction is completed, add 10g of tetra-n-butylammonium chloride, Extracted with methyl chloride (50mL×2), took the dichloromethane layer, concentrated the dichloromethane until the flow was cut off, added isopropyl ether to the residue, stirred and crystallized, filtered with suction, and dried to obtain 17.8g of compound formula 1, with a yield of 96%. Content 90%.

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Abstract

The invention provides a method for synthesizing an intermediate of cefcapene pivoxil, and the intermediate is 7-beta-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-buteneacyl] amino-3-hydroxymethyl-3-cephem-4-carboxylic acid shown in formula (I). The invention particularly provides the method for preparing the 7-beta-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-buteneacyl] amino-3-hydroxymethyl-3-cephem-4-carboxylic acid shown in the formula (I) by a hydrolysis reaction of 7-beta-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-buteneacyl] amino-3-acetyloxymethyl-3-cephem-4-carboxylic acid shown in formula (II) under an alkaline condition. Through use of the method, reaction steps ate reduced, the operation is convenient, and the preparation cost is reduced.

Description

technical field [0001] The present invention relates to the preparation method of cefcapene proxetil intermediate in the field of medicine and chemical industry, specifically, the present invention relates to 7β-[(Z)-2-(2-tert-butoxycarbonylaminothiazol-4-yl)-2-butan Enenoyl]amino-3-hydroxymethyl-3-cephem-4-carboxylic acid (formula 1) preparation method. Background technique [0002] Cefcapene pivoxil is a third-generation oral cephalosporin antibiotic developed by Shionogi Co., Ltd. of Japan, which was launched in 1997. A large number of clinical application practices show that this product has a broad antibacterial spectrum and strong antibacterial activity. [0003] There are many reports on the process route of cefcapene pivoxil. [0004] JP19850067280, GB2173194, US 4731361, BE 904517, the process route reported by US 4731361 are as follows: [0005] [0006] J. Antibiot. 47, 466 (1994) reported the process route as follows: [0007] [0008] In Route 1 and ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D501/34C07D501/04
Inventor 贾春荣王宗玉刘军
Owner CHONGQING CHANGJIE MEDICINE CHEM
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