Crystalline acid salts of cefdinir and process for preparing cefdinir using same

A technology of cefdinir and crystalline acid, which is applied in the field of preparing cefdinir and can solve the problems of low purity and poor stability

Inactive Publication Date: 2004-07-14
HANMI SCI CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, acid addition salts formed as intermediates in this process are amorphous loose substances with poor stability and low purity

Method used

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  • Crystalline acid salts of cefdinir and process for preparing cefdinir using same
  • Crystalline acid salts of cefdinir and process for preparing cefdinir using same
  • Crystalline acid salts of cefdinir and process for preparing cefdinir using same

Examples

Experimental program
Comparison scheme
Effect test

reference example 1

[0035] Reference Example 1: Preparation of 7β-[(Z)-2-(2-aminothiazol-4-yl)-2-trityloxyiminoacetamido]-3-vinyl-3-cephalosporin (Cephem) -4-Carboxylic acid·p-TsOH·2DMAC

[0036] 8.0 grams of 7-amino-3-vinyl-3-cephalosporin-4-carboxylic acid and 21.5 grams of (Z)-(2-aminothiazol-4-yl)-2-trityloxyiminoacetic acid 2- Benzothiazole thioate was suspended in 80 ml of N,N-dimethylacetamide, and 16.8 ml of tri-n-butylamine was added thereto. Then, the mixture was stirred for 1 hour while maintaining a temperature of 15-20°C. 240 ml of diethyl ether was added thereto and stirred for 30 minutes, then filtered through cellite. To the filtrate was added 20.2 g of p-toluenesulfonic acid monohydrate dissolved in 40 ml of methanol, and the resulting solution was stirred at room temperature for 2 hours. After adding 160 ml of diethyl ether thereto, the resulting mixture was further stirred at room temperature for 1 hour, cooled to 0-5°C, stirred for 1 hour and filtered. The precipitate thus...

Embodiment 1

[0039] Example 1: Preparation of 7β-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-vinyl-3-cephalosporin-4-carboxylic acid·H 2 SO 4

[0040]40 g of 7β-[(Z)-2-(2-aminothiazol-4-yl)-2-trityloxyiminoacetamido]-3-vinyl-3 obtained in Reference Example 1 - Cephalo-4-carboxylic acid · p-TsOH · 2DMAC was suspended in 200 mL of acetonitrile. 20 milliliters of 90% formic acid and 6.0 milliliters of 98% sulfuric acid were added thereto, and the reaction was maintained at a temperature of 15-20° C. for 20 hours. The precipitate thus obtained was filtered and washed sequentially with 100 ml of acetonitrile and 100 ml of diethyl ether, and then dried to obtain 18.2 g (yield: 91%) of the title compound as a pale yellow crystalline solid.

[0041] HPLC purity: 99.9%

[0042] E isomer: 0.08%

[0043] Melting point: 180°C (decomposition)

[0044] IR (cm -1 , KBr): 3391, 3225, 3116, 1774, 1651, 1526, 1164, 1042, 877, 672, 589, 570

[0045] H-NMR (δ, DMSO-d 6 ): 3.62, 3.85 (2H, ...

Embodiment 2

[0050] Example 2: Preparation of 7β-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-vinyl-3-cephalosporin-4-carboxylic acid·CH 3 SO 3 h

[0051] 100 g of 7β-[(Z)-2-(2-aminothiazol-4-yl)-2-trityloxyiminoacetamido]-3-vinyl-3 obtained in Reference Example 1 - Cephalo-4-carboxylic acid · p-TsOH · 2DMAC was suspended in 200 mL of acetonitrile. Add 40 milliliters of 85% formic acid and 18.5 milliliters of methanesulfonic acid therein, and then maintain the temperature of 20-25 DEG C for 20 hours. The precipitate thus obtained was filtered and washed sequentially with 100 ml of acetonitrile and 100 ml of diethyl ether, and then dried to obtain 43.9 g (yield: 88%) of the title compound as a pale yellow crystalline solid.

[0052] HPLC purity: 99.8%

[0053] E isomer: 0.12%

[0054] Melting point: 210°C (decomposition)

[0055] IR (cm -1 , KBr): 3285, 3231, 1775, 1684, 1636, 1527, 1356, 1195, 1145, 1043, 782, 590

[0056] H-NMR (δ, DMSO-d 6 ): 2.37 (3H, s, CH 3 S), 3....

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Abstract

High purity cefdinir is prepared in a high yield by a process comprising the steps of: treating a cefdinir intermediate with a formic acid-sulfuric acid mixture or a formic acid-methanesulfonic acid mixture to obtain a crystalline salt of cefdinir and reacting the crystalline salt with a base in a solvent.

Description

technical field [0001] The present invention relates to cefdinir crystalline salts, their preparation method, and the method of using the salt to prepare cefdinir Background technique [0002] In the preparation of the cephalosporin antibiotic cefdinir, the deprotection reaction of carboxy-protected cefdinir is usually carried out in a strongly acidic medium such as trifluoroacetic acid (US Patent No. 4,559,334). However, this strongly acidic treatment step produces undesirable by-products, including the E-isomer (trans) of cefdinir; therefore, a number of methods have been developed to remove the contaminant E-isomer. For example, the process disclosed in International Publication WO 98 / 45299 involves converting crude cefdinir into a dicyclohexylamine salt, removing impurities, and reconverting the purified salt into cefdinir. However, this multi-step process is inefficient and gives low productivity. [0003] U.S. Patent No. 4,935,507 discloses a process for the preparat...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07B61/00C07D501/00C07D501/14C07D501/22
CPCC07D501/00C07D501/22
Inventor 李宽淳张永佶金弘先朴哲玄朴柯胜金哲庆
Owner HANMI SCI CO LTD
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