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Cephalosporin nucleus derivative compound, cephaene onium salt compound prepared from same, and method for preparing cefpiramide sulfate from cephalosporin nucleus derivative compound and cephaene onium salt compound

A technology for cefepizole sulfate and compound, which is applied in the field of preparing cefepizole sulfate and cephem onium salt compounds, and achieves the effects of mild reaction conditions, three-waste treatment and easy three-waste

Inactive Publication Date: 2013-07-31
YANTAI BAOHUA BIO TECH +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The overall idea of ​​the method is similar to the Japanese patent JP Ping 4-173792, and there is also the problem of purification of the compound

Method used

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  • Cephalosporin nucleus derivative compound, cephaene onium salt compound prepared from same, and method for preparing cefpiramide sulfate from cephalosporin nucleus derivative compound and cephaene onium salt compound
  • Cephalosporin nucleus derivative compound, cephaene onium salt compound prepared from same, and method for preparing cefpiramide sulfate from cephalosporin nucleus derivative compound and cephaene onium salt compound
  • Cephalosporin nucleus derivative compound, cephaene onium salt compound prepared from same, and method for preparing cefpiramide sulfate from cephalosporin nucleus derivative compound and cephaene onium salt compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] Embodiment 1, the first step: 7β-amino-3-hydroxymethyl-3-cephalosporin-4-carboxylic acid ( II ) synthesis: put 20 ml of methanol and 20 ml of water into a 100 ml three-neck flask, add 6 g of 7-ACA, cool to -40°C, add 1.76 g of sodium hydroxide in 5 ml of aqueous solution dropwise, after the addition, keep stirring After 30 minutes, adjust the pH to 1-2 with 15% hydrochloric acid, stir for 2 hours, filter with suction, wash the filter cake with water, and dry it in vacuum at 40 degrees to obtain 4.5 grams of white solid with a yield of 90% and a purity of 98.7%;

[0043] 1 H-NMR (DMSO-d 6 )d 3.45 (1H,d, J=18Hz), 3.55 (2H,d,J=18Hz),4.18 (1H, d, J=13.6Hz) 4.23 (1H,d, J=13.6Hz), 4.72 (1H ,d, J=4.8Hz), 4.92 (1H,d, J=4.8Hz),6.25 (2H,brs)

[0044] The second step: 7β-[2-(2-formylaminothiazol-4-yl)-2-(methoxyiminoacetamide)]-3-hydroxymethyl-3-cephem-4-carboxylic acid Synthesis of (III): Put 40 ml of tetrahydrofuran and 20 ml of water into a 200 ml three-neck flask, add 4 g...

Embodiment 2

[0052] Embodiment 2, the first step is with embodiment 1;

[0053] The second step: 7β-[2-(2-formylaminothiazol-4-yl)-2-(methoxyiminoacetamide)]-3-hydroxymethyl-3-cephem-4-carboxylic acid Synthesis of (III): Put 30 ml of acetonitrile and 20 ml of water into a 200 ml three-necked flask, add 4 g of the compound (II) synthesized in the first step, add dropwise saturated sodium bicarbonate solution to pH=7-8, and cool to 0-5°C, add 4.0 grams of active ester in batches, while adding, use saturated sodium bicarbonate solution to control pH = 7-8, after the addition, slowly heat up to about 40°C, stir for 6 hours, filter, add 30 ml of water to the filtrate , cooled to about 5°C, adjusted the pH to 1-2 with 10% hydrochloric acid, stirred for 8 hours after dripping, filtered with suction, washed with ice water, and dried in vacuum at 30°C to obtain 6.6 grams of light yellow solid with a yield of 87% and a purity of 95 %;

[0054] The third step: 7β-[2-(2-formylaminothiazol-4-yl)-2-(m...

Embodiment 3

[0057] Embodiment 3, the first step is with embodiment 1;

[0058] The second step: 7β-[2-(2-formylaminothiazol-4-yl)-2-(methoxyiminoacetamide)]-3-hydroxymethyl-3-cephem-4-carboxylic acid Synthesis of (III): Put 20 ml of N,N-dimethylformamide and 20 ml of water into a 200 ml three-necked flask, add 3 g of the compound (II) synthesized in the first step, and add a saturated sodium bicarbonate solution dropwise to pH=7-8, cooled to 0-5°C, added 4.0g of active ester in batches, controlled pH=7-8 with saturated sodium bicarbonate solution while adding, slowly raised the temperature to about 50°C after adding, stirred and reacted for 4h , filter, add 30 ml of water to the filtrate, cool to about 5°C, adjust the pH to 1-2 with 10% hydrochloric acid, stir for 8 hours after dripping, filter with suction, wash with ice water, and vacuum-dry at 30°C to obtain 6.5 g of light yellow solid , yield 86%, purity 95%;

[0059] The third step: 7β-[2-(2-formylaminothiazol-4-yl)-2-(methoxyimino...

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Abstract

The invention discloses cephalosporin nucleus derivative compound and cephaene onium salt compound prepared from the cephalosporin nucleus derivative compound, which are respectively intermediates for synthesizing cefpiramide sulfate, and a method for preparing the cefpiramide sulfate from the two intermediates, namely preparing 7beta-[2-(2-alkanol aminothiazol-5-yl)-2-methoxyimino acetamid]]-3-[3-alkanol amino-2-(2-alkanol oxy ethyl)-1-pyrazol onium]methyl-3-cephem-4-carboxylate (IV) by coupling 7beta-[2(2-alkanol aminothiazol-5-yl)-2-methoxyimino acetamid]]-3-(hydrocarbon sulfonate)-3-cephem-4-carboxylic acid (I) serving as a raw material with 5-alkanol amino-2-(2-alkanol oxy ethyl)-1-pyrazol, and then converting to obtain the cefpiramide sulfate. The method has the advantages of mild reaction conditions, short steps, cheap raw materials, industrial production, no special reagents, simple process and easy amplification.

Description

Technical field: [0001] The invention belongs to the field of cephalosporin antibiotic drug synthesis, and more specifically relates to a cephem onium salt compound prepared from a cephalosporin derivative compound and a method for preparing cefpirazole sulfate by using the two compounds. technical background: [0002] The preparation of cefpirazole sulfate has been seen in the Chinese patent (88106644.3) and Japanese patent JP Ping 4-173792 reported by Sakane Kazuo and Kawazui Koji of Fujisawa Pharmaceutical Co., Ltd. in Japan; the Chinese patent applications of Meng Hong et al. Chinese patent application (200710035488.1) by Huang Pengmian et al. [0003] Chinese patent 88106644.3 uses 7β-tert-butoxycarbonylamino-3-chloromethyl-3-cephalosporin 4-carboxylic acid benzhydryl ester as the starting material, and is mixed with 5-formylamino-2-(2-formyl Oxyethyl)-1-pyrazole coupling reaction to obtain the three-position substituted product, and then react with a-(2-formylaminothi...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D501/34C07D501/46C07D501/04
Inventor 陈锦春赵国华金海珠殷军港付学军
Owner YANTAI BAOHUA BIO TECH
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