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Preparation method of 7beta-amino-7lapha-methoxy-3-cephem compound

A compound, methoxy technology, applied in the field of preparation of pharmaceutical raw materials 7β-amino-7α-methoxy-3-cephem compound, can solve the problems of long steps, many steps, low yield, etc., and achieve easy reaction , fewer side reactions, good reaction selectivity

Inactive Publication Date: 2013-07-03
ZHEJIANG NHU CO LTD +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Two, CN101117337A has introduced a kind of with 7-amino-3-cephem compound as raw material, obtains the method for 7β-amino-7α-methoxyl-3-cephem compound through methoxylation, first by dimethyl di Sulfur reacts with chlorine to obtain thiomethyl hypochlorite, and thiomethyl hypochlorite reacts with 7-amino-3-cephem compounds to obtain 7-methylsulfimine-3-cephem compounds. The imine-3-cephem compound obtains the 7β-amino-7α-methoxy-3-cephem compound under aluminum chloride, sodium bicarbonate and methanol. This method has many steps and needs to use dangerous chlorine and secondary Thiomethyl chlorate, low yield
3. The Chinese journal "Chemical Reagents" 2009, 31(2), 146-148 introduced a 7-amino-3-cephem compound as a raw material, which was methoxylated to obtain 7β-amino-7α-methoxy -The method of 3-cephem compound, first use 4-hydroxyl-3,5-di-tert-butyl benzaldehyde to protect 7-position amino to obtain 7-(4-hydroxyl-3,5-di-tert-butylbenzylidene )-3-cephem compound, then 7-(4-hydroxyl) of 7-(4-hydroxyl-3,5-di-tert-butylbenzylidene)-3-cephem compound is obtained by nickel peroxide oxidation Amine-3-cephem compound, the imine-3-cephem compound is added with methanol to add a methoxyl group, and then deprotected with Girard T reagent to obtain 7β-amino-7α-methoxy-3-cephem compound, This synthetic method has lengthy steps and low yield

Method used

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  • Preparation method of 7beta-amino-7lapha-methoxy-3-cephem compound
  • Preparation method of 7beta-amino-7lapha-methoxy-3-cephem compound
  • Preparation method of 7beta-amino-7lapha-methoxy-3-cephem compound

Examples

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Embodiment 1

[0043] Example 1: 7β-amino-7α-methoxy-3(1-methyl-1H-tetrazol-5-ylthiomethyl)-1-oxo-3-cephem-4-carboxylic acid di Preparation of Benzyl Ester

[0044] In a 1000mL three-neck flask with mechanical stirring and a thermometer, add 500mL of dichloromethane, and drop 30.7g (0.05mol) of compound (1a) (R 1 = phenyl, R 2 = 1-methyl-1H-tetrazol-5-ylsulfomethylene R 3 =-CH(C 6 h 5 ) 2 , X=O), add 15.2g (0.15mol) of triethylamine, stir to dissolve, protect with nitrogen, cool to -30°C with a cryogenic bath, add 14.9g (0.05mol) of bis(trichloromethyl)carbonate in batches , control the temperature not higher than -15°C, add in 0.5 to 1 hour, slowly raise the temperature to 0°C for 1 hour and react for 2 hours; after the reaction is completed, cool to -30°C in a low-temperature bath, add methanol 32g (1mol) dropwise in 15 minutes ), continue to react at -20~-10°C for 1 hour; warm up to -5°C, add saturated sodium bicarbonate solution dropwise to pH=7-8; separate the organic layer, and...

Embodiment 2

[0045] Example 2: 7β-amino-7α-methoxy-3(1-methyl-1H-tetrazol-5-ylthiomethyl)-1-oxo-3-cephem-4-carboxylic acid di Preparation of Benzyl Ester

[0046] In a 1000mL three-neck flask with mechanical stirring and a thermometer, add 400mL of dichloromethane, and drop 30.7g (0.05mol) of compound (1a) (R 1 = phenyl, R 2 = 1-methyl-1H-tetrazol-5-ylsulfomethylene R 3 =-CH(C 6 h 5 ) 2, X=O), add pyridine 15.8g (0.2mol), stir to dissolve, nitrogen protection, cool to -25°C with a cryogenic bath, add bis(trichloromethyl)carbonate 19.8g (0.0667mol) in batches, control The temperature is not higher than -10°C, the addition is completed in 0.5 to 1 hour, and the temperature is slowly raised to 5°C for 1 hour to react for 2 hours; after the reaction is completed, cool to -25°C in a low-temperature bath, and add methanol 32g (1mol) dropwise in 15 minutes. Continue to react at -20~-10°C for 1 hour; warm up to -5°C, add saturated sodium bicarbonate solution dropwise to pH = 7-8; separate ...

Embodiment 3

[0047] Example 3: 7β-amino-7α-methoxy-3(1-methyl-1H-tetrazol-5-ylthiomethyl)-1-oxo-3-cephem-4-carboxylic acid di Preparation of Benzyl Ester

[0048] In a 1000mL three-neck flask with mechanical stirring and a thermometer, add 400mL of dichloroethane, and drop 30.7g (0.05mol) of compound (1a) (R 1 = phenyl, R 2 = 1-Methyl-1H-tetrazol-5-ylsulfomethylene R 3 =-CH(C 6 h 5 ) 2 , X=O), add 11.4 g (0.1 mol) of N, N'-dimethylpiperazine, stir to dissolve, protect with nitrogen, cool to -25°C with a cryogenic bath, add bis(trichloromethyl)carbonic acid in batches Ester 19.8g (0.0667mol), control the temperature not higher than -10°C, add in 0.5-1 hour, slowly raise the temperature to 5°C for 2 hours and react for 2 hours; after the reaction, cool to -25°C in a low-temperature bath for 15 minutes Add methanol 32g (1mol) dropwise, continue to react at -10~0°C for 1 hour; warm up to 5°C, add saturated sodium bicarbonate solution dropwise until the pH value = 7-8; separate the orga...

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Abstract

The invention relates to a preparation method of a medical raw material 7beta-amino-7lapha-methoxy-3-cephem compound. Methods in prior arts have the problems of more steps and low yield. According to the 7beta-amino-7lapha-methoxy-3-cephem compound preparation method provided by the invention, a beta-lactam compound is adopted as a raw material, and is subjected to a reaction with bis(trichloromethyl)carbonate under the existence of an organic alkali, such that a iminochloride-beta-lactam compound is produced; methanol is added for alcoholysis, such that the 7beta-amino-7lapha-methoxy-3-cephem compound is produced. The method provided by the invention has the advantages of mild and easy-to-control reaction conditions, high yield, no product of 7alpha-methoxy-7beta-amino-3-cephem compound isomer, and easy separation. With the method, the 7beta-amino-7lapha-methoxy-3-cephem compound product with ultrahigh purity can be obtained.

Description

technical field [0001] The invention relates to a preparation method of a medical raw material 7β-amino-7α-methoxy-3-cephem compound. Background technique [0002] The 7β-amino-7α-methoxy-3-cephem compound is introduced into the side chain at the 7β-amino group, and can be used to synthesize various antibiotics. 7β-Amino-7α-methoxy-3-cephem compound (3) is a key intermediate in the synthesis of cephamycin and oxycephem. Cephamycin products include: cefoxitin, cefmetazole, cefotetan, cefbuperazone, and cefminox. Oxyceph products include: Latamoxef and Fluoxetal. Cephamycin has the effect of resisting the mixed infection of aerobic and anaerobic bacteria and the infection of ESBLs-producing Gram-negative bacteria; the structure of Latamoxef in Oxefef is close to that of Cephamycin antibiotics, but there is an S atom at the 1 position of the mother nucleus Replaced by O atoms, the antibacterial properties are similar to the third-generation cephalosporins, and have good anti...

Claims

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Application Information

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IPC IPC(8): C07D501/18C07D501/04C07D501/16C07D505/06
Inventor 张玉红刘陆平钱洪胜鲁国彬汤泽锛
Owner ZHEJIANG NHU CO LTD
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