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Process for synthesizing D-alpha-(6-methyl-4-hydroxyl nicotinamide base)p-hydroxyphenylacetic acid

A technology based on hydroxynicotinamide and p-hydroxyphenyl, which is applied in the field of synthesis of pharmaceutical intermediates, can solve the problems of high equipment and operation requirements, harsh reaction conditions, long synthesis routes, etc., and achieve easy control of process parameters, strong Competitive advantage, the effect of high product yield

Active Publication Date: 2008-10-29
QILU ANTIBIOTICS PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The structure of the compound is complex, the synthetic route is long, and the reaction conditions are harsh, thereby restricting the production of cefpiramide bulk drug
Patent JP 54-030197 introduces a synthetic method of D-α-(6-methyl-4-hydroxynicotinamide) p-hydroxyphenylacetic acid (I) in the form of a reference example, but because its intermediate needs to pass Adding dry hydrogen chloride gas to make hydrochloride has high requirements on equipment and operation, which is not conducive to large-scale industrial production

Method used

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  • Process for synthesizing D-alpha-(6-methyl-4-hydroxyl nicotinamide base)p-hydroxyphenylacetic acid
  • Process for synthesizing D-alpha-(6-methyl-4-hydroxyl nicotinamide base)p-hydroxyphenylacetic acid
  • Process for synthesizing D-alpha-(6-methyl-4-hydroxyl nicotinamide base)p-hydroxyphenylacetic acid

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Effect test

Embodiment 1

[0030] Synthesis (III-a) of embodiment 1.D-p-hydroxyphenylglycine methyl ester

[0031] Add 180g of D-p-hydroxyphenylglycine to 600ml of methanol, add 100ml of concentrated sulfuric acid under rapid stirring, keep warm at 40°C-50°C for 2 hours, slowly transfer the reaction solution into 1200ml of ice water, keep warm at 0°C to 5°C, The pH was adjusted to neutral with ammonia water, the white crystals were filtered out, and washed with 300 ml of purified water to obtain 171 g of D-p-hydroxyphenylglycine methyl ester.

Embodiment 2

[0032] The synthesis (III-b) of embodiment 2.D-p-hydroxyphenylglycine ethyl ester

[0033] Add 150g of D-p-hydroxyphenylglycine to 600ml of ethanol, add 100ml of concentrated sulfuric acid under rapid stirring, keep warm at 40°C-50°C for 3 hours, transfer the reaction solution slowly into 1200ml of ice water, keep warm at 0°C to 5°C, The pH was adjusted to neutral with ammonia water, the white crystals were filtered out, and washed with 300 ml of purified water to obtain 175 g of D-p-hydroxyphenylglycine ethyl ester.

Embodiment 3

[0034] Example 3.D-α-(6-methyl-4-hydroxynicotinamide base) synthesis of methyl p-hydroxyphenylacetate (II-a)

[0035] 122.5 g of 4-hydroxy-6-methylnicotinic acid were put into 600 ml of dichloromethane. Add 97ml of triethylamine dropwise, drop the temperature at -35°C, add 114g of thionyl chloride dropwise, keep it at -25°C to -20°C for 1 hour, add 160g of D-hydroxyphenylglycine methyl ester, keep it at -25°C to -20°C ℃ for 2 hours, and the temperature was raised to 0 ℃ to continue the reaction for 2 hours. Add 400 ml of purified water and stir rapidly for 3 hours, filter out the solid, wash with 200 ml of purified water, and dry in vacuo to obtain 209 g of methyl D-α-(6-methyl-4-hydroxynicotinamide) p-hydroxyphenylacetate.

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Abstract

The invention relates to a method for synthesizing an intermediate of cephalosporins antibiotics cefpiramide, D-alpha-(6-methyl-4-hydroxy nicotinamido)-p-hydroxyphenyl acetic acid. The method comprises the steps of: reacting carboxyl group protected D-p-hydroxyphenyl glycine and anhydride or acyl chloride of 4-hydroxy-6-methylnicotinic acid to obtain acylated product, and hydrolyzing to remove the protecting group to obtain the target product D-alpha-(6-methyl-4-hydroxy nicotinamido)-p-hydroxyphenyl acetic acid. The method has the advantages of easy and feasible operation, and applicability to large scale production.

Description

technical field [0001] The invention relates to a synthesis method of D-α-(6-methyl-4-hydroxynicotinamide) p-hydroxyphenylacetic acid, an acid intermediate at the 7-position of cefpiramide, a cephalosporin antibiotic, and belongs to the technical field of synthesis of pharmaceutical intermediates . Background technique [0002] The chemical name of cefpiramide (cefpiramide) is (6R, 7R)-7-[(R)-2-(4-hydroxy-6-methyl-3-pyridinecarbonylamino)-2-(p-hydroxyphenyl)acetyl Amino]-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4,2,0] Oct-2-ene-2-carboxylic acid. Its structural formula is: [0003] [0004] Cefpiramide is a third-generation cephalosporin antibiotic jointly developed by Sumitomo Pharmaceutical Co., Ltd. and Yamanouchi Pharmaceutical Co., Ltd. It was first listed in Japan in 1985 and has been included in the American, Japanese, British and European Pharmacopoeias. It is characterized by broad antibacterial spectrum and bactericidal power, st...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/82
CPCY02P20/55
Inventor 赵振华董付敏王勇进
Owner QILU ANTIBIOTICS PHARMA
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