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3-cefaclor derivative as well as synthesis method and application thereof in preparation of cefaclor

A synthetic method, the technology of cefaclor, applied in the field of drug synthesis, can solve the problems of no preparation of cefaclor, etc., and achieve the effect of high yield, less reaction steps and stable process

Active Publication Date: 2014-07-09
浙江东邦药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0011] Both patents DE2709292 and DE2725519 also mentioned the similar structure of 3-chlorocephalosporins, but the focus is on researching the ester group protected by Lewis acid cleavage, and it is not really applied to the preparation of cefaclor

Method used

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  • 3-cefaclor derivative as well as synthesis method and application thereof in preparation of cefaclor
  • 3-cefaclor derivative as well as synthesis method and application thereof in preparation of cefaclor
  • 3-cefaclor derivative as well as synthesis method and application thereof in preparation of cefaclor

Examples

Experimental program
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Effect test

Embodiment 1

[0046] Example 1: Typical N-R 1 Preparation of yl-D-phenylglycine (Formula II).

[0047] D-phenylglycine was added to the 4 mol / L aqueous sodium hydroxide solution pre-cooled to 0 °C, and the chloride (R) of the corresponding protecting group was slowly added. 1 Cl) (such as benzyl chloroformate, benzyl chloride or benzyl chloromethyl ether, etc.), add water to dilute after the reaction, filter out insolubles, extract the filtrate with ether, adjust the pH to 3-6 with 5mol / L hydrochloric acid, filter The precipitated solid is recrystallized from a mixed solution of ethyl acetate and n-hexane to obtain the corresponding N-R 1 yl-D-phenylglycine.

Embodiment 2

[0048] Example 2: Typical 7-amino-3-chloro-3-cephem-4-carboxylic acid R 2 Preparation of Esters (Formula III).

[0049] Refer to the preparation method of the precursor compound "7-amino-3-chloro-3-cephem-4-carboxylic acid p-nitrobenzyl ester" of 7-ACCA: Penicillin G is used as the raw material. First use the corresponding R 2 Protecting group chloride (R 2 Cl) (such as benzyl chloride, α-chloroacetophenone or benzyl chloromethyl ether, etc.) protects the carboxyl group on penicillin G, and then oxidizes it to sulfoxide with hydrogen peroxide or peracetic acid. Chlorination and ring expansion are carried out under the action of N-chlorosuccinimide or N-chlorophosphorphthalamide. First ozonated and then reduced to form a hydroxyl group at the 3-position. Then, under phosphorus trichloride, the 3-position is converted into chlorine; then under the action of phosphorus pentachloride and pyridine, the 7-position is alcoholylated to form the hydrochloride of the free amino gr...

Embodiment 3

[0050] Example 3: (6R,7R)-benzyl 7-[(R)-2-(benzylamino)-2-phenylacetamido]-3-chloro-8-oxo-5-thia-1-nitrogen Preparation of Heterobicyclo[4.2.0]oct-2-ene-2-carboxylate (I-2).

[0051] N-benzyl-D-phenylglycine (26.54g, 0.11mol), benzyl 7-amino-3-chloro-3-cephem-4-carboxylate (32.48g, 0.1mol) were added to 300g DMF and stirred 15 minutes. Then, diethyl chlorophosphoric acid (19.00g, 0.11mol) and pyridine (8.70g, 0.11mol) were added, and the reaction was carried out at room temperature (25°C) for about 24 hours. The reaction was followed by TLC or HPLC, and it was confirmed that 7-amino-3-chloro- Benzyl 3-cephem-4-carboxylate was consumed. The reaction solution was concentrated under reduced pressure, diluted with ethyl acetate, washed with acid water, water and sodium chloride aqueous solution successively, the organic layer was concentrated to a volume of about 100 ml, slowly added to 200 g of n-hexane with stirring, and a precipitate was precipitated. After filtration and d...

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Abstract

The present invention discloses 3-chlorocephalosporin derivatives, namely (6R,7R)-7-[(R)-2-amino-2-phenylacetamido]-3-chloro-8-oxo-5-sulfur Hetero-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid derivative, its synthesis method and its application in the preparation of cefaclor, said derivative being the compound of formula I. Cefaclor can be obtained in high yield by deprotecting the compound of formula I through hydrogenation of the "palladium-carbon (Pd-C) / chloroform (CHCl3)" system. The invention provides a preparation method of a compound of formula I, wherein amino-protected D-phenylglycine and 7-amino-3-chloro-3-cephem-4-carboxylate are reacted with a phosphoric acid ester (or phosphorus oxychloride) activator Mixed reaction with the presence of a basic acid-binding agent to obtain the compound of formula I in high yield. (I).

Description

technical field [0001] The invention relates to the technical field of drug synthesis, in particular to 3-chlorocephalosporin derivatives, their synthesis method and their application in the preparation of cefaclor. Background technique [0002] Cefaclor, its English name is Cefaclor, its chemical name is: (6R,7R)-7-[(R)-2-amino-2-phenylacetamido]-3-chloro-8-oxo-5-sulfur Hetero-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid monohydrate, formula C 15 h 14 ClN 3 o 4 S·H 2 O, molecular weight 385.82, structural formula: [0003] . [0004] Cefaclor is the second-generation oral cephalosporin antibiotic created by Eli Lilly and Company of the United States. It was first listed in 1985 under the trade name "Hicero". Its patent expired in 1993. Cefaclor has stronger antibacterial effect than cephalexin and cephradine, is stable to β-lactamase, has low toxicity, and can penetrate the blood-brain barrier. It is suitable for the elderly and children, and has a wide range of...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D501/59C07D501/06C07D501/04
CPCY02P20/55
Inventor 王海平池骋池正明许关煜
Owner 浙江东邦药业有限公司
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