Method for preparing 7-phenylacetyl amino-3-allyl-4-cefazolin acid p-methoxybenzyl acetate

A technology of p-methoxybenzyl ester and phenylacetamide, which is applied in the field of preparation of cephalosporin pharmaceutical intermediates, can solve the problems of high manufacturing cost, large toxic and side effects, high production cost, etc., to reduce the cost of raw materials and speed up the reaction speed , the effect of reducing production costs

Active Publication Date: 2016-11-09
湖北凌晟药业股份有限公司
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  • Abstract
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  • Claims
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Problems solved by technology

[0004] In Chinese patent CN102030762A, it is reported that chloroform is used as the reaction solvent, GCLE first reacts with sodium iodide and triphenylphosphine, then adds sodium hydroxide solution to react, and after separating the water layer, adds isopropanol and excess acetaldehyde Reaction, isopropanol is used as a crystallization solvent to prepare p-methoxybenzyl 7-phenylacetamido-3-propenyl-4-cephenoic acid. This process uses chloroform as a solvent, which has relatively large toxic and side effects. Sodium iodide Expensive and not recycled. Isopropanol is used as a crystallization solvent. Since isopropanol and water azeotrope, it is not easy to recycle, and the product manufacturing cost is high
In Chinese patent CN1694888A, it is reported that with dichloromethane as the reaction solvent, GCLE reacts with sodium iodide and triphenylphosphine to undergo quaternary phosphine reaction, then adds sodium hydroxide solution for reaction, and after separating the water layer, adds DMF and excess Anhydrous acetaldehyde reaction, isopropanol is used as the crystallization solvent to prepare 7-phenylacetamido-3-propenyl-4-cephenoic acid p-methoxybenzyl ester, and the DMF waste water produced in the preparation process is not easy to handle. And there is the same sodium iodide as the Chinese patent CN102030762A, which is not recycled and isopropanol is difficult to recover.
[0005] To sum up, in the known process of preparing 7-phenylacetamido-3-propenyl-4-cephenoic acid p-methoxybenzyl ester from GCLE, expensive sodium iodide is used without recycling, resulting in The production cost is high; isopropanol cannot be recycled and used mechanically as a crystallization solvent, and DMF wastewater is not easy to treat. problems that need to be studied in depth

Method used

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  • Method for preparing 7-phenylacetyl amino-3-allyl-4-cefazolin acid p-methoxybenzyl acetate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] (1) Mix 30.75g (0.063mol) of compound Ⅰ 7-phenylacetamido-3-chloromethyl-4-cephenoic acid p-methoxybenzyl ester, 8.0g (0.077mol) of sodium bromide, 2.04g (0.012 mol) Potassium iodide, 19.8g (0.075mol) triphenylphosphine were successively added to the mixed solution of 185mL methylene chloride and 125mL water, the pH of the reaction process was controlled by adding 2mol / L hydrochloric acid to be 2-3, stirred evenly, and heated to reflux After reacting for 2 hours, compound III was obtained, and the reaction progress was monitored by HPLC (when the compound I decreased below 0.5%, the reaction was terminated).

[0027] (2) After 2 hours, the reaction is basically completed, and the layers are statically separated. The temperature of the organic layer and the dichloromethane layer is lowered to 0-5°C, and 100mL of sodium hydroxide aqueous solution with a mass concentration of 3% is added dropwise, and the temperature is controlled at 5-10°C. The addition was controlled wit...

Embodiment 2

[0030]After the reaction in step (2) of Example 1 is completed, add 25 mL of water, 185 mL of dichloromethane, 0.8 g of sodium bromide, and 0.2 g of potassium iodide to the aqueous layer of step (2) of separation and recovery, and then add 30.75 g (0.063 mol ) p-methoxybenzyl 7-phenylacetamido-3-chloromethyl-4-cephemate, 19.8 g (0.075 mol) of triphenylphosphine. The pH of the reaction process is controlled to be 2-3 by adding 2 mol / L hydrochloric acid, and the mixture is stirred evenly; the temperature is raised to reflux for 2 hours, and the reaction process is monitored by HPLC. After 2 hours, the reaction was basically completed, and the layers were static and separated, and the organic phase was cooled to 0-5 ° C. The subsequent operations were carried out according to the method of Example 1, and 24.5 g of compound V 7-phenylacetamido-3-propene was obtained as a white solid. The yield of p-methoxybenzyl-4-cephemic acid was 81.4%, the purity was 97.3%, and the Z / E ratio wa...

Embodiment 3

[0032] According to the feeding ratio and operation method of Examples 1 and 2, the process of step (2) water layer application is investigated respectively. Add a small amount of activated carbon to decolorize and filter the water layer obtained in step (2) each time, and apply it 5 times. The experimental results are shown in the table below.

[0033]

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Abstract

The invention discloses a method for preparing 7-phenylacetyl amino-3-allyl-4-cefazolin acid p-methoxybenzyl acetate, and relates to the technical field of preparation of cephalosporin medical intermediates. The method comprises the following steps that 1, a compound I, sodium bromide, potassium iodide and triphenylphosphine react in a mixed solution of dichloromethane and water, and a compound III is obtained; 2, after the reaction in the step 1 is finished, a water layer in the step 1 is separated out, alkali liquor is dropwise added into an organic layer in the step 1 for reacting, and a compound IV is obtained; 3, after the reaction in the step 2 is finished, a water layer in the step 2 is separated and recycled and circularly used for the reaction in the step 1, and the addition of sodium bromide and potassium iodide is reduced; a solvent and acetaldehyde are added into an organic layer in the step 2 for a Wittig reaction, and a compound V is prepared. According to the method, after the alkali liquor is added to generate the compound IV, the water phase can be used for circulated to be applied to the next reaction, use of sodium bromide and potassium iodide is saved, and the production cost is reduced.

Description

technical field [0001] The invention relates to the technical field of preparation of cephalosporin pharmaceutical intermediates. Background technique [0002] 7-Amino-3-propenyl-4-cephalosporin (7-APCA) is the mother nucleus for the production of cefprozil. The preparation methods reported in the literature include: 1. Starting from 7-aminocephalosporanic acid (7-ACA), protected by an organosilane reagent, iodized, and reacted with acetaldehyde under strong alkali anhydrous conditions; 2. Prepared with 7-ACA Phenylacetamido-3-chloromethyl-4-cephronoic acid p-methoxybenzyl ester (GCLE) is used as raw material, prepared by quaternization, propenylation, and removal of 4-carboxyl and 7-amino protecting groups respectively. Although the first preparation route has easy-to-obtain raw materials and short reaction steps, the reaction system is required to be anhydrous, and the proportion of the product E and related substances are too large. The industrial production of 7-APCA mo...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D501/22C07D501/04
CPCC07D501/04C07D501/22
Inventor 门万辉金联明
Owner 湖北凌晟药业股份有限公司
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