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Synthetic method of 7-amino-3-chloro-3-cephem-4-carboxylic acid

A synthetic method, cephalosporin technology, applied in the field of drug synthesis, can solve the problems of high cost, by-products, and many steps, and achieve the effect of low cost, good quality, and simple operation

Active Publication Date: 2013-11-13
YANCHENG KAIYUAN MEDICINE CHEM
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The synthesis of 7-ACCA is difficult and involves many steps
The Shionogi route has many steps, and the use of trimethyl phosphite, morpholine, p-toluenesulfonyl chloride and bromine causes serious environmental pollution. Ozonation must be carried out at low temperature (-70°C), requiring high operating conditions. The time of passing ozone should also be properly controlled, otherwise other groups may be oxidized and unnecessary by-products will be produced, which will cause trouble for separation
The route of synthesizing 7-ACCA with 7-ACA as a raw material has the disadvantage that the process of reducing compound 5 to compound 6 requires continuous reaction at -10°C for more than 12 hours, and the obtained product contains part of 3-methyl cephalosporins. Step yield is only 55%
There are few steps to synthesize 7‐ACCA from 7‐ACA, but the cost is high and it is not suitable for industrial production
[0013] In summary, since the existing 7‐ACCA synthesis is difficult, there are many steps, and the preparation process is not perfect, it is very meaningful to develop a 7‐ACCA process route suitable for industrial production

Method used

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  • Synthetic method of 7-amino-3-chloro-3-cephem-4-carboxylic acid

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Experimental program
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Effect test

Embodiment 1

[0038] Synthesis of compound 2

[0039] Add 150mL of dichloromethane and 22g of compound 1 (40mmol) to a 250mL four-necked bottle, cool down to -10°C, add 3.83g (44mmol) of morpholine, add 6.4g (40mmol) of liquid bromine dropwise within 30min, and the addition is complete ,-20°C and continued to stir for 30 minutes to obtain a solution of compound 2.

Embodiment 2

[0041] Synthesis of 3‐OH cephalosporin (compound 3)

[0042] Add 32 mL of 8.5% sulfuric acid aqueous solution to the solution of compound 2 to make the pH around 0.7, add 160 mL of methanol and 1.0 g of trioctylmethylammonium chloride, and react at 15°C for 12 hours (monitoring the reaction by TLC). Add 20 mL of water, stir at room temperature for 5 min, separate the liquids, wash the organic phase twice with 50 mL of 2% dilute sulfuric acid solution, extract the water phase with 150 mL of dichloromethane, combine the organic phases, wash with saturated brine, and concentrate the organic phase under reduced pressure at 30°C. phase, after the content becomes viscous, add 80 mL of methanol, heat to dissolve, cool down and crystallize, stir at 0-5°C for 1 hour, filter with suction, and wash the filter cake with 40 mL of ice methanol to obtain 19.5 g of a light yellow solid with a melting point of 141.4-142.7 °C, the yield was 97.5%.

Embodiment 3

[0047] Synthesis of 7‐phenylacetamido‐3‐chloro‐3‐cephronoic acid benzhydryl ester (compound 4)

[0048] Add 120mL of N,N‐dimethylformamide to a 250mL four-neck bottle, add 8.0g of PCl dropwise at 0~5℃3 (58.3mmol), the dropwise addition was completed, stirred and reacted at 20°C for 1h, added 20g (40.0mmol) of 3‐OH cephalosporin prepared in the previous step, and reacted at 20°C for 3h (monitored by TLC). After the reaction is complete, pour the reaction solution into 300 mL of water pre-cooled to below 5°C, stir at 0-5°C for 1 hour, filter with suction, wash the filter cake with aqueous sodium bicarbonate solution and distilled water, and dry under vacuum at 50°C to obtain a yellow solid 7‐ 20.5 g of benzhydryl phenylacetamido-3-chloro-3-cephemate, the melting point is 171.2-172.3°C, and the yield is 98.8%.

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Abstract

The invention discloses a synthetic method of 7-amino-3-chloro-3-cephem-4-carboxylic acid. With ENM compound 1 used as the raw material, the 7-amino-3-chloro-3-cephem-4-carboxylic acid is obtained through bromination, cyclization, chlorination, and finally successive removal of a phenylacetyl group at carbon 7 of the parent structure and a benzhydryl group on a carboxyl group at carbon 4 of the parent structure, both of which are protecting groups. The method is easy for operation and low in cost. The yield rate is up to 92.7%. The produced 7-amino-3-chloro-3-cephem-4-carboxylic acid is white solid powder, with a purity greater than 98.0% and good quality. Thus the method is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of medicine synthesis, and relates to a synthesis method of 7-amino-3-chloro-3-cephalosporin-4-carboxylic acid. Background technique [0002] 7-amino-3-chloro-3-cephalosporin-4-carboxylic acid (7-ACCA for short), English name: 7‐amino‐3‐chloro‐3‐cephem‐4‐carboxylic acid, molecular formula: C 7 h 7 ClN 2 o 3 S, molecular weight: 234.66, appearance is white or off-white crystalline powder, the structure is as follows: [0003] [0004] 7‐ACCA is a key intermediate in the synthesis of the second-generation cephalosporin cefaclor. my country successfully developed cefaclor raw material in the 1990s, but the synthesis of raw material has not yet achieved large-scale industrialization. Domestically produced cefaclor preparations mainly rely on imported foreign raw materials for packaging. The main reason is that 7‐ACCA The synthesis process is not yet mature. Domestic 7‐ACCA is mainly imported from India, ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D501/18C07D501/04
CPCY02P20/55
Inventor 徐波伊正革刘悉承
Owner YANCHENG KAIYUAN MEDICINE CHEM
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