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Method for recovering candesartan cilexetil intermediate mother liquor

A technology of candesartan cilexetil and recovery method, which is applied in the field of candesartan cilexetil intermediate mother liquor, can solve the problems of inability to directly recycle mother liquor, high impurity content, waste of resources, etc., achieve cheap raw materials and avoid by-products Diester impurity, avoid interference effect

Active Publication Date: 2021-09-28
珠海润都制药股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] Candesartan tert-butyl ester is an important intermediate in the front end of the synthesis of candesartan cilexetil. During production, by-products will be produced during the synthesis of candesartan cilexetil: diester impurities and decomposition impurities. The chemical structure of the diester impurities is , the chemical structure of the decomposed impurity is , Candi-tert-butyl ester, diester impurities and decomposed impurities exist in the mother liquor for the preparation of candi-tert-butyl ester, and the content of impurities is relatively high, so the mother liquor cannot be directly recycled. In the existing process, the mother liquor is generally directly discharged as waste water. Cause waste of resources and increase costs
No document discloses how to recycle the candi tert-butyl ester mother liquor that contains above-mentioned impurity in the prior art

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0017] (1) Take 100 grams of concentrated candi tert-butyl ester mother liquor, add 200ml of dichloromethane and 50ml of water, 9g of potassium carbonate, 13g of Boc anhydride, and react at 25°C for 8 hours. After the reaction was completed, the layers were separated and washed. The organic layer was concentrated to give crude product. Add 250mL of methanol to the crude product, heat to dissolve, cool to room temperature to crystallize, and filter to obtain 16.8g of candi-tert-butyl ester, and the filtrate is used in the next reaction. The purity is 99.1%, and the yield is 82%.

[0018] (2) Concentrate the filtrate in step (1), add 30ml of dichloromethane, 30ml of water, add 3g of sodium hydroxide, and react at room temperature for 12 hours. After the reaction is completed, adjust the pH=2 to obtain 30.1g of 3-nitrophthalic acid , with a purity of 98.3% and a yield of about 83%.

[0019] (3) Dissolve the 3-nitrophthalic acid obtained in step (2) in 100mL ethanol solution co...

Embodiment 2

[0022] (1) Take 100 grams of concentrated candi tert-butyl ester mother liquor, add 200ml of dichloromethane and 50ml of water, 9g of potassium carbonate, 13g of Boc anhydride, and react at 25°C for 8 hours. After the reaction was completed, the layers were separated and washed. The organic layer was concentrated to give crude product. Add 250mL of ethanol to the crude product, heat to dissolve, cool to room temperature to crystallize, and filter to obtain 16.6g of candi-tert-butyl ester, and the filtrate is used for the next reaction. The purity is 99.3%, and the yield is 81%.

[0023] (2) Concentrate the filtrate in step (1), add 30ml of dichloromethane, 30ml of water, add 3g of sodium hydroxide, and react for 12 hours. After the reaction is completed, adjust the pH=2 to obtain 30.0g of 3-nitrophthalic acid. The purity is 98.3%, and the yield is about 83%.

[0024] (3) Dissolve the 3-nitrophthalic acid obtained in step (2) in 100mL ethanol solution containing 20g sulfuric...

Embodiment 3

[0027] (1) Take 100 grams of concentrated candi-tert-butyl ester mother liquor, add 200 mL of tetrahydrofuran and 50 mL of water, 9 g of potassium carbonate, and 13 g of Boc anhydride, and react at 25 ° C for 8 hours. After the reaction was completed, the layers were separated and washed. The organic layer was concentrated to give crude product. Add 250mL of methanol to the crude product, heat to dissolve, cool to room temperature for crystallization, and filter. 16.1 g of tert-butyl candiester was obtained, and the filtrate was used for the next reaction. The purity is 99.4%, and the yield is 78%.

[0028] (2) Concentrate the filtrate in step (1), add 30ml tetrahydrofuran, 30ml water, add 3g sodium hydroxide, react for 12 hours, adjust pH=2 after the reaction is completed, and obtain 30.2g of 3-nitrophthalic acid with a purity of 98.9 %, the yield is about 83%.

[0029] (3) Dissolve the 3-nitrophthalic acid obtained in step (2) in 100mL ethanol solution containing 20g sul...

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Abstract

The invention provides a recovery method of candesartan cilexetil intermediate mother liquor. The candesartan cilexetil intermediate mother liquor obtained in real production comprises candesartan tert-butyl ester, candesartan tert-butyl ester decomposition impurities and candesartan tert-butyl ester diester impurities; and the mother liquor is not treated in conventional production procedures and is directly treated as waste liquor, so resources are wasted and cost is increased. The method for recovering the mother liquor provided by the invention can recover candesartan cilexetil in the mother liquor, convert decomposed impurities and diester impurities into candesartan cilexetil for recovery, and recover more than 90% of substances in the mother liquor, so the production cost of candesartan cilexetil is greatly reduced. According to the recovery method, interference of diester impurities can be avoided when the decomposed impurities are recycled, and generation of byproduct diester impurities is avoided as much as possible when the diester impurities are recycled; and operation is easy and convenient, and raw materials are low in price, so the method is suitable for industrial production and popularization.

Description

technical field [0001] The invention relates to the field of synthesis of pharmaceutical chemicals, in particular to a method for treating the mother liquor of candesartan cilexetil intermediate. Background technique [0002] Candesartan cilexetil is the prodrug of candesartan, which is rapidly decomposed into the active metabolite candesartan in the body. Candesartan is a selective angiotensin IIAT receptor antagonist, which is suitable for the treatment of primary Sexual hypertension. The chemical name of candesartan cilexetil is 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl ]-1H-benzimidazole-7-carboxylic acid-1-[[(cyclohexyloxy)carbonyl]oxy]ethyl ester, the chemical structural formula is: . [0003] Candesartan tert-butyl ester is an important intermediate in the front end of the synthesis of candesartan cilexetil. During production, by-products will be produced during the synthesis of candesartan cilexetil: diester impurities and decomposition impuri...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C231/02C07C231/10C07C233/54C07C201/12C07C205/57C07C263/00C07C265/12
CPCC07C231/02C07C231/10C07C201/12C07C263/00C07C233/54C07C205/57C07C265/12Y02P20/55
Inventor 范志雄周文祥肖双喜祁红林
Owner 珠海润都制药股份有限公司
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