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Preparation method of candesartan cilexetil

A technology of candesartan cilexetil and sartan medoxomil, applied in the field of chemistry, can solve problems such as excessive dosage and types, high cost and environmental protection, increase solvent residue, etc., and achieves less dosage, low production cost, and product yield. and excellent product purity

Active Publication Date: 2015-12-16
山西皇城相府药业股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The low-temperature reaction conditions and cumbersome column chromatography purification of this step bring costs to large-scale production; and the amount and types of solvents are too much, which not only increases the residual solvent in the product, but also is not conducive to environmental protection
The candesartan cilexetil crude product that the 3rd step obtains still needs through silica gel column chromatography, uses ethanol / water mixed solvent recrystallization again at last, finally just can obtain the qualified candesartan cilexetil crude drug of purity (candesartan cilexetil purity Greater than 98.5%), yield is about 81% (the total yield of above-mentioned three-step reaction 70%-80%); Above-mentioned loaded down with trivial details operation brings high cost and environmental protection problem to large-scale production equally

Method used

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  • Preparation method of candesartan cilexetil
  • Preparation method of candesartan cilexetil
  • Preparation method of candesartan cilexetil

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0054] Example 1 A kind of preparation method of candesartan cilexetil

[0055] 1. Candesartan (10kg) and dichloromethane (100kg) are added in the reactor, cooled to 15°C, slowly drip triethylamine (4.5kg); after the dropwise addition, the temperature of the reaction system rises to 23°C, Add triphenylchloromethane (7kg) in batches; After addition, keep the temperature of the reaction system at 23° C., and react for 3.5 hours; TLC monitoring (developing agent dichloromethane:methanol=10:1 (V / V), R f =0.78) After the reaction is complete, add 0.1mol / L HCl30L at one time (system pH=5.4), then slowly add 5L9mol / LHCl to pH=2.2; let it stand, separate the water layer and the organic layer, and use 60L saturated saline for the organic layer After washing, move it into a vacuum kettle, and recover dichloromethane under reduced pressure; add 65L of ethanol to the residue in the kettle, raise the temperature to 45°C and stir for 3 hours until a large amount of white solid precipitate...

Embodiment 2

[0075] Example 2 A kind of preparation method of candesartan cilexetil

[0076] 1. Candesartan (10kg) and dichloromethane (100kg) are added in the reactor, cooled to 10°C, slowly drip triethylamine (4.5kg); after the dropwise addition, the temperature of the reaction system rises to 21°C, Add triphenylchloromethane (7kg) in batches; Add, keep reaction system temperature 21 ℃, react for 4 hours; TLC monitoring (developing agent dichloromethane:methanol=10:1 (V / V), R f =0.78) After the reaction is complete, add 0.1mol / L HCl at one time (system pH=5.2), then slowly add 9mol / L HCl dropwise to adjust to pH=2.2; let stand, separate the water layer and the organic layer, and use 60L saturated salt for the organic layer After washing with water, move it into a vacuum kettle, and recover dichloromethane under reduced pressure; add 65L of ethanol to the residue in the kettle, raise the temperature to 40°C and stir for 3 hours until a large amount of white solids are precipitated, stop...

Embodiment 3

[0089] Example 3 A kind of preparation method of candesartan cilexetil

[0090] 1. Candesartan (10kg) and dichloromethane (100kg) are added in the reactor, cooled to 13°C, slowly drip triethylamine (4.5kg); after the dropwise addition, the temperature of the reaction system rises to 25°C, Triphenylchloromethane (7kg) was added in batches; the addition was completed, and the temperature of the reaction system was kept at 25°C for 4 hours of reaction; TLC monitoring (developing agent dichloromethane:methanol=10:1 (V / V)) after the reaction was complete, Add 0.1mol / L HCl at one time to make the system pH = 6, then slowly add 9mol / L HCl dropwise to adjust to pH = 2.6; let it stand, separate the water layer and the organic layer, wash the organic layer with 60L saturated saline, and then transfer it to a vacuum kettle. Recover dichloromethane under reduced pressure; add 65L of ethanol to the residue in the kettle, raise the temperature to 50°C and stir for 3 hours until a large am...

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Abstract

The invention provides a preparation method of candesartan cilexetil. The preparation method comprises steps I-IV. The step I concretely comprises the following substeps of adding candesartan and dichloromethane in a reaction container; slowly and dropwise adding triethylamine at the temperature of 10-15 DEG C; raising the temperature of a reaction system to 21-25 DEG C after dropwise adding of the triethylamine is fnished; adding triphenylchloromethane in batches; reacting for 3-4 hours; adding 0.1 mol / L HCl at one step after reaction is complete and adjusting pH (potential of hydrogen) to be 5-6; then slowly and dropwise adding 9 mol / L HCl and adjusting pH to be 2-3; leaving standstill; separating a water layer and an organic layer; adding saturated salt water in the organic layer to wash the organic layer; leaving standstill to achieve a layering effect; separating out the organic layer; performing decompress concentration on the organic layer to remove the dichloromethane; adding absolute ethyl alcohol in residual viscous substances; raising temperature to 45-50 DEG C; stirring for 3 hours; stopping heating after a large amount of white solids are separated out; reducing to room temperature; performing suction filtration; washing filter cakes with ethyl alcohol; and drying to obtain trityl candesartan.

Description

technical field [0001] The invention belongs to the field of chemistry, and in particular relates to a preparation method of candesartan cilexetil. Background technique [0002] Candesartan cilexetil, the chemical name is (±)-1-(cyclohexyloxycarbonyloxy)ethyl-[2-ethoxy-1-[[2'-(1H-tetrazolyl-5 ) biphenyl-4-methyl]-1H-benzimidazole-7] carboxylate, the structural formula is as shown in 1. [0003] [0004] Candesartan cilexetil is an angiotensin II receptor antagonist with significant blood pressure lowering effect. It was jointly developed and marketed by Takeda of Japan and Astra of Sweden in 1997. In 2010, among the global "sartan" drugs, candesartan occupied a market share of 17.84%, second only to valsartan. [0005] The prior art discloses various synthetic routes of candesartan cilexetil. Among them, the synthetic route disclosed in the Chinese invention patent application with the publication number CN1666989A and the name "New Process for the Preparation of Cande...

Claims

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Application Information

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IPC IPC(8): C07D403/10
CPCC07D403/10
Inventor 张建国赵荷英
Owner 山西皇城相府药业股份有限公司
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