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Preparation method of azilsartan

A technology of molar ratio, methyl carboxylate, applied in the field of preparation of drugs for treating hypertension, can solve the problems of increased risk, unpublished, and high synthesis cost, and achieves reduction of production cost and cycle, emission and treatment cost, and process. mild effect

Inactive Publication Date: 2012-11-07
WENZHOU PEOPLES HOSPITAL
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0003] In 1996, the US5583141 patent reported that azilsartan methyl ester was used as a raw material, and after the last step of hydrolysis, azilsartan was directly obtained, but the specific method and the specific process before it were not published
The PCT2006015134 patent report in 2006 used 2-carboxy-3-nitro-methyl formate as a raw material to synthesize the intermediate 1-[(2`-cyanobiphenyl-4- base) methyl]-2-ethoxybenzimidazole-7-methyl carboxylate; the technology adopted in this patent is similar to the previous one, the thionyl chloride used in the first step, and in the second step The use of sodium azide is a relatively dangerous chemical raw material, which increases the danger of production during use and is not conducive to industrial safety.
The PCT2011145100 patent in 2011 reported using 3-nitrophthalic acid as the starting material to synthesize intermediate 1 through seven steps of esterification, acylation, rearrangement, alkylation, deprotection, reduction, and ring closure. -[(2`-cyanobiphenyl-4-yl)methyl]-2-ethoxybenzimidazole-7-methyl carboxylate; the patent involves a long route, a long process cycle, and many types of raw materials , the synthesis cost is high, and the yield is low, especially for the thionyl chloride used in the second step, and the sodium azide used in the third step, which belong to relatively dangerous chemical raw materials, and increase the production in use. Hazardous, not conducive to industrial safety

Method used

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  • Preparation method of azilsartan
  • Preparation method of azilsartan

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] (1) Methyl ethoxybenzimidazole-7-carboxylate

[0048] Dissolve methyl 2,3-diaminobenzoate (166.18g, 1mol) and tetraethyl orthocarbonate (192.3g, 1mol) in acetic acid (2L), add tetrabutylammonium fluoride (13g, 5%mol), heated up and refluxed for 10 hours, cooled to room temperature, evaporated solvent acetic acid, and the thick product was filtered with water, and the solid was recrystallized with ethanol, and dried to obtain methyl ethoxybenzimidazole-7-carboxylate (202.6 g, yield 92%);

[0049] (2) Synthesis of 2-cyano-4'-bromomethylbiphenyl

[0050] Dissolve 2-cyano-4'-methylbiphenyl (193g, 1mol) in dichloromethane (2L), add N-bromosuccinimide (178g, 1mol) in batches at room temperature, and stir at room temperature for 4 Hours, after the reaction was over, washing with water, distillation, beating with petroleum ether, filtering, and drying to obtain 2-cyano-4'-bromomethylbiphenyl, the crude product did not need to be further purified (243.3g, yield 89.4%);

[0051]...

Embodiment 2

[0056] (1) Methyl ethoxybenzimidazole-7-carboxylate

[0057] Dissolve methyl 2,3-diaminobenzoate (166.18g, 1mol) and tetraethyl orthocarbonate (384.6g, 2mol) in acetic acid (2L), add tetrabutylammonium fluoride (13g, 5%mol), heated up and refluxed for 10 hours, cooled to room temperature, evaporated solvent acetic acid, and the thick product was filtered with water, and the solid was recrystallized with ethanol, and dried to obtain methyl ethoxybenzimidazole-7-carboxylate (204.8 g, yield 93%);

[0058] (2) Synthesis of 2-cyano-4'-bromomethylbiphenyl

[0059] Dissolve 2-cyano-4'-methylbiphenyl (193g, 1mol) in dichloromethane (2L), add N-bromosuccinimide (356g, 2mol) in batches at room temperature, and stir at room temperature for 4 Hours, after the reaction was over, washing with water, distillation, beating with petroleum ether, filtration, and drying to obtain 2-cyano-4'-bromomethylbiphenyl, the crude product did not need to be further purified (244.9g, yield 90%);

[0060...

Embodiment 3

[0065] (1) Methyl ethoxybenzimidazole-7-carboxylate

[0066] Dissolve methyl 2,3-diaminobenzoate (166.18g, 1mol) and tetraethyl orthocarbonate (384.6g, 2mol) in acetic acid (2L), add tetrabutylammonium fluoride (13g, 5%mol), heated up and refluxed for 16 hours, cooled to room temperature, evaporated solvent acetic acid, the thick product was filtered with water, and the solid was recrystallized with ethanol, dried to obtain methyl ethoxybenzimidazole-7-carboxylate (211.4 g, yield 96%);

[0067] (2) Synthesis of 2-cyano-4'-bromomethylbiphenyl

[0068] Dissolve 2-cyano-4'-methylbiphenyl (193g, 1mol) in dichloromethane (2L), add N-bromosuccinimide (356g, 2mol) in batches at room temperature, and stir at room temperature for 8 Hours, after the reaction was over, washing with water, distillation, beating with petroleum ether, filtration, and drying to obtain 2-cyano-4'-bromomethylbiphenyl, the crude product did not need to be further purified (255.8g, yield 94%);

[0069] (3) Sy...

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Abstract

The invention relates to a preparation method of azilsartan, comprising the following steps of: (1) preparing ethoxybenzimidazole-7-methyl carboxylate; (2) preparing 2-cyan-4'-bromomethyl biphenyl; (3) dissolving the ethoxybenzimidazole-7-methyl carboxylate and the 2-cyan-4'-bromomethyl biphenyl into ethanol; adding potassium carbonate to react to obtain 1-[(2'-cyan diphenyl-4-yl)methyl]-2-ethoxybenzimidazole-7-methyl carboxylate; (4) suspending the 1-[(2'-cyan diphenyl-4-yl)methyl]-2-ethoxybenzimidazole-7-methyl carboxylate in water; adding hydroxylamine hydrochloride, sodium hydroxide and tetrabutylammonium fluoride; heating and reflowing, and then cooling; adding the sodium hydroxide and ethyl chloroformate, heating and reflowing to obtain azilsartan methyl ester; and (5) hydrolyzing the azilsartan methyl ester to obtain a product. The preparation method of the azilsartan, disclosed by the invention, has the advantages of being short in process route, high in yield, and safe and reliable; and the purity of the azilsartan obtained by using the method is high.

Description

technical field [0001] The invention belongs to the field of preparation of drugs for treating hypertension, in particular to a preparation method of azilsartan. Background technique [0002] Azilsartan is an angiotensin II receptor antagonist drug for the treatment of hypertension. It is mostly used for the treatment of hypertension and is currently the only angiotensin II receptor antagonist (sartan) drug in the late clinical stage. . The drug was launched by Japan's Takeda Pharmaceutical Company in 2012, and its efficacy in the clinical stage is remarkable. According to the forecast of Thomson Reuters Pharma, a well-known drug intelligence agency, the annual sales of this drug will exceed 300 million US dollars in 2016. The demand for such intermediates is increasing day by day. It is an important intermediate for the synthesis of various drugs including fasudil hydrochloride, and it is widely used in antioxidants, foaming agents, cosmetics, emulsifiers, energetic mate...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D413/10
Inventor 陈林
Owner WENZHOU PEOPLES HOSPITAL
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