Method for preparing telmisartan and its intermediate

A compound and reaction technology, applied in the field of preparation of intermediates

Active Publication Date: 2017-07-28
TOPHARMAN SHANGHAI CO LTD +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] The above synthetic methods are two-step, and there is still the possibility of further simplifying the process and reducing the cost

Method used

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  • Method for preparing telmisartan and its intermediate
  • Method for preparing telmisartan and its intermediate
  • Method for preparing telmisartan and its intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0103] Example 1: Preparation of 4'-chloromethylbiphenyl-2-carboxylic acid (II, R=COOH, X=CI)

[0104] Add 4′-methylbiphenyl 2-carboxylic acid (IV) (10 g, 0.047 mol), azobisisobutylcyanide (AIBN) (0.11 g, 1.5 mol%) into chlorobenzene (35 mL), stir, Heat to 90°C, slowly add SO 2 Cl 2 (3.8mL, 0.047mol) of chlorobenzene solution (15mL), after the dropwise addition, stir for 1 hour, and TLC detects that the reaction is over; the reaction solution is naturally cooled to room temperature, and solids are precipitated, then cooled in an ice bath for 1 hour, and suction filtered , the obtained filtrate was washed with toluene (10 mL×2), and dried to obtain white granular solid II (9.5 g, yield 82%). 1 H NMR (300 MHz, DMSO-d6): 12.79 (s, 1H, OH), 7.21-7.75 (m, 8H, ArH), 4.81 (s, 2H, CH2), MS: 246.1.

Embodiment 2

[0105] Example 2: Preparation of 4'-chloromethylbiphenyl-2-carboxylic acid (II, R=COOH, X=Cl)

[0106] Add 4′-methylbiphenyl 2-carboxylic acid (IV) (10 g, 0.047 mol), azobisisobutylcyanide (AIBN) (0.11 g, 1.5 mol%) into chlorobenzene (70 mL), stir, Heated to 80° C., added trichloroisocyanuric acid (10.9 g, 0.047 mol), stirred and reacted for 12 hours, and insoluble matter was filtered off by heat; the reaction solution was naturally cooled to room temperature, and solids were precipitated, and the resulting filtrate was washed with toluene ( 10mL×2), dried to obtain white granular solid II (6g, yield 52%).

Embodiment 3

[0107] Example 3: Preparation of 4'-chloromethylbiphenyl-2-carboxylic acid (II, R=COOH, X=Cl)

[0108] 4'-methylbiphenyl 2-carboxylic acid (IV) (10 g, 0.047 mol) was dissolved in dichloromethane (150 mL), benzoyl peroxide (0.23 g, 2 mol%) was added, and 1.1 equivalent of chlorine was added, The reaction was stirred for 12 hours; saturated aqueous sodium bicarbonate solution was added to the reaction solution for extraction, the organic layer was separated, and the solvent was evaporated to dryness to obtain off-white solid II (6 g, yield 52%).

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PUM

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Abstract

Disclosed is a telmisartan preparation method, characterized in that: 2-n-propyl-4-methyl-6-(1-methyl benzimidazole-2-yl) benzimidazole (compound I) and 4'-halomethyl diphenyl-2-substituted compound (compound II) conduct a nucleophilic substitution reaction to obtain a compound III; when R is COOH, the compound III is telmisartan; and when R is COOR' or CN, the compound III can be hydrolyzed to obtain telmisartan.

Description

technical field [0001] The present invention relates to a kind of preparation method of antihypertensive medicine telmisartan (Telmisartan) and its intermediate, also relate to the preparation method of these intermediates. Background technique [0002] Telmisartan is a new type of non-peptide angiotensin II (AT II) receptor antagonist, clinically used in the treatment of hypertension, its chemical name is 4′-[(1,4′-dimethyl- 2'-Propyl[2,6'-di-1H-benzimidazole]-1'-yl)methyl]-[1,1'-biphenyl]-2-carboxylic acid, the structure is as follows: [0003] [0004] The existing synthetic route of telmisartan mainly uses 3-methyl-4-aminobenzoic acid methyl ester as the starting material to obtain the intermediate through N-acylation, nitration, reduction, cyclization, ester hydrolysis, and condensation reactions. 2-n-propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)benzimidazole (I), I and 4′-bromomethylbiphenyl-2-carboxylic acid tert-butyl The ester (V) undergoes a two-step reaction ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D235/18C07C63/06C07C69/76
CPCC07C69/76C07C63/06C07C63/72C07D235/18
Inventor 吴明军李剑峰陈伟铭田广辉朱富强索瑾沈敬山
Owner TOPHARMAN SHANGHAI CO LTD
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