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Synthesis path of Timisatem

A technology of telmisartan and synthetic method, which is applied in the fields of drug combination, cardiovascular system diseases, organic chemistry, etc., can solve the problems of reduced yield, unfavorable large-scale industrial production, and many impurities, and achieve high yield and product quality Improved effect

Inactive Publication Date: 2002-04-17
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In this preparation method, the carboxyl group of 4'-bromomethylbiphenyl-2-carboxylic acid is first protected with tert-butyl, and then reacted with I, but 4'-bromomethylbiphenyl-2-carboxylic acid tert-butyl In the process of operation, the ester is unstable, especially under acidic conditions, and the tert-butyl group is easy to remove, making the reaction difficult to control, with more impurities and lower yield, which is not conducive to large-scale industrial production

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0017] Example 1 4'-[(1,4'-dimethyl-2'-propyl[2,6'-di-1H-benzimidazol]-1'yl)methyl]-[1,1' -Biphenyl]-2-Carboxylic acid methyl ester (IVa)

[0018] I (30.4g, 0.10mol), methyl 4'-bromomethylbiphenyl-2-carboxylate (32.0g, 0.105mol), K 2 CO 3 Fine powder (or other inorganic bases as mentioned above) (41.4 g, 0.3 mol) was mixed with DMF (or other solvents as mentioned above) (600 ml), and reacted at room temperature (20-30° C.) for 10 hours. The reaction solution was poured into ice water (1000g), extracted with ethyl acetate (500ml×3), the organic phases were combined, washed with water (500ml×2), and washed with saturated brine (500ml). After drying over anhydrous sodium sulfate, it was concentrated under reduced pressure to a small volume, and petroleum ether was added dropwise with stirring until solids were precipitated. Crude IVa was obtained (42.9 g, 81.3%). It can be directly used in the next reaction without purification. The analytical sample was recrystallized from ...

Embodiment 2

[0019] Example 2 4'-[(1,4'-dimethyl-2'-propyl[2,6'-di-1H-benzimidazol]-1'-yl)methyl]-[1,1 '-Biphenyl]-2-carboxylic acid methyl ester (IVa)

[0020] I (30.4g, 0.10mol), methyl 4'-bromomethylbiphenyl-2-carboxylate (32.0g, 0.105mol), sodium ethoxide (or other organic bases as previously described) (20.4g, 0.3 mol) was mixed with dry DMF (or other solvents as mentioned above) (500ml), and reacted at 60°C for 8 hours. Aftertreatment is with embodiment 1.

Embodiment 3

[0021] Example 3 4'-[(1,4'-dimethyl-2'-propyl[2,6'-di-1H-benzimidazol]-1'-yl)methyl]-[1,1 '-biphenyl]-2-carboxylic acid (III)

[0022] Take IVa (26.4g, 0.05mol) obtained in the previous step, mix with glacial acetic acid (150ml) and concentrated hydrochloric acid (150ml) (or other acids as mentioned above), and react at 100°C for 5 hours. Concentrate under reduced pressure to remove most of the mixed acid, and the residue is slowly poured into ice (500g), cooled with cold saturated K 2 CO 3 The pH of the aqueous solution was adjusted to neutral, and the precipitate was filtered out and washed with water to obtain crude product III, which was recrystallized from DMF to obtain III (20.1 g, 78.4%, HPLC>99.0%). mp 261-263°C. 1HNMR (CDCl 3 ): 1.05 (3H,t,CH 2 CH 3 ), 1.88 (2H, m, CH 2 CH 2 CH 3 ), 2.79 (3H, s, ArCH 3 ), 2.92 (2H, t, CH 2 CH 2 CH 3 ), 3.86 (3H, s, NCH 3 ), 5.44 (2H, s, ArCH 2), 7.17-7.82 (14H, m, ArH). MS (EI) m / z: 515 (M+1), 469 (base peak), 442, 30...

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Abstract

The present invention relates to the preparation of Timisatan as one active component for antihypertensive medicine. The carboxylic ester derivative is first obtained through the nucleophilic substitution reaction between some intermediate and 4'-bromomethyl biphenyly-2-carboxylic ester, and then hydrolyzed to eliminnate protection radical and to obtain the destination product. In the technological process of the present invention, methyl radical and ethyl radical are used as protecting radical, and this facilitates and stabilizes the preparation of 4'-bromomethyl biphenylyl-2-methyl carboxylic ester and 4'-bromomethyl biphenylyl-2-ethyl carboxylic ester, and results in easy to control reaction with the intermediate, less impurity, easy elimination of protecting radical and high product yield and quality.

Description

technical field [0001] The invention relates to a preparation method of a novel antihypertensive drug telmisartan (Telmisartan). [0002] Telmisartan is a novel non-peptide angiotensin II (ATII) receptor antagonist. Its structure is as follows: Background technique [0003] 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 undergoes nucleophilic substitution reaction to obtain compound II, which is then hydrolyzed to the final product Telmisartan (III) (Ries U, Mihm G, Narr B et al., J Med Chem, 1993, 36: 4040-4051). In this preparation method, the carboxyl group of 4'-bromomethylbiphenyl-2-carboxylic acid is first protected with tert-but...

Claims

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Application Information

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IPC IPC(8): A61P9/12C07D235/14
Inventor 沈敬山李剑峰严铁马李卉君嵇汝运
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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