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Key intermediate of telmisartan, synthesis method thereof and method for synthesizing telmisartan by intermediate

A technology of telmisartan and a synthetic method, applied in directions such as organic chemistry, can solve problems such as unfavorable analysis judgment and central control, high price, unfavorable product separation and purification, etc.

Active Publication Date: 2011-05-11
NANTONG SHIMEIKANG PHARMA CHEM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But this technique still needs to use N-methyl o-phenylenediamine (or its hydrochloride) that is expensive, industrially difficult to produce, and pollutes greatly as raw material, and when preparing amide intermediate 4, will inevitably generate iso The conformation 4' is not conducive to the analysis and judgment of the reaction and the central control, and is also not conducive to the separation and purification of the product

Method used

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  • Key intermediate of telmisartan, synthesis method thereof and method for synthesizing telmisartan by intermediate
  • Key intermediate of telmisartan, synthesis method thereof and method for synthesizing telmisartan by intermediate
  • Key intermediate of telmisartan, synthesis method thereof and method for synthesizing telmisartan by intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0057] Example 1: N-(2-aminophenyl)-1-((2′-cyanobiphenyl-4-yl)methyl)-4-methyl-2-propyl-1H-benzimidazole- Preparation of 6-Carboxamide (Compound 6a).

[0058] In a 1000ml four-necked flask, add 50g (0.122mol) 1-((2′-cyanobiphenyl-4-yl)methyl)-4-methyl-2-propyl-1H-benzimidazole-6- Carboxylic acid (5), 300ml of dichloroethane and 200ml of thionyl chloride were heated to 80°C, refluxed for 4 hours, evaporated to dryness under reduced pressure, and the residue was dissolved in 200ml of dichloromethane for the next amide reaction.

[0059] Add 26g (0.244mol) of o-phenylenediamine, 300ml of dichloromethane and 49g (0.488mol) of triethylamine into a 1000ml four-neck flask, control the temperature below 10°C and add the acid chloride solution in one step dropwise, after the addition is complete, stir for 3h , add 400ml of water, separate the liquids, add 1000ml of water and 100ml of hydrochloric acid to the organic phase for extraction, adjust the pH value of the aqueous phase to 9 w...

Embodiment 2

[0062] Example 2: N-(2-aminophenyl)-1-((2′-cyanobiphenyl-4-yl)methyl)-4-methyl-2-propyl-1H-benzimidazole- Preparation of 6-Carboxamide (Compound 6a).

[0063] In a 1000ml four-necked flask, add 50g (0.122mol) 1-((2′-cyanobiphenyl-4-yl)methyl)-4-methyl-2-propyl-1H-benzimidazole-6- Carboxylic acid (5), 15g (0.139mol) of triethylamine, 300ml of tetrahydrofuran, stirring and dissolving, under the protection of nitrogen, lower the temperature to below 5°C, add 13g of methyl chloroformate dropwise, and keep the temperature below 10°C for 3 hours. Then, 26 g (0.241 mol) of o-phenylenediamine was added to the flask, 22 g (0.204 mol) of triethylamine was added dropwise under ice-cooling, and the mixture was reacted at room temperature for 4 h under nitrogen protection. Aftertreatment according to the method of Example 1, the product N-(2-aminophenyl)-1-((2'-cyanobiphenyl-4-yl)methyl)-4-methyl-2-propyl- 1H-benzimidazole-6-carboxamide 55.1g, yield 90.5%, detection parameters are as fol...

Embodiment 3

[0066] Example 3: 4'-[(4'-methyl-2'-propyl[2,6'-di-1H-benzimidazol]-1'-yl)methyl]-1,1'-link Preparation of Benzene-2-carbonitrile (Compound 6).

[0067] In a 1000ml three-necked flask, add 50g (0.1mol) N-(2-aminophenyl)-1-((2′-cyanobiphenyl-4-yl)methyl)-4-methyl-2-propane Base-1H-benzimidazole-6-carboxylic acid amide and 300ml (4.5mol) of glacial acetic acid, heated up to 120°C, refluxed for 4h, cooled to room temperature, concentrated to dryness under reduced pressure, added 500ml of water to the residue to dilute, Adjust the pH value to 9 with ammonia water, precipitate a white solid, filter and dry to obtain the product 4'-[(4'-methyl-2'-propyl[2,6'-di-1H-benzimidazole]-1 '-yl)methyl]-1,1'-biphenyl-2-carbonitrile 47.2g, yield 98%, detection parameters are as follows:

[0068] HNMR1 (CDCl 3 ): 1.01(t, 3H), 1.80(m, 2H), 2.14(s, 3H), 2.84(t, 2H), 5.22(s, 2H), 6.99~7.93(m, 14H);

[0069] MS (M+1): 482.33.

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Abstract

The invention discloses a key intermediate of telmisartan. A chemical name of the key intermediate is 4'-[(4'-methyl-2'propyl[2,6'-bi-1H-benzimidazole]-1'-yl) methyl], and the key intermediate has a structural formula (6) shown below. The invention also discloses a synthetic method for the key intermediate of the telmisartan and a method for synthesizing the telmisartan by the intermediate. A newprocess for synthesizing the telmisartan by the intermediate thereof has the advantages of low-cost and readily available materials, mild reaction condition, low production cost, high yield and quality and the like.

Description

technical field [0001] The invention belongs to the technical field of chemical synthesis, and in particular relates to a key intermediate of an antihypertensive drug telmisartan, a synthesis method thereof and a method for synthesizing telmisartan from the intermediate. Background technique [0002] Telmisartan, an angiotensin II receptor (AT 1 type) non-peptide antagonists, clinically used in the treatment of hypertension. The chemical name of telmisartan is 4'-[(1,4'-dimethyl-2'-propyl[2,6'-di-1H-benzimidazole]-1'-yl)methyl]- 1,1'-biphenyl-2-carboxylic acid, molecular formula C 33 h 30 N 4 o 2 , the structural formula is shown in 1. [0003] [0004] EP502314 discloses the preparation method of telmisartan at the earliest, and this method prepares telmisartan by hydrolyzing the tert-butyl ester intermediate of telmisartan. [0005] CN1344712 ​​discloses a method for preparing telmisartan by hydrolyzing the methyl ester intermediate of telmisartan. [0006] WO20...

Claims

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Application Information

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IPC IPC(8): C07D235/18
Inventor 王俊华刘一超王维李云
Owner NANTONG SHIMEIKANG PHARMA CHEM
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