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Preparation method of telmisartan key intermediate 4 '-methylbiphenyl-2-carboxylate

A technology of biphenyl carboxylate and methyl biphenyl, applied in the field of drug preparation, can solve the problems of few by-products, high cost, complicated operation, etc., and achieve the effect of less by-products, high specificity, and simple operation

Pending Publication Date: 2022-05-06
南京红太阳医药研究院有限公司 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0010] The purpose of the present invention is to solve the defects of low yield of 4'-methylbiphenyl-2-carboxylate, low conversion rate of raw materials or high by-products, complicated operation, high cost and unsuitability for industrialized production in the existing preparation method. , provide a kind of preparation method of telmisartan intermediate 4'-methylbiphenyl-2-carboxylate, the preparation method is simple to operate, the raw material conversion rate is high, the by-product is few, the yield is high, the cost is low, more Suitable for industrial production

Method used

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  • Preparation method of telmisartan key intermediate 4 '-methylbiphenyl-2-carboxylate
  • Preparation method of telmisartan key intermediate 4 '-methylbiphenyl-2-carboxylate
  • Preparation method of telmisartan key intermediate 4 '-methylbiphenyl-2-carboxylate

Examples

Experimental program
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Effect test

Embodiment 1

[0040] Add 38.7g (0.2mol) of 2-cyano-4'-methylbiphenyl and 116g n-butanol to a 1L reaction flask, heat up to 80°C, and add 40.0g (0.4mol) of concentrated sulfuric acid (mass Fraction 98%, the same below); after dropping, heat up to 118°C for reflux reaction, HPLC control, after 4h, 2-cyano-4'-methylbiphenyl reaction ≤ 0.1%, stop the reaction; concentrate under reduced pressure to the remaining The n-butanol is about 38g, lower the temperature to ≤15°C, add 116g of purified water to the system; after adding, stir at room temperature for 1.5h, filter, and dry the filter cake under reduced pressure at 50°C to constant weight to obtain 4′-methyl- 50.7 g of n-butyl 2-biphenylcarboxylate (white solid), molar yield 94.5%.

[0041] Add 40.3g (0.15mol) of n-butyl 4'-methyl-2-biphenylcarboxylate to 200g n-hexane and 33.4g mass fraction 40% hydrobromic acid (0.165mol), then add 0.05g (0.15mmol) TBAB; after the addition, heat up to 60°C under stirring, start to drop 17.0g (0.15mol) of hy...

Embodiment 2

[0043] Add 38.7g (0.2mol) of 2-cyano-4'-methylbiphenyl and 116g of isobutanol to a 1L reaction flask, heat up to 80°C, and add 78.4g (0.784mol) of concentrated sulfuric acid dropwise while stirring; After completion, heat up to 105°C for reflux reaction, controlled by HPLC, after 6 hours, 2-cyano-4′-methylbiphenyl reaction ≤ 0.1%, stop the reaction; concentrate under reduced pressure until the remaining isobutanol is about 38g, cool down to ≤15°C, add 116g of purified water to the system; after addition, stir at room temperature for 1.5h, filter, and dry the filter cake under reduced pressure at 50°C to constant weight to obtain isobutyl 4′-methyl-2-biphenylcarboxylate (White solid) 50.5g, molar yield 94.2%.

[0044] 40.3g (0.15mol) of isobutyl 4'-methyl-2-biphenylcarboxylate was added to 200g of n-hexane and 33.4g of 40% hydrobromic acid (0.165mol), and then 0.15g (0.45mmol) of TBAB was added; After completion, heat up to 60°C under stirring, start to add 34.0g (0.30mol) of ...

Embodiment 3

[0046] Add 38.7g (0.2mol) of 2-cyano-4'-methylbiphenyl and 194g of n-butanol to a 1L reaction flask, heat up to 80°C, and add 40.0g (0.4mol) of concentrated sulfuric acid dropwise while stirring; After completion, the system reacted at 5-10Mpa by controlling the temperature to 150°C, controlled by HPLC, and after 1 hour, the reaction of 2-cyano-4′-methylbiphenyl was ≤0.1%; the reaction was stopped, and concentrated under reduced pressure to the remaining n-butanol It is about 37g, lower the temperature to ≤15°C, add 116g of purified water to the system; after the addition, stir at room temperature for 1.5h, filter, and dry the filter cake under reduced pressure at 50°C to constant weight to obtain 4′-methyl-2-linked 51.1 g of n-butyl benzenecarboxylate (white solid), molar yield 95.3%.

[0047] Add 40.3 g (0.15 mol) of n-butyl 4'-methyl-2-biphenylcarboxylate to 200 g of n-hexane and 33.4 g of 40% hydrobromic acid (0.165 mol), then add 0.125 g (0.45 mmol) of TBAC; After comple...

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Abstract

The invention discloses a preparation method of telmisartan intermediate 4 '-methyl biphenyl-2-carboxylic ester. The preparation method comprises the following steps: heating 2-cyano-4'-methyl biphenyl in the presence of an alcohol compound under an acidic condition, hydrolyzing, and esterifying by a'one-pot method 'to prepare the 4'-methyl biphenyl-2-carboxylic ester; an organic solvent is used as a reaction solvent, 4 '-methyl biphenyl-2-carboxylic ester, hydrogen peroxide and a bromine source are subjected to a bromination reaction under the action of a catalyst, and 4'-bromomethyl biphenyl-2-carboxylic ester is prepared. The method is easy to operate, high in specificity and few in by-product, the residual 4 '-methylbiphenyl-2-carboxylic ester can be controlled to be 0.1% or below, the residual 4', 4 '-dibromomethylbiphenyl-2-carboxylic ester can be controlled to be 0.1% or below, finally, the target product with the purity of 99.3% or above can be prepared under the condition that refining is not needed, the total molar yield reaches 90% or above, and the method is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of medicine preparation, and relates to a preparation method of telmisartan key intermediate 4'-methylbiphenyl-2-carboxylate. Background technique [0002] Telmisartan is a new type of AT antagonist with long-acting, high-efficiency and low-toxicity. It was developed by German Bellinger-Ingelheim Pharmaceutical Company and launched in 1997. It is also a non-peptide angiotensin Ⅱ receptor antagonist, which can selectively and irreversibly block AT1 receptors, but has no effect on other receptor systems, especially those involved in the cardiovascular system. [0003] The chemical name of Telmisartan is: 4′-[4-methyl-6-(1-methyl-1H-benzimidazol-2-yl)-2-propyl-1H-benzimidazol-1-yl Methyl] biphenyl-2-carboxylic acid, its chemical structural formula is as follows: [0004] [0005] 4'-Methylbiphenyl-2-carboxylate is the key intermediate of Telmisartan. At present, the preparation method of 4'-methyl bipheny...

Claims

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Application Information

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IPC IPC(8): C07C67/307C07C69/76
CPCC07C67/307C07C67/22C07C69/76
Inventor 黄双李维思徐强柳贞唐景玉时超史凌云
Owner 南京红太阳医药研究院有限公司
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