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Preparation method for telmisartan

A technology of telmisartan and methyl, which is applied in the field of preparation of telmisartan, can solve the problems of non-combustible vapor pressure and few application reports of ionic liquids, and achieve mild reaction conditions, convenient recovery and reuse, and simple operation Effect

Inactive Publication Date: 2015-05-13
HENAN NORMAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Compared with traditional organic solvents, ionic liquids have many advantages such as extremely low vapor pressure, non-flammability, good thermal stability and recyclability, but there are few reports on the application of ionic liquids in drug synthesis.

Method used

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  • Preparation method for telmisartan
  • Preparation method for telmisartan
  • Preparation method for telmisartan

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Synthesis of Telmisartan

[0037]

[0038] (1) Synthesis of 3-methyl-4-nitro-benzoic acid methyl ester Ⅲ

[0039] Compound II (181g, 1.00mol) was added to ionic liquid 1-n-butyl-3-methylimidazolium tetrafluoroborate [bmim]BF 4 (800mL), stir, heat to dissolve, introduce HCl gas (prepared from 120g sodium chloride and 100mL concentrated sulfuric acid), remove the airway after 1h, maintain the reflux state for 6h, cool to room temperature, pour into 2500mL ice water, wash with saturated carbonic acid The sodium solution was adjusted to pH = 8, filtered, washed with water until neutral, and dried to obtain light yellow solid III (180 g, yield of 3-methyl-4-nitro-benzoic acid methyl ester 92.3%). Ionic liquid 1-n-butyl-3-methylimidazolium tetrafluoroborate [bmim]BF 4 Recrystallized, mp 81-83°C.

[0040] (2) Synthesis of 3-methyl-4-amino-benzoic acid methyl ester IV

[0041] Compound III (130g, 0.67mol), ionic liquid 1-n-butyl-3-methylimidazolium tetrafluoroborate [bmi...

Embodiment 2

[0056] Effect of Reaction Time on the Yield of Telmisartan

[0057] When telmisartan is synthesized in ionic liquid, other conditions are fixed, only the reaction time is changed, and the influence of different reaction times on the yield of telmisartan is investigated, see figure 1 . Depend on figure 1 It can be seen that when the reaction time is short, the yield is low, and when the reaction time is long, the yield does not increase much, the by-products increase, and the product purity decreases (HPLC mass fraction is only 96.3%). The optimal reaction time should be controlled at about 6 hours, the reaction yield is high, the product purity is high (the HPLC mass fraction of the crude product is 99.1%, the HPLC mass fraction of the refined product is 99.96%), and it is more economical.

Embodiment 3

[0059] The Effect of Reuse Times of Ionic Liquids on the Reaction Yield

[0060] Whether the reaction medium used can be recovered and reused is an important content of "green chemistry". This example examines the reusability of ionic liquids for the synthesis of telmisartan. In the ionic liquid used for the synthesis of telmisartan , add compound IX again, add anhydrous potassium carbonate and 4 ， -Bromomethylbiphenyl-2-methyl carboxylate, heated to 65°C for reaction, this ionic liquid was reused more than 5 times, the results are shown in figure 2 . Depend on figure 2 It can be seen that after 5 repeated uses of ionic liquids, the yield of the product begins to decrease significantly, which indicates that ionic liquids can be recovered and reused effectively, and the reusable performance is good, which is a kind of recyclable green solvent.

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Abstract

The invention discloses a preparation method for telmisartan, and belongs to the technical field of pharmaceutical synthesis. The key points of the technical scheme lie in that in the preparation method for the telmisartan takes ionic liquid as a reaction medium, and 3-methyl-4-nitryl-benzoic acid as a raw material, 2-n-propyl-4-methyl-6- carboxyl benzimidazole is obtained successively through an esterification reaction, a reduction reaction, an acylation reaction, a nitratlon reaction, a reduction reaction and a cyclization reaction, then under the action of a polyphosphoric acid, the 2-n-propyl-4-methyl-6-carboxyl benzimidazole and N-methyl-o-phenlenediamine dihydrochloride are condensed to obtain 2-n-propyl-4-methyl-6-[1-methylbenzimidazole-2-yl] benzimidazole, 2-n-propyl-4-methyl-6-[1-methylbenzimidazole-2-yl] benzimidazole is condensed with 4,-bromine biphenyl-2-carboxylic acid methyl ester, and hydrolysis is carried out to obtain the telmisartan. According to the method, the ionic liquid is used for replacing methanol with larger toxicity in an original technology to be used as the reaction medium, raw materials are easy to obtain, the operation is simple and convenient, the yield is high, the purity of products is high, the residual quantity of an organic solvent is small, and the method is environmentally-friendly and is suitable for industrialized production.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis, and in particular relates to a preparation method of telmisartan. Background technique [0002] Telmisartan (Telmisartan Ⅰ), trade name Micardis, chemical name 4 ， -[[1,4 ， -Dimethyl-2 ， -Propyl[2,6 ， -Di-1hydro-benzimidazole]-1 ， base]methyl]-[1,1 ， -biphenyl]-2-carboxylic acid, is a non-peptide angiotensin II receptor antagonist. It selectively blocks the association of angiotensin II with AT in many tissues 1 Receptor binding, thereby blocking the vasoconstriction and aldosterone secretion caused by angiotensin II, but does not affect other receptor systems in cardiovascular regulation. It was the first to be marketed in the United States in 1999. At present, telmisartan is still in the initial stage of clinical application in my country, and has made rapid progress in recent years, and the market application prospect is broad. Due to the high cost of foreign production processe...

Claims

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Application Information

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IPC IPC(8): C07D235/18
CPCC07D235/18
Inventor 郝二军蒋小涵郭利兵刘玉侠张倩王海霞谢明胜王东超郭海明李恭新
Owner HENAN NORMAL UNIV
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