CN108752328B

CN108752328B - Simple method for synthesizing azilsartan

Info

Publication number: CN108752328B
Application number: CN201810839137.4A
Authority: CN
Inventors: 李正义; 殷乐; 刘大伟; 肖唐鑫; 孙小强
Original assignee: Changzhou University
Current assignee: Changzhou University
Priority date: 2018-07-27
Filing date: 2018-07-27
Publication date: 2020-04-24
Anticipated expiration: 2038-07-27
Also published as: CN108752328A

Abstract

The invention relates to the field of medicine, and discloses a method for simply and conveniently synthesizing azilsartan, which comprises the steps of mixing 1- [ (2' - (hydroxycarbamimidoyl) [1, 1-biphenyl ] -4-yl) methyl ] -2-ethoxy-1H-benzimidazole-7-methyl formate with a carbonylation reagent, using water as a solvent, and reacting at 25 ℃ to obtain an O-acylated intermediate; mixing the O-acylated intermediate with an alkaline reagent, taking water as a solvent, carrying out reflux reaction at 100 ℃, filtering, adjusting the pH of the filtrate to 3-4 by using 1mol/L diluted HCl, carrying out suction filtration, and recrystallizing the solvent to obtain the azilsartan. The invention combines two steps of reaction of cyclization and hydrolysis into one step under the action of alkali, obtains the azilsartan in two steps in a water phase, reduces the synthesis steps, is simple and convenient to operate, takes water as a solvent, and has high industrial application value.

Description

Simple method for synthesizing azilsartan

Technical Field

The invention belongs to the field of medicines, and particularly relates to a simple method for synthesizing azilsartan.

Background

Hypertension is one of the most major public health problems in the world today, and only the hypertensive patients in China reach 2.7 hundred million and are in an increasing trend every year, and now become one of the countries with the most serious hypertension harm in the world, and the disease is seriously threatening and affects the daily life of people. Azilsartan (Azilsartan) as a new generation angiotensin II receptor antagonist, and the improvement of the production process and the high requirement of the product quality determine the core competitiveness of the pharmaceutical industry in the field.

US patent 5243054 reports that 1- [ (2'- (ethoxyimino) [1, 1-biphenyl ] -4-yl) methyl ] -2-ethoxy-1H-benzimidazole-7-methyl formate is used as a raw material, and reacts with ethyl chloroformate in DMP (2, 6-lutidine) to generate 1- [ (2' - [ (ethoxycarbonylimino) ethoxy ] [1, 1-biphenyl ] -4-yl) methyl ] -2-ethoxy-1H-benzimidazole-7-methyl formate, and the latter is subjected to cyclization and hydrolysis steps to obtain azilsartan; or 3-amino-2- [ (2' -cyanobiphenyl-4-yl) methyl ] ethyl aminobenzoate is taken as a raw material and reacts with ethyl chloroformate in the presence of triethylamine under the alkaline condition to generate 1- [ (2' - [ N ' - [ (ethoxycarbonyl) oxy ] amidino ] [1, 1-biphenyl ] -4-yl) methyl ] -2-ethoxy-1H-benzimidazole-7-methyl formate, and the latter is cyclized and hydrolyzed to obtain azilsartan. The preparation of the starting raw materials selected by the method is relatively difficult and complicated, and a large amount of organic solvent is used, so that the prior art has the defects of low atom economy and the like.

The existing process for synthesizing azilsartan uses a large amount of expensive reagents and organic solvents, the atom economy of the reaction is not high, and the great value of azilsartan in clinical medical treatment is considered, so that the development of a new process for synthesizing azilsartan, which is simple, convenient, economic, efficient, environment-friendly, safe and high-quality, is necessary.

Disclosure of Invention

The technical problem to be solved by the invention is to provide a simple and convenient method for synthesizing azilsartan. Preparing and separating an O-acylation intermediate by using water as a solvent and 1- [ (2' - (hydroxycarbamimidoyl) [1, 1-biphenyl ] -4-yl) methyl ] -2-ethoxy-1H-benzimidazole-7-methyl formate and a carbonylation reagent as raw materials; and then cyclizing and hydrolyzing the O-acylated intermediate under the action of alkali to prepare the azilsartan. The reaction equation is as follows:

a method for simply and conveniently synthesizing azilsartan comprises the following specific operation steps:

(1) mixing 1- [ (2' - (hydroxycarbamimidoyl) [1, 1-biphenyl ] -4-yl) methyl ] -2-ethoxy-1H-benzimidazole-7-methyl formate and a carbonylation reagent in a molar ratio of 1: 1-3, reacting for 0.5-3H at 25 ℃ by using water as a solvent, stopping the reaction, standing, filtering, collecting a filter cake, and washing with clear water to obtain an O-acylation intermediate;

(2) mixing the O-acylated intermediate and an alkaline reagent at a molar ratio of 1: 1-5, taking water as a solvent, refluxing for 1-5 h at 100 ℃, stopping reaction, cooling, standing, filtering, acidifying the filtrate with 1mol/L diluted HCl until the pH value is 3-4, performing suction filtration, collecting a filter cake, and recrystallizing with the solvent to obtain the azilsartan.

The carbonylation reagent in the step (1) is one of methyl chloroformate, ethyl chloroformate, isopropyl chloroformate, tert-butyl chloroformate and phenyl chloroformate.

The alkaline reagent in the step (2) is inorganic alkali: NaOH, KOH, Ca (OH)₂、Na₂CO₃、NaHCO₃、K₂CO₃、KHCO₃Or Cs₂CO₃(ii) a Or an organic base: NaOMe, Et₃N, DMAP, DBU, DBN, DIPEA, DABCO or pyridine.

The solvent for recrystallization in the step (2) is one or more of methanol, ethanol, acetone, tetrahydrofuran, acetonitrile, 1, 4-dioxane, toluene and xylene.

The reaction time of the step (1) is preferably 2 hours; the molar ratio of methyl 1- [ (2' - (hydroxycarbamimidoyl) [1, 1-biphenyl ] -4-yl) methyl ] -2-ethoxy-1H-benzimidazole-7-carboxylate to carbonylating agent is preferably 1: 2.5.

The reaction time in the step (2) is preferably 3 h; the molar ratio of the O-acylated intermediate to the basic reagent is preferably 1: 3.

The invention has the beneficial effects that: 1- [ (2' - (hydroxyl amidino) [1, 1-biphenyl ] -4-yl) methyl ] -2-ethoxy-1H-benzimidazole-7-methyl formate and a carbonylation reagent are adopted as raw materials to carry out carbonylation, and cyclization and hydrolysis are carried out under the action of alkali to prepare azilsartan in two steps.

Detailed Description

The present invention will be described in detail with reference to examples, but the present invention is not limited to these examples.

Example 1

The first step is as follows: 1- [ (2' - (hydroxycarbamimidoyl) [1, 1-biphenyl ] -4-yl) methyl ] -2-ethoxy-1H-benzimidazole-7-carboxylic acid methyl ester (5mmol), phenyl chloroformate (12.5mmol) and 30mL of water were charged in a 100mL two-necked flask and reacted at 25 ℃ for 2 hours. After the reaction was complete, the reaction was allowed to stand, filtered, the filter cake was collected and washed with clean water (2X 20mL) to give the O-acylated intermediate in 93% yield.

The second step is that: adding an O-acylated intermediate (5mmol), NaOH (15mmol) and 30mL of water into a 100mL two-neck flask, carrying out reflux reaction at 100 ℃ for 3h, cooling, standing, filtering, adjusting the pH of the filtrate to 3-4 by using 1mol/L diluted HCl, and recrystallizing the solid obtained by suction filtration by using ethanol to obtain azilsartan, wherein the purity is 99.5%, and the yield is 84%.

A white solid; mp:201-204 ℃;¹H NMR(300MHz,DMSO-d₆):δ＝13.15(bs,1H,NH),12.5(bs,1H,OH),7.68-7.63(m,3H,ArH),7.56-7.53(m,2H,ArH),7.51-7.45(m,1H,ArH),7.25(d,J＝8.3Hz,2H,ArH),7.21(t,1H,ArH),7.06(d,J＝8.3Hz,2H,ArH),5.67(s,2H,N-CH₂-ArH),4.59(q,2H,OCH₂CH₃),1.38(t,J＝7.1Hz,3H,OCH₂CH₃).¹³C NMR(75MHz,DMSO-d₆):δ＝168.03,159.97,158.75,142.13,141.20,138.21,137.67,132.35,131.77,131.14,130.69,129.35,128.28,127.12,123.98,122.63,121.94,121.17,117.07,66.98,46.84,14.83.

example 2

Referring to the method of example 1, isopropyl chloroformate was used as a starting material in the first reaction step, and the yield of O-acylated intermediate was 90%.

Example 3

Referring to the procedure of example 1,1- [ (2' - (hydroxycarbamimidoyl) [1, 1-biphenyl ] -4-yl) methyl ] -2-ethoxy-1H-benzimidazole-7-carboxylic acid methyl ester and phenyl chloroformate were reacted in a molar ratio of 1:1.5 in the first reaction step, and the yield of the O-acylated intermediate was 65%.

Example 4

Referring to the procedure of example 1,1- [ (2' - (hydroxycarbamimidoyl) [1, 1-biphenyl ] -4-yl) methyl ] -2-ethoxy-1H-benzimidazole-7-carboxylic acid methyl ester and phenyl chloroformate were reacted in a molar ratio of 1:3 in the first reaction step, and the yield of the O-acylated intermediate was 91%.

Example 5

Referring to the method of example 1, in the second reaction step, KOH was used as a basic reagent, and azilsartan was 99.5% pure and 82% in yield.

Example 6

Referring to the method of example 1, the second reaction step is carried out with a molar ratio of the O-acylated intermediate to NaOH of 1:4, and azilsartan has a purity of 99.5% and a yield of 84%.

Example 7

Referring to the method of example 1, when acetonitrile was used as a recrystallization solvent in the second reaction, azilsartan was 99.3% in purity and 81% in yield.

Comparative example 1

Referring to the method of example 1, dimethyl carbonate was used as a raw material in the first reaction step, and the yield of the O-acylated intermediate was 0%.

Among them, methyl 1- [ (2' - (hydroxycarbamimidoyl) [1, 1-biphenyl ] -4-yl) methyl ] -2-ethoxy-1H-benzimidazole-7-carboxylate used in the examples of the present invention can be prepared as follows:

hydroxylamine hydrochloride (60.8mmol), triethylamine (63.2mmol) and 60mL of dimethyl sulfoxide are weighed and added into a 100mL two-neck round-bottom flask, the mixture is stirred and reacted for 30min at normal temperature, 1- [ (2 '-cyanobiphenyl-4-yl) methyl ] -2-ethoxy-1H-benzimidazole-7-methyl formate (6.08mmol) is added into the reaction system to react for 6H at 75 ℃, after the reaction is finished, the reaction system is cooled to room temperature, products in the reaction solution are extracted by dichloromethane, the solvent is removed by reduced pressure distillation, and recrystallization is carried out to obtain 1- [ (2' - (hydroxyamidino) [1, 1-biphenyl ] -4-yl) methyl ] -2-ethoxy-1H-benzimidazole-7-methyl formate, wherein the yield is 35%.

Claims

1. A simple method for synthesizing azilsartan is characterized in that:

(2) mixing an O-acylated intermediate and an alkaline reagent at a molar ratio of 1: 1-5, taking water as a solvent, carrying out reflux reaction at 100 ℃ for 1-5 h, stopping the reaction, cooling, standing, filtering, acidifying the filtrate with 1mol/L of dilute HCl until the pH value is 3-4, carrying out suction filtration, collecting a filter cake, and recrystallizing with the solvent to obtain azilsartan.

2. The simple method for synthesizing azilsartan according to claim 1, wherein: the carbonylation reagent in the step (1) is one of methyl chloroformate, ethyl chloroformate, isopropyl chloroformate, tert-butyl chloroformate and phenyl chloroformate.

3. The simple method for synthesizing azilsartan according to claim 1, wherein: the alkali reagent in the step (2) is inorganic alkali or organic alkali, and the inorganic alkali is NaOH, KOH or Ca (OH)₂、Na₂CO₃、NaHCO₃、K₂CO₃、KHCO₃Or Cs₂CO₃(ii) a The organic base is NaOMe and Et₃N, DMAP, DBU, DBN, DIPEA, DABCO or pyridine.

4. The simple method for synthesizing azilsartan according to claim 1, wherein: the solvent for recrystallization in the step (2) is one or more of methanol, ethanol, acetone, tetrahydrofuran, acetonitrile, 1, 4-dioxane, toluene and xylene.