CN102558148A

CN102558148A - Synthesis process of lansoprazole important intermediate

Info

Publication number: CN102558148A
Application number: CN2010106075408A
Authority: CN
Inventors: 赵海桥; 范兴山; 王飞龙; 穆子齐; 苏贵勇
Original assignee: SHANDONG FANGMING PHARMACEUTICAL CO Ltd
Current assignee: SHANDONG FANGMING PHARMACEUTICAL CO Ltd
Priority date: 2010-12-15
Filing date: 2010-12-15
Publication date: 2012-07-11

Abstract

The invention discloses a preparation method of a lansoprazole important intermediate, and particularly discloses preparation of 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]mercapto]-1H-benzimidazole by neutralizing 2-chloromethyl methyl ether-3-methyl-4-(2,2,2-trifluoroethoxy)pyridine hydrochloride with an alkali and directly condensing with 2-mercaptobenzimidazole. According to a process, the product yield can be over 98 percent, the melting point is 151-153 DEG C, the yield is high, and the quality is good. The method has a simple process, is safe and environmentally-friendly, and can be applied to industrial production of 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]mercapto]-1H-benzimidazole.

Description

A kind of synthesis technique of lansoprazole important intermediate

Technical field

The present invention relates to the pharmaceutical intermediate synthesis technical field, especially lansoprazole important intermediate 2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridyl]-methyl] sulfydryl]-1H-benzoglyoxaline is synthetic.

Background technology

[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridyl]-methyl] sulfydryl]-the 1H-benzoglyoxaline is the precursor of novel proton pump inhibitor lansoprazole to lansoprazole important intermediate 2-, and these article generate lansoprazole through oxidation.Lansoprazole can promptly change sulfenic acid into through the parietal cell film under acidic conditions brings into play drug effect with time sulfonyl derivative, the bacteriostatic activity of HP is risen to 4 times of omeprazole.Lansoprazole gastric acid inhibitory secretion, impel that ulcer healing is faster than other proton pump inhibitors, effect is stronger, the time length is longer, prototype medicine and metabolite thereof do not have in vivo to be accumulated.

Making solvent with acetone among the Chinese patent CN200910000899.6, is that catalyst reaction makes with the Soiodin, and yield is 95%, and fusing point is 150～152 ℃.The present invention avoids the use of organic solvent, in basic soln, is directly made by 2-chloromethyl-3-methyl-4-(2,2, the 2-trifluoro ethoxy) pyridine hydrochloride and 2-mercaptobenzimidazole condensation, and yield is more than 98%, and fusing point is 151～153 ℃.This law was both nontoxic, harmless, safety and environmental protection, had improved yield and quality simultaneously again.

Summary of the invention

The object of the present invention is to provide a kind of simple and easy to control, yield is high, free of contamination preparation the pharmaceutical intermediate 2-[[[3-methyl-4-(2 that is applicable to large-scale industrial production; 2,2-trifluoro ethoxy)-the 2-pyridyl]-methyl] sulfydryl]-synthesis technique of 1H-benzoglyoxaline.

Technical scheme of the present invention is:

(1) in the water of certain temperature, adds 2-chloromethyl-3-methyl-4-(2,2, the 2-trifluoro ethoxy) pyridine hydrochloride, stir and make dissolving half a hour;

(2) in above-mentioned solution, drip alkaline solution, transfer to the appropriate pH value;

(3) add 2-mercaptobenzimidazole in batches, and certain temperature reaction 2～3 hours;

(4) suction filtration, washing promptly gets 2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridyl]-methyl] sulfydryl]-1H-benzoglyoxaline to neutral after the drying.

Embodiment:

Embodiment 1: in the 1000ml three-necked bottle, add the 600ml purified water, be warming up to 45 ℃, whipped state adds 2-chloromethyl-3-methyl-4-(2; 2, the 2-trifluoro ethoxy) pyridine hydrochloride 55.2g, stirred 30 minutes; Dripping 10% sodium hydroxide solution adjust pH is 11, divides 5 times and adds 2-mercaptobenzimidazole 34.5g, 45 ℃ of reactions 3 hours; Suction filtration, washing is drying to obtain these article 70.3g to neutral.Yield is 99.6%.Fusing point is 151～153 ℃.

Embodiment 2: in the 1000ml three-necked bottle, add the 500ml purified water, be warming up to 50 ℃, whipped state adds 2-chloromethyl-3-methyl-4-(2; 2, the 2-trifluoro ethoxy) pyridine hydrochloride 55.2g, stirred 30 minutes; Dropwise 5 % potassium hydroxide solution adjust pH is 12, divides 5 times and adds 2-mercaptobenzimidazole 35g, 50 ℃ of reactions 2.5 hours; Suction filtration, washing is drying to obtain these article 69.8g to neutral.Yield is 98.9%.Fusing point is 151～153 ℃.

Claims

1. lansoprazole important intermediate 2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridyl]-methyl] sulfydryl]-1H-benzoglyoxaline is synthetic: in the water of certain temperature, add 2-chloromethyl-3-methyl-4-(2; 2, the 2-trifluoro ethoxy) pyridine hydrochloride, stir and make dissolving half a hour; Drip alkaline solution, transfer to the appropriate pH value, add a certain proportion of 2-mercaptobenzimidazole in batches; And certain temperature reaction 2～3 hours, suction filtration, washing is to neutral; Promptly get 2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridyl]-methyl] sulfydryl]-1H-benzoglyoxaline after the drying.

2. according to the process of claim 1 wherein, alkaline solution is meant 1%～30% sodium hydroxide or potassium hydroxide solution.

3. according to the process of claim 1 wherein, the appropriate pH value is meant more than 10.

4. according to the process of claim 1 wherein, certain temperature is meant 40～60 ℃.

5. according to the process of claim 1 wherein, certain proportion is meant that the mol ratio of 2-chloromethyl-3-methyl-4-(2,2, the 2-trifluoro ethoxy) pyridine hydrochloride and 2-mercaptobenzimidazole is 1.0: 1.0～1.3.