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Method for preparing lansoprazole

A technology for lansoprazole and benzimidazole, which is applied in the field of preparation of lansoprazole, can solve the problems of high discharge of three wastes, high environmental protection cost, long reaction steps and the like, and achieves high total yield and easy operation. , the effect of short reaction steps

Active Publication Date: 2018-12-07
迪嘉药业集团股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

In this preparation method, it involves the use of a large number of oxidants (step 1, step 8), strong acid (step 2), strong base (step 3, step 5, step 7), and strong corrosive materials (step 4, step 6) , more three wastes are discharged, the cost of environmental protection is high, and the reaction steps are longer, the total yield is only 15%-20%

Method used

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  • Method for preparing lansoprazole
  • Method for preparing lansoprazole
  • Method for preparing lansoprazole

Examples

Experimental program
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Effect test

Embodiment 1

[0041] (1) Preparation of trifluoroethoxyacrolein (IV)

[0042] Add 7.5 g (75 mmol) trifluoroethanol and 75 mL tetrahydrofuran to a 250 mL reaction flask, cool down to 0 °C, add 3.4 g (30 mmol) potassium tert-butoxide, add dropwise 4.1 g (75 mmol) propynaldehyde, After dropping, the temperature was controlled at 0°C for 15 minutes. After the reaction was complete, 140 mL of water was added, extracted three times with 200 mL of dichloromethane, the organic phases were combined, and concentrated under reduced pressure at 35°C to obtain trifluoroethoxyacrolein with a yield of 92.6% and a GC purity of 98.72%.

[0043] (2) Preparation of benzimidazole-2-sulfenyl chloride (V)

[0044] Add 10.0 g (67 mmol) of 2-mercaptobenzimidazole and 120 mL of chloroform to a 250 mL reaction flask, cool down to 0°C, add 11.9 g (100 mmol) of thionyl chloride dropwise, after dropping, control the temperature at 0°C for reaction 1 h. After the reaction was completed, it was concentrated under redu...

Embodiment 2

[0052] (1) Preparation of trifluoroethoxyacrolein (IV)

[0053] Add 7.5 g (75 mmol) trifluoroethanol and 75 mL tetrahydrofuran to a 250 mL reaction flask, cool down to 0°C, add 1.7 g (15 mmol) potassium tert-butoxide, add dropwise 3.8 g (71 mmol) propiolealdehyde, After dropping, the temperature was controlled at 0°C for 15 minutes. After the reaction was completed, 140 mL of water was added, extracted three times with 200 mL of dichloromethane, the organic phases were combined, dried with 10.0 g of anhydrous sodium sulfate, and concentrated under reduced pressure at 35°C to obtain trifluoroethoxyacrolein, yield: 87.4 %, GC purity: 98.12%.

[0054] (2) Preparation of benzimidazole-2-sulfenyl chloride (V)

[0055] Add 10.0 g (67 mmol) of 2-mercaptobenzimidazole and 120 mL of dichloromethane to a 250 mL reaction flask, cool down to 0°C, add 13.6 g (114 mmol) of thionyl chloride dropwise, after dropping, control the temperature at 0 ℃ for 1 h. After completion of the reaction...

Embodiment 3

[0063] (1) Preparation of trifluoroethoxyacrolein (IV)

[0064] Add 7.5 g (75 mmol) trifluoroethanol and 75 mL tetrahydrofuran to a 250 mL reaction flask, cool down to 0 °C, add 2.0 g (30 mmol) sodium ethoxide, add dropwise 4.1 g (75 mmol) propynaldehyde, dropwise , and the temperature was controlled at 25°C for 15 minutes. After the reaction was completed, 140 mL of water was added, extracted three times with 200 mL of dichloromethane, the organic phases were combined, dried with 10.0 g of anhydrous sodium sulfate, and concentrated under reduced pressure at 35°C to obtain trifluoroethoxyacrolein, yield: 92.6 %, GC purity: 98.50%.

[0065] (2) Preparation of benzimidazole-2-sulfenyl chloride (V)

[0066] Add 10.0 g (67 mmol) of 2-mercaptobenzimidazole and 120 mL of dichloromethane to a 250 mL reaction flask, cool down to 0°C, add 8.0 g (67 mmol) of thionyl chloride dropwise, after dropping, heat up to reflux React for 1 h. After completion of the reaction, concentrate unde...

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Abstract

The invention belongs to the field of medicinal chemistry and in particular relates to a method for preparing lansoprazole. The method disclosed by the invention comprises the following reaction steps: carrying out an addition reaction on acraldehyde and trifluoroethanol to produce a compound IV, chlorinating 2-mercapto benzimidazole to condense with 3-hydroxy-2-butanone, performing rearrangementto produce a compound VI, performing condensation on the compounds IV and VI and ammonia to produce a compound VII, and further oxidizing the compound VII, thereby obtaining the lansoprazole I. The method disclosed by the invention has the advantages that the reaction does not involve strong acids such as sulfuric acid and nitric acid, and emission of three wastes is reduced while convenience is brought to after-treatment; and the reaction step is short, and the total yield is high and can reach 41-62%. The cost per kilogram is one half that of the conventional process, and cheap and high-quality bulk drugs are provided for the preparation.

Description

technical field [0001] The present invention belongs to the field of medicinal chemistry, and in particular relates to a preparation method of Lansoprazole. Background technique [0002] Lansoprazole (chemical name: 2-({[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl}sulfinyl)-1H-benzene and imidazole), which was successfully developed by Japan's Takeda Corporation, and was subsequently launched in France, Japan, and the United States. It is the second proton pump inhibitor to be launched after omeprazole. Its chemical structure is as follows: [0003] [0004] Lansoprazole is an antacid and an anti-ulcer drug. As a new generation of proton pump inhibitors, it binds to the H+-K+-ATPase of the stomach wall and inactivates it, thereby inhibiting gastric acid secretion and affecting basic gastric acid and all Gastric acid secretion caused by stimulants has obvious inhibitory effect, and its inhibitory effect is obviously better than that of H2 receptor blockers. It i...

Claims

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Application Information

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IPC IPC(8): C07D401/12
CPCC07D401/12
Inventor 梁松军王宁宁刘彦东李路路孔令强苗华明蔡亚辉
Owner 迪嘉药业集团股份有限公司
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