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Method for preparing high-purity razole intermediate and medicine by using green technology instead of phosgene, thionyl chloride and other toxic and harmful substances

A technology of thionyl chloride and harmful substances, which is applied in the field of preparation of merazole drugs, and can solve the problems of inability to obtain merazole chloride in purity and yield, potential safety hazards in storage and transportation, and environmental pollution of by-product sulfides. , to achieve good promotion and application prospects, low atom utilization and high yield

Active Publication Date: 2017-08-04
ZHEJIANG UNIV OF TECH +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At the same time, thionyl chloride also has many disadvantages as a reagent: 1) it is liquid at normal temperature, and there are potential safety hazards in storage and transportation; 2) the acidic substances produced by thionyl chloride severely corrode workshop equipment; 3) thionyl chloride Excessive in the reaction process, atom economy is not high, and the by-product sulfide of generation easily pollutes environment, and " three wastes " treatment cost is bigger; The content of chlorinated intermediates is relatively low, and the impurities introduced during the chlorination reaction will have a certain impact on the subsequent reaction, resulting in lansoprazole, esomeprazole, pantoprazole, and levopantoprazole The total heterogeneity of azoles and other azoles increased
Therefore take prazole hydroxylate as raw material, directly use BTC as reagent, can carry out acyl chlorination reaction to hydroxymethyl position, can form chloroformate product and be not pure prazole hydroxylate (as figure 2 Shown), by the report of literature and the verification of experiment, directly add BTC, can't obtain prazole chloride with better purity and yield

Method used

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  • Method for preparing high-purity razole intermediate and medicine by using green technology instead of phosgene, thionyl chloride and other toxic and harmful substances
  • Method for preparing high-purity razole intermediate and medicine by using green technology instead of phosgene, thionyl chloride and other toxic and harmful substances
  • Method for preparing high-purity razole intermediate and medicine by using green technology instead of phosgene, thionyl chloride and other toxic and harmful substances

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0064] In a 500mL three-necked bottle, the Ph 3 PO (43.78g, 157.5mmol) was dissolved in toluene (100mL), BTC (14.84g, 50mmol) was dissolved in toluene (60mL) and put into a 150mL constant pressure dropping funnel, BTC was added dropwise at room temperature, and After completion, the temperature was raised to 60°C; after 4 hours of heat preservation reaction, 2-hydroxymethyl-4-methoxy-3,5-lutidine (25.05g, 150mmol) was dissolved in 75mL of toluene, and at 40°C Added, a white solid was precipitated, after 2 hours of heat preservation reaction, after stopping the reaction, the white solid was obtained by suction filtration, and dried to obtain 32.49g of 2-chloromethyl-4-methoxyl-3,5-lutidine hydrochloride, The product yield is 98%, and the content is 99.92%. After the filtrate is concentrated, Ph is precipitated at a low temperature of 20°C 3 PO, Ph 3 After PO was washed with petroleum ether, suction filtered and dried, the obtained Ph 3 PO repeated application; among them, ...

Embodiment 2

[0066] In a 500mL three-necked bottle, the Ph 3 PO (43.78g, 157.5mmol) was dissolved in toluene (100mL), BTC (14.84g, 50mmol) was dissolved in toluene (60mL) and put into a 150mL constant pressure dropping funnel, BTC was added dropwise at room temperature, and After completion, the temperature was raised to 40°C. After 4 hours of heat preservation reaction, 2-hydroxymethyl-4-methoxy-3,5-lutidine (25.05g, 150mmol) was dissolved in 75mL of toluene, added at 25°C, a white solid was precipitated, and kept After reacting for 8 hours, stop the reaction, obtain a white solid by suction filtration, and dry to obtain 27.18 g of 2-chloromethyl-4-methoxy-3,5-lutidine hydrochloride, the product yield is 82%, and the content is 99.40 %. After the filtrate part is concentrated, Ph is precipitated at 10°C 3 PO, washed with n-hexane, suction filtered, and dried to obtain Ph 3 PO (43.27g) was reusable.

Embodiment 3

[0068] In a 500mL three-necked bottle, the Ph 3PO (43.78g, 157.5mmol) was dissolved in toluene (100mL), BTC (14.84g, 50mmol) was dissolved in toluene (60mL) and put into a 150mL constant pressure dropping funnel, BTC was added dropwise at room temperature, and After completion, the temperature was raised to 40°C. After 4 hours of heat preservation reaction, 2-hydroxymethyl-4-methoxy-3,5-lutidine (25.05g, 150mmol) was dissolved in 75mL of toluene, added at 100°C, and a white solid was precipitated. After reacting for 1 hour, stop the reaction, obtain a white solid by suction filtration, and dry to obtain 30.82 g of 2-chloromethyl-4-methoxy-3,5-lutidine hydrochloride. The product yield is 93%, and the content is 96.59 g. %. Part of the filtrate was concentrated and precipitated Ph at 30°C 3 PO, washed with ether, suction filtered, and dried to obtain Ph 3 PO (43.36g) was reusable.

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Abstract

The invention discloses a method for preparing a high-purity razole intermediate and a medicine by using a green technology instead of phosgene, thionyl chloride and other toxic and harmful substances. The preparation method comprises the following steps: dissolving Ph3PO in an organic solvent, placing the obtained solution in a reaction bottle, dropwise adding BTC to form a high-efficiency chloration reagent, carrying out a heat insulation reaction for a period of time after the dropwise addition is finished, dissolving a razole hydroxide in the organic solvent, dropwise adding the obtained solution to the above system, carrying out a heat insulation reaction for a period of time, carrying out suction filtration, and drying the obtained dried reaction product to obtain razole chloride. In the process, the Ph3PO is equivalently regenerated, a mother liquor part is concentrated to precipitate the Ph3PO at a low temperature, and the Ph3PO can be repeatedly used after being washed with a solvent with small polarity. The method has the advantages of few side reactions, high product quality, few "three wastes" pollutions, high atomic economy, and good promotion and application prospect. The invention also provides a relevant razole medicine prepared from the razole chloride obtained through the green technology. The medicine has obviously higher purity than medicines obtained through traditional methods.

Description

technical field [0001] The present invention relates to the field of preparation of prazoles, in particular to a method for preparing high-purity prazoles intermediates using green technology that replaces toxic and harmful substances such as phosgene and thionyl chloride, and using the intermediates to further synthesize prazoles drug-like process. Background technique [0002] Meprazoles are currently the main drugs for the treatment of peptic ulcer, including pantoprazole sodium, levopantoprazole sodium, rabeprazole sodium, omeprazole, esomeprazole, lansoprazole, etc. . Prazole chloride (2-chloromethylpyridine substituted with different substituents, such as figure 1 Shown) is the key intermediate of prazole drugs, and the preparation of this intermediate mainly takes prazole hydroxylate (2-hydroxymethylpyridine derivatives substituted by different substituents) as raw material. [0003] The figures appearing in the instructions should be classified as part of the acco...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/68C07D213/69C07D401/12
CPCC07D213/68C07D213/69C07D401/12
Inventor 翁意意苏为科汪金灿汪宁卿仲达朱志欣
Owner ZHEJIANG UNIV OF TECH