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Channelized method for continuously producing N-[(2Z)-piperazine-2-subunit]-2, 2, 2-trifluoroacetyl hydrazine

A pipeline and piperazine technology, applied in the field of six-membered heterocyclic compounds, can solve the problems of high energy consumption, long reaction time, and low yield, and achieve the effects of reducing control conditions, short reaction time, and high product purity

Active Publication Date: 2013-01-30
ZHEJIANG UNIV OF TECH +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The reaction requires very strict temperature control, high energy consumption, long reaction time and low yield

Method used

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  • Channelized method for continuously producing N-[(2Z)-piperazine-2-subunit]-2, 2, 2-trifluoroacetyl hydrazine
  • Channelized method for continuously producing N-[(2Z)-piperazine-2-subunit]-2, 2, 2-trifluoroacetyl hydrazine
  • Channelized method for continuously producing N-[(2Z)-piperazine-2-subunit]-2, 2, 2-trifluoroacetyl hydrazine

Examples

Experimental program
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Effect test

Embodiment 1

[0027] Mix the methanol solution of 1mol / L 5-trifluoromethyl-2-chloromethyl-1,3,4-oxadiazole with the methanol solution of 4mol / L ethylenediamine at a volume ratio of 1:1.125 to obtain a reaction Raw material solution, control the temperature of the reaction raw material solution at 0°C, send the solution to the pipeline reactor (15 meters in length, 2 mm in inner diameter) through the liquid delivery pump, control the flow rate in the tube in the reactor to 0.04m / s, and make the solution The residence time in the pipeline reactor is 375s, the reaction temperature is 10°C, the outflowing reaction solution enters the crystallization tank, stirred and cooled to 0°C to crystallize, and the solid is filtered to obtain the target product with a yield of 94.3% and a purity of 98.1%. .

Embodiment 2

[0029] Mix 1 mol / L methanol solution of 5-trifluoromethyl-2-chloromethyl-1,3,4-oxadiazole with 6 mol / L methanol solution of ethylenediamine at a volume ratio of 1:0.417 to obtain a reaction Raw material liquid, the temperature of the reaction raw material liquid is controlled to be 10°C. The solution is sent to the pipeline reactor (the length of the tube is 15 meters, the inner diameter of the tube is 4 mm) through the liquid delivery pump, the flow rate in the tube in the reactor is controlled to 0.1m / s, the reaction temperature is 20°C, and the retention time is 150s. The crystallization kettle was stirred and cooled to 0°C to crystallize, and the solid was separated by filtration to obtain the target product with a yield of 86% and a purity of 98.3%.

Embodiment 3

[0031] Mix the methanol solution of 1mol / L 5-trifluoromethyl-2-chloromethyl-1,3,4-oxadiazole with the methanol solution of 4mol / L ethylenediamine at a volume ratio of 1:1.5 to obtain a reaction Raw material liquid, the temperature of the reaction raw material liquid is controlled to be 35°C. The solution is sent to the pipeline reactor (15 meters in length and 4 mm in diameter) through the liquid delivery pump. The flow rate in the tube in the reactor is controlled to 0.15m / s, the reaction temperature is 35°C, and the retention time is 100s. The outflowing reaction solution enters the The crystallization kettle was stirred and cooled to 0°C to crystallize out, and the solid was separated by filtration to obtain the target product with a yield of 89% and a purity of 97.5%.

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Abstract

The invention discloses a tubular continuous production technology for generating six-membered heterocyclic compounds by means of dehydration cyclization, particularly N-((2Z)-piperazine-2-subunit)-2, 2, 2-trifluoroacetyl hydrazine (1) by taking 5-trifluoromethyl-2-chloromethyl methyl ether-1, 3, 4-NBD-F as a raw material in the presence of ethidene diamine. The channelized method for continuously producing 1 comprises the following steps of: firstly, putting methanol solution of ethidene diamine into one storage tank, putting the methanol solution of raw material NBD-F into the other storage tank, and keeping at a proper temperature T1; directly charging the methanol solution in the two storage tanks into a tubular reactor according to a certain proportion, and controlling the reaction temperature in the tubular reactor at T2, and the reaction time at t; and charging the obtained reaction liquid into a crystallization kettle to be cooled to separate out white solid. The synthesis technology provided by the invention has the advantages of being simple in device, good in technological safety, mild in reaction conditions, easy to control, continuous in production, environment-friendly, high in yield, stable in product quality and the like.

Description

(1) Technical field [0001] The present invention relates to a kind of 5-trifluoromethyl-2-chloromethyl-1,3,4-oxadiazole as raw material in the presence of ethylenediamine, dehydration and cyclization to generate six-membered heterocyclic compounds, especially A tubular continuous production process for N-[(2Z)-piperazin-2-ylidene]-2,2,2-trifluoroacetylhydrazide. (2) Background technology [0002] Sitagliptin is a dipeptidyl peptidase-IV (DDP-IV) inhibitor that was approved by the FDA in 2006 for the treatment of type II diabetes. 3-trifluoromethyl-5,6,7,8-tetrahydro-1,2,4-triazol[4,3-α]pyrazine hydrochloride (formula 2) is an important compound for the preparation of sitagliptin The quality of intermediates and products is related to the cost of sitagliptin as a whole. The compound (Formula 2) can be synthesized from N-[(2Z)-piperazin-2-ylidene]-2,2,2-trifluoroacetylhydrazide (Formula 1) through acidification and cyclization. [0003] [0004] There are mainly three me...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D241/06
Inventor 李坚军吕宏初夏建胜苏为科谢媛媛葛进东陈惠明
Owner ZHEJIANG UNIV OF TECH
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