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Method for preparing sofosbuvir intermediate by using microfluid reaction device

A technology for microfluidic reactions and intermediates, which is applied in the field of preparation of sofosbuvir intermediates, can solve the problems of "three wastes" pollution, high production cost, large refrigeration energy consumption, etc., and achieves improved reaction efficiency, stable reaction, and improved conversion rate. Effect

Active Publication Date: 2020-04-07
SOUTHEAST UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0012] In order to solve the low yield of N-(S)-(2,3,4,5,6-pentafluorophenoxy)phenoxyphosphoryl]-L-alanine isopropyl ester in the traditional reactor synthesis process , many by-products lead to serious pollution of "three wastes", large refrigeration energy consumption leads to technical problems such as high production costs, the invention provides a method for preparing a sofosbuvir intermediate using a microfluidic reaction and extraction coupling device, specifically using two 2N-(S)-(2,3,4,5, 6-Pentafluorophenoxy)phenoxyphosphoryl]-L-alanine isopropyl ester

Method used

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  • Method for preparing sofosbuvir intermediate by using microfluid reaction device
  • Method for preparing sofosbuvir intermediate by using microfluid reaction device
  • Method for preparing sofosbuvir intermediate by using microfluid reaction device

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Embodiment 1

[0047] Dissolve 2.1g of phenyl dichlorophosphate in 25mL of chloroform to form reaction solution A, and then dissolve 1.84g of pentafluorophenol in 25mL of chloroform containing 1.01g of triethylamine to form reaction solution B. Liquids A and B were respectively pumped into the first microchannel reactor for mixed reaction. The flow rate of the metering pump was set to 0.5mL / min, the temperature of the microchannel reactor was set to 0°C, and the pressure was about 1.5Mpa. The reaction effluent and 2.02g of triethylamine is mixed and injected into the second microchannel reactor, the flow rate of the metering pump is set to 0.5mL / min, 1.68g of L-alanine isopropyl hydrochloride is dissolved in 50mL of chloroform, and the reaction Liquid D, the reaction solution D is pumped into the second microchannel reactor, and the flow rate of the metering pump is set to 0.5mL / min, and reacts with the mixed solution of the reaction effluent and triethylamine in the second microchannel react...

Embodiment 2

[0050] Dissolve 2.1g of phenyl dichlorophosphate in 25mL of chloroform to form reaction solution A, and then dissolve 1.84g of pentafluorophenol in 25mL of chloroform containing 1.01g of triethylamine to form reaction solution B. Liquids A and B were respectively pumped into the first microchannel reactor for mixed reaction. The flow rate of the metering pump was set at 1mL / min, the temperature of the microchannel reactor was set at 20°C, and the pressure was about 1.5Mpa. After the mixed flow of g triethylamine is injected into the second microchannel reactor, the flow rate of the metering pump is set to be 1mL / min, and 1.68g of L-alanine isopropyl hydrochloride is dissolved in 50mL of chloroform to configure the reaction solution D , the reaction solution D is pumped into the second microchannel reactor, the flow rate of the metering pump is set to 1mL / min, and reacts with the mixed solution of the reaction effluent and triethylamine in the second microchannel reactor to obta...

Embodiment 3

[0053] Dissolve 2.1g of phenyl dichlorophosphate in 15mL of chloroform to form reaction solution A, and then dissolve 1.84g of pentafluorophenol in 15mL of chloroform containing 1.01g of triethylamine to form reaction solution B. Liquids A and B were respectively pumped into the first microchannel reactor for mixed reaction. The flow rate of the metering pump was set to 0.5mL / min, the temperature of the microchannel reactor was set to 0°C, and the pressure was about 1.5Mpa. The reaction effluent and Mix 2.02g of triethylamine and inject it into the second microchannel reactor, set the flow rate of the metering pump to 0.5mL / min, dissolve 1.68g of L-alanine isopropyl hydrochloride in 50mL of chloroform, and configure it as a reaction solution D, the reaction solution D is pumped into the second microchannel reactor, the flow rate of the metering pump is set to 0.5mL / min, and the mixed solution of the reaction effluent and triethylamine is reacted in the second microchannel react...

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Abstract

The invention discloses a method for preparing a sofosbuvir intermediate by using a microfluid reaction device. The method comprises the following steps: pumping phenyl dichlorophosphate and pentafluorophenol into a first micro-channel reactor, carrying out a first-step acylation reaction, pumping the product obtained in the first step and L-alanine isopropyl hydrochloride into a second micro-channel reactor, carrying out a second-step substitution reaction to prepare a racemic sofosbuvir intermediate mixture, enabling the product to directly enter a micro-flow extraction device, and finally re-crystallizing to obtain a single-configuration target compound. Compared with the method in the prior art, the method disclosed by the invention has the advantages that the integration of efficientreaction and separation can be realized, the operation is simple, the problems caused by intermittent operation of extraction after product collecting are avoided, the reaction steps are few, the yield of the final product is high, the energy consumption is low, and the continuous large-scale production operation can be realized.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis, and in particular relates to a method for preparing a sofosbuvir intermediate by utilizing a microfluidic reaction and extraction coupling device. Background technique [0002] According to the World Health Organization (WHO), about 190 million people are currently infected with hepatitis C, and the global infection rate is about 3%. Anti-HCV drugs currently on the market are mainly divided into the following categories: interferon, NS5B RNA polymerase inhibitors, NS5A inhibitors and NS3 / 4 protease inhibitors. [0003] The chemical name of sofosbuvir is (S)-isopropyl 2-((S)-(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidine -1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)-(phenoxy)phosphorylamino)propionate, manufactured by the U.S. pharmaceutical Developed by the company Pharmasset, the anti-HCV drug developed and marketed by the American company Gilead belongs to ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/24
CPCC07F9/242C07F9/2458
Inventor 孙伯旺印玉洁张雨晨程凯武王森林周钰明王明亮
Owner SOUTHEAST UNIV
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