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A kind of method utilizing microreactor to prepare tenofovir

A technology of microreactor and tenofovir, which is applied in the field of drug synthesis, can solve the problems of safety risks in operation, low yield, and large amount of waste liquid, and achieve low price, high yield and purity, and waste liquid generation. less effect

Active Publication Date: 2021-06-08
山东安弘制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This invention uses concentrated hydrochloric acid as the deesterification reagent, and there are safety risks in the operation, and the amount of waste liquid is large; and the yield of anhydrous tenofovir is the highest by (R)-9-(2-hydroxypropyl)adenine. 61%, the yield is still low

Method used

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  • A kind of method utilizing microreactor to prepare tenofovir
  • A kind of method utilizing microreactor to prepare tenofovir
  • A kind of method utilizing microreactor to prepare tenofovir

Examples

Experimental program
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Effect test

Embodiment 1

[0054] A kind of method utilizing microreactor to prepare tenofovir comprises steps:

[0055] (1) Dissolve 40g of adenine (II) and 39.32g of (R)-propylene carbonate (III) in 120g of DMF, add 2g of sodium hydroxide as a catalyst, mix well, protect with nitrogen, and heat up to 130°C for reaction 7h, liquid phase detection raw material residue is less than 0.5%; lower to room temperature, then add 160g toluene to crystallize, cool to 5°C, grow crystal for 1h, filter, wash, dry at 80°C for 7h to obtain (R)-9-(2-hydroxypropane Base) adenine (IV) 44g; product purity > 99%, molar yield 77%.

[0056] (2) (R)-9-(2-hydroxypropyl) adenine (IV), 30g magnesium tert-butoxide, 86.68g p-toluenesulfonyloxyphosphonic acid diethyl ester ( V) Dissolve in 120g DMF, react at 80°C for 5h, detect HPA (compound of formula IV) remaining less than 1%, add glacial acetic acid to quench, remove DMF by distillation under reduced pressure, add dichloromethane and water for extraction and layering, take T...

Embodiment 2

[0059] A kind of method utilizing microreactor to prepare tenofovir comprises steps:

[0060] (1) Dissolve 40g of adenine (II) and 39.32g of (R)-propylene carbonate (III) in 120g of NMP, add 2g of sodium hydroxide as a catalyst, mix well, protect with nitrogen, and heat up to 125°C for reaction 7h, liquid phase detection raw material residue is less than 0.5%; lower to room temperature, then add 160g ethanol to crystallize, cool to 5°C, grow crystal for 1h, filter, wash, dry at 80°C for 7h to obtain (R)-9-(2-hydroxypropane Base) adenine (IV) 40g; product purity > 99%, molar yield 70%.

[0061] (2) 40g of (R)-9-(2-hydroxypropyl)adenine (IV), 28g of magnesium tert-butoxide, 85g of diethyl p-toluenesulfonyloxyphosphonate (V) obtained in step (1) ) was dissolved in 120g of NMP, and after reacting at 80°C for 5h, it was detected that the remaining HPA was less than 1%. It was quenched by adding glacial acetic acid, and after the NMP was distilled off under reduced pressure, dichlo...

Embodiment 3

[0064] A kind of method utilizing microreactor to prepare tenofovir comprises steps:

[0065] (1) Dissolve 40g of adenine (II) and 39.32g of (R)-propylene carbonate (III) in 120g of DMF, add 2g of sodium hydroxide as a catalyst, mix well, protect with nitrogen, and heat up to 130°C for reaction 7h, liquid phase detection raw material residue is less than 0.5%; lower to room temperature, then add 160g toluene to crystallize, cool to 5°C, grow crystal for 1h, filter, wash, dry at 80°C for 7h to obtain (R)-9-(2-hydroxypropane Base) adenine (IV) 44g; product purity > 99%, molar yield 77%.

[0066] (2) (R)-9-(2-hydroxypropyl) adenine (IV), 30g magnesium tert-butoxide, 86.68g p-toluenesulfonyloxyphosphonic acid diethyl ester ( V) Dissolve in 120g DMF, react at 80°C for 5h, detect HPA remaining less than 1%, add glacial acetic acid to quench, remove DMF by distillation under reduced pressure, add dichloromethane and water to extract and separate layers, take the organic layer, and w...

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Abstract

The invention provides a method for preparing tenofovir using a microreactor. Adopt adenine and (R)-propylene carbonate as raw material to prepare (R)-9-(2-hydroxypropyl) adenine through condensation reaction, then under the effect of magnesium tert-butoxide and p-toluenesulfonyloxyphosphine (R)-9-[2-(diethylphosphonomethoxy)propyl]adenine is prepared by condensation reaction of diethyl ester; then, using a microreactor, hydrogen chloride gas is used as a deesterification reagent to carry out a deesterification reaction Preparation of tenofovir. The deesterification reaction of the present invention adopts hydrogen chloride as a deesterification reagent, and the hydrogen chloride used is cheap and low in cost; adopts quantitative reaction, and utilizes micro-reactor technology to carry out deesterification reaction, improves reaction pressure, temperature, and enhances mixing effect; waste liquid generation Less, green and environmentally friendly; fast reaction rate, high reaction efficiency, less side reactions, high purity and yield of target products, which is conducive to industrial production.

Description

technical field [0001] The invention relates to a method for preparing tenofovir by using a microreactor, belonging to the technical field of drug synthesis. Background technique [0002] Tenofovir Disoproxil Fumarate (Tenofovir Disoproxil Fumarate, TDF, trade name Viread), is a new type of nucleotide reverse transcriptase inhibitors (NRTIs) produced by Gilead Sciences, USA, by inhibiting HIV -1 reverse transcriptase activity inhibits HIV viral replication. Wherein, tenofovir (I) is the key intermediate for preparing tenofovir disoproxil fumarate, and its structural formula is as follows: [0003] [0004] In the prior art, there have been reports on the preparation of tenofovir (I). [0005] Chinese patent document CN101870713A discloses a kind of industrial production process of tenofovir disoproxil, which involves the preparation of tenofovir, including the steps: using adenine and R-propylene carbonate as starting materials to prepare (R) -9-(2-hydroxypropyl)adenin...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07F9/6561B01J19/00
CPCB01J19/0093C07F9/65616
Inventor 赵卫良周臣生姚甲玉刘朝建赵立波杨英英朱成峰张春雪
Owner 山东安弘制药有限公司
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