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A kind of preparation method of 2-amino-6-chloro-9-(4-acetoxy-3-acetoxymethylbutyl)purine

A technique of acetoxymethylbutyl and acetoxy, which is applied in the field of preparation of 2-amino-6-chloro-9-purine, can solve the problem of low overall yield and achieve good process safety and reduced amount, to avoid the effect of esterification reaction process

Active Publication Date: 2020-08-21
LIVZON GROUP CHANGZHOU KONY PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0016] Compared with method one, the decarboxylation reaction step is omitted, but there will be a lot of N-7 isomers 2-amino-6-chloro-7-(2-ethoxycarbonyl butyric acid ethyl ester- 4-yl) purine generation, need to be separated through recrystallization, the overall yield is not high

Method used

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  • A kind of preparation method of 2-amino-6-chloro-9-(4-acetoxy-3-acetoxymethylbutyl)purine
  • A kind of preparation method of 2-amino-6-chloro-9-(4-acetoxy-3-acetoxymethylbutyl)purine
  • A kind of preparation method of 2-amino-6-chloro-9-(4-acetoxy-3-acetoxymethylbutyl)purine

Examples

Experimental program
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Effect test

Embodiment 1

[0036] 129g of 1,3-dichloro-2-propanol, 1000ml of DMF, 300g of potassium acetate, and 53.5g of ammonium chloride were put into the reaction bottle, and the reaction was stirred and kept at 100-110°C for 10 hours. After heat preservation, cool to room temperature, filter out the solids in the system, concentrate the filtrate to remove DMF under reduced pressure, add ethyl acetate to dissolve the concentrated solution, wash with water twice, dry with anhydrous sodium sulfate, add triethylamine hydrobromic acid 270g of salt, heat up to 70-80°C, stir and keep warm for 5-6 hours, cool to room temperature, filter out the solids in the system, then wash twice with saturated sodium chloride solution, concentrate under reduced pressure to remove ethyl acetate, then carry out Rectification gave 110 g of 1,3-diacetoxy-2-bromopropane with a GC content of 90.4%.

[0037] Add 100ml of THF, 9g of anhydrous lithium bromide and 33g of zinc powder into the reaction flask, replace with nitrogen ...

Embodiment 2

[0042] Zinc reagent (1,3-diacetoxy-2-zinc bromide propane) and catalyst were prepared according to the method of Example 1, and were ready for use.

[0043] Add 300ml of THF and 50g of bromoethanol benzyl ether into the reaction bottle, add the newly prepared catalyst under nitrogen protection, heat to 50-60°C, slowly add the newly prepared zinc reagent dropwise, and react at 50-60°C for 10h after dropping. Cool down to 15-20°C, add 10ml of ethanol dropwise, and stir for 2h. Concentrate under reduced pressure to dryness, add 300ml ethyl acetate, 200ml 25% aqueous ammonium chloride solution, stir for 0.5h, let stand, separate layers, wash the organic layer twice with water, transfer to an autoclave, add palladium carbon (5% , containing 50% water) 2g, reacted at a temperature of 30-40°C and a pressure of 0.1-0.2MPa for 10 hours, filtered to remove palladium carbon, washed the filtrate twice with water, and concentrated to dryness under reduced pressure to obtain 1,3-diacetoxy ...

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Abstract

The invention relates to a preparation method for 2-amino-6-chloro-9-(4-acetoxy-3-acetoxymethylbutyl)purine. The method comprises the following steps: performing a reaction on 1,3-dichloro-2-propanoland an acetate to obtain 1,3-diacetoxy-2-propanol, performing a bromination reaction to obtain 1,3-diacetoxy-2-bromopropane, performing a reaction on the 1,3-diacetoxy-2-bromopropane and zinc powder to obtain 1,3-diacetoxy-2-zinc bromide propane, performing a coupling reaction on the 1,3-diacetoxy-2-zinc bromide propane and 2-bromoethanol protected by hydroxyl, and performing a de-protection reaction to obtain 1,3-diacetoxy-2-(2-hydroxyethyl)propane, and performing a Mitsunobu reaction on the 1,3-diacetoxy-2-(2-hydroxyethyl)propane and 2-amino-6-chloropurine to obtain the 2-amino-6-chloro-9-(4-acetoxy-3-acetoxymethylbutyl)purine. According to the method provided by the invention, the 2-amino-6-chloro-9-(4-acetoxy-3-acetoxymethylbutyl)purine prepared by the method has purity of 99.5% or more detected by HPLC, and can be used to prepare famciclovir and penciclovir.

Description

technical field [0001] The invention belongs to the technical field of chemical synthesis, and relates to a preparation method of 2-amino-6-chloro-9-(4-acetoxy-3-acetoxymethylbutyl)purine. Background technique [0002] Penciclovir and famciclovir are antiviral drugs developed by SmithKline Beecham in the United Kingdom in the 1990s. They mainly exert antiviral effects by inhibiting viral DNA replication, and are suitable for the treatment of severe herpes zoster patients and primary genital herpes and other viral infections . Famciclovir is the first oral drug approved for cold sores and genital herpes in the United States, and it is also the only antiviral drug to reduce postherpetic neuralgia. Viruses, cytomegalovirus, Epstein-Barr virus, etc. are active. Penciclovir is the active metabolite of famciclovir in the human body, and famciclovir has better oral bioavailability. [0003] In the preparation methods of famciclovir and penciclovir widely used at present, the key...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D473/40
CPCC07D473/40
Inventor 刘可可张之建朱小芳殷波陆琴亚潘亮
Owner LIVZON GROUP CHANGZHOU KONY PHARMA
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