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Method for synthesizing famciclovir

A famciclovir and amino technology, applied in organic chemistry, antiviral agents, etc., can solve the problem of high cost, achieve the effect of simple control, mild experimental conditions, and easy access to synthetic raw materials

Active Publication Date: 2009-10-14
ZHEJIANG HISUN PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] This method has high selectivity, but the cost of N-(2-amino-4,6-dichloro-5-pyrimidine) formamide compound preparation is higher

Method used

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  • Method for synthesizing famciclovir
  • Method for synthesizing famciclovir
  • Method for synthesizing famciclovir

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0051] 1. 2-Amino-6-chloro-4-(3-hydroxymethyl-4-hydroxyl)-1-butyramine

[0052] In a 2000ml reaction bottle, dissolve 82 grams of 2-amino-4,6-dichloropyrimidine and 50 grams of 2-hydroxymethyl-4-amino-1-butanol in 1000ml of n-butanol, add potassium carbonate, and reflux for 5 Hour. The reaction solution was cooled, filtered, concentrated, dissolved in distilled water, and the aqueous phase was sequentially extracted with dichloromethane and n-butanol, dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain light yellow oil or milky white solid. 1 H NMR (400MHz, d 6 -DMSO) δ6.94 (broad, 1H), 6.22 (s, 2H), 5.73 (s, 1H), 4.31 (t, J=4.6Hz, 2H), 3.45-3.43 (m, 4H), 3.24 (m , 2H), 1.49-1.55(m, 1H), 1.44-1.49(m, 2H); 13 C NMR (100MHz, d 6 -DMSO) δ164.5, 163.4, 157.6, 93.2, 62.0, 41.3, 38.7, 28.2; ESI-MS: 247 (M + +1); IR(film, cm -1 ): 3435, 3285, 3158, 1647, 1584, 1486; UV: 212.8nm.

Embodiment 2

[0054] 2. 2-Amino-6-chloro-4-(3-acetoxymethyl-4-acetoxy)-1-butyraminopyrimidine

[0055] Dissolve 5 grams of the crude product 2-amino-6-chloro-4-(3-hydroxymethyl-4-hydroxy)-1-butyraminopyridine in 50 ml of dichloromethane, add 8 ml of triethylamine at 0-10 °C, N, N-Dimethylaminopyridine and 4ml acetic anhydride, after reacting for 2-5 hours, the organic phase was washed with ice water, acetic acid aqueous solution and saturated sodium bicarbonate solution successively, dried over anhydrous magnesium sulfate, filtered and concentrated to obtain Pale yellow solid 2-amino-6-chloro-4-(3-acetoxymethyl-4-acetoxy)-1-butyraminopyrimidine (6.67 g, yield: 99%). The solid was recrystallized from ethyl acetate, petroleum ether, dichloromethane, etc. 1 H NMR (400MHz, CDCl 3 )δ5.79(s, 1H), 5.21(s, 2H), 4.09-4.16(m, 4H), 3.51(broad), 2.10(s, 7H), 1.67(dt, J=7, 14Hz, 2H) ; 13 C NMR (100MHz, CDCl 3 )δ171.1, 164.1, 162.5, 93.0, 63.9, 38.7, 35.1, 28.2, 20.9, 20.6; ESI-MS: 331 (M + +1); IR...

Embodiment 3

[0057] 3. 2-Amino-6-chloro-5-p-chloroanilinodiazo-4-(3-acetoxymethyl-4-acetoxy)-1-butyraminopyrimidine

[0058] Dissolve 3 g of p-chloroaniline and 2 g of sodium nitrite in 20 ml of water, and react under the action of 3N hydrochloric acid at 0-10°C for 0.5-2 hours to prepare p-chloroaniline diazonium hydrochloride. The prepared diazonium salt was added to 6.7 g of 2-amino-6-chloro-4-(3-acetoxymethyl-4-acetoxy)-1-butyramine in a buffered solution of sodium acetate / acetic acid , reacted at 10-40°C for 0.5-5 hours, a large number of yellow solids precipitated out of the solution, filtered the yellow solids, and recrystallized from methanol to obtain 8.12 grams (yield: 86%) of 2-amino-6-chloro-5-p-chloroaniline Diazo-4-(3-acetoxymethyl-4-acetoxy)-1-butyraminopyrimidine. 1 H NMR (400MHz, CDCl 3 )δ10.32(m, 1H), 7.76(d, J=4.9Hz, 2H), 7.45(d, J=4.8Hz, 2H), 5.56(s, 2H), 4.26(dd, J=5.1, 11Hz , 2H), 4.18(dd, J=6.2, 11Hz, 2H), 3.68(dt, J=6.7, 13.6Hz, 2H), 2.14-2.17(m, 1H), 2.11(s, 6H)...

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Abstract

The invention provides a method for efficiently, simply and conveniently synthesizing famciclovir. 2-amidogen-4, 6-dichloro pyrimidine is used as a raw material, and the famciclovir is high selectively synthesized by coupling reaction, acidylation reaction, diazotization reaction, reduction reaction and ring closure reaction of the raw material. The synthesizing raw material is easy to obtain, experiment conditions are moderate, the reactions are easy to control and simple, and a midbody is not purified if permitted not to be purified so that middle operation links are increased, thereby the method is suitable for the industrialized production.

Description

technical field [0001] The invention relates to a synthetic route of Famciclovir. Background technique [0002] Famciclovir (Famciclovir) is a kind of new nucleoside broad-spectrum antiviral drug that was first listed in the UK in 1993, and was listed in the United States, Europe and other countries, and was approved by the United Kingdom and the United States in 1995. For genital herpes, the trade name is Famvi. The drug not only has a strong inhibitory effect on herpes viruses (including types I and II), HIV, etc., but also has a strong inhibitory effect on hepatitis B and C viruses. Therefore famciclovir has larger market demand, and its molecular formula is: [0003] [0004] There are many synthetic routes of famciclovir: [0005] (1) Synthetic Famciclovir (Famciclovir) from 2-amino-6-chloropurine in EP182024 and US5684153, the reaction formula is as follows: [0006] [0007] Here X represents a halogen atom. Yet the main problem that this preparation method...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D473/32A61P31/12
Inventor 王亚平杨晓霞张友华魏海鹏李居彪古志国
Owner ZHEJIANG HISUN PHARMA CO LTD
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