Preparation method of penciclovir

The technology of penciclovir and amino group is applied in the preparation field of antiviral drug penciclovir, which can solve the problems of increasing reaction steps, three wastes, unfavorable industrialized production and the like, and achieves the advantages of less reaction steps, good product quality and easy operation. Effect

Inactive Publication Date: 2020-01-21
ZHEJIANG MEDICINE CO LTD XINCHANG PHAMACEUTICAL FACTORY +1
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] It can be seen that the following deficiencies mainly exist in the current synthetic route: 1. Column chromatography is required to remove the N-7 by-product, which not only produces a large amount of three wastes, but also causes the N-9 product yield to be low, which is unfavorable for industrialized production 2. The side chain hydroxyl group introduces an ester group protecting group, and then hydrolyzes the deesterification group and dechlorination to get penciclovir, which not only increases the reaction steps, but also introduces impurities such as new mono- and di-ester compounds

Method used

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  • Preparation method of penciclovir

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0021] 1) Preparation of 2-amino-6-chloro-9-(3,3-dimethoxycarbonyl-1-propyl)purine

[0022] N,N-dimethylformamide 250ml (DMF, 3.24mol), potassium carbonate 15.6g (0.113mol), 2-amino-6-chloropurine 17.0g (0.1mol), bromopropane triethyl ester 36.6g ( 0.108mol) into the reaction flask, stirred, heated to 80°C, reacted overnight, filtered, washed the filter cake with DMF, combined the filtrates, and recovered DMF under reduced pressure. Add 375ml (9.3mol) of methanol and 10.7g of 21% sodium methoxide methanol solution to the remaining liquid, react at RT for 1-2h, filter, wash with methanol, and dry the wet product in vacuum at 50°C to obtain off-white solid 2-amino-6-chloro -9-(3,3-dimethoxycarbonyl-1-propyl)purine 24.8g, yield 75.6%.

[0023] 2) Preparation of 2-amino-6-chloro-9-(3-hydroxymethyl-4-hydroxyl-1-butyl)purine

[0024] Add 92ml (1.43mol) of dichloromethane, 41ml (1.01mol) of methanol, and 20g (0.06mol) of 2-amino-6-chloro-9-(3-hydroxymethyl-4-hydroxyl-1-butyl)purine...

Embodiment 2

[0028] 1) Preparation of 2-amino-6-chloro-9-(3,3-dimethoxycarbonyl-1-propyl)purine

[0029] See Example 1

[0030] 2) Preparation of 2-amino-6-chloro-9-(3-hydroxymethyl-4-hydroxyl-1-butyl)purine

[0031] See Example 1

[0032] 3) Preparation of Penciclovir

[0033] Put 8ml (0.09mol) of 36% hydrochloric acid, 80ml (4.4mol) of water, and 12g (0.044mol) of 2-amino-6-chloro-9-(3-hydroxymethyl-4-hydroxyl-1-butyl) into the reaction bottle, stirred, and heated to reflux for 4h-6h. Cool to 20°C, add ammonia water dropwise at ≤30°C to adjust the pH value to 6.5-7.5, solidify, filter, and wash the filter cake with purified water. Vacuum drying at 50°C gave 10.18 g of penciclovir with a yield of 91.1%.

Embodiment 3

[0035] 1) Preparation of 2-amino-6-chloro-9-(3,3-dimethoxycarbonyl-1-propyl)purine

[0036] See Example 1

[0037] 2) Preparation of 2-amino-6-chloro-9-(3-hydroxymethyl-4-hydroxyl-1-butyl)purine

[0038] See Example 1

[0039] 3) Preparation of Penciclovir

[0040] Add 90ml (5mol) of purified water, 3.6ml of 98% concentrated sulfuric acid and 12g (0.044mol) of 2-amino-6-chloro-9-(3-hydroxymethyl-4-hydroxyl-1-butyl) into the reaction bottle under stirring. ), heated to reflux for 3-5h. Cool to RT, add dropwise 25% sodium hydroxide aqueous solution to adjust the pH value to 6.5-7.5, precipitate solid, filter, and wash the filter cake with purified water. Vacuum drying at 50°C gave 10.3 g of penciclovir with a yield of 92.1%.

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Abstract

The invention discloses a preparation method of penciclovir. An existing synthetic route mainly has the following defects that the N-7 site by-products need to be removed through column chromatography, a large amount of three wastes are generated, and the yield of N-9 site products is not high. According to the technical scheme adopted by the invention, the preparation method comprises the following steps: carrying out alkylation on 2-amino-6-chloropurine and triethyl bromopropane under an alkaline condition to introduce an N-9 site side chain, carrying out decarboxylation and transesterification in a methanol solution of sodium methoxide to generate the 2-amino-6-chloro-9-(3,3-dimethoxycarbonyl-1-propyl)purine; then reducing the 2-amino-6-chloro-9-(3,3-dimethoxycarbonyl-1-propyl)purine togenerate 2-amino-6-chloro-9-(3-hydroxymethyl-4-hydroxy-1-butyl)purine with sodium borohydride; and finally, directly hydrolyzing under acidic conditions to obtain penciclovir. According to the method, the target product is obtained by directly hydrolyzing the reduction product, ester group protection and deprotection are not needed, and the method has the advantages of few reaction steps, good product quality, simplicity and convenience in operation, suitability for industrial production and the like.

Description

technical field [0001] The invention belongs to the field of antiviral drugs, in particular to a preparation method of antiviral drug penciclovir. Background technique [0002] Penciclovir (Penciclovir, chemical name 9-[4-hydroxy-3-(hydroxymethyl)-butyl]-guanine) is mainly used to treat herpes simplex virus-I (HSV-I), herpes simplex Virus-Ⅱ (HSV-Ⅱ), varicella-zoster virus (VZV), Epstein-Barr virus (EBV). [0003] The British Smithkline Beecham company first reported the synthesis method of penciclovir and applied for related patents, including EP 0141927; ES 8602791; ES 8603887; US 5075445; JP 1994293764 and so on. Its synthesis is mainly based on the condensation reaction of 2-amino-6-chloropurine and halogenated esters under alkaline conditions to generate mixed intermediates at N-9 and N-7 positions, and then purified by column chromatography to remove N-7 isomers The obtained N-9 compound is dechlorinated and deesterified by hydrolysis under acidic conditions to obtain...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D473/18
CPCC07D473/18
Inventor 谢斌赵凡杨建锋张伟伟潘楷明简绪清
Owner ZHEJIANG MEDICINE CO LTD XINCHANG PHAMACEUTICAL FACTORY
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