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Preparation method of penciclovir

A technology of penciclovir and chloropurine is applied in the field of preparation of purine derivative penciclovir, which can solve problems such as being unsuitable for large-scale production, reducing the yield of N9-position product, and achieving low cost, good product purity and high yield. high rate effect

Inactive Publication Date: 2011-05-25
ZHEJIANG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the above method N7 by-product still needs to be removed by column chromatography, which reduces the yield of the N9 product and is not suitable for large-scale production

Method used

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  • Preparation method of penciclovir

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Experimental program
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Effect test

Embodiment 1

[0021] 1) Preparation of 2-(di-tert-butoxycarbonylamino)-6-chloro-9H-9-tert-butoxycarbonylpurine

[0022] Under the protection of N2, 2.00g (11.8mmol) of 2-amino-6-chloropurine and 0.22g (1.48mmol) of 4-pyrrolidinylpyridine were dissolved in 112mL of anhydrous ether, stirred evenly by magnetic force, and then added to Boc 2 O 5.20g (23.6mmol), react at room temperature for 8h, distill off ether, dissolve the solid in 400mL AcOEt, wash with aqueous hydrochloric acid (2 N, 1 × 30 mL), take the organic phase and wash with water (2 × 50 mL ), after standing for stratification, the organic phase was used Na 2 SO 4 Drying and distillation under reduced pressure gave 5.43 g (98.2%) of 2-(di-tert-butoxycarbonylamino)-6-chloro-9H-9-tert-butoxycarbonylpurine as a white solid.

[0023] 2) Preparation of 2-(di-tert-butoxycarbonylamino)-6-chloropurine

[0024] Dissolve 14.0 g (30 mmol) of 2-(di-tert-butoxycarbonylamino)-6-chloro-9H-9-tert-butylcarboxypurine in 177 mL of ethanol, then a...

Embodiment 2

[0032] 1) Preparation of 2-(di-tert-butoxycarbonylamino)-6-chloro-9H-9-tert-butoxycarbonylpurine

[0033] Under the protection of N2, 2.00g (11.8mmol) of 2-amino-6-chloropurine and 0.14g (1.18mmol) of 4-dimethylaminopyridine were dissolved in 100mL of anhydrous THF, stirred evenly by magnetic force, and then added Boc2O 10.30g (47.2mmol), reacted at room temperature for 6h, distilled off THF, dissolved the solid in 400mL AcOEt, washed with aqueous hydrochloric acid (2 N, 1 × 30 mL), took the organic phase and washed with water (2 × 50 mL) , after standing and stratifying, the organic phase was washed with Na 2 SO 4 Dry and distill under reduced pressure to obtain 5.40 g (97.5%) of white solid 2-(di-tert-butoxycarbonylamino)-6-chloro-9H-9-tert-butoxycarbonylpurine.

[0034] 2) Preparation of 2-(di-tert-butoxycarbonylamino)-6-chloropurine

[0035] Dissolve 14 g (30 mmol) of 2-(di-tert-butoxycarbonylamino)-6-chloro-9H-9-tert-butylcarboxypurine in 265 mL of methanol, then add 5...

Embodiment 3

[0043] 1) Preparation of 2-(di-tert-butoxycarbonylamino)-6-chloro-9H-9-tert-butoxycarbonylpurine

[0044] Under the protection of N2, 2.00g (11.8mmol) of 2-amino-6-chloropurine and 0.13g (0.98mmol) of 1-hydroxybenzotriazole were dissolved in 117mL of anhydrous 2-methyltetrahydrofuran, and stirred by magnetic force Mix well, then add Boc 2 O 15.43g (70.8mmol), reacted at room temperature for 4h, distilled off 2-methyltetrahydrofuran, dissolved the solid in 400mL AcOEt, washed with aqueous hydrochloric acid (2 N, 1 × 30 mL), and washed the organic phase with water (2 × 50 mL), after static separation, the organic phase was washed with Na 2 SO 4 Drying and distillation under reduced pressure gave 5.36 g (96.8%) of 2-(di-tert-butoxycarbonylamino)-6-chloro-9H-9-tert-butoxycarbonylpurine as a white solid.

[0045] 2) Preparation of 2-(di-tert-butoxycarbonylamino)-6-chloropurine

[0046] Dissolve 14 g (30 mmol) of 2-(di-tert-butoxycarbonylamino)-6-chloro-9H-9-tert-butylcarboxypu...

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Abstract

The invention discloses a preparation method of penciclovir. The preparation method comprises the following steps: in the presence of a catalyst, reacting 2-amino-6-dichloropurine with butoxycarbonyl (Boc) anhydride to generate 2-(dibutoxycarbonylamino)-6-chloro-9H-9-butoxycarbonyl-purine; subsequently, removing 9-butoxycarbonyl under the action of weak base so as to generate 2-(dibutoxycarbonylamino)-6-choropurine; coupling with 5-(2-hydroxyethyl)-2,2-dimethyl-1,3-dipxane under the conditions of Mitsunobu reaction to obtain intermediate 2-(dibutoxycarbonylamino)-6-chloro-9-[2-(2,3-dimethyl-1,3-dioxin-5-yl)ethyl]purine in which N is positioned at the ninth site; and carrying out de-Boc protection by the one pot method, and carrying out side chain ring opening and hydrolytic dechlorination to obtain penciclovir. The preparation method of the penciclovir in the invention has the advantages of short route, high yield, good product purity and low cost.

Description

Technical field [0001] The present invention involves a preparation method of purine derivatives with antiviral activity. Background technique [0002] Synthetic spit cosmovir usually uses 2-amino-6-chopine (ACP) as the raw material and alkyl halogen.Poor sex and multiple official groups bring a lot of problems to the synthesis process. The most difficult one is the selective problem of N7 and N9 -bit on the niolehi ring.Usually under alkaline conditions, N7-bit and N9-bit alkylated alkylation occurs at the same time, and the ratio of N-9 / N-7 is generally less than 6: 1. In order to obtain N9-bit productsThe method is separated from the N7 by -products.In order to increase the ratio of N-9 / N-7, some research methods have been reported one after another, such as: GEEN and others reported that the ratio of 2-amino-6-iodine can increase the ratio of N-9 / N-7 7 to increase the ratio of N-9 / N-7 7By 9: 1, the ratio of N9 -bit products can also be increased by changing the side chain str...

Claims

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Application Information

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IPC IPC(8): C07D473/18
Inventor 戴立言杨建海王晓钟陈英奇
Owner ZHEJIANG UNIV
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