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Method for synthesizing penciclovir analogue

A technology for penciclovir and analogs, applied in the field of pharmaceutical intermediate synthesis, can solve problems such as insufficient research, and achieve the effects of high selectivity and excellent yield

Active Publication Date: 2019-06-21
HENAN NORMAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] However, the research on the method of preparing penciclovir analogues by using cheap and easy-to-obtain phenyl / aminocyclopropanes and using catalytic amounts of Lewis acids is still insufficient, and new synthetic methods still need to be developed.

Method used

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  • Method for synthesizing penciclovir analogue

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022]

[0023]

[0024] [a] Unless otherwise noted, the reaction conditions were as follows: 1a0.1mmol), catalyst (x mol%), MS(30mg),solvent(1mL)for 3h.[b]Isolated yield.[c]Reaction time:0.5h.

[0025] In the screening process of reaction conditions, the influence of different Lewis acid catalysts on the reaction was first investigated (entries1-5), and finally the Sc(OTf) 3 as the best catalyst. At the same time, considering the influence of solvent, temperature, the ratio of reactants and the amount of catalyst on the reaction, DCE was finally selected as the solvent, the reaction temperature was 70°C, the ratio of reactants was 1a:2a=1:2, and the amount of catalyst was 20mol%.

[0026] Investigation of reaction conditions (taking entry 13 as an example):

[0027] In the reaction tube, 6-chloropurine 1a (0.1mmol, 15.4mg), amino cyclopropane methyl ester 2a (0.2mmol, 60.6mg), Sc(OTf) 3 (20mol%, 9.8mg) and MS (30 mg) was added to the reaction tube, and 1 mL of 1,2...

Embodiment 2

[0034] In a reaction tube, 2-fluoro6-chloropurine 1c (0.1mmol, 17.1mg), amino cyclopropane methyl ester 2a (0.2mmol, 60.6mg), Sc(OTf) 3 (20mol%, 9.8mg) and MS (30 mg) was added to the reaction tube, and 1 mL of 1,2-dichloroethane was added to the reaction system, and the reaction tube was placed in an oil bath at 70° C. for 0.5 h. After the reaction was terminated by TLC detection, the target compound 3ca was obtained by concentration and column chromatography with a yield of 90%.

[0035] 3ca Colorless oil, 42.7mg, 90% yield. 1 H NMR (600MHz, CDCl 3 )δ8.71(s,1H),7.91-7.88(m,2H),7.81-7.78(m,2H),6.95-6.92(m,1H),3.73(s,3H),3.68(s,3H) ,3.40-3.35(m,2H),3.27-3.22(m,1H). 13 C NMR (150MHz, CDCl 3 )δ168.0, 167.9, 166.7, 158.4, 156.9, 153.33, 153.26, 153.21, 153.15, 145.11, 145.09, 135.3, 131.0, 129.64, 129.60, 124.4, 57.0, 53.43, 53.35, 48. 20 h 15 o 6 N 5 ClFNa[M+Na] + 498.0587,found 498.0592.

Embodiment 3

[0037] In the reaction tube, 6-methoxypurine 1e (0.1mmol, 15.0mg), amino cyclopropane methyl ester 2a (0.2mmol, 60.6mg), Sc (OTf) 3 (20mol%, 9.8mg) and MS (30 mg) was added to the reaction tube, and 1 mL of 1,2-dichloroethane was added to the reaction system, and the reaction tube was placed in an oil bath at 70° C. for 0.5 h. After the reaction was terminated by TLC detection, the target compound 3ea was obtained by concentration and column chromatography with a yield of 67%.

[0038] 3ea Colorless oil, 30.6mg, 67% yield. 1 H NMR (400MHz, CDCl 3)δ8.58(s,1H),8.53(s,1H),7.90-7.85(m,2H),7.78-7.73(m,2H),7.08-7.03(m,1H),4.16(s,3H) ,3.72(s,3H),3.67(s,3H),3.40-3.24(m,3H). 13 C NMR (100MHz, CDCl 3 )δ168.2, 168.1, 166.9, 161.3, 153.0, 151.7, 141.4, 135.0, 131.2, 124.2, 120.7, 56.5, 54.4, 53.3, 53.2, 48.5, 31.0.HRMScalcd for C 21 h 20 o 7 N 5 [M+H] + 454.1357, found 454.1357.

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Abstract

The invention discloses a method for synthesizing a penciclovir analogue and belongs to the technical field of medicine intermediate synthesis. The method comprises the following steps: by taking purine 1 and amino cyclopropane 2 as raw materials, and lewis acid as a catalyst, carrying out a molecular sieve reaction, thereby obtaining non-cyclic purine nucleoside 3. The reaction is single in areaselectivity and has a medium or excellent yield. The non-cyclic purine nucleoside 3 can be further reduced by using a reducing agent to obtain the penciclovir analogue. The method is easy in raw material obtaining and simple to operate, and a novel way is provided for synthesis of penciclovir analogues.

Description

technical field [0001] The invention relates to a method for synthesizing Penciclovir (Penciclovir) analogues, belonging to the technical field of pharmaceutical intermediate synthesis. Background technique [0002] Acyclic purine nucleosides have received increasing attention due to their important antiviral activities, such as penciclovir, a nucleoside antiviral drug that inhibits herpes simplex virus types I and II in vitro, Clinically, it is mainly used for lip or facial herpes simplex and genital herpes. Therefore, developing a method for synthesizing Penciclovir (Penciclovir) analogues has great application prospects and significance. [0003] The method of traditional synthetic penciclovir and its analogue mainly comprises following two kinds: [0004] One is to use 2-(2-bromoethyl)-1,3-propanediol diacetate to couple with 2-amino-6-chloropurine to obtain 9-(4-acetoxy-3-acetoxymethyl butyl)-2-amino-6-chloropurine, hydrolytic dechlorination and deacetylation give pe...

Claims

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Application Information

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IPC IPC(8): C07D473/40C07D473/30C07D473/34C07D473/38
Inventor 郭海明谢明胜梁涛王海霞王东超渠桂荣
Owner HENAN NORMAL UNIV
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