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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Problems solved by technology

[0007] However, the research on the method of preparing penciclovir analogues by using cheap and easy-to-obtain phenyl/aminocycl

Method used

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  • Method for synthesizing penciclovir analogue
  • Method for synthesizing penciclovir analogue

Examples

Experimental program
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Example Embodiment

[0021] Example 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 firstly investigated (entries1-5), and finally the Sc(OTf) was determined. 3 the best catalyst. At the same time, considering the influence of solvent, temperature, ratio of reactants and catalyst dosage on the reaction, DCE was finally selected as 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 (take entry 13 as an example):

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

Example Embodiment

[0033] Example 2:

[0034] In a reaction tube, 2-fluoro6-chloropurine 1c (0.1 mmol, 17.1 mg), aminocyclopropane methyl ester 2a (0.2 mmol, 60.6 mg), Sc(OTf) 3 (20mol%, 9.8mg) and MS (30 mg) was added to the reaction tube, 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. Detection by TLC, after termination of the reaction, and then concentration and column chromatography to obtain the target compound 3ca in 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 RMS 20 H 15 O 6 N 5 ClFNa[M+Na] + 498.0587, found 498.0592.

Example Embodiment

[0036] Example 3:

[0037] In a reaction tube, 6-methoxypurine 1e (0.1 mmol, 15.0 mg), aminocyclopropane methyl ester 2a (0.2 mmol, 60.6 mg), Sc(OTf) 3 (20mol%, 9.8mg) and MS (30 mg) was added to the reaction tube, 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. Detection by TLC, after termination of the reaction, and then concentration through column chromatography to obtain the target compound 3ea in 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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