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Method for synthesizing ganciclovir analogue

A technology for nucleoside analogs and acyclic nucleosides, applied in the field of ganciclovir analog synthesis, can solve the problems of low yield, insufficient research, inconvenient separation of allogeneic bodies by column chromatography, etc.

Active Publication Date: 2021-05-11
HENAN NORMAL UNIV
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  • Abstract
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Problems solved by technology

However, the above-mentioned methods for synthesizing antiviral ganciclovir drugs all require a large amount of silylating reagents, the catalyst of the condensation reaction contains highly toxic mercury cyanide, and column chromatography is very inconvenient to separate the variants, and the yield is not high.
[0004] Therefore, select cheap and easy-to-get D-A oxirane for use, adopt catalytic amount Lewis acid to prepare the method research of ganciclovir analogue not yet sufficient, still need To develop new synthetic methods

Method used

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  • Method for synthesizing ganciclovir analogue
  • Method for synthesizing ganciclovir analogue
  • Method for synthesizing ganciclovir analogue

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Experimental program
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Effect test

Embodiment 1

[0020] Investigation of reaction conditions (taking entry 5 as an example):

[0021] In a reaction tube, benzotriazole 1a (0.1mmol, 12mg), phenyloxirane gem-diethylcarboxylate compound 2a (0.1mmol, 26.4mg), Y(OTf) 3 (5mol%, 2.7mg) and MS (30 mg) was added to the reaction tube, and 2 mL of 1,2-dichloroethane was added to the reaction system, and the reaction tube was placed in an 80° C. oil bath for 10 h. After TLC detection, the reaction was terminated, and the compound 3a was obtained by column chromatography after concentration, with a yield of 94%.

[0022]

[0023]

[0024] a Reaction conditions: 1a(0.1mmol), 2a(0.1mmol), catalyst(xmol%), MS(30mg) and solvent for 10h in the pressure tube. b The yield was determined by 1 HNMR using CH 2 Br 2 as an internal standard. c The ratio was determined by 1 H NMR Analysis of crude product. d Isolated yield of 3a in parentheses.

[0025] In the screening process of reaction conditions, the influence of different Lew...

Embodiment 2

[0032] In the reaction tube, benzotriazole 1a (0.1mmol, 12mg), o-tolyl oxide oxirane gem diethyl carboxyl compound 2b (0.1mmol, 27.8mg), Y (OTf) 3 (5mol%, 2.7mg) and MS (30 mg) was added to the reaction tube, and 2 mL of 1,2-dichloroethane was added to the reaction system, and the reaction tube was placed in an 80° C. oil bath for 10 h. After TLC detection, the reaction was terminated, and the compound 3b was obtained by column chromatography after concentration, with a yield of 84%. Colorless solid, 33.4mg, m.p.: 65.6-70.3℃. 1 H NMR (400MHz, CDCl 3 )δ8.21(d, J=8.0Hz, 1H), 8.03(d, J=8.0Hz, 1H), 7.44(s, 1H), 7.42-7.25(m, 4H), 7.12-7.09(m, 2H ),4.81(s,1H),4.35-4.27(m,2H),3.92(q,J=7.2Hz,2H),1.93(s,3H),1.30(t,J=7.2Hz,3H),1.02 (t,J=7.2Hz,3H). 13 C NMR (150MHz, CDCl 3 )δ165.8,165.1,147.0,136.2,132.4,131.5,131.3,129.8,128.0,126.7,126.3,124.5,120.1,111.7,87.2,76.4,62.6,62.2,19.0,14.2,13.8)m / ESI :[M+Na] + Calcd for C 21 h 23 N 3 NaO 5 420.1530; Found 420.1524.

Embodiment 3

[0034]In the reaction tube, benzotriazole 1a (0.1mmol, 12mg), p-tolyl oxirane gem diethyl ester compound 2c (0.1mmol, 27.8mg), Y (OTf) 3 (5mol%, 2.7mg) and MS (30 mg) was added to the reaction tube, and 2 mL of 1,2-dichloroethane was added to the reaction system, and the reaction tube was placed in an 80° C. oil bath for 10 h. After TLC detection, the reaction was terminated, and after concentration, column chromatography obtained compound 3c with a yield of 87%. Colorless oil, 34.6mg, 1 H NMR (400MHz, CDCl 3 )δ8.07-8.05(m,1H),7.37-7.29(m,5H),7.25-7.22(m,1H),7.18(d,J=8Hz,2H),4.68(s,1H),4.36- 4.27(m,2H),3.92(q,J=7.2Hz,2H),2.35(s,3H),1.31(t,J=7.2Hz,3H),1.00(t,J=7.2Hz,3H). 13 C NMR (100MHz, CDCl 3 )δ165.9, 165.0, 147.2, 139.5, 131.8, 131.4, 129.5, 127.9, 126.2, 124.6, 120.0, 112.2, 89.5, 76.5, 62.6, 62.2, 21.4, 14.2, 13.7. HRMS (ESI) m / z: [M+ Na] + Calcd for C 21 h 23 N 3 NaO 5 420.1530; Found 420.1530.

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Abstract

The invention discloses a method for synthesizing a ganciclovir analogue, and belongs to the technical field of synthesis of medical intermediates. N-aryl heterocycle 1 and D-A ethylene oxide 2 are used as raw materials, Lewis acid is used as a catalyst, a molecular sieve is added, and a non-cyclic nucleoside analogue 3 is obtained through reaction. The reaction is relatively single in chemical selectivity, high in regioselectivity and good to excellent in yield. The non-cyclic purine nucleoside 3 is further reduced to obtain a ganciclovir analogue 4. The raw materials are easy to obtain, the operation is simple, and a new way is provided for synthesis of the ganciclovir analogue.

Description

technical field [0001] The invention relates to a method for synthesizing Ganciclovir (Ganciclovir) analogues, belonging to the technical field of pharmaceutical intermediate synthesis. Background technique [0002] Acyclic nucleosides have received increasing attention due to their important antiviral activities. For example, ganciclovir, a nucleoside antiviral drug, is commonly used to treat cytomegalovirus infections. Prevention of cytomegalovirus disease that may occur in organ transplant recipients at risk for cytomegalovirus infection. Treatment of cytomegalovirus retinitis in immunocompromised patients, including AIDS patients. Therefore, developing a method for synthesizing Ganciclovir (Ganciclovir) analogues has great application prospects and significance. [0003] The method of traditional synthetic penciclovir mainly comprises following two kinds: 1) with hydroxymethyl dioxane initial substrate, first acetyl chloride carries out esterification reaction, then wi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D249/18C07D233/60C07D473/40C07D473/18
CPCC07D249/18C07D233/60C07D473/40C07D473/18Y02P20/55
Inventor 王东超桑冀威谢明胜郭海明渠桂荣
Owner HENAN NORMAL UNIV
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