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Method for synthesis of chiral five-membered carbocyclic purine nucleoside by asymmetric [3+2] cyclization reaction

A carbocyclic purine nucleoside and cyclization reaction technology, applied in asymmetric synthesis, organic chemistry methods, chemical instruments and methods, etc., can solve the problems of high cost and difficult preparation of chiral substrates, and achieve efficient synthesis methods, The effect of rich product structure and easy availability of reaction raw materials

Active Publication Date: 2018-02-16
HENAN NORMAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

And chiral substrates are relatively difficult to prepare and the cost is high

Method used

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  • Method for synthesis of chiral five-membered carbocyclic purine nucleoside by asymmetric [3+2] cyclization reaction
  • Method for synthesis of chiral five-membered carbocyclic purine nucleoside by asymmetric [3+2] cyclization reaction
  • Method for synthesis of chiral five-membered carbocyclic purine nucleoside by asymmetric [3+2] cyclization reaction

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Experimental program
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Effect test

Embodiment 1

[0020]

[0021]

[0022]

[0023] a Unless otherwise specified, the reaction steps are as follows: under nitrogen atmosphere, catalyst (20mol%), 1 (0.05 mmol), 2 (0.06 mmol) in CH 2 Cl 2 (1.0mL) for 4 days. b The dr value of the crude product was tested by NMR. c Separation yield. d The ee value was separated by high performance liquid chromatography. .

[0024] During the screening of the reaction conditions, the effect of the phosphine catalyst on the reaction was first examined (entries 1-8). At the same time, by comparing the effects of different ligands on the reaction and considering the price factor, the ligand P6 was finally determined to be the best ligand.

[0025] Investigation of reaction conditions: In a 10mL vacuum tube, add α-purine substituted ethyl 6-chloroacrylate 1a (23.8mg, 0.1mmol), (S)-SITCP (3.5mg, 20mmol%) and phenyl MBH methyl carbonate Ester 2a (35.1 mg, 0.12 mmol). The reaction tube was filled with nitrogen gas by nitrogen replacemen...

Embodiment 2

[0036] In a 10 mL vacuum tube, α-purine-substituted 6-piperidine methyl acrylate (28.7 mg, 0.1 mmol), (S)-SITCP (3.5 mg, 20 mmol%) and phenyl MBH methyl carbonate (35.1 mg, 0.12 mmol). The reaction tube was filled with nitrogen gas by nitrogen replacement 3 times, and then 1 mL of dichloromethane was added. The reaction tube was sealed, and the reaction tube was placed in a cryopump at -10°C to react for 4 days. Track the reaction with TLC, after terminating the reaction, add dichloromethane / water for extraction, dry the organic phase over anhydrous sodium sulfate, concentrate the organic phase in vacuo, and then obtain the target compound 3ea through column chromatography. The yield is 87%, 9:1dr and 90 %ee.

Embodiment 3

[0038]In a 10 mL vacuum tube, α-purine substituted methyl 6-propylthioacrylate (27.8 mg, 0.1 mmol), (S)-SITCP (3.5 mg, 20 mmol%) and methyl phenyl MBH carbonate (35.1 mg, 0.12 mmol). The reaction tube was filled with nitrogen gas by nitrogen replacement 3 times, and then 1 mL of dichloromethane was added. The reaction tube was sealed, and the reaction tube was placed in a cryopump at -10°C to react for 4 days. Track the reaction with TLC, after terminating the reaction, add dichloromethane / water for extraction, dry the organic phase over anhydrous sodium sulfate, concentrate the organic phase in vacuo, and then obtain the target compound 3ea through column chromatography. The yield is 85%, 9:1dr and 90 %ee.

[0039] Representative compound characterization data are as follows:

[0040] 3ea White solid; 85% yield, 9:1dr, 90% ee.[α] D 20 =66.1 (c=0.5, CH 2 Cl 2 ).HPLC CHIRALCEL IA, n-hexane / isopropanol=70 / 30, flow rate=0.5 mL / min, column temperature=25°C, λ=254nm, retenti...

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Abstract

Belonging to the field of asymmetric synthesis in organic chemistry, the invention discloses a method for synthesis of chiral five-membered carbocyclic purine nucleoside by asymmetric [3+2] cyclization reaction. The method includes: taking alpha-purine substituted acrylic ester and MBH carbonic ester as the raw materials, adopting chiral SITCP as the catalyst, and carrying out reaction to obtain achiral five-membered carbocyclic nucleoside compound. The reaction has good diastereoselectivity and enantioselectivity, and the yield is up to 93%.

Description

technical field [0001] The invention relates to a synthesis method of chiral carbocyclic purine nucleosides, in particular to a method for synthesizing chiral five-membered carbocyclic purine nucleosides through an asymmetric [3+2] cyclization reaction, belonging to the field of asymmetric synthesis in organic chemistry . Background technique [0002] Chiral five-membered carbocyclic purine nucleoside compounds have a wide range of physiological activities, such as Abacavir, Entecavir and Carbovir can be used to treat HIV and HBV respectively. Other chiral five-membered carbocyclic nucleosides such as: Noraristeromycin, Aristeromycin, Neplanocin A and HNPA have different pharmaceutical activities. At the same time, the product configuration of chiral compounds has a great influence on their biological activity, so the synthesis and preparation of optically pure chiral compounds and the testing and research of some physiological and pharmacological activities have great appl...

Claims

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Application Information

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IPC IPC(8): C07D473/40C07D473/34C07D473/30C07D473/38C07D473/00
CPCC07B53/00C07B2200/07C07D473/00C07D473/30C07D473/34C07D473/38C07D473/40
Inventor 郭海明黄可心谢明胜王东超张齐英王海霞渠桂荣
Owner HENAN NORMAL UNIV
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