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A method for synthesizing chiral six-membered carbocyclic purine nucleosides by asymmetric [3+3] cyclization

A carbocyclic purine nucleoside and cyclization reaction technology, applied in organic chemistry and other directions, can solve the problems of difficult preparation of chiral substrates and high cost, and achieve the effects of rich product structure, efficient synthesis method, and easy availability of reaction raw materials

Active Publication Date: 2020-03-13
HENAN NORMAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

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

Method used

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  • A method for synthesizing chiral six-membered carbocyclic purine nucleosides by asymmetric [3+3] cyclization
  • A method for synthesizing chiral six-membered carbocyclic purine nucleosides by asymmetric [3+3] cyclization
  • A method for synthesizing chiral six-membered carbocyclic purine nucleosides by asymmetric [3+3] cyclization

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0021]

[0022]

[0023]

[0024] a Unless otherwise specified, the steps of the reaction are as follows: catalyst (20mol%), 1a (0.75mmol), 2a (0.05mmol) in ClCH 2 CH 2 Cl (0.5mL) 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. .

[0025] In the screening process of reaction conditions, the effect of thiourea catalyst on the reaction was first investigated (entries 1-7). At the same time, by comparing the effects of different ligands on the reaction and considering the price factor, the catalyst 4e was finally determined to be the best catalyst.

[0026] Investigation of reaction conditions: In a 10mL vacuum tube, α-(6-chloro)purine-substituted acetone 1a (25.2mg, 0.12mmol), catalyst 4e (8.2mg, 20mol%), anhydrous potassium acetate (9.8mg, 1equiv ) and α,β-unsaturated ketoester 2a (19.0 mg, 0.10 mmol). Add 1 mL of 1,2-dichloroethane. Seal the reaction...

Embodiment 2

[0033] In a 10 mL vacuum tube, α-(6-methoxy)purine-substituted acetone 1b (24.7 mg, 0.12 mmol), catalyst 4e (8.2 mg, 20 mol%), anhydrous potassium acetate (9.8 mg, 1 equiv) and α , β-unsaturated ketoester 2a (19.0mg, 0.10mmol), add 1mL of 1,2-dichloroethane. The reaction tube was left at room temperature 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, then obtain the target compound 3ba yield 81%, 5:1dr and 97% through column chromatography %ee.

Embodiment 3

[0035] In a 10 mL vacuum tube, α-(6-propylthio)purine substituted acetone 1e (30.0 mg, 0.12 mmol), catalyst 4e (8.2 mg, 20 mol%), anhydrous potassium acetate (9.8 mg, 1 equiv) and α , β-unsaturated ketoester 2a (19.0mg, 0.10mmol), add 1mL of 1,2-dichloroethane. The reaction tube was left at room temperature 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%, 5:1dr and 96 %ee.

[0036] Representative compound characterization data are as follows:

[0037] 3ea colorless liquid, 87% yield, 5:1dr, 96% ee.[α] D 20 =54.1 (c=0.20, CH 2 Cl 2).HPLC CHIRALCEL IA, n-hexane / isopropanol=70 / 30, flow rate=0.8mL / min, column temperature=25°C, wavelength=254nm, retention time: 14.761min, 17.968min.1H NMR (600MHz, CDCl3) :δ8.55(s,1H),7.93(s,1H),7.1...

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Abstract

The invention discloses a method for synthesizing a chiral six-membered carbocyclic purine nucleoside by asymmetric [3+3] cyclization reaction, and belongs to the field of asymmetric synthesis in organic chemistry. Using acetone substituted by α-purine and β, γ-unsaturated ketoester as raw materials, using chiral thiourea as catalyst, after the reaction, a chiral six-membered carbocyclic purine nucleoside compound is obtained, and the reaction diastereoselectivity and Good enantioselectivity and high yield.

Description

technical field [0001] The invention relates to a synthesis method of chiral carbocyclic purine nucleosides, in particular to a method for synthesizing chiral six-membered carbocyclic purine nucleosides through an asymmetric [3+3] cyclization reaction, belonging to the field of asymmetric synthesis in organic chemistry . Background technique [0002] Chiral carbocyclic purine nucleosides have a wide range of physiological activities, such as chiral five-membered carbocyclic nucleoside Abacavir, Entecavir and Carbovir can be used to treat HIV and HBV respectively; chiral four-membered carbocyclic Lobucavir has been used Treatment of HBV; chiral three-membered carbocyclic nucleoside A-5021 has been clinically used to treat HSV. Other chiral carbocyclic nucleosides such as OxetanocinA, Lamivudine, Amdoxovir and SPD754 all have different pharmaceutical activities. At the same time, the product configuration of chiral compounds has a great influence on their biological activity...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D473/40C07D473/30C07D473/00
CPCC07D473/00C07D473/30C07D473/40
Inventor 郭海明黄可心谢明胜牛红英王东超王海霞张齐英渠桂荣
Owner HENAN NORMAL UNIV