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A method for synthesizing 2'-spirocyclyl substituted three-membered carbocyclic nucleosides

A three-membered carbocyclic and spirocyclic group technology, applied in the field of spirocyclic nucleoside synthesis, can solve the problems of increased reaction, long synthesis steps, and poor substrate universality, so as to achieve simple and easy-to-obtain raw materials, avoid numerous steps, The effect of rich product structure

Active Publication Date: 2020-07-28
HENAN NORMAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0008] This method has long synthesis steps and poor substrate universality. Firstly, o-bromoaniline condensation is used, and finally n-Bu 3 SnH method free radical debromination, increasing unwanted reactions

Method used

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  • A method for synthesizing 2'-spirocyclyl substituted three-membered carbocyclic nucleosides
  • A method for synthesizing 2'-spirocyclyl substituted three-membered carbocyclic nucleosides
  • A method for synthesizing 2'-spirocyclyl substituted three-membered carbocyclic nucleosides

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Experimental program
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Effect test

Embodiment 1

[0025]

[0026]

[0027]

[0028] a Unless otherwise specified, the reaction steps are as follows: 1a (0.1 mmol), 2a (1.5 equiv), base (1.5 equiv) in air for 5 hours. b Separation yield c Potassium tert-butoxide (1.2 equiv) d Potassium tert-butoxide (2.0equiv) e 1h f 0.5h.

[0029] During the screening of reaction conditions, the effect of base on the reaction was first investigated (entries 1-6). Secondly, the solvent and temperature were investigated, and by comparing the yields, potassium tert-butoxide was finally determined as the optimal base, acetonitrile as the optimal solvent, and -20°C as the optimal temperature.

[0030] Typical reaction condition operation:

[0031] In a reaction flask, dissolve α-pyrimidine-substituted methyl acrylate 1a (0.1 mmol) and 1.5 eq (0.15 mmol) potassium tert-butoxide in 1 mL of acetonitrile, and place at -20°C for 10 minutes with stirring and cooling, then α-chloro Substituted cycloalkanone 2a (0.15 mmol) was added to the...

Embodiment 2

[0035] In a 10 mL vacuum tube, dissolve α-(3-benzoyl-5-methyl)uracil-substituted ethyl acrylate 1b and 1.5 eq (0.15 mmol) potassium tert-butoxide in 1 mL of acetonitrile and place at -20 °C for stirring After cooling for 10 minutes, α-chlorocycloalkanone 2a (0.15 mmol) was added to the reaction solution to react for 0.5 h. The reaction was monitored by TLC, quenched by adding water, and extracted with ethyl acetate. The combined organic phases were dried, filtered and concentrated in vacuo to give a crude oil. Then the target compound 3ba was obtained by column chromatography with a yield of 85%.

Embodiment 3

[0037] In a 10 mL vacuum tube, dissolve α-(3-benzoyl-5-methyl)uracil-substituted tert-butyl acrylate 1c and 1.5 eq (0.15 mmol) potassium tert-butoxide in 1 mL of acetonitrile and place at -20 °C Stir and cool for 10 minutes, then add α-chlorocycloalkanone 2a (0.15 mmol) into the reaction liquid for reaction, and react for 0.5 h. The completion of the reaction was monitored by TLC, quenched with water, and extracted with ethyl acetate. The combined organic phases were dried, filtered and concentrated in vacuo to give a crude oil. Then the target compound 3ca was obtained by column chromatography with a yield of 83%.

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Abstract

The invention discloses a method for synthesizing three-membered carbocyclic nucleosides substituted by 2'-spirocyclic groups, belonging to the technical field of organic chemistry. Using α-pyrimidine-substituted acrylate and α-chlorocycloalkanone as raw materials, a series of novel spirocyclic nucleosides were synthesized through the cyclopropanization reaction initiated by the Mike reaction. The invention adopts simple and easy-to-obtain raw materials, and avoids the shortcomings of many steps, low yield and poor universality in the previous methods in the synthesis process. The yield of the spirocyclic pyrimidine nucleoside synthesized by this method is as high as 84%, and the product structure is rich.

Description

technical field [0001] The invention relates to a method for synthesizing spirocyclic nucleosides, in particular to a method for synthesizing 2'-spirocyclyl-substituted three-membered carbocyclic nucleosides by cyclopropanization reaction, and belongs to the technical field of organic chemistry. Background technique [0002] Most of the spironucleosides are conformationally restricted nucleosides, and their molecular conformational composition is relatively single. Before the substrate is combined with the enzyme, the conformation of the active center of the enzyme will first change according to the conformation of the substrate, and then form an active complex with the substrate. A substrate with a single conformation will be more conducive to the conformation transformation of the active center of the enzyme, so the development of Conformational restricted nucleosides have certain advantages over non-conformational restricted nucleoside drugs. At present, the publicly rep...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D239/54C07D239/553
CPCC07D239/54C07D239/553
Inventor 郝二军张庆郭海明张齐英苏富赢
Owner HENAN NORMAL UNIV
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