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Method for synthesizing chiral isonucleoside analogues through asymmetric cycloaddition reaction

An asymmetric and isonucleoside technology, which is applied in the field of asymmetric cycloaddition synthesis of chiral isonucleosides and chiral isonucleosides, can solve the problem of low yield, high cost, and difficult preparation of chiral substrates and other problems, to achieve the effect of efficient synthesis method, easy access to reaction raw materials, and rich product structure

Active Publication Date: 2019-12-20
HENAN NORMAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The yield of this method is very low, and the chiral substrate is difficult to prepare and the cost is high

Method used

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  • Method for synthesizing chiral isonucleoside analogues through asymmetric cycloaddition reaction
  • Method for synthesizing chiral isonucleoside analogues through asymmetric cycloaddition reaction
  • Method for synthesizing chiral isonucleoside analogues through asymmetric cycloaddition reaction

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Experimental program
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Effect test

Embodiment 1

[0026]

[0027]

[0028]

[0029] a Unless otherwise specified, the steps of the reaction are as follows: under nitrogen atmosphere, metal (10mol%), ligand (12mol%), 1a (0.1mmol), 2 (0.12mmol) were reacted for 1 day in a solvent. b Separation yield. c The dr value of the crude product was tested by NMR. d The ee value was separated by high performance liquid chromatography.

[0030] During the screening of reaction conditions, the effect of ligand on the reaction (label 1-14), the effect of reaction solvent on the reaction (label 15-18), and the influence of temperature on the reaction (label 19-21) were investigated. Pd(PPh 3 ) 4 is the best metal, ligand L6 is the best ligand, and toluene is the best solvent.

[0031] Investigation of reaction conditions: In a 10mL vacuum tube, add α-5-methyluracil substituted methyl acrylate 1a (31.4mg, 0.1mmol), Pd(PPh 3 ) 4 (5.8mg, 5mol%) and L6 (3.6mg, 6mol%). Nitrogen was replaced 3 times, then 0.5 mL of dichloromethane...

Embodiment 2

[0036] In a 10mL vacuum tube, add α-5-ethyluracil substituted methyl acrylate 1b (32.8mg, 0.1mmol), Pd(PPh 3 ) 4 (5.7mg, 5mol%) and L6 (3.7mg, 6mol%). Nitrogen was replaced 3 times, then 0.5 mL of toluene was added and stirred for half an hour, then epoxybutene 2 (9.0 mg, 0.12 mmol) was dissolved in 0.5 mL of toluene and added to the reaction tube. The reaction tube was left to react at room temperature for 1 day. 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 3b through column chromatography, the yield is 90%, 6:1dr and 92% ee.

Embodiment 3

[0038] In a 10mL vacuum tube, add α-5-fluorouracil substituted methyl acrylate 1c (32.8mg, 0.1mmol), Pd(PPh 3 ) 4(11.4 mg, 10 mol%) and L6 (7.4 mg, 12 mol%). Nitrogen was replaced 3 times, then 0.5 mL of toluene was added and stirred for half an hour, then epoxybutene 2 (9.0 mg, 0.12 mmol) was dissolved in 0.5 mL of toluene and added to the reaction tube. The reaction tube was left to react at room temperature for 1 day. 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 3c through column chromatography, the yield is 81%, 6:1dr and 91% ee. HPLC CHIRALCEL IA, n-hexane / isopropanol=90 / 10, flow rate 0.8mL / min, column temperature 25°C, wavelength 250nm, retention time: 34.007min(major), 37.667min(minor). 1 H NMR (600MHz, CDCl 3 ): δ7.90(d, J=7.8Hz, 2H), 7.73(d, J=6.6Hz, 1H), 7.69-7.67(m, 1H), 7.53-7.50(...

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Abstract

The invention discloses a method for synthesizing chiral isonucleoside analogues through asymmetric cycloaddition reaction, and belongs to the field of asymmetric synthesis in organic chemistry. Purine substituted olefin 1 and epoxy butene 2 are used as raw materials; in the presence of a palladium catalyst and a chiral diphosphine ligand SegPHOS or MeOBIPHEP, asymmetric cycloaddition reaction iscarried out to obtain a chiral isonucleoside analogue 3, dr is 1 / 1-7 / 1, the maximum enantiomeric excess ee reaches 95%, and a variety of functional group substituted chiral isonucleosides 7-11 are obtained after derivation. The method provides a simple, convenient, cheap and efficient way for synthesizing the chiral isonucleoside compound series.

Description

technical field [0001] The invention relates to a synthesis method of chiral isonucleosides, in particular to a method for synthesizing chiral isonucleosides through an asymmetric cycloaddition reaction, and belongs to the field of asymmetric synthesis in organic chemistry. Background technique [0002] Natural nucleoside drugs are easily hydrolyzed and enzymatically hydrolyzed due to the aminal structure. In order to increase the stability, the bases were shifted to construct a new class of nucleoside compounds called isonucleosides. Chiral isonucleoside compounds play an important role in biology and medicinal chemistry. For example, the anti-HIV activity and selectivity of the isonucleoside compound Iso-ddA are equivalent to those of the nucleoside compound ddA. However, very few types of isonucleoside structures have been discovered and applied so far, and it is of great significance to further modify their structures in order to change or enhance their antiviral or ant...

Claims

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Application Information

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IPC IPC(8): C07B53/00C07D405/04C07D473/40C07D473/30C07D473/34
CPCC07B53/00C07D405/04C07D473/40C07D473/30C07D473/34C07B2200/07Y02P20/55
Inventor 郭海明黄可心王东超谢明胜王海霞渠桂荣
Owner HENAN NORMAL UNIV
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