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Method for synthesizing ridecevirthrough asymmetric catalysis of protecting-group-free nucleoside

A remdesivir and asymmetric technology, which is applied in the field of asymmetric catalyzed unprotected nucleoside synthesis of remdesivir, achieves good industrial application prospects, reduces costs, and is easy for industrial production

Active Publication Date: 2021-12-07
SHANGHAI JIAO TONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Therefore, so far, no asymmetric method has been reported to synthesize remdesivir

Method used

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  • Method for synthesizing ridecevirthrough asymmetric catalysis of protecting-group-free nucleoside
  • Method for synthesizing ridecevirthrough asymmetric catalysis of protecting-group-free nucleoside
  • Method for synthesizing ridecevirthrough asymmetric catalysis of protecting-group-free nucleoside

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] In a 25mL double-necked reaction flask, add unprotected nucleoside (290mg, 1mmol, 1equiv), Molecular sieve (300mg), chiral imidazole catalyst (C1, 0.1mol, 0.1equiv), the system passed through the vacuum line, replaced with nitrogen for 3 times, added ionic liquid (1-ethyl-3-methylimidazolium tetrafluoroborate , 5ml), dropwise added chlorophosphoramidate (1.2mmol, 1.2equiv), then added dropwise base (2,6-lutidine, 1.2mol, 1.2equiv), the solution was stirred at 80°C for 12 hours, The end of the reaction was detected by TLC, quenched by dropping water, filtered, extracted, concentrated, and column chromatography gave remdesivir (217 mg, 36%) with a diastereomeric excess (dr) of 1.2:1. 1 H NMR (400MHz, CD 3OD): δ7.87(s,1H),7.33-7.27(m,2H),7.21-7.16(m,3H),6.92-6.87(dd,J=4.0,8.0Hz,1H),4.79(d, J=5.2Hz, 1H), 4.40-4.35(m, 2H), 4.31-4.28(m, 1H), 4.17(t, J=5.6Hz, 1H), 4.02(dd, J=5.2, 10.8Hz, 1H ),3.95-3.87(m,2H),1.47-1.43(m,1H),1.35-1.27(m,8H),0.85(t,J=7.2Hz,6H); 31 P NMR (16...

Embodiment 2

[0041] In a 25mL double-necked reaction flask, add unprotected nucleoside (290mg, 1mmol, 1equiv), Molecular sieve (300mg), chiral imidazole catalyst (C2, 0.1mol, 0.1equiv), the system passed through the vacuum line, replaced with nitrogen for 3 times, added ionic liquid (1-ethyl-3-methylimidazolium tetrafluoroborate , 5ml), dropwise added chlorophosphoramidate (1.2mmol, 1.2equiv), then added dropwise base (2,6-lutidine, 1.2mol, 1.2equiv), the solution was stirred at 80°C for 12 hours, The end of the reaction was detected by TLC, quenched by dropping water, filtered, extracted, concentrated, and column chromatography gave remdesivir (253 mg, 42%) with a diastereomeric excess (dr) of 1.5 / 1. 1 H NMR (400MHz, CD 3 OD): δ7.87(s,1H),7.33-7.27(m,2H),7.21-7.16(m,3H),6.92-6.87(dd,J=4.0,8.0Hz,1H),4.79(d, J=5.2Hz, 1H), 4.40-4.35(m, 2H), 4.31-4.28(m, 1H), 4.17(t, J=5.6Hz, 1H), 4.02(dd, J=5.2, 10.8Hz, 1H ),3.95-3.87(m,2H),1.47-1.43(m,1H),1.35-1.27(m,8H),0.85(t,J=7.2Hz,6H); 31 P NMR (1...

Embodiment 3

[0043] In a 25mL double-necked reaction flask, add unprotected nucleoside (290mg, 1mmol, 1equiv), Molecular sieve (300mg), chiral imidazole catalyst (C3, 0.1mol, 0.1equiv), the system passed through the vacuum line, replaced with nitrogen for 3 times, added ionic liquid (1-ethyl-3-methylimidazolium tetrafluoroborate , 5ml), dropwise added chlorophosphoramidate (1.2mmol, 1.2equiv), then added dropwise base (2,6-lutidine, 1.2mol, 1.2equiv), the solution was stirred at 80°C for 12 hours, The end of the reaction was detected by TLC, quenched by dripping water, filtered, extracted, concentrated, and column chromatography gave remdesivir (307 mg, 51%) with a diastereomeric excess (dr) of 2.0 / 1. 1 H NMR (400MHz, CD 3 OD): δ7.87(s,1H),7.33-7.27(m,2H),7.21-7.16(m,3H),6.92-6.87(dd,J=4.0,8.0Hz,1H),4.79(d, J=5.2Hz, 1H), 4.40-4.35(m, 2H), 4.31-4.28(m, 1H), 4.17(t, J=5.6Hz, 1H), 4.02(dd, J=5.2, 10.8Hz, 1H ),3.95-3.87(m,2H),1.47-1.43(m,1H),1.35-1.27(m,8H),0.85(t,J=7.2Hz,6H); 31 P NMR (1...

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Abstract

The invention discloses a method for synthesizing ridecevir through asymmetric catalysis of protecting-group-free nucleoside. In a single or mixed solvent, under the catalytic action of the chiral bicyclic imidazole catalyst, nucleoside without a protecting group and chloraminophosphate are directly and asymmetrically synthesized into single-configuration ridecevir in one step, the reaction condition is mild, the operation is simple and convenient, the steps of protecting group feeding and protecting group removing are omitted, the reaction efficiency is relatively high, and the industrial application prospect is good.

Description

technical field [0001] The invention belongs to the technical field of asymmetric catalytic synthesis in the field of chemical engineering, and relates to a method for synthesizing remdesivir by asymmetric catalysis of nucleosides without protective groups, and in particular to a method of using a chiral bicyclic imidazole catalyst under the action of a base to directly A one-step asymmetric catalysis method for preparing single-configuration remdesivir from nucleosides without protective groups. Background technique [0002] Remdesivir, English name: Remdesivir, molecular formula C 27 h 35 N 6 o 8 P, is an antiviral drug under investigation. However, it has a certain therapeutic effect on the current epidemic of new coronary pneumonia virus (COVID-19). In view of the urgency of the treatment of new coronary pneumonia, the efficient synthesis of remdesivir and its important intermediates has attracted the attention of researchers and companies. The direct one-step prepa...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/6561B01J31/02
CPCC07F9/6561B01J31/0244B01J31/0245B01J31/0274Y02P20/54Y02P20/55
Inventor 张万斌陈建中张露袁乾家霍小红张振锋
Owner SHANGHAI JIAO TONG UNIV