Preparation method of high diastereoisomer phosphonyl chloride

A technology of diastereoisomers and phosphonyl chlorides, which is applied in the field of medicinal chemistry, can solve the problems of process stability and molecular utilization that need to be further improved, low conversion rate of high diastereoisomer monophenylphosphonyl chlorides, non- Problems such as difficulty in the stability of the symmetrical conversion reaction process, etc., to achieve the effects of simple operation, improved purity, and shortened time

Pending Publication Date: 2022-06-28
ZHEJIANG CHARIOTEER PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In the related synthesis process reported so far, there is no method to improve the solid-phase morphology in the heterogeneous reaction to improve the uniformity of the solid-phase reaction particles and the reaction contact surface, nor to determine the mediation in the asymmetric synthesis process. The control of solvent components makes the conversion rate of synthesizing high diastereomer monophenylphosphonyl chloride relatively low, and the reaction rate is slow, and the ratio of two diastereoisomers in the asymmetric conversion reaction product is S P / R P It can only be maintained at about 90:10, and there are certain challenges and difficulties in the stability of the asymmetric conversion reaction process
Process stability and molecular utilization need to be further improved

Method used

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  • Preparation method of high diastereoisomer phosphonyl chloride
  • Preparation method of high diastereoisomer phosphonyl chloride
  • Preparation method of high diastereoisomer phosphonyl chloride

Examples

Experimental program
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Effect test

Embodiment 1

[0043] 1) At room temperature, put compound I (10 g, 0.028 mol), acetonitrile (77 mL), thionyl chloride (8.2 g, 0.069 mol) into a 250 ml reactor under nitrogen protection, heat up to 70 ° C and keep the reaction for 4 h. The racemate of compound II was obtained (HPLC analysis of the S of II P :R P =49:51); underpressure distillation, slowly concentrating to remove the reaction solvent acetonitrile, until the reaction system is slurry or solid;

[0044] 2) add anhydrous dichloromethane (50g) to the system, be warming up to about 40 DEG C and reflux stirring and beating for 1 hour to obtain a slurry with uniform particle distribution of compound II; again slowly distill and concentrate to remove dichloromethane to obtain the slurry of compound II;

[0045] 3) Add anhydrous toluene (80g, 8w) to the system, stir at 60° C. and slowly distill and concentrate again to remove toluene and residual solvent acetonitrile and dichloromethane to obtain the solid of compound II;

[0046] 4...

Embodiment 2

[0048] 1) At room temperature, put compound I (15 g, 0.041 mol), acetonitrile (115 mL), thionyl chloride (12.28 g, 0.103 mol) into a 500 ml reactor under nitrogen protection, heat up to 70 ° C and keep the reaction for 4 h. The racemate of compound II was obtained (HPLC analysis of the S of II P :R P =49:51); underpressure distillation, slowly concentrating to remove the reaction solvent acetonitrile, until the reaction system is slurry or solid;

[0049] 2) Add anhydrous dichloromethane (150g, 10w) to the system, heat up to about 40° C., reflux, stir and beat for 1 hour to obtain a slurry with uniform particle distribution of compound II, and again slowly distill and concentrate to remove dichloromethane to obtain compound II. slurry or solid;

[0050] 3) Add anhydrous toluene (120g, 8w) to the system, stir at 60°C and again slowly distill and concentrate to remove toluene and residual solvent acetonitrile and dichloromethane to obtain the slurry or solid of compound II;

...

Embodiment 3

[0053] 1) At room temperature, put compound I (20 g, 0.055 mol), acetonitrile (154 mL), thionyl chloride (16.4 g, 0.137 mol) into a 500 ml reactor under nitrogen protection, heat up to 70 ° C and keep the reaction for 4 h. The racemate of compound II was obtained (HPLC analysis of the S of II P :R P =48.5:51.5); distillation under reduced pressure, slowly concentrating to remove the reaction solvent acetonitrile, until the reaction system is slurry or solid;

[0054] 2) add anhydrous toluene (160g, 8w) to the system, be warming up to about 60 DEG C and keep stirring and beating for 1.5 hours to obtain a slurry with uniform particle distribution of compound II, and again slowly distill and concentrate to remove toluene to obtain the slurry of compound II;

[0055] 3) adding anhydrous toluene (160g, 8w) to the system, stirring at 60°C and slowly distilling and concentrating again to remove toluene and residual solvent acetonitrile to obtain the slurry or solid of compound II; ...

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Abstract

The invention discloses a preparation method of high diastereoisomer phosphoryl chloride, which comprises the following steps: 1) carrying out halogenation reaction on monophenyl tenofovir shown in a formula I and thionyl chloride in a solvent A to generate monophenyl tenofovir phosphoryl chloride raceme shown in a formula II; removing the solvent A to obtain a solid or slurry of the monophenyl tenofovir phosphonyl chloride racemate; (2) adding a solvent C into the solid or slurry of the monophenyl tenofovir phosphonyl chloride racemate obtained in the step (1), and stirring and pulping to obtain uniform solid slurry; (3) replacing the slurry of the monophenyl tenofovir phosphonic chloride racemate obtained in the step (2) with a solvent B to obtain uniform slurry of the monophenyl tenofovir phosphonic chloride racemate; and 4) carrying out solvent B-mediated asymmetric conversion reaction on the slurry of the monophenyl tenofovir phosphonic chloride racemate obtained in the step 3) to obtain the monophenyl tenofovir phosphonic chloride with high diastereoisomer content. According to the invention, the reaction rate of the asymmetric conversion reaction is obviously improved.

Description

(1) Technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a method for improving the conversion rate and the reaction rate during asymmetric transformation of a key intermediate of tenofovir alafenamide, monophenyl tenofovir dronate. (2) Background technology [0002] L-Alanine, N-[(S)-[[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl]phenoxyoxy Phosphino]-,1-methylethyl ester, (2E)-2-butenedioic acid (2:1), the generic name is Tenofovir Alafenamide Hemifumarate, which The chemical structure is as follows [0003] [0004] Tenofovir alafenamide hemifumarate (TAF) is a new nucleoside reverse transcriptase inhibitor (NRTI) researched and developed by Gilead Sciences Co., Ltd., which is newer than tenofovir dipivoxil (TDF) A first-generation prodrug of tenofovir. Clinical data show that TAF has a smaller dose, lower side effects, and higher safety and tolerability under the condition of comparable viral clearan...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/6561C07B53/00
CPCC07F9/65616C07B53/00C07B2200/07
Inventor 陈恬李建学王乃星赵翔宇李丰庭朱燕萍钟惺
Owner ZHEJIANG CHARIOTEER PHARMA
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