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An intermediate for synthesizing (2s,3r)-3-substituted phenylpyrrolidine-2-carboxylic acid and its preparation method and application

A technology of trimethylchlorosilane and oxygen group, which is applied in the field of synthesis of pharmaceutical intermediates, can solve the problems of low total yield, poor stereoselectivity, long route and the like, and achieves the effects of convenient operation, easy reaction and reliable synthesis route.

Active Publication Date: 2021-11-05
浙江晖石药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method has a long route and poor stereoselectivity, resulting in low overall yield, and requires the use of stoichiometric chiral prosthetic groups, which is not conducive to large-scale preparation

Method used

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  • An intermediate for synthesizing (2s,3r)-3-substituted phenylpyrrolidine-2-carboxylic acid and its preparation method and application
  • An intermediate for synthesizing (2s,3r)-3-substituted phenylpyrrolidine-2-carboxylic acid and its preparation method and application
  • An intermediate for synthesizing (2s,3r)-3-substituted phenylpyrrolidine-2-carboxylic acid and its preparation method and application

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0055]

[0056] Preparation of Compound IV-1:

[0057]Bromobenzene (327.7g, 2.09mol, 3.0eq.) was dissolved in THF (500mL), cooled to -78°C under nitrogen protection, and n-BuLi (2.5M, 807mL, 2.9eq.) was added dropwise, and the addition was completed , keep stirring for 30min, add CuCN (97.68g, 1.04mol, 1.5eq.), raise the temperature to about -50°C, keep the reaction for 30min, below -78°C, dropwise add compound II (140.1g, 695.7mmol, 1eq.) THF (500mL) solution, after the addition was completed, TMSCl (188.9g, 1.74mol, 2.5eq.) was added dropwise, after the addition was completed, stirred for 30min, the temperature was naturally raised to -40°C, and the reaction was detected by TLC. At -40~0°C, add saturated ammonium chloride aqueous solution (2.0L) dropwise to quench the reaction, add EA (2.0L), extract and separate the liquid, and use saturated ammonium chloride aqueous solution (1.0L) and saturated chloride Wash with aqueous sodium solution (1.0L), dry over anhydrous magn...

Embodiment 2

[0069]

[0070] Preparation of Compound IV-2:

[0071] Compound III-2 (757.65g, 3.475mol, 5.0eq.) was dissolved in anhydrous THF (700mL), under nitrogen protection, Mg powder (83.4g, 3.475mol, 5.0eq.) was added, and a small amount of iodine was added to initiate the reaction at room temperature. After the reaction, heat to reflux and stir for 20 minutes, then add the suspension to CuBr-Me at -40°C 2 S (357.2g, 1.737mol, 2.5eq.) in 300mL diethyl ether solution, after stirring for 1h, the Grignard reagent was formed for later use. Compound II (140.1g, 695.75mmol, 1eq.) was dissolved in THF (500mL), cooled to -78°C, and CuCN (97.68g, 1.04mol, 1.5eq.) was added under nitrogen protection,

[0072] TMSCl (377.5g, 3.475mol, 5.0eq.) was incubated and reacted for 30min, below -78°C, added the spare Grignard reagent dropwise, after the addition was complete, stirred for 2h, and the temperature was naturally raised to -40°C, and the reaction was detected by TLC. At -40~0°C, add satu...

Embodiment 3

[0084]

[0085] Preparation of compound IV-3:

[0086] Compound III-3 (751.43g, 2.783mol, 4.0eq.) was dissolved in THF (800mL), cooled to -78°C under nitrogen protection, and n-BuLi (2.5M, 834mL, 3.0eq.) was added dropwise, After the feeding is completed, keep stirring for 30 minutes, then add CuBr-Me 2 S (213.8g, 1.04mol, 1.5eq.), the temperature was raised to about -50°C, and the reaction was incubated for 30min. Below -78°C, a THF (500mL) solution of compound II (140.1g, 695.75mmol, 1eq.) was added dropwise, After the addition was completed, TMSCl (264.6 g, 2.43 mol, 3.5 eq.) was added dropwise. After the addition was completed, the mixture was stirred for 30 minutes, and the temperature was naturally raised to -40°C. TLC detected that the reaction was complete. At -40~0°C, add saturated ammonium chloride aqueous solution dropwise to quench the reaction, add EA, extract and separate the liquids, wash the organic phase with saturated ammonium chloride aqueous solution an...

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Abstract

The present invention relates to an intermediate of (2S,3R)-3-substituted phenylpyrrolidine-2-carboxylic acid and its preparation method and application, mainly solving the problem of (2S,3R)-3-substituted phenylpyrrolidine-2-carboxylic acid 2‑Carboxylic acids have no technical problems amenable to industrial synthetic methods. The present invention uses compound II and halogenated benzene as raw materials, and under the action of organometallic reagents, it is prepared through successive reaction steps such as Michael addition reaction, reduction reaction, debenzylation reaction, Boc protection reaction, oxidation and removal of Boc protection group, etc. Compound I ((2S,3R)-3-substituted phenylpyrrolidine-2-carboxylic acid) is obtained. The method is convenient to operate, stable in yield and suitable for large-scale production.

Description

technical field [0001] The invention relates to the field of synthesis of pharmaceutical intermediates, in particular to an intermediate for synthesizing (2S, 3R)-3-substituted phenylpyrrolidine-2-carboxylic acid, a preparation method and application thereof. Background technique [0002] The 3-position substituted proline is a kind of unnatural chiral amino acid. When it is introduced into a polypeptide, its secondary amine forms a tertiary amide, which can prevent the formation of hydrogen bonds and stabilize the secondary structure of the polypeptide; this type of unnatural chiral Amino acids are important building blocks for peptides and proteins, and can be used in the synthesis of various drugs. [0003] (2S,3R)-3-substituted phenylpyrrolidine-2-carboxylic acids belong to conformationally constrained 3-substituted proline derivatives, which have a variety of physiological activities, while optically pure 3-phenyl substituted Proline derivatives have become a hotspot i...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D498/04C07D207/08C07D207/16
CPCC07B2200/07C07D207/08C07D207/16C07D498/04
Inventor 巩沛王正江夏爱华吴希罕
Owner 浙江晖石药业有限公司
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