Preparation method of chiral CBS catalyst

A catalyst and chiral technology, applied in the field of preparation of chiral CBS catalysts, can solve the problems of cumbersome operation, long reaction steps, increased cost, etc., and achieve the effect of shortening the reaction steps and simplifying the operation.

Active Publication Date: 2016-06-01
CANGZHOU PURUI DONGFANG SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] The above-mentioned synthesis method has the following defects: the reagents used involve highly toxic drugs, the purchase is controlled, or the reaction steps are long, the operation is cumbersome, the product changes color during the high-vacuum distillation product process, or boric acid needs to be purchased, which increases additional costs

Method used

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  • Preparation method of chiral CBS catalyst
  • Preparation method of chiral CBS catalyst
  • Preparation method of chiral CBS catalyst

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] Synthesis of S-MeCBS:

[0024]

[0025] The first step: In the reaction flask, add L-proline (115g, 1mol), triethylamine (253g, 2.5mol) and dichloromethane (1600mL) in sequence, cool to -5°C to 5°C, drop Chlorotrimethylsilane (239g, 2.2mol), after the reaction was completed, the reaction solution was evaporated to dryness, after adding 650mL of toluene, the triethylamine hydrochloride produced during the reaction was filtered off, and the filtrate was directly used in the next step after evaporation;

[0026] The second step: add the product of the first step above into 850mL tetrahydrofuran, cool to -10°C to 0°C, slowly add 2M phenylmagnesium chloride (1.1L, 2.2mol) dropwise, after the reaction is completed, add 15% hydrochloric acid aqueous solution to adjust the pH = 1-2, filter the generated off-white solid, add 15% sodium hydroxide to adjust PH=10-12, extract four times with dichloromethane (1500mL), combine the organic layers, dry over anhydrous magnesium sul...

Embodiment 2

[0030] Synthesis of R-MeCBS:

[0031]

[0032] The first step: In the reaction flask, add D-proline (115g, 1mol), triethylamine (253g, 2.5mol) and dichloromethane (1600mL) successively, cool to -10°C to -5°C, drop Add trimethylchlorosilane (239g, 2.2mol), after the reaction is completed, evaporate the reaction solution to dryness, add 650mL of toluene, filter out the triethylamine hydrochloride produced during the reaction, and directly use the filtrate in the next step after evaporation ;

[0033] The second step: add the product of the first step above into 850mL tetrahydrofuran, cool to -10°C to 0°C, slowly add 1M phenylmagnesium bromide (2.2L, 2.2mol) dropwise, after the reaction is completed, add 15% hydrochloric acid aqueous solution Adjust the pH to 1-2, filter the generated off-white solid, add 15% sodium hydroxide to adjust the pH to 10-12, extract four times with dichloromethane (1700mL), combine the organic layers, dry over anhydrous magnesium sulfate, and dis...

Embodiment 3

[0037] Synthesis of R-BuCBS:

[0038]

[0039] Step 1: In the reaction flask, add D-proline (115g, 1mol), pyridine (172g, 2.2mol) and dichloromethane (1600mL) in sequence, cool to -5°C to 5°C, add trimethyl Chlorochlorosilane (239g, 2.2mol), after the completion of the reaction, evaporate the reaction solution to dryness, add 700mL of toluene, filter out the pyridine hydrochloride produced in the reaction process, and directly use the filtrate in the next step after evaporation;

[0040]The second step: Add the above-mentioned first step product into 850mL tetrahydrofuran, cool to -10°C to 0°C, slowly add 1M phenylmagnesium bromide (2.2L, 2.2mol) dropwise, after the reaction is completed, add 10% hydrochloric acid aqueous solution Adjust the pH to 1-2, filter the resulting off-white solid, add 10% sodium hydroxide to adjust the pH to 10-12, extract four times with dichloromethane (1800mL), combine the organic layers, dry over anhydrous magnesium sulfate, and distill the o...

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Abstract

The invention provides a preparation method of a chiral CBS catalyst. The preparation method comprises the following steps: by adopting proline as a raw material, protecting nitrogen and carboxylic acid by trimethyl chlorosilane, and reacting with a phenyl grignard reagent to obtain diphenyl prolinol; then reacting with boron trihalide and lithium alkylide, after the reaction is ended, quenching by acetic acid, performing backflow filtering on alkane, and performing cooling crystallization to obtain a chiral product. The process is short in synthetic route, the operation is simple, the raw material is easy to get, the yield and the product purity are high, racemization of a chiral center is avoided in the whole preparation process, and the method is more suitable for large-scale production.

Description

technical field [0001] The invention relates to a preparation method of a chiral CBS catalyst, which belongs to the field of synthesis of pharmaceutical intermediates. Background technique [0002] Chiral compounds have widely existed in many marketed drugs, and there are usually two methods of synthesis: resolution and asymmetric reduction. CBS catalysts, as one of the methods for reducing carbonyl groups to chiral alcohols, have recently been widely favored by academia and industry due to their high enantioselectivity. [0003] The current common methods for the synthesis of CBS catalysts are: chiral prolin alcohol and boric acid or boric acid trimer are refluxed in toluene and dehydrated to obtain a toluene solution or a solid product after high vacuum distillation. There are many synthetic methods of chiral prolin alcohols, starting from proline, using methyl chloroformate to protect nitrogen and carboxylic acid at the same time, or using Boc to protect nitrogen in a st...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): B01J31/02C07F5/02
CPCB01J31/0275C07F5/025
Inventor 冷延国余锦华桂迁
Owner CANGZHOU PURUI DONGFANG SCI & TECH
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