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A kind of synthesis technique of chiral catalyst

A synthesis process, chiral technology, applied in the field of low-cost and high-efficiency synthesis process, can solve problems such as difficulty in realization, high energy consumption at low temperature control, and strong odor

Active Publication Date: 2020-10-27
上海福乐医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although triphosgene is less harmful to the environment and human body than the toluene solution of phosgene, it is still toxic
[0027] 5) The hydrochloride of diphenylprolinol is converted into free base with sodium hydroxide, and (R)-diphenylprolinol is obtained through post-processing steps such as extraction and concentration, and its total yield is 56.7%, but the product Optical purity not confirmed
[0034] The existing method for synthesizing chiral diphenylprolinol mainly has the following disadvantages: (1) when protecting the amino and carboxyl groups of proline, use toxic, irritating, smelly, etc. unsafe, environmentally friendly or expensive Reagents, such as phosgene, triphosgene, acetyl chloride or trimethylsilyl chloride, etc.; (2) formatted reagent consumption is large, and the yield is also low under laboratory scale; (3) need to strictly control formatted reaction at low temperature Higher yield and better optical purity can only be obtained if carried out under low temperature conditions. The formatting reaction is a violent exothermic reaction, and the control of low temperature in industrial production consumes a lot of energy and is difficult to achieve; (4) the process operation is complicated. Complex and costly; (5) The process has not been verified by industrial mass production and lacks practicability

Method used

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  • A kind of synthesis technique of chiral catalyst
  • A kind of synthesis technique of chiral catalyst
  • A kind of synthesis technique of chiral catalyst

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0077] The industrialized production of embodiment 1 (R)-diphenylprolinol hydrochloride

[0078]

[0079] 1. A 100-liter reactor was pumped into 22.0 kilograms of anhydrous methanol under nitrogen protection. Control the internal temperature of the reactor below 30°C. 7.0 kg of concentrated sulfuric acid (mass concentration 98%) is slowly pumped into the reactor. Open the lid of the reaction kettle, and quickly add 8.0 kg of D-proline. After the addition, adjust the inner temperature of the reaction kettle to 25-30° C., and continue stirring for 7 hours. The solvent was distilled off under reduced pressure at 55°C.

[0080] 2. Pump 35.0 kg of dichloromethane into the reactor. Cool down to 15°C, add 14.8 kg of sodium carbonate in batches, keep the temperature below 20°C during the addition, and continue stirring for 30 minutes after the addition. Pump the dichloromethane (11.2 kg) solution of di-tert-butyl dicarbonate (16.1 kg) into the supporting dropping tank of the re...

Embodiment 2

[0085] The industrialized production of embodiment 2 (R)-diphenylprolinol hydrochloride

[0086] 1. A 100-liter reactor was pumped into 22.0 kilograms of anhydrous methanol under nitrogen protection. Control the internal temperature of the reactor below 30°C. Slowly pump 7.0 kg of concentrated sulfuric acid into the reactor. Open the lid of the reaction kettle, and quickly add 8.0 kg of D-proline. After the addition, adjust the inner temperature of the reaction kettle to 25-30° C., and continue stirring for 7 hours. The solvent was distilled off under reduced pressure at 55°C.

[0087] 2. 34.3 kg of tetrahydrofuran was pumped into the reaction kettle. Cool down to 15°C, add 19.2 kg of potassium carbonate in batches, keep the temperature below 20°C during the addition, and continue stirring for 30 minutes after the addition. Pump the dichloromethane (11.2 kg) solution of di-tert-butyl dicarbonate (16.1 kg) into the supporting dropping tank of the reaction kettle, add dropwi...

Embodiment 3

[0090] The industrialized production of embodiment 3 (S)-diphenylprolinol hydrochloride

[0091]

[0092] 1. A 100-liter reactor was pumped into 22.0 kilograms of anhydrous methanol under nitrogen protection. Control the internal temperature of the reactor below 30°C. Slowly pump 7.0 kg of concentrated sulfuric acid into the reactor. Open the lid of the reaction kettle, and quickly add 8.0 kg of L-proline. After the addition, adjust the inner temperature of the reaction kettle to 25-30° C., and continue stirring for 7 hours. The solvent was distilled off under reduced pressure at 55°C.

[0093] 2. Pump 35.0 kg of dichloromethane into the reactor. Cool down to 15°C, add 14.8 kg of sodium carbonate in batches, keep the temperature below 20°C during the addition, and continue stirring for 30 minutes after the addition. Pump the dichloromethane (11.2 kg) solution of di-tert-butyl dicarbonate (16.1 kg) into the supporting dropping tank of the reaction kettle, add dropwise at...

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Abstract

The invention relates to a low-cost efficient synthesis process of both a chiral catalyst chiral (R)-(+)-2-(Diphenylhydroxymethyl)pyrrolidine and a hydrochloride thereof. According to the process, rawmaterials which can be commercially obtained easily and are environmentally friendly are used; a one-kettle method is used for operation; through esterification reaction, Boc protecting group addition on amino group, Grignard reaction and Boc protecting group removal, high-optical-purity (R)-(+)-2-(Diphenylhydroxymethyl)pyrrolidine hydrochloride is obtained. The process is simplified; the production cost is reduced; the requirements of green chemistry at present are met. The content of (R)-(+)-2-(Diphenylhydroxymethyl)pyrrolidine and the hydrochloride thereof, prepared by the process, is higher than 99.0 percent; the optical purity is not smaller than 99.5 percent; the total yield is higher than 80 percent.

Description

technical field [0001] The invention relates to a low-cost and high-efficiency synthesis technique of a chiral catalyst, in particular to a low-cost and high-efficiency synthesis technique of chiral diphenylprolinol and its hydrochloride. Background technique [0002] Chiral catalysis and chiral synthesis have always been research hotspots in the field of drug synthesis. Chiral prolinol compounds are an important class of chiral reagents, which can be used for asymmetric reduction of carbonyl groups, asymmetric alkyl groups at the α-position of carbonyl and chiral resolution of carboxylic acids. Chiral diphenylprolinol and its hydrochloride can be derived from cheap proline, and they exhibit excellent asymmetric catalytic effects on many reactions. [0003] In 1988, Corey et al. (Angew.Chem.Int.Ed.1998,37,1986-2012) synthesized oxazolborane B-H-4 from chiral diphenylprolinol and borane tetrahydrofuran, and also used chiral Diphenylprolinol and methylboronic acid synthesize...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D207/08
CPCC07B2200/07C07D207/08Y02P20/55
Inventor 张蕴仪于晓琳高雅黄小满
Owner 上海福乐医药科技有限公司
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