Synthesis process of chiral catalyst

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...

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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

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