Improved synthetic method of (R)-1-aryl-2-propylamine

Abstract

The invention provides an improved synthetic method of (R)-1-aryl-2-propylamine. The improved synthetic method comprises the following steps of: adopting 1-arylacetone as a raw material, adding (R)-1-phenylethylamine, carrying out reductive amination reaction with hydrogen under a common action of a Lewis acid additive and a transitional metal hydrogenation catalyst; carrying out Pd / C catalytic hydrogenation on an obtained intermediate to remove phenethyl on nitrogen and thus obtaining (R)-1-aryl-2-propylamine. The improved synthetic method provided by the invention has the beneficial effectsthat the operation is simple, the adopted Lewis acid additive is low in cost and easy in obtaining, the yield and the enantioselectivity of a product are high, and the application value for industrialsynthesis of (R)-1-aryl-2-propylamine is very high.

Description

technical field [0001] The invention relates to an improved synthesis method of (R)-1-aryl-2-propylamine, which belongs to the field of drug synthesis. Background technique [0002] Chiral 1-aryl-2-propanamine drugs such as selegiline, tamsulosin, silodosin, formoterol, lisdexamphetamine dimesylate, and darunavir are widely used in Clinical treatment has very important social and economic value. Among these drugs, all have the core structure of (R)-1-aryl-2-propanamine, and basically all use (R)-1-aryl-2-propanamine as raw material for synthesis. At present, a variety of different methods have been developed for the synthesis of (R)-1-aryl-2-propanamine, mainly including: (1) preparation of (R)- 1-aryl-2-propanamine (J. Med. Chem. 2016, 59, 3826). The yield of this method is no more than 50%, half of the raw material is wasted, and the economy is poor; (2) prepared by the asymmetric catalytic reductive amination reaction of 1-aryl acetone (Angew.Chem.Int.Ed.2016, 55 , 53...

AI Technical Summary

Problems solved by technology

The yield of this method is no more than 50%, half of the raw material is wasted, and the economy is poor; (2) prepared by the asymmetric catalytic reductive amination reaction of 1-aryl acetone (Angew.Chem.Int.Ed.2016, 55 , 5309)

This method has high atom economy, but needs expensive and difficult-to-synthesize chiral noble metal catalysts and chiral ligands, and the production cost is too high; (3) through 1-aryl acetone and (R)-1-phenylethyl ether Amines are prepared by reductive amination under the action of transition metal hydrogenation catalysts (Org.Lett.2005, 7, 2005)

This method raw material is easy to get, and operation is simple, and production cost is low, but there is low yield for many 1-aryl acetone substrates, the shortcoming that diastereoselectivity is not high

[0003] In summary, the existing synthetic methods of multiple (R)-1-aryl-2-propylamines have their own shortcomings and cannot fully meet the requirements of high yield, low cost and environmental protection. Therefore, the development of (R) - The new process of efficient and low-cost synthesis of 1-aryl-2-propanamine has high industrial application value

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