Chiral synthesis method of ephedrine key intermediate (S)-2-methylamino-1-phenyl-1-acetone

Abstract

The invention discloses a chiral synthesis method of an ephedrine key intermediate (S)-2-methylamino-1-phenyl-1-acetone. The method comprises the following steps: carrying out nucleophilic substitution reaction on dimethyl-(4S, 5S)-2-[(R)-1-bromoethyl]-2-phenyl-1, 3-dioxyethane-4, 5-dicarboxylate (2a) and methylamine in an SN2 reaction environment to finish Walden inversion to generate dimethyl-(4S, 5S)-2-[(S)-1-methylamino]-2-phenyl-1, 3-dioxyethane-4, 5-dicarboxylate(3a); and then removing a chiral auxiliary agent (2S, 3S)-dimethyl tartrate to obtain (S)-2-methylamino-1-phenyl-1-acetone (1a). The compound can be used as a substrate for potassium borohydride reduction in the ephedrine preparation process, so that traditional complicated physical and chemical coexisting splitting operation of dibenzoyl tartaric acid is avoided, and the method has an important industrial application value.

Description

technical field

[0001] The invention belongs to the field of synthesis of pharmaceutical intermediates, and in particular relates to a chiral synthesis method of (S)-2-methylamino-1-phenyl-1-acetone, a key intermediate of ephedrine. Background technique

[0002] Ephedrine is an important drug, which has been produced by the following process routes for a long time:

[0003]

[0004] In this process route, the brominated propiophenone generated by bromination is first carried out at the α-position of propiophenone, and the obtained brominated propiophenone is a racemic mixture of S and R. Then carry out the methylation reaction, methylamine nucleophilic substitution of bromine, due to the experience of SN 1 The process of generating methylaminopropiophenone is also a racemic mixture of S and R, the ratio is also 50:50, and the optical rotation is 0°.

[0005] However, whether it is ephedrine or pseudoephedrine, the carbon atom connected by the methylamine group is in the...

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