Method for synthesizing tetrabenazine

Abstract

The invention discloses a method for synthesizing tetrabenazine. The method comprises: step one, using a dimethylamine aqueous solution and a formaldehyde aqueous solution as initial materials to be reacted1 to obtain tetramethyl methane diamine; step two, dissolving the tetramethyl methane diamine obtained in the step one in an organic solvent, dropwise adding acetyl chloride and 5- methyl-2-hexanone, and performing amine methylation to obtain an intermediate 3-[(dimethyl amino) methyl]-5-methyl-2-hexanone; and step three, reacting the 3-[(dimethyl amino) methyl]-5-methyl-2-hexanone obtained in the step two with 6,7-dimethoxy-3,4-dihydroisoquinoline hydrochloride to obtain the tetrabenazine. According to the method for synthesizing tetrabenazine, the cheap and accessible materials are used as the initial materials, imine salts serve as amine methylation reagents to perform amine methylation reaction on the 5- methyl-2-hexanone, and accordingly, the region-selectivity of chemical reactions is improved; and water serves as a reaction solvent to prepare the tetrabenazine, so that the operation is simple and convenient, no complex post-processing process exists, and good industrial application prospects are provided.

Description

technical field [0001] The invention belongs to the field of pharmaceutical chemical synthesis, in particular to a synthetic method of tetrabenazine. Background technique [0002] Tetrabenazine was first listed in Switzerland and was initially used for the treatment of schizophrenia. In August 2008, it was approved by the U.S. Food and Drug Administration (FDA) for fast-track approval, becoming the first and only drug for the treatment of Huntington's disease (HD) in the United States. HD is an inherited, fatal, degenerative brain disease characterized by personality changes, slurred speech, emotional lability, involuntary movements, and drunkenness. Usually occurs in middle age. Due to the death of cells in the caudate nucleus of the brain, the ability to speak, move, think and swallow is gradually lost. The disease will continue to develop for about 15 to 20 years and eventually lead to death. Tetrabenazine produces pharmacological activity mainly by reversibly inhibitin...

AI Technical Summary

Problems solved by technology

The disadvantage of this method is that the preparation yield of 3-isobutyl-3-buten-2-one is very low, easy to polymerize, and more toxic

The shortcoming of this method is that when 5-methyl-2-hexanone carries out Mannich reaction to prepare 3-[(dimethylamino)methyl]-5-methyl-2-hexanone, generate isomer 1-(di Methylamino)-6-methyl-3-heptanone (content as high as 30%), and the boiling point of the isomer is close to that of the product, so it cannot be purified by rectification, which makes purification difficult and requires column chromatography to separate and purify , and the reaction yield is extremely low (16%), it is necessary to recycle excess 5-methyl-2-hexanone raw material

The disadvantage of this method is that the preparation of 3-[(dimethylamino)methyl]-5-methyl-2-hexanone requires the use of expensive 1-bromo-2-methylpropane and the use of a large amount of potassium carbonate And a large amount of methyl tert-butyl ether solvent, difficult to filter, many and complicated operation steps, low yield (20%), the above shortcomings lead to high raw material costs, high solvent recovery costs, and a large amount of solid waste; Synthesis of butylbenzene During nazine, use a large amount of acetone as solvent, and yield is lower

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