Half-quantity resolution method of racemic mixture of tetrahydroisoquinoline type compound

Abstract

The invention discloses a half-quantity resolution method of a racemic mixture of a tetrahydroisoquinoline type compound. The half-quantity resolution method comprises the following steps: dissolving hydrochloride of the tetrahydroisoquinoline type compound into water and alkalifying under an alkaline condition to obtain the racemic mixture; dissolving the racemic mixture into a polar solvent; under a heating condition, enabling the racemic mixture to react with a single half-quantity resolution agent N-acyl-D-amino acid or D-diphenylacyl tartaric acid, so as to form salt; or after enabling the racemic mixture to react with the resolution agent N-acyl-D-amino acid for a period of time, adding the other resolution agent D-diphenylacyl tartaric acid and reacting to form the salt; after reacting, slowly cooling and crystalizing and carrying out a post-treatment process, so as to directly obtain R configuration tetrahydroisoquinoline type compound salt with high optical purity. According to the half-quantity resolution method, the half quantity of the mixed resolution agent or the half quantity of the single resolution agent is utilized, so that the dosage of the resolution agent is saved; recrystallization is not needed and a design is reasonable; the preparation method is simple and convenient and has high practicability; the total yield of an R configuration product can reach 83.25 percent at maximum and the purity can reach 97 percent or more at maximum.

Description

technical field

[0001] The invention relates to a half-quantity resolution method for racemates of tetrahydroisoquinoline compounds, belonging to the technical field of medicine. Background technique

[0002] R-tetrahydroisoquinoline compounds are important raw materials for the synthesis of other derivatives, have high pharmacological activity, can inhibit the biosynthesis of dopamine, and are used for the treatment of cardiovascular and cerebrovascular sclerosis, surgical anesthesia and cardiovascular diseases. Among them, R-tetrahydropapaverine is an important intermediate of the anesthetic cisatracurium besylate and is widely used.

[0003] Patents US5453510 and CN10147529A use N-acetyl-L-leucine as a resolving agent to resolve tetrahydroisoquinoline racemates, all of which require multiple recrystallizations to obtain products with higher purity, which is time-consuming and complicated to operate, which is not conducive to industrial production. Patent CN200710020587 ...

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