Synthetic method of (S)-1,2,3,4-tetrahydroisoquinoline tert-butyrylamide with high optical purity

Abstract

The invention relates to a synthetic method of (S)-1,2,3,4-tetrahydroisoquinoline tert-butyrylamide with high optical purity, comprising the following steps: 1. allowing a quinoline carboxylic acid compound (2) to react with dimethyl carbonate at the temperature of 0-95 DEG C to prepare a N-methyl formate compound (3), wherein, halogeno salt is taken as a catalyst and dimethyl carbonate is taken as solvent; 2. performing aminolysis to the compound (3) by tert-butylamine at the temperature of 20-160 DEG C to prepare a compound (4), wherein, arene or halogenated hydrocarbon inert solvent is adopted; 3. carrying out decarboxylation reaction to the compound (4) by halogenated acid at the temperature of -50-80 DEG C to prepare an amide compound (5), wherein, the mixed solvent of arene or halogenated hydrocarbon and water is adopted; and 4. mixing alkali with sodium hydroxide, extracting, concentrating and crystallizing to obtain a target product. An environmental-friendly and clean raw material of dimethyl carbonate is adopted, highly toxic raw materials such as phosgene and the like are not used so as to avoid reaction with certain danger in case of low temperature, ultralow temperature, hydrogenation and the like. The synthetic method has low raw material cost and is suitable for industrial production.

Description

technical field

[0001] The invention relates to a synthesis method of (S)-1,2,3,4-tetrahydroisoquinoline tert-butyramide with high optical purity. Background technique

[0002] (S)-1,2,3,4-Tetrahydroisoquinoline tert-butyramide is a key intermediate in the synthesis of anti-AIDS drug nelfinavir. Currently reported synthesis methods mainly include the following three categories:

[0003] (1) Using (S)-1,2,3,4-tetrahydroisoquinolinecarboxylic acid as raw material, adopting phosgene or diphosgene to prepare internal acid anhydride, and then acylation with tert-butylamine to obtain the target compound (see patent us6433177, 6340760, 5587481).

[0004] (2) Using phenylalanine as a raw material, using benzyl chloroformate to protect the amino group to obtain a compound, and then using tert-butyl chloroformate to make an active ester, and performing amination to obtain a compound, which is cyclized to form N-benzyloxycarbonyl 1 , 2,3,4-Tetrahydroisoquinoline tert-butyramide (com...

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