Preparation method of DGAT1 inhibitor

Abstract

Belonging to the field of medical technology, the invention specifically relates to a new preparation method of a DGAT1 inhibitor 4-amino-6-(3, 5-dimethyl-4-(3-methyl-1-(2, 2, 2-trifluoroethyl)-1H-pyrazole-4-yl)phenyl)-7, 8-dihydropyrimidine[5, 4-f][1, 4]oxazepine-5(6H)-one-hydrochloride. The method includes: taking 3, 5-dimethyl-4-(3-methyl-1-(2, 2, 2-trifluoroethyl)-1hydro-pyrazole-4-yl)aniline-hydrochloride as the starting raw material for condensation reaction with chloroethyl chloroformate to generate an intermediate 1; alkylating the intermediate 1 in an alcohol and alkali solution and then performing hydrolysis to generate an intermediate 2; subjecting the intermediate 2 to condensation reaction with 4, 6-dichloropyrimidine-5-acyl chloride to generate an intermediate 3; alkylating the intermediate 3, then carrying out intramolecular ring closure reaction to generate an intermediate 4; subjecting the intermediate 4 to ammoniation in a dioxane solution of ammonia to generate an intermediate 5; and subjecting the intermediate 5 to salt formation in an acetone solution to obtain a finished product. All the reaction intermediates involved in the invention are all solids, thus being easy for purification.

Description

technical field [0001] The invention belongs to the field of medical technology, in particular to a DGAT1 inhibitor 4-amino-6-(3,5-dimethyl-4-(3-methyl-1-(2,2,2-trifluoroethyl) )-1H-pyrazol-4-yl)phenyl)-7,8-dihydropyrimidin[5,4-f][1,4]oxazepine-5(6H)-one-hydrochloride New preparation method. Background technique [0002] DGAT1 inhibitors are diacylglycerol acyltransferases whose indications include familial chylomicronemia syndrome (FCS), diabetes, obesity, hyperlipoproteinemia or hypertriglyceridemia. Genetic deficiency and inhibition of DGAT1 prevents obesity caused by high-fat diets and improves insulin sensitivity without side effects. [0003] The structural formula of the DGAT1 inhibitor is: [0004] [0005] The current patent application number for the DGAT1 inhibitor compound is 201310371069.0, and there are two specific preparation methods, [0006] Route 1 [0007] [0008] Route 1 has the following defects: in this route, intermediate 9 needs to be sep...

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Problems solved by technology

[0008] Route 1 has the following defects: in this route, intermediate 9 needs to be separated and purified by column to remove isomers, which is difficult, low yield, and unfavorable for process amplification; intermediates 3 to 5 need to be recrystallized with methanol to obtain higher purity product, but the yield is on the low side; the last step of the Suzuki reaction requires multiple beating methods to obtain a high-purity product, the yield is reduced, and the removal of the heavy metal Pd is difficult to reach the limit

[0011] Route 2 has the following defects: the number of steps is long, and the multi-step intermediates are all oily; the polarity is too small, it is not suitable for purification, and the quality control of the intermediates is difficult; in the first step, disubstituted by-products are easily produced, which cannot Removed in workup; intermediate 13 still needs to be purified by column separation to remove isomers

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