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A kind of preparation method of dgat1 inhibitor

A technology of inhibitors and acid-binding agents, applied in the field of medicine, can solve problems such as unsuitable purification, inability to remove, unfavorable process amplification, etc., to achieve the effects of avoiding post-processing, suitable process amplification, and reducing residues

Active Publication Date: 2021-10-08
QINGDAO HUANGHAI PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

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

Method used

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  • A kind of preparation method of dgat1 inhibitor
  • A kind of preparation method of dgat1 inhibitor
  • A kind of preparation method of dgat1 inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] Step 1: Condensation procedure, synthesis of intermediate 1

[0036] 950 g of starting material 3,5-dimethyl-4-(3-methyl-1-(2,2,2 trifluoroethyl)-1 hydrogen-pyrazol-4-yl)aniline-hydrochloride and 9.5L of dichloromethane were added to a 50L reactor, 630g of pyridine was added, the temperature of the reactor was adjusted to -5°C, 472g of chloroethyl chloroformate was added dropwise into the reactor, and stirred for 2 hours.

[0037] After the reaction was complete, water was added for extraction, and the organic phase was concentrated in vacuo to obtain 1.09 kg of Intermediate 1 with a yield of 98%.

[0038] Step 2: Cyclization, hydrolysis process, synthesis of intermediate 2

[0039] 1.09kg of Intermediate 1 and 11L of methanol were added to a 30L reactor, a solution of sodium hydroxide (408.9g) in water (2.2L) was added, the temperature of the reactor was adjusted to 80°C, and stirred at this temperature for 16 hours.

[0040] After the reaction was complete, the syst...

Embodiment 2

[0054] Step 1: Condensation procedure, synthesis of intermediate 1

[0055] 1.5 kg of starting material 3,5-dimethyl-4-(3-methyl-1-(2,2,2 trifluoroethyl)-1 hydrogen-pyrazol-4-yl)aniline-hydrochloric acid Add salt and 15L of dichloromethane into a 50L reactor, add 667g of pyridine, adjust the temperature of the reactor to -8°C, add 1.2kg of chloroethyl chloroformate dropwise into the reactor, and stir for 2 hours.

[0056] After the reaction was complete, water was added for extraction, and the organic phase was concentrated in vacuo to obtain 1.63 kg of Intermediate 1 with a yield of 99%.

[0057] Step 2: Cyclization, hydrolysis process, synthesis of intermediate 2

[0058] 1.6kg of Intermediate 1 and 16L of methanol were added to a 30L reactor, a solution of sodium hydroxide (985g) in water (3.2L) was added, the temperature of the reactor was adjusted to 80°C, and stirred at this temperature for 16 hours.

[0059] After the reaction was complete, the system was concentrated...

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Abstract

The invention belongs to the technical field of medicine, 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‑dihydropyrimidine[5,4‑f][1,4]oxazepine‑5(6H)‑one‑hydrochloride New preparation method. Starting from 3,5-dimethyl-4-(3-methyl-1-(2,2,2-trifluoroethyl)-1hydro-pyrazol-4-yl)aniline-hydrochloride Condensation reaction with chloroethyl chloroformate to generate intermediate 1; intermediate 1 is hydrolyzed after alkylation in alcohol and alkali solution to generate intermediate 2; intermediate 2 undergoes condensation reaction with 4,6-dichloropyrimidine-5-acyl chloride Intermediate 3 is generated; intermediate 3 is alkylated and intramolecular ring-closing reaction generates intermediate 4; intermediate 4 is ammonified in ammonia dioxane solution to generate intermediate 5; intermediate 5 is in acetone solution of hydrochloric acid Salt is made into finished products. All reaction intermediates of the present invention are solid and easy to purify.

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...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D498/04
CPCC07D498/04
Inventor 刘宁宁伦晓妮辛海强李延顺
Owner QINGDAO HUANGHAI PHARM CO LTD