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A kind of preparation method of dgat-1 inhibitor intermediate

A technology of reagents and reaction solvents, applied in the field of preparation of pharmaceutical intermediates, can solve problems such as high raw material costs, many reaction steps, and instability, and achieve the effects of simplifying carbon chains, reducing raw material costs, and increasing total yield

Active Publication Date: 2016-09-14
PORTON FINE CHEM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] These processes have problems such as high cost of raw materials, many reaction steps, low or unstable yields, etc.

Method used

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  • A kind of preparation method of dgat-1 inhibitor intermediate
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  • A kind of preparation method of dgat-1 inhibitor intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0035] 1. Synthesis of trans-4-(4-chlorophenyl)cyclohexylformyl chloride:

[0036]

[0037] Add 28.7g of trans-4-(4-chlorophenyl)cyclohexyl-1-carboxylic acid into a 250ml four-necked flask, then add 103.9g of toluene and 0.72g of N,N-dimethylformamide, and raise the temperature under nitrogen protection to 50°C. Shake 15.0 g of thionyl chloride and 19.9 g of toluene to form a uniform solution, control the temperature at 50° C., and slowly drop the above thionyl chloride solution into the reaction system. After dropping, the temperature was controlled and stirred at 50°C for 4 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and 247.7 g of toluene was added under nitrogen protection, and shaken to form a toluene solution of trans-4-(4-chlorophenyl)cyclohexylformyl chloride. It is a light yellow liquid, containing a small amount of white solid. This solution is directly used in the step of trans-4-(4-chlorophenyl)cyclohexyldiazone, ...

Embodiment 2

[0048] 1. Synthesis of trans-4-(4-bromophenyl)cyclohexylformyl chloride:

[0049]

[0050]Add 34g of trans-4-(4-bromophenyl)cyclohexyl-1-carboxylic acid into a 250ml four-necked flask, then add 105g of toluene and 0.75g of N,N-dimethylformamide, and heat up to 50 ℃. Shake 15.0 g of thionyl chloride and 20.5 g of toluene to form a uniform solution, control the temperature at 50° C., and slowly drop the above thionyl chloride solution into the reaction system. After dropping, the temperature was controlled and stirred at 50°C for 4 hours. After the reaction, the solvent was evaporated under reduced pressure, and 251.6 g of toluene was added under nitrogen protection, and shaken to form a toluene solution of trans-4-(4-bromophenyl)cyclohexylformyl chloride. It is a light yellow liquid, containing a small amount of white solid. This solution is directly used in the step of trans-4-(4-bromophenyl)cyclohexyldiazone, and the yield is quantitative.

[0051] 2. Synthesis of trans-...

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Abstract

The invention discloses a method for preparing a DGAT-1 inhibitor intermediate. The method comprises the following steps: reacting trans-4-(4-halogeno phenyl)cyclohexanecarboxylic acid chloride with diazomethane, and generating trans-4-(4-halogeno phenyl)cyclohexyl diazo-ketone; and performing Wolff rearrangement on trans-4-(4-halogeno phenyl)cyclohexyl diazo-ketone, and generating trans-4-(4-halogeno phenyl)cyclohexyl acetic acid. According to the method disclosed by the invention, the reaction steps are reduced, and the raw material cost is reduced.

Description

technical field [0001] The invention relates to a preparation method of a pharmaceutical intermediate, in particular to a preparation method of a DGAT-1 inhibitor intermediate. Background technique [0002] Trans-4-p-halophenylcyclohexyl acetate, especially trans-4-p-chlorophenylcyclohexyl acetate and trans-4-p-iodophenylcyclohexyl acetate is an important class of The pharmaceutical intermediate of diacylglycerol acyltransferase (DGAT) can be used to synthesize the drug LCQ-908, which is being researched by Novartis for the treatment of chylomicronemia syndrome, diabetes and hypertriglyceridemia. The project is currently in the third phase of clinical trials and is expected to be launched in the near future. [0003] The synthesis method of LCQ-908 reported in WO2007126957 uses 4-(4-hydroxyphenyl)cyclohexanone as raw material to synthesize compound A, and then obtain LCQ-908: [0004] [0005] In addition, JP2008255024 reported that the synthetic method of trans-4-p-iod...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C57/62C07C51/00C07C69/65C07C67/08C07C245/14
CPCC07C51/00C07C67/08C07C245/14C07C2601/14C07C57/62C07C69/65
Inventor 王雷明陈洪利杨志路
Owner PORTON FINE CHEM
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