Method for preparing lurasidone hydrochloride intermediate

A technology for lurasidone hydrochloride and intermediates, which is applied in the field of medicine, can solve problems such as being unfavorable to industrial production and increasing production costs, and achieve the effects of low content of chiral impurities and promoting solvation

Inactive Publication Date: 2017-05-10
BEIJING VENTUREPHARM BIOTECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method will produce a large amount of highly toxic methanesulfonic acid during the process, which brings great challenges to the

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0021] Dissolve 200.0 g (0.4419 mol) (S,R)-cyclohexanedimethyl p-toluenesulfonate, 48.5 g (0.2210 mol) benzisothiazolylpiperazine and 30.5 g (0.2210 mol) potassium carbonate in 2000.0 ml In acetonitrile, the temperature was raised to reflux of the reaction system, and the reaction was carried out for 14 h. Naturally cooled to room temperature, stirred and crystallized for 4 h. Filter and rinse the filter cake with a small amount of acetonitrile. The filter cake was washed with 800.0 ml saturated aqueous sodium bicarbonate solution for 2 h. Filter again to collect the filter cake. The filter cake was dried in a forced air oven at 40°C for 14 h to obtain 80.8 g of beige powdery solid with a yield of 73.1%.

Embodiment 2

[0023] Dissolve 200.0 g (0.4419 mol) (S, R)-cyclohexanedimethyl p-toluenesulfonate, 53.8 g (0.2455 mol) benzisothiazolylpiperazine and 33.9 g (0.2455 mol) potassium carbonate in 2000.0 ml In acetonitrile, the temperature was raised to reflux of the reaction system, and the reaction was carried out for 14 h. Naturally cooled to room temperature, stirred and crystallized for 4 h. Filter and rinse the filter cake with a small amount of acetonitrile. The filter cake was washed with 1120.0 ml saturated aqueous sodium bicarbonate solution for 2 h. Filter again to collect the filter cake. The filter cake was dried in a blast oven at 40°C for 16 h to obtain 90.7 g of a beige powdery solid with a yield of 74.0%.

Embodiment 3

[0025] Dissolve 200.0 g (0.4419 mol) (S, R)-cyclohexanedimethyl p-toluenesulfonate, 53.8 g (0.2455 mol) benzisothiazolylpiperazine and 33.9 g (0.2455 mol) potassium carbonate in 2000.0 ml In acetonitrile, the temperature was raised to reflux of the reaction system, and the reaction was carried out for 14 h. Naturally cooled to room temperature, stirred and crystallized for 6 h. Filter and rinse the filter cake with a small amount of acetonitrile. The filter cake was washed with 1120.0 ml saturated aqueous sodium bicarbonate solution for 2 h. Filter again to collect the filter cake. The filter cake was dried in a blast oven at 40°C for 19 h to obtain 98.7 g of a beige powdery solid with a yield of 80.5%.

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Abstract

The invention discloses a method for preparing a lurasidone hydrochloride intermediate (formula I). (S,R)-p-toluene sulfonic acid cyclohexane dimethyl ester (formula II) and benzisothiazole piperazine (formula III) are dissolved in an aprotic polar solvent, a basic catalyst is used to serve as an acid binding agent, and heating reaction is performed for 10-24 h. The proper aprotic polar solvent is adopted to serve as a reaction medium for substitution reaction, a mixed feeding method is adopted, so that the reaction is performed quickly, the content of chiral impurities is low, and a postprocessing process is simple and convenient.

Description

technical field [0001] The invention belongs to the field of medical technology, and mainly relates to the drug lurasidone hydrochloride precursor (S, R)-cycloN, N-cyclohexane dimethylene-(N-benzisothiazolyl)-piperazine p-toluene Process research on sulfonates. Background technique [0002] Lurasidone hydrochloride, trade name Latuda, chemical name (3aR,4S,7R,7aS)-2-[(1R,2R)-2-[4-(1,2Benzisothiazol-3-yl ) piperazin-1-ylmethyl]cyclohexylmethyl]hexahydro-1H-4,7-methylisoindole-1,3-dione, which has both 5-HT2 receptors and dopamine D2 receptors It has a high affinity and has a significant effect on both positive and negative symptoms of mental patients, and is used for the treatment of schizophrenia. On October 28, 2010, it was approved by the US Food and Drug Administration (FDA) to be marketed in its territory. (S,R)-CycloN,N-cyclohexanedimethylene-(N-benzisothiazolyl)-piperazine p-toluenesulfonate is an atypical antipsychotic drug lurasidone hydrochloride (lurasidone) An...

Claims

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Application Information

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IPC IPC(8): C07D487/10
CPCC07D487/10
Inventor 吴雁斌赵国磊
Owner BEIJING VENTUREPHARM BIOTECH
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