Method for preparing lurasidone with high purity and high yield

A lurasidone, high-yield technology, applied in the field of preparation of pharmaceutical compounds, can solve the problems of easy generation of impurities, shortened reaction time, and lack of quality of patents, and achieve the effect of controlling reaction impurities and reducing reaction reflux temperature

Inactive Publication Date: 2016-11-23
SHANGAI PHARMA GRP CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Other related patents or documents WO2012131606, US20110003994, CN102863437, etc. reported similar routes, the first step to synthesize condensate 1 uses acetonitrile or DMF as a solvent, and all at reflux temperature (85-150°C), and the reaction time is 20- 30h, such a high temperature and long time reaction will easily produce impurities, and with the shortening of the reaction time, the yield will decrease, and there is no quality report in the relevant patent

Method used

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  • Method for preparing lurasidone with high purity and high yield
  • Method for preparing lurasidone with high purity and high yield
  • Method for preparing lurasidone with high purity and high yield

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] 6g (20mmol) (1R, 2R)-1,2-bis(methanesulfonate oxymethyl)cyclohexane and 4.9g (22.3mmol) 3-(1-piperazinyl)-1 were put into the reaction flask, Add 2-benzisothiazole and 3.5g (25.3mmol) of potassium carbonate, add 50ml of acetonitrile and 1.5g (83mmol) of water, heat to reflux (82°C) for 3 hours, cool to room temperature after the reaction, filter to remove inorganic salts, the solution reduces Concentrate under reduced pressure until the solvent is exhausted, add 25ml of ethyl acetate, stir and crystallize, filter at 5°C, and dry in vacuo to obtain 7.7g of white crystals (condensate 1) (91% yield, HPLC≥98.0%).

[0029] Put 7.7g (18.2mmol) condensate 1 and 4.5g (32.6mmol) potassium carbonate and 60ml toluene in the reaction flask, stir for 5min, add 3.2g (19.4mmol) (3aR, 4S, 7R, 7aS) 4,7- Methylene-1H-isoindole-1,3(2H)-dione, heated to reflux (108°C) for 3 hours, cooled to room temperature after the reaction, added 50ml of water and stirred, then stood still, separated to...

Embodiment 2

[0031] 6g (20mmol) (1R, 2R)-1,2-bis(methanesulfonate oxymethyl)cyclohexane and 4.9g (22.3mmol) 3-(1-piperazinyl)-1 were put into the reaction flask, Add 2-benzisothiazole and 3.5g (25.3mmol) potassium carbonate, add 45ml acetonitrile, 2g (62.5mmol) methanol and 1g (55.5mmol) water, heat to reflux (78°C) for 3h, cool to room temperature after the reaction, Filter to remove inorganic salts, concentrate the solution under reduced pressure until the solvent is exhausted, add 25ml of ethyl acetate to stir and crystallize, filter at 5°C, and vacuum-dry to obtain 7.6g of white crystals (condensate 1) (yield 89.8%, HPLC≥97.5%) .

[0032] Put 7.6g (17.9mmol) condensate 1 and 4.5g (32.6mmol) potassium carbonate and 60ml toluene in the reaction flask, stir for 5min, add 3.2g (19.4mmol) (3aR, 4S, 7R, 7aS) 4,7- Methylene-1H-isoindole-1,3(2H)-dione, heated to reflux (108°C) for 3 hours, cooled to room temperature after the reaction, added 50ml of water and stirred, then stood still, separa...

Embodiment 3

[0035] 6g (20mmol) (1R, 2R)-1,2-bis(methanesulfonate oxymethyl)cyclohexane and 4.9g (22.3mmol) 3-(1-piperazinyl)-1 were put into the reaction flask, Add 2-benzisothiazole and 3.5g (25.3mmol) potassium carbonate, add 50ml acetonitrile and 3.2g (100mmol) methanol, heat to reflux (75°C) for 3.5h, cool to room temperature after the reaction, filter to remove inorganic salts, the solution Concentrate under reduced pressure until the solvent is exhausted, add 25ml of ethyl acetate, stir and crystallize, filter at 5°C, and dry in vacuo to obtain 7.4g of white crystals (condensate 1) (yield 87.5%, HPLC≥95.0%).

[0036] Put 7.4g (17.5mmol) condensate 1 and 4.4g (31.9mmol) potassium carbonate and 60ml toluene in the reaction flask, stir for 5min, add 3.1g (18.8mmol) (3aR, 4S, 7R, 7aS) 4,7- Methylene-1H-isoindole-1,3(2H)-dione, heated to reflux (108°C) for 3 hours, cooled to room temperature after the reaction, added 50ml of water and stirred, then stood still, separated to remove the wa...

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Abstract

The invention provides a method for preparing lurasidone with high purity and high yield. On the basis of an existing lurasidone preparation method, a small quantity of specific protic solvent is added in the preparation process of (R,R)-3a,7a-9H-isoindole-2-1'-[4'-(1,2-benzisothiazole-3-yl)] piperazine mesylate, so that the reaction rate is greatly increased, the time is shortened to 3 h from 23 h in the prior art, the yield is increased from 82% to 90%, the total yield is up to 71%, and the prepared finished product has the consistent quality with original drugs.

Description

technical field [0001] The invention relates to the preparation of a pharmaceutical compound, in particular to a preparation method of lurasidone. Background technique [0002] Lurasidone (lurasidone) is a new type of atypical antipsychotic drug. On October 28, 2010, the U.S. Food and Drug Administration (FDA) approved it to go on the market. Its trade name is Latuda, and it is used for the treatment of schizophrenia. [0003] The original research patent EP0464846 reports that the synthetic route is that (1R,2R)-1,2-bis(methanesulfonic acid oxymethyl)cyclohexane and 3-(1-piperazinyl)-1,2-benzoiso Add sodium carbonate to thiazole, reflux with acetonitrile as solvent for 23h to obtain condensate 1, use xylene as solvent and (3aR, 4S, 7R, 7aS) 4,7-methylene-1H-isoindole-1,3( Add potassium carbonate to 2H)-diketone, react under 18 crown 6 ether phase transfer catalyst to obtain condensate 2, and then obtain lurasidone through salt formation. The reaction time of this route is...

Claims

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Application Information

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IPC IPC(8): C07D417/12
Inventor 朱阳张红敏王恽青刘俊耀韩建生
Owner SHANGAI PHARMA GRP CO LTD
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