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Method for preparing lurasidone

A technology of lurasidone and benzo, which is applied in the field of preparation of lurasidone, can solve the problems of complex process operation and low product yield, and achieve cheap and easy reagents, high total yield and short reaction time Effect

Active Publication Date: 2014-06-18
四川弘远药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] In order to solve the problems of complex process operation, low product yield and lurasidone that need to be disassembled in the above-mentioned prior art, the present invention provides a simple operation process, high product yield and no disassembly. Preparation method of lurasidone capable of obtaining single enantiomer

Method used

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  • Method for preparing lurasidone
  • Method for preparing lurasidone
  • Method for preparing lurasidone

Examples

Experimental program
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Effect test

Embodiment 1

[0041] Add (R,R)-1,2-bis(methylsulfonyl-2-oxymethyl)cyclohexane (10.0 g, 0.033 mol) and 1-(1,2-benzisothiazole-3 - Base) piperazine (7.7g, 0.033mol), then add 100ml of acetonitrile, 7.0g (0.066mol) of sodium carbonate, stir and reflux for 24 hours, TLC (methanol:petroleum ether=8:1) detects that there is still raw material 1- (1,2-benzisothiazol-3-yl)piperazine did not complete the reaction, continue to react for 24 hours, TLC (methanol:petroleum ether=8:1) detection raw material point 1-(1,2-benzisothiazole-3 - Base)piperazine had a little unreacted, the solvent was spin-dried, slurried with 50ml of toluene at 100°C for 2 hours, filtered hot, and the solid was dried to obtain 7.12g of the product, with a yield of 51.0%.

[0042] Add 7.12g of the product from the previous step and 2.78g (0.0168mol) of bicyclo[2.2.1]heptane-2,3-dicarboximide (Compound V) into the reaction flask, add 70ml of solvent toluene, 5.8g of potassium carbonate ( 0.042mol), heated and refluxed for 12 ho...

Embodiment 2

[0044]Add (R,R)-1,2-bis(methylsulfonyl-2-oxymethyl)cyclohexane (10 g, 0.033 mol) and 1-(1,2-benzisothiazole-3- Base) piperazine (7.7g, 0.033mol), then add 50ml of acetonitrile, sodium carbonate 9.5g (0.090mol), stir and reflux for 48 hours, TLC (methanol:petroleum ether=8:1) detection of raw materials 1-(1, 2 benzisothiazol-3-yl)piperazine was not completely reacted, and the reaction was continued for 8 hours, and then bicyclo[2.2.1]heptane-2,3-dicarboximide (compound V) (5.45g. 0.033mol) and toluene 100ml, continue to reflux for 12 hours, TLC (ethyl acetate:petroleum ether=1:1) detects that compound IV has not reacted completely, the target product lurasidone is rarely formed, and there are many impurities, spin-dried organic solvent, recrystallization from ethyl acetate failed to yield a solid.

Embodiment 3

[0046] Add (R,R)-1,2-bis(methylsulfonyl-2-oxymethyl)cyclohexane (10 g, 0.033 mol) and 1-(1,2-benzisothiazole-3- Base) piperazine (7.7g, 0.033mol), then add 100ml acetonitrile, sodium carbonate 9.5g (0.090mol), stir and reflux for 48 hours, TLC (methanol:petroleum ether=8:1) detection raw material 1-(1, 2 benzisothiazol-3-yl)piperazine was not completely reacted, and the reaction was continued for 8 hours, and then bicyclo[2.2.1]heptane-2,3-dicarboximide (compound V) (5.45g. 0.033mol), continue to reflux for 12 hours, TLC (ethyl acetate:petroleum ether=1:1) detects that compound Ⅳ has not reacted completely, the target product lurasidone is less generated, and there are more impurities. Recrystallization from ethyl ester failed to yield a solid.

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Abstract

The invention provides a method for preparing lurasidone. The preparation method comprises reacting 1-(1,2-benzisothiazol-3-yl) piperazine with (R, R)-1,2-bis(methylsulfonyl-methoxy) cyclohexane in a mixed solvent of acetonitrile / water in presence of bicarbonate as a base, adding toluene or xylene, separating an organic layer out, adding bicyclo [2.2.1] heptane-2,3-dicarboximide and carbonate into the organic layer and reacting to obtain lurasidone. The conventional separation and purification steps are omitted and the cost of production is greatly reduced; at the same time, the method has the characteristics of high yield and high purity of the product.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a preparation method of lurasidone. Background technique [0002] Lurasidone (Lurasidone, trade name Latuda) is a new type of atypical antipsychotic, which belongs to benzisothiazole derivatives. Lurasidone is a dopamine D2 and 5-hydroxytryptamine 2A (5-HT2A) receptor antagonist with high affinity for both receptors and dopamine receptors. On October 28, 2010, the US Food and Drug Administration (FDA) approved its listing for the treatment of schizophrenia. [0003] The Chinese chemical name of lurasidone is: (3aR,4S,7R,7aS)-2{(1R,2R)-2-[4-(1,2-benzisothiazol-3-yl)piperazine- 1-ylmethyl]cyclohexylmethyl}hexahydro-1H-4,7-methylisoindole-1,3-dione, the structure is shown in formula 1, that is, compound Ⅰ: [0004] Formula 1: [0005] [0006] US5532372 discloses a synthesis method of lurasidone: adding the compound of formula (V) and compound of formula (IV) sodium carbonate in...

Claims

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Application Information

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IPC IPC(8): C07D417/12
CPCC07D417/12
Inventor 柯潇杨俊
Owner 四川弘远药业有限公司
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