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Preparation method of lurasidone intermediate and lurasidone

A lurasidone and body type technology, applied in the preparation of sulfonates, organic chemistry and other directions, can solve the problems of long reaction time, high cost, troublesome post-processing, etc., and achieve short reaction time, low cost and simple post-processing. Effect

Active Publication Date: 2012-10-17
天津泰普制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] 1. The reaction time is long. It takes 23 hours to prepare the compound of formula (II), and 16 hours to prepare the racemate of formula (I)
[0006] 2. The post-processing is troublesome, and the finished product needs to be separated by column chromatography. The cost is high and it is difficult to transform into industrial production

Method used

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  • Preparation method of lurasidone intermediate and lurasidone
  • Preparation method of lurasidone intermediate and lurasidone
  • Preparation method of lurasidone intermediate and lurasidone

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] 27g of compound of formula (Ⅴ), 18g of compound of formula (Ⅳ), 10g of potassium carbonate (ground and sieved, average particle size 198 microns), 1g of tetrabutylammonium bromide and 300ml of toluene are added in the reaction flask equipped with water separator , heated to reflux to separate water, and after 12 hours, the TLC plate was spotted, and the raw materials basically disappeared. Stop the reaction, filter while hot, evaporate the filtrate to dryness, and recrystallize from acetonitrile to obtain 26 g of the compound of formula (II), with a yield of 75% and a melting point of 228-230°C. 1 H-NMR (CDCl 3 )δ: 1.25-1.31 (4H, m), 1.82-2.22 (8H, m), 2.72 (3H, s), 3.36 (2H, t), 3.88-4.08 (10H, m), 7.37 (1H, t) , 7.46(1H, t), 7.78(1H, d), 7.94(1H, d) (see figure 2 ).

Embodiment 2

[0030] 27g of compound of formula (Ⅴ), 18g of compound of formula (Ⅳ), 8g of sodium carbonate (grinding and sieving, average particle diameter of 198 microns), 1g of tetrabutylammonium bromide and 300ml of toluene are added in the reaction flask equipped with water separator , heated to reflux to separate water, and after 11 hours, the TLC plate was spotted, and the raw materials basically disappeared. Stop the reaction, filter while hot, evaporate the filtrate to dryness, and recrystallize from acetonitrile to obtain 25.8 g of the compound of formula (II), with a yield of 74% and a melting point of 228-230°C. 1 H-NMR (CDCl 3 )δ: 1.25-1.31 (4H, m), 1.82-2.22 (8H, m), 2.72 (3H, s), 3.36 (2H, t), 3.88-4.08 (10H, m), 7.37 (1H, t) , 7.46(1H, t), 7.78(1H, d), 7.94(1H, d) (see figure 2 ).

Embodiment 3

[0032] 27g of compound of formula (Ⅴ), 18g of compound of formula (Ⅳ), 10g of potassium carbonate (ground and sieved, average particle diameter of 165 microns), 1g of tetrabutylammonium bisulfate and 300ml of toluene are added in the reaction flask equipped with water separator , heated to reflux to separate water, and after 10 hours, the TLC plate was spotted, and the raw materials basically disappeared. Stop the reaction, filter while hot, evaporate the filtrate to dryness, and recrystallize from acetonitrile to obtain 26.4 g of the compound of formula (II), with a yield of 76% and a melting point of 228.5-230.5°C. 1 H-NMR (CDCl 3 )δ: 1.25-1.31 (4H, m), 1.82-2.22 (8H, m), 2.72 (3H, s), 3.36 (2H, t), 3.88-4.08 (10H, m), 7.37 (1H, t) , 7.46(1H, t), 7.78(1H, d), 7.94(1H, d) (see figure 2 ).

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Abstract

The invention provides a preparation method of a lurasidone intermediate, a compound as shown in formula (II). The method comprises: in the presence of an acid binding agent and a phase transfer catalyst, adding a compound as shown in formula (V) and a compound as shown in formula (IV) into a solvent, conducting heating, refluxing, and water division so as to obtain the compound as shown in formula (II), and in the presence of an acid binding agent, adding the compound as shown in formula (II) and a compound as shown in formula (III) into the solvent for refluxing and water division reaction so as to obtain a formula (I)-racemate, then performing splitting with a tartaric acid enantiomer, thus obtaining the compound lurasidone as shown in formula (I). The preparation method of the lurasidone intermediate and lurasidone of the invention is characterized by short reaction time, simple post-treatment, abolition of column chromatography, and low cost, thus being suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a lurasidone intermediate and a preparation method of lurasidone. Background technique [0002] Lurasidone (Lurasidone) was developed by Japan's Sumitomo Pharma Co., Ltd. (Dainipon Sumitomo Pharma Co., Ltd.). Lurasidone is a dual-action antipsychotic drug, which has high affinity for both 5-HT2 receptors and dopamine D2 receptors, and has a significant effect on both positive and negative symptoms of psychosis. European patent EP464864 reports the preparation method of lurasidone: add the compound of formula (V) and sodium carbonate of compound of formula (IV) into acetonitrile for reflux reaction for 23 hours, filter while hot, and filter under cooling to obtain the compound of formula (II). Then the compound of formula (II) and compound of formula (III), salt of wormwood and dibenzo-18-crown ether-6 were added and refluxed in xylene for 16 hours, separated by colu...

Claims

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Application Information

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IPC IPC(8): C07D487/10C07D417/12C07C309/04C07C303/32
Inventor 陈蔚潘毅陶勇康江鹏程玉红
Owner 天津泰普制药有限公司
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