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Lurasidone key intermediate preparation method

A technology of lurasidone and intermediates, applied in the field of compound synthesis, can solve the problems of low total yield, high cost, and large consumption of resolution reagents, and achieve the effect of easy industrial production and simple operation

Inactive Publication Date: 2017-07-14
CHANGZHOU VOCATIONAL INST OF ENG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method consumes a lot of resolution reagents, the total yield is low, and the cost is high, so it is not suitable for industrial production

Method used

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  • Lurasidone key intermediate preparation method
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  • Lurasidone key intermediate preparation method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022] The synthetic route of compound 1 is as follows:

[0023]

[0024] 4,-(1,2-Benzisothiazol-3-yl)-(3aR,7aR)-octahydrospiro-(2H-isoindole-2,1,-piperazine) methanesulfonate (5) Synthesis: In a reaction flask, add compound 4 (30.0g), compound 3 (20g), anhydrous potassium carbonate (12g), cyclodextrin (0.6g), toluene (200ml), reflux reaction for 4h, HPLC normalization Chemical method detection (detection condition: column Shim-pack VP-ODSC18 150mm*4.6mm / 5um, mobile phase acetonitrile: phosphate buffer = 80; 20, wavelength 230nm, flow velocity 1.0ml / min) raw material compound 4 is less than 0.5%, reaction After finishing, the reaction solution containing the product is directly used in the next step reaction.

[0025] Synthesis of lurasidone (2): Add compound 6 (18.1 g), anhydrous potassium carbonate (15.2 g), and water (1 ml) to the reaction flask containing compound 5 reaction solution, and reflux for 10 h. At the end, add water (300ml), stir, let the layers stand still...

Embodiment 2

[0028] 4,-(1,2-Benzisothiazol-3-yl)-(3aR,7aR)-octahydrospiro-(2H-isoindole-2,1,-piperazine) methanesulfonate (5) Synthesis: In a reaction flask, add compound 4 (30.0g), compound 3 (30g), anhydrous potassium carbonate (18g), cyclodextrin (0.6g), toluene (240ml), reflux reaction for 6h, HPLC normalization The chemical method detects that the raw material compound 4 is less than 0.5%, and the reaction is completed, and the reaction solution containing the product is directly used for the next reaction.

[0029] Synthesis of lurasidone (2): Add compound 6 (18.1 g), anhydrous potassium carbonate (15.2 g), and water (1 ml) to the reaction flask containing compound 5 reaction solution, and reflux for 10 h. Finished, add water (300ml), stir, static layering, the oil layer is adjusted to pH=4.5 with 1% hydrochloric acid, washed with water (200ml), the oil layer is concentrated under reduced pressure to quick dryness, and isopropanol is added for recrystallization, and a white solid 2 (...

Embodiment 3

[0032] 4,-(1,2-Benzisothiazol-3-yl)-(3aR,7aR)-octahydrospiro-(2H-isoindole-2,1,-piperazine) methanesulfonate (5) Synthesis: In a reaction flask, add compound 4 (30.0g), compound 3 (35g), anhydrous potassium carbonate (20g), cyclodextrin (0.6g), toluene (240ml), reflux reaction for 6h, HPLC normalization The chemical method detects that the raw material compound 4 is less than 0.5%, and the reaction is completed, and the reaction solution containing the product is directly used for the next reaction.

[0033]Synthesis of lurasidone (2): Add 6 (18.1g), anhydrous potassium carbonate (15.2g) and water (1ml) to the reaction flask containing the reaction solution of compound 5, reflux for 10h, and the reaction ends , add water (300ml), stir, static layering, the oil layer is adjusted to pH=5.5 with 5% hydrochloric acid, washed with water (200ml), the oil layer is concentrated under reduced pressure to quick dryness, isopropanol is added for recrystallization, and a white solid 2 (46...

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Abstract

The present invention relates to a lurasidone key intermediate preparation method, and belongs to the technical field of compound synthesis. According to the method, when 4,-(1,2-benzisothiazol-3-yl)-(3aR,7aR)-octahydrospiro(2H-isoindole-2,1-piperazine)methanesulfonate is generated, 4-(1,2-benzisothiazol-3-yl)-1-piperazine is adopted as a raw material, the 4-(1,2-benzisothiazol-3-yl)-1-piperazine, (1R,2R)-1,2-bis(methanesulfonyloxymethyl)cyclohexane and potassium carbonate are subjected to a reaction in a solvent toluene, and a cyclodextrin phase transfer catalyst is added to the reaction system. According to the present invention, by using the cyclodextrin as the phase transfer catalyst, the incomplete reaction problem is solved, and the yield is substantially improved.

Description

technical field [0001] The invention relates to a method for preparing a key intermediate of lurasidone, belonging to the technical field of compound synthesis. Background technique [0002] Lurasidone hydrochloride (Lurasidone HCl, 1) chemical name: (3aR,4S,7R,7aS)-2-[(1R,2R)-2-[4-(1,2-benzisothiazole-3- Base) piperazin-1-ylmethyl] cyclohexylmethyl] hexahydro-1H-4,7-methylisoindole-1,3-dione hydrochloride, which is developed by Japan Dainippon Sumitomo Atypical antipsychotic drugs, approved by the US FDA on October 28, 2010, for the first-line treatment of patients with schizophrenia, and its trade name is Latuda. In July 2013, it was approved for the treatment of bipolar depression in adults. Lurasidone (2) is the key intermediate of lurasidone hydrochloride. [0003] There are not many synthetic methods of lurasidone (2) reported in the literature, and the practical ones are mainly divided into five kinds. [0004] Method 1, U.S. Patent (US 5532372A, 1996-07-02) uses ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D417/12C07D471/10
CPCC07D417/12C07B2200/07C07D471/10
Inventor 祁秀秀陈文华郭亚楠
Owner CHANGZHOU VOCATIONAL INST OF ENG
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