Novel process for production of 5-{2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]-ethyl}-6-chloro-1,3-dihydro-2h-indol-2-one (ziprasidone)

A technology of benzisothiazole and ziprasidone base, applied in the preparation of 5-{2-[4-(1, which can solve the problem of not providing information on the source of the compound or the preparation method

Inactive Publication Date: 2009-05-20
RICHTER GEDEON NYRT
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This description provides no information about the source or method of preparation of the compound, but only demonstrates its use in place of the compound of formula VII

Method used

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  • Novel process for production of 5-{2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]-ethyl}-6-chloro-1,3-dihydro-2h-indol-2-one (ziprasidone)
  • Novel process for production of 5-{2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]-ethyl}-6-chloro-1,3-dihydro-2h-indol-2-one (ziprasidone)
  • Novel process for production of 5-{2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]-ethyl}-6-chloro-1,3-dihydro-2h-indol-2-one (ziprasidone)

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Example 1: Preparation of 5-(2-bromoethyl)-6-chloro-1,3-dihydro-2H-indol-2-one (III)

[0029] 40g (0.3mol) of anhydrous AlCl 3 Suspend in 80ml of dichloromethane, cool it to a temperature of 0-10°C and add dropwise 9.6ml (0.11mol) of bromoacetyl bromide after stirring for 30 minutes, then add 16.7g of 6-chloro-1,3- dihydro-2H-indol-5-one, and the reaction mixture was stirred at room temperature for 24 hours. The completion of the reaction was checked by thin layer chromatography. 35.1 ml (0.22 mol) of triethylsilane was added dropwise to the reaction mixture and heated to boiling point. After 30 minutes the mixture was poured onto ice, the precipitated material was filtered off, washed three times with 40 ml of water, then with 20 ml of methanol and dried.

[0030] 19.7 g of 5-(2-bromoethyl)-6-chloro-1,3-dihydro-2H-indol-2-one of the formula IV are obtained.

[0031] The material was characterized by the following NMR data:

[0032]1H NMR: 3.17t(2H)[H2-12]; 3.46s(2...

Embodiment 2a

[0033] Example 2a: Preparation of 5-(2-bromo-acetyl)-6-chloro-1,3-dihydro-2H-indol-5-one (IV)

[0034] 40g (0.3mol) of anhydrous AlCl 3 Suspended in 80ml of dichloromethane, cooled to 0-10°C, and after stirring for 30 minutes, 9.6ml (0.11mol) of bromoacetyl bromide was added dropwise, and then 16.7g of 6-chloro-1,3- dihydro-2H-indol-5-one, and the reaction mixture was stirred at room temperature for 24 hours. The completion of the reaction was checked by thin layer chromatography. The reaction mixture was poured onto ice, and the precipitated material was filtered off, then washed three times with 40 ml of water, then with 20 ml of methanol, and dried.

[0035] 25.9 g of 5-(2-bromo-acetyl)-6-chloro-1,3-dihydro-2H-indol-5-one of the formula IV are obtained.

[0036] The material was characterized by the following NMR data:

[0037] 1H NMR: 3.54s(2H)[H2-3]; 4.79s(2H)[H2-14]; 6.91s(1H)[H-9]; 7.71s(1H)[H-6]; 10.81s( 1H) [NH].

Embodiment 2b

[0038] Example 2b: Preparation of 5-(2-bromoethyl)-6-chloro-1,3-dihydro-2H-indol-2-one (III)

[0039] 25.0g (0.087mol) of 5-(2-bromoacetyl)-6-chloro-1,3-dihydro-2H-indol-5-one of formula IV was dissolved in 50ml methanesulfonic acid and 50ml dichloromethane The mixture was heated to the boiling point, and then 30.5ml (0.191mol) of trimethylsilane was added dropwise thereto. After stirring for 30 minutes, the completion of the reaction was checked by thin layer chromatography, then the mixture was cooled to 0-10° C. and 60 ml of water were added dropwise. The precipitated material was filtered off, washed three times with 40 ml of water, then with 20 ml of methanol, and dried.

[0040] 22.5 g of 5-(2-bromoethyl)-6-chloro-1,3-dihydro-2H-indol-2-one of the formula III are obtained.

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Abstract

The present invention provides a novel, industrially easily realisable and economically preferable process for production of pure 5-{2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]-ethyl}-6-chloro-1,3-dihydro-2H-indol-2-one i.e., ziprasidone hydrochloride shown in the reaction scheme (II), (III), (IV), (V) and (VI). According to the invention the intermediate compound 5-(2-bromoethyl)-6-chloro-1,3-dihydro-2H-indol-2-one of Formula (III) is produced from 5-(2-bromoacethyl)-6-chloro-1,3-dihydro-2H-indole-2-one of Formula (IV). The highly pure ziprasidone base of Formula (II) is obtained in the reaction of 3-piperazinyl-1,2-benzisothiazol of Formula (VI) with 5-(2-bromoethyl)-6-chloro-1,3-dihydro-2H-indol-2-one of Formula (III) in an organic solvent or organic solvent mixture.

Description

field of invention [0001] The field of the invention relates to the preparation of pure ziprasidone, namely 5-{2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]-ethyl}-6-chloro- A new method for 1,3-dihydro-2H-indol-2-ones. The present invention also relates to an intermediate, 5-(2-bromoethyl)-6-chloro-1,3-dihydro-2H-indol-2-one, and a process for its preparation. Background of the invention [0002] Ziprasidone hydrochloride of formula I, 5-{2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]-ethyl}-6-chloro-1,3 -Dihydro-2H-indol-2-one is disclosed in US Patent No. 4,831,031 (equivalent to European EP 0 281 309), and is known as an active ingredient of neuroleptics. [0003] [0004] According to this patent, if 5-(2-chloroethyl)-6-chloro-1,3-dihydro-2H-indol-2-one of formula VII and 3-piperazinyl-1 hydrochloride of formula VI , 2-benzisothiazole was reacted in methyl-isobutyl-ketone in the presence of sodium carbonate and sodium iodide, and the mixture was boiled for 40 hours...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D417/12
CPCC07D417/12
Inventor J·纽J·托雷S·加拉德内
Owner RICHTER GEDEON NYRT
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