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Preparation method of ziprasidone

A technology of ziprasidone and benzisothiazole, which is applied in the field of preparation of ziprasidone, can solve the problems of long reaction time, low preparation yield, complicated operation, etc., and achieve short reaction time, simple operation and high yield high effect

Active Publication Date: 2007-07-11
ZHEJIANG MENOVO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] In order to solve the deficiencies of low yield, complex operation, long reaction time and high cost in the preparation of ziprasidone in the prior art, the present invention provides a ziprasidone with high yield, simple operation, short reaction time and low cost. Method for the preparation of ketones

Method used

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  • Preparation method of ziprasidone
  • Preparation method of ziprasidone
  • Preparation method of ziprasidone

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Embodiment 1 (comparative example):

[0031] 0.73g (3.20mmol) 5-(2-chloroethyl) 6-chloro-indolinone, 0.70g (3.2mmol) N-(1,2-benzisothiazol-3-yl) piperazine, 0.68g (.40mmol) sodium carbonate, 2mg sodium iodide, 30ml methyl isobutyl ketone, join in the 125ml round bottom flask that nitrogen inlet and condenser are equipped with, react reflux 40hr, cool, filter, distill. The distillate was purified by column chromatography, the by-product was eluted with 11 ethyl acetate, the product was eluted with 1.51 ethyl acetate containing 4% methanol, the washed product was distilled, the distillate was added to dichloromethane, and then added Diethyl ether was saturated with hydrochloric acid gas, resulting in precipitation, filtered, washed with ether, filtered, and the filter cake was washed with acetone, filtered to obtain ziprasidone hydrochloride with a yield of 20%.

Embodiment 2

[0032] Example 2: 5-(2-(4-(1,2-benzisothiazol-3-yl)-piperazine)acetyl)-6-chloro-1,3-dihydro-2H-indole- Preparation of 2-keto:

[0033] Add 7.9 g (31 mmol) of N-(1,2-benzisothiazol-3-yl) piperazine hydrochloride into a 250 ml three-necked flask, add 40 ml of DMF (dimethylformamide), and stir. Add 4.88g (20mmol) of 5-(2-chloroacetyl) 6-chloro-indolinone, 6g of potassium iodide, and 10g of potassium carbonate, and start to heat up to 70°C. After 4 hours of heat preservation, distill under reduced pressure, add 40ml of water, and add 6N hydrochloric acid, adjust the pH to 3-4, filter, wash the filter cake with water until neutral, and dry at 55°C to obtain 7.21g of product, yield: 82.5%. 5-(2-(4-(1,2-Benzisothiazol-3-yl)-piperazine)acetyl)-6-chloro-1,3-dihydro-2H-indol-2-one Physical parameters:

[0034] MS(%) M +1 426+1

[0035] NMR (d, CDCl 3 ): 3.2-3.6(m, 8H), 7.4-7.7(m, 2H), 7.8(d, 1H), 7.87(d, 1H), 2.7(s, 2H), 6.9(s, 1H), 10.8( s,1H), 3.8(s,2H), 7.7(s,1H)

Embodiment 3

[0036] Example 3: 5-(2-(4-(1,2-benzisothiazol-3-yl)-piperazine)acetyl)-6-chloro-1,3-dihydro-2H-indole- Preparation of 2-keto:

[0037] Add 6.8 g (31 mmol) of N-(1,2-benzisothiazol-3-yl) piperazine into a 250 ml three-neck flask, add 30 ml of DMF (dimethylformamide), and stir. Add 4.88g (20mmol) of 5-(2-bromoacetyl)6-chloro-indolinone, 7g of sodium iodide, and 11g of sodium bicarbonate, start to heat up to 50°C, keep warm for 12 hours, distill under reduced pressure, and add 40ml Add water, add 6N hydrochloric acid, adjust the pH to 3-4, filter, wash the filter cake with water until neutral, and dry at 55°C to obtain 6.02g of product, yield: 68.9%. Example 4: 5-(2-(4-(1,2-benzisothiazol-3-yl)-piperazine)acetyl)-6-chloro-1,3-dihydro-2H-indole- Preparation of 2-keto:

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Abstract

The invention discloses a making method of qilaxi ketone with structural formula as formula (I), which is characterized by the following: the chemical name of compound is 5-(2-(4-(1,2-benzo isothiazole-3-base)-piperazine) acetyl)-6-chloride-1, 3-dihydrogen-2H-indole-2-ketone, which is reduced in the organic acid solvent; the solvent is C1-C6 paraffin acid substituted by at least one halogenate atom with carboxyl function group.

Description

(1) Technical field [0001] The invention relates to a preparation method of ziprasidone. (2) Background technology [0002] Ziprasidone (ziprasidone) is a newer atypical antipsychotic, it is serotonin and dopamine D 2 Receptor antagonist, it can effectively treat negative and positive symptoms of schizophrenia, including hallucinations, delusions and lack of initiative, etc., developed by Pfizer of the United States, first listed in Sweden in September 2000, the chemical name of ziprasidone For: 5-(2-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)ethyl)-6-chloro-1,3-dihydro-2H-indole -2-ketone, the structural formula is as follows: [0003] [0004] U.S. Patent No. 4,831,031 discloses a method for preparing ziprasidone: [0005] [0006] The method takes sodium iodide as a catalyst, and in the presence of sodium carbonate, methyl isobutyl ketone is a solvent, compound N-(1,2-benzisothiazol-3-yl) piperazine and compound 5-(2- Chloroethyl) 6-chloro-indolinone was refluxe...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D417/14C07D275/00C07D209/00C07D241/00
Inventor 唐朝军姚成志
Owner ZHEJIANG MENOVO PHARMA
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