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Method for preparing ziprasidone

A ziprasidone and water-soluble technology, applied in the field of ziprasidone preparation, can solve the problems of cumbersome and low-efficiency production process, unfavorable scale production, long reaction time and the like, and achieves increased acid binding effect, increased solubility, impurities low content effect

Active Publication Date: 2011-11-23
QILU PHARMA HAINAN +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] Patent WO2005040160A2 (CN1898236A) discloses a method for preparing ziprasidone in a mixed solvent of water and low-molecular-weight alcohol solvents (such as n-butanol, isobutanol, etc.), although this method can basically make CEI and BITP raw materials Exhausted, but it takes a long time. The conversion rate of ziprasidone is only 88% after 35 hours of reflux, and the purity of the obtained product is 93.6%. Obviously, it needs subsequent purification treatment before it can be put into the salt-forming reaction
[0012] The reaction of CEI and BITP in the water phase has its own advantages, such as safety, environmental protection, no need to use organic solvents in the reaction, but due to the poor solubility of CEI and BITP in water, the reaction is carried out in a heterogeneous system, resulting in such as The shortcoming of long reaction time and low product purity, the prepared product cannot be used for the salt-forming reaction because it contains a large proportion of BITP or CEI, and generally needs to be purified by solvent beating and recrystallization
This not only loses the previous advantages, but also makes the whole production process cumbersome and inefficient, which is not conducive to large-scale production

Method used

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  • Method for preparing ziprasidone
  • Method for preparing ziprasidone

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] Add 320mL of acetone into a 500ml three-necked flask, start stirring, and put in 20.0g (86.9mmol) of 5-(2-chloroethyl)-6-chloro-1,3-dihydro-indol-2-(2H)-one , 3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride 23.3g (91.1mmol), then add 80mL 20%K 2 CO 3 Heat the aqueous solution to 60-70°C and keep it warm for 5 hours. After the reaction is detected by TLC, cool down to 30°C, add 480mL of purified water, stir at 20°C to 30°C for 30 minutes, filter with suction, rinse the filter cake with 40mL of purified water, and The solid material was dried in a vacuum oven at 60° C. for 4 hours to obtain 32.0 g of ziprasidone, with a yield of 89.2%, and a purity of 99.0% by HPLC.

Embodiment 2

[0025] Add 210mL tetrahydrofuran into a 500ml three-necked flask, start stirring, and add 15.0g (65.2mmol) of 5-(2-chloroethyl)-6-chloro-1,3-dihydro-indol-2-(2H)-one , 3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride 17.0g (66.5mmol), then add 90mL 20%Na 2 CO 3 As an aqueous solution, heat up to 60-70°C, keep it warm for 5 hours, cool down to 30°C after the reaction is detected by TLC, add 225mL of purified water, keep stirring for 45 minutes after cooling down, filter with suction, and rinse the filter cake with 30mL of purified water. The solid material was dried in a vacuum oven at 60° C. for 4 hours to obtain 24.4 g of ziprasidone with a yield of 90.6% and a purity of 99.1% by HPLC.

Embodiment 3

[0027] Add 280mL of N,N-dimethylformamide into a 500ml three-necked flask, start stirring, and add 5-(2-chloroethyl)-6-chloro-1,3-dihydro-indole-2-(2H) - Ketone 20.0g (86.9mmol), 3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride 23.3g (91.1mmol), then add 120mL 20%Na 2 CO 3 aqueous solution. Raise the temperature to 60-70°C and react for 4 hours. After the reaction is detected by TLC, cool down to 30°C, add 280mL of purified water, stir at 20°C to 30°C for 30 minutes, filter with suction, rinse the filter cake with 40mL of purified water, and remove the solid material Put it into a vacuum oven at 60° C. and dry for 4 hours to obtain 32.8 g of ziprasidone with a yield of 91.4% and a purity of 99.3% by HPLC.

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Abstract

The invention discloses a method for preparing ziprasidone, which comprises the following steps of: dissolving 5-(2-chloroacetyl)-6-chloro-1,3-dihydro-indol-2-(2H)-one and 3-piperazinyl-1,2-benzisothiazole hydrochloride in a mixed system of a water-soluble polar nonprotonic solvent and an aqueous solution of inorganic base, and reacting at the temperature of between 60 and 70DEG C for 3 to 6 hours; and after the reaction is finished, adding purified water, performing suction filtration, washing, and drying to obtain the ziprasidone. A reaction solvent is a mixed solution of the water-soluble polar nonprotonic solvent and the aqueous solution of the inorganic base, so that the dissolubility of reactants is increased, the acid binding effect is enhanced, and the reaction time is shortened; reaction conditions are concise, the operation is simple and the method is suitable for industrial production; and posttreatment is simple, the product yield is high, and impurity content is low.

Description

technical field [0001] The invention relates to a preparation method of ziprasidone, which belongs to the technical field of medicine. Background technique [0002] Ziprasidone is a new atypical broad-spectrum antipsychotic developed by Pfizer for the treatment of schizophrenia. This product is a 5-hydroxytryptamine and dopamine receptor antagonist, especially for 5-HTA2 / DAD2 receptors with strong affinity. It was listed in Sweden for the first time in September 2000, entered the Chinese market in 2007, and is currently listed in more than 50 countries around the world. The drug is effective for both positive and negative symptoms of schizophrenia, especially for negative symptoms, and has high safety. Compared with traditional antipsychotic drugs, this drug can not only improve positive symptoms, but also improve negative symptoms, improve Cognitive function and tolerance are significantly improved; compared with widely used olanzapine, quindipine, risperidone, etc., this...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D417/12
Inventor 李昌瑜杨庆坤周先国张雷雷吴柯张兆珍董廷华
Owner QILU PHARMA HAINAN
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