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Preparation method of iloperidone

A technology of iloperidone and step method, applied in a new field of preparation, can solve the problems of a large number of solvents, cumbersome operation, and long reaction process

Active Publication Date: 2013-02-13
CSPC ZHONGQI PHARM TECH (SHIJIAZHUANG) CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] 2. The two-step method is used for the reaction. There are many steps and the operation is cumbersome. The two-step reaction requires a post-treatment process. After the compound of formula 5 is obtained, it must be separated from the reaction system, and then the cyclization reaction is carried out
A large amount of solvent is required, and the reaction process is long, which increases energy consumption and equipment loss in production, and increases the cost

Method used

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  • Preparation method of iloperidone
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  • Preparation method of iloperidone

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] 1, the preparation of 4-(3-chloropropyloxy)-3-methoxyacetophenone (i.e. formula 3 compound)

[0026] Dissolve 17.6 g of vanillone in 75 ml of acetone, add 13.8 g of potassium carbonate, heat to reflux, dropwise add a mixed solution of 83.4 g of 1-bromo-3-chloropropane and 20 ml of acetone, and react at reflux for 10 h. Cool to room temperature, filter with suction to obtain the filtrate, evaporate acetone and 1-bromo-3-chloropropane, and distill under reduced pressure to obtain 21.2 g of crude product of (3-chloropropyloxy)-3-methoxyacetophenone. The rate is 82.4%.

[0027] 2. Preparation of (Z)-4-(2,4-difluorophenyl)-piperidinyl ketone oxime (i.e. compound of formula 4)

[0028] Add 136ml of absolute ethanol and 11.2g of hydroxylamine hydrochloride into a 500ml three-necked flask, add 54.7g of 20% NaOH aqueous solution under stirring, and control the temperature at 20-30°C. After the dropwise addition is completed, stir for 15 minutes, and the pH is about 10. Then 2...

Embodiment 2

[0034] Example 2, (Z)-4-(2,4-fluorophenyl)-piperidinyl ketone oxime 5.0g, absolute ethanol 50ml, add 4-(3-chloropropyloxy)-3- Methoxyacetophenone 4.58g, Potassium iodide 2.16g, 2% KOH 176.5g, TLC detection reaction, heating up to 60°C for 14 hours, heating up to 70°C, reacting for 1.5 hours, cooling down to room temperature, precipitated solid, filtered, 10ml Wash with water to obtain crude iloperidone. The crude product was dissolved by heating with 120ml of ethanol, 1g of activated carbon was added, stirred, filtered hot, the filtrate was cooled to room temperature, and filtered to obtain 7.35g of the product with a yield of 91.2% and a purity of 99.4%.

Embodiment 3

[0035] Example 3, (Z)-4-(2,4-difluorophenyl)-piperidinyl ketone oxime 21.0g, acetonitrile 210ml, was added to a 500ml four-necked flask, and 20.1g 4-(3-chloro Propyloxy)-3-methoxyacetophenone, potassium iodide 1.5g, potassium hydroxide 7.3g was added, the temperature was raised to reflux for 26 hours, and the reaction was detected by TLC. After the reaction is completed, cool down to room temperature, pour the reaction solution into 700ml of water, and cool down to about 20°C±2°C. Stir for 4 hours, filter with suction, and wash the filter cake with 35ml of water. The product was dried at 50°C±2°C for 24 hours under a vacuum of 0.090Mpa to obtain 33.5g of a white solid with a yield of 94.5% and a purity of 99.4%. .

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Abstract

The invention provides a method for preparing iloperidone by a one-step method. Iloperidone is obtained directly by a one-step base catalytic reaction of a compound in formula 3 and a compound in formula 4. The operation is simplified greatly, and the product quality is not compromised; the obtained iloperidone has purity of more than 99% and a yield of more than 90%.

Description

technical field [0001] The invention relates to a new preparation method of iloperidone. Background technique [0002] Iloperidone, English name iloperidone, chemical name: 1-[4-[3-[4-(6-Fluoro-1, 2-benzisoxazol-3-y1)-1-piperidinyl]propoxy]-3-methoxyphenyl] ethanone. The structural formula is as follows: [0003] Iloperidone is an antagonist of 5-hydroxytryptamine and dopamine D2 receptors, which is used for the treatment of atypical schizophrenia. Iloperidone is an atypical antipsychotic patented drug developed by Titan Company. It was approved by the US FDA in 2009 for the treatment of acute schizophrenia in adults. This represents a new opportunity for schizophrenia to better control their symptoms in patients with schizophrenia who are only partially responsive to many existing drug treatments. Iloperidone could be the first personalized psychiatric treatment. With the launch of iloperidone, it may become the first gene-targeted drug for the treatment of schizophr...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D413/04
Inventor 郑利刚尚振华梁敏王世霞哈婧何元刘勋涛韩雨珊邢松松何丽娟
Owner CSPC ZHONGQI PHARM TECH (SHIJIAZHUANG) CO LTD
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