Method for synthesizing Iloperidone

A technology of iloperidone and a synthesis method, which is applied in the field of synthesis of iloperidone, can solve the problems of low water solubility and removal of dimers, and achieves the effects of simple operation and mild reaction conditions

Inactive Publication Date: 2010-06-16
EAST CHINA NORMAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] During the reaction, the fluorine atom at the adjacent position reacts with the oxime hydroxyl group to obtain compound (7), but the fluorine atom at the para position also participates in the reaction to generate a dimer (8). low and can not be removed by recrystallization, therefore, due to the existence of the dimer, it directly leads to the impurity compound (9) in the final product while synthesizing iloperidone

Method used

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  • Method for synthesizing Iloperidone
  • Method for synthesizing Iloperidone
  • Method for synthesizing Iloperidone

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] Preparation of compound (2) hydrochloride

[0030] Under nitrogen protection, 2,4-difluorophenyl-4-piperidinyl ketone hydrochloride (1) (60.0g, 0.25mol) and hydroxylamine hydrochloride (60g, 0.86mol) were added to a 1L reaction flask, Add 600ml of absolute ethanol, add triethylamine (75.0ml, 0.54mol) dropwise under stirring, control the temperature below 30°C, heat to reflux after dropping, react for 5 hours, and when the reaction is over, filter out the solid while it is hot, and dry it to obtain Compound (2) hydrochloride 2,4-difluorophenyl (4-piperidinyl) ketone oxime hydrochloride 44.0 g, yield 80.0%.

[0031] Preparation of compound (2)

[0032] Dissolve 25.0 g of 2,4-difluorophenyl (4-piperidinyl) ketone oxime hydrochloride in 100 ml of water, heat to 50 ° C, neutralize to PH = 10 with 10% sodium hydroxide solution, and cool After reaching room temperature, the solid was obtained by suction filtration, and dried to obtain compound (2) 2,4-difluorophenyl(4-piperi...

Embodiment 2

[0042] Preparation of compound (5)

[0043]Under nitrogen protection, 2,4-difluorophenyl (4-piperidinyl) ketone oxime hydrochloride (20.0 g, 72.4 mmol) was added to a 250 ml reaction flask, 150 ml of acetonitrile was added, and sodium bicarbonate ( 14.0g, 166.7mmol), sodium iodide 0.8g, stirred for 10 minutes, 1-(4-(3-chloropropyl)-3-methoxy)acetophenone (17.6g, 72.5mmol) was added to the reaction In the bottle, heated to reflux at 100°C, kept stirring at reflux for 20 hours, cooled to room temperature, cooled to 0°C in an ice bath, precipitated solid, filtered with suction, washed the solid with 50ml of water, and dried to obtain 28.1g of compound (5). 87.0%.

[0044] Preparation of compound (6) iloperidone

[0045] Under nitrogen protection, compound 5 (10.0g, 22.4mmol) was added to a 250ml reaction flask, then 100ml of acetone was added, potassium hydroxide (2.51g, 44.8mmol) was added and heated to reflux at 60°C, kept stirring at reflux for 10 hours, cooled To room temp...

Embodiment 3

[0047] Preparation of compound (5)

[0048] Under the protection of nitrogen, 2,4-difluorophenyl (4-piperidinyl) ketone oxime hydrochloride (10.0g, 36.2mmol) was added to a 250ml reaction flask, and N,N-dimethylformaldehyde was added Amide 100ml, add potassium hydroxide (6.1g, 108.6mmol), stir for 10 minutes, add 1-(4-(3-chloropropyl)-3-methoxy)acetophenone (8.8g, 36.2mmol) Put it into a reaction bottle, heat it to 100°C, keep the temperature and stir for 15 hours, cool down to room temperature, cool to 0°C in an ice bath, precipitate a solid, filter it with suction, wash the solid with 30ml of water, and dry to obtain compound (5) 13.49, yield 83.0%.

[0049] Preparation of compound (6) iloperidone

[0050] Under the protection of nitrogen, compound 5 (20.0g, 22.4mmol) was added to a 250ml reaction flask, then 100ml of tetrahydrofuran was added, potassium hydroxide (3.779, 67.2mmol) was added and heated to reflux at 80°C, kept stirring at reflux for 8 hours, and cooled to ...

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Abstract

The invention provides a method for synthesizing Iloperidone, relating to a technology for synthesizing Iloperidone. The Iloperidone (6) is prepared by condensation reaction between 2,4-difluorophenyl-(4-piperidinyl)-Methanone oxime or hydrochloride (2) thereof with 1-[4-(3-Chloropropyl)-3-methoxy]acetophenone (4) and ring closing reaction. The invention has the advantages of simple operation, no special equipment, and mild reaction condition, and has no compound difficult to be separated; the obtained product can be prepared by recrystallization rather than column chromatography purification; and the majority of the used reagents can be purchased from market, thus being applicable to industrialized production.

Description

technical field [0001] The invention relates to a method for synthesizing iloperidone, which belongs to the technical field of chemical and medical synthesis. Background technique [0002] The English name of iloperidone is ILOPERIDONE, and its chemical name is 1-[4-[3-[4-(6-Fluoro-1, 2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3 -methoxyphenyl]ethanone, the drug was transferred from Titan to Novartis. Iloperidone is a mixed dopamine D2 / 5-hydroxytryptamine 5HT2A receptor blocker, which is an atypical antipsychotic for the treatment of schizophrenia. Compared with currently used antipsychotic drugs, the results of short-term and long-term safety trials show that iloperidone has fewer side effects, lower weight gain in patients, iloperidone will not induce diabetes in patients, and patients with extrapyramidal symptoms Also less (no akathisia, no hyperprolactinemia, decreased incidence of drowsiness, less cognitive decline. Literature (J.Med.Chem.1995, 38, 1119-1131) reported...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D413/04
Inventor 胡文浩徐勤耀任白燕杨琍苹
Owner EAST CHINA NORMAL UNIV
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