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Preparation method of Iloperidone

A technology of ethyl ketone and methoxyacetophenone, applied in nervous system diseases, organic chemistry, drug combination, etc., can solve problems such as long reaction time, increase reaction cost, increase operation difficulty, etc., and shorten reaction time , Prevention of by-products, strong controllable effect

Active Publication Date: 2010-09-08
AVENTIS PHARMA HAINAN
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] The method uses N,N-dimethylformamide as a solvent, potassium carbonate as a catalyst, and reacts at about 90° C. for 16 hours to synthesize the compound of formula I. The reaction time is too long, which increases the difficulty of operation and increases the reaction cost.

Method used

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  • Preparation method of Iloperidone
  • Preparation method of Iloperidone
  • Preparation method of Iloperidone

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0020] 4-Hydroxy-3-methoxyacetophenone (88.0g, 0.53mole), K 2 CO 3 (69.1g, 0.5mol) was added to 375ml of acetone solution and heated to reflux. After refluxing for 30 minutes, a mixed solution of 1-chloropropanol (66.1 g, 0.70 mol) and acetone (75 ml) was added dropwise to the reaction solution. Stir evenly, and keep the reaction at 50°C for 5 hours. After the reaction, the solid was filtered out, the filtrate was concentrated, and the remaining oily liquid was slurried with petroleum ether to obtain 110 g (93%) of an off-white solid, which was pure 1-[4-(3-hydroxypropoxy)-3-methyl Oxyphenyl] ethyl ketone m.p. 161-163°C.

Embodiment 2

[0022] A mixture of p-toluenesulfonyl chloride (3.8g, 0.02mol) and dimethylformamide (10ml) was added dropwise to 1-[4-(3-hydroxypropoxy)-3-methoxyphenyl]ethyl In a mixed system composed of ketone (5.3g, 0.022mol) and dimethylformamide (60ml), stir at room temperature for 30 minutes, add 6-fluoro-3-(4-piperidinyl)-1,2-benzo Isoxazole hydrochloride (5.1g, 0.02mol), K 2 CO 3 (5.2g, 0.04mol), and react at 90°C for 3 hours. The mixture was poured into water, extracted with ethyl acetate, the ethyl acetate layer was washed with water, MgSO 4 Dry and concentrate to give a brown solid. Recrystallized with ethanol to obtain 7.0 g (82%) of 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propane Oxy]-3-methoxyphenyl]ethyl ketone as a beige solid, m.p. 118-120°C.

[0023] NMR analysis:

[0024] 1 H NMR (400MHz, DMSO-d 6 )δ6.85-7.20 (m, 3H), 3.90-4.02 (t, 2H), 3.70-3.75 (s, 2H), 3.48-3.59 (t, 2H), 2.51-2.63 (s, 3H), 2.03- 1.99(s, 1H), 1.82-1.91(m, 2H).

[0025] 13 C N...

Embodiment 3

[0030] A mixture of p-toluenesulfonyl chloride (3.8g, 0.02mol) and toluene (10ml) was added dropwise to 1-[4-(3-hydroxypropoxy)-3-methoxyphenyl]ethylketone (5.3 g, 0.022mol) and toluene (60ml) in a mixed system composed of toluene (60ml), stirred at room temperature for 30 minutes, added 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride (5.1 g, 0.02mol), K 2 CO 3 (5.2g, 0.04mol), heated and stirred at 90°C for 3 hours. The mixture was poured into water, extracted with ethyl acetate, the ethyl acetate layer was washed with water, MgSO 4 Dry and concentrate to give a brown solid. Recrystallized from ethanol to obtain 6.8 g (80%) of 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propane Oxy]-3-methoxyphenyl]ethyl ketone as a beige solid, m.p 118-120°C.

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Abstract

The invention relates to a preparation method of a compound of 1-[4-[3-[4- (6-fluoro-1, 2-benz isoxazole -3-yl)-1-piperidyl] propoxy]-3-methoxyphenyl] ethyl ketone in the formula I, which can be used as a drug for preventing psychosis and / or analgesia.

Description

technical field [0001] The present invention relates to a new method for the synthesis of iloperidone: 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl] Process for the preparation of propoxyl]-3-methoxyphenyl]ethylketone and its use as an antipsychotic and / or analgesic. Background technique [0002] It is very common to take antipsychotic drugs to treat schizophrenic patients. Such drugs such as haloperidol and thiobenzamide have been successful in controlling schizophrenia, but they cannot cure psychotic patients. And some antipsychotic drugs can produce adverse side effects, for example, causing patients to have extravertebral syndrome, weight gain, blood pressure reduction and other side effects. There is therefore a need in the field of antipsychotic drugs for drugs that have few or fewer severe symptoms of these common side effects. [0003] Iloperidone is a substituted N-(aryloxyalkyl)heteroarylpiperidine derivative, which is a newly developed drug for the ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D413/04A61P25/18A61P25/04
Inventor 高晓婷郭夏张志强
Owner AVENTIS PHARMA HAINAN
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