Preparation method of antipsychotic drug iloperidone

A technology of iloperidone and ethyl ketone, which is applied in the field of anti-schizophrenia drugs, can solve the problems of low yield, high cost, and increased treatment of activated carbon waste residue, and achieve the effects of high yield, low cost, and shortened reaction time

Active Publication Date: 2012-06-27
HARBIN SANLIAN PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Can cause fetal damage, irritating and carcinogenic] dimethylformamide is used as a solvent, dimethylformamide is basically insoluble to potassium carbonate, and the reaction system is completely in a heterogeneous state, which is not conducive to 6-fluoro-3-(4 -piperidinyl)-1,2-benzisoxazole hydrochloride is rapidly dissociated and reacted, and the waste liquid generated after the reaction will cause environmental problems and needs special treatment; post-reaction treatment requires ethyl acetate extraction, and then Washing, the process is cumbersome; the reaction time is 16 hours, the cycle is long, and the yield of the refined product iloperidone is 58%, the yield is low, and the cost is high
[0009] Chinese patent CN 101768154 has improved above-mentioned patent, and its key technology is to replace DMF as reaction solvent with water, although improved the yield of iloperidone crude product (yield is 91%~92.20%), refining needs to use Recrystallization of toluene and decolori

Method used

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  • Preparation method of antipsychotic drug iloperidone
  • Preparation method of antipsychotic drug iloperidone
  • Preparation method of antipsychotic drug iloperidone

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] React 4-hydroxy-3-methoxyacetophenone with 1-bromo-3-chloropropane in the solvent acetone and in the presence of potassium carbonate to obtain a crude product, which is purified with isopropyl ether to obtain 1-[4-(3 -chloropropoxy)-3-methoxyphenyl]ethanone.

[0033] With 26.670g (0.110mol) reactant 1-[4-(3-chloropropoxy)-3-methoxyphenyl] ethyl ketone and 25.650g (0.100mol) reactant 6-fluoro-3-(4- Piperidinyl)-1,2-benzisoxazole hydrochloride was placed in a 1000ml reaction flask, and 41.400g (0.300mol) of anhydrous potassium carbonate, 2.490g (0.015mol) of potassium iodide and 0.05% T 320.200g of the prepared solution in an aqueous solution at a temperature of 80°C, stirred and mixed, heated to 70-85°C, and reacted with stirring for 3-5 hours. Naturally cool to room temperature, then cool down to 15±5°C and keep for 1 hour. Suction filtration, wash the filter cake twice with 150ml of water, then wash with 50ml of cold anhydrous methanol, suction filtration to dryness,...

Embodiment 2

[0035]With 26.670g (0.110mol) reactant 1-[4-(3-chloropropoxy)-3-methoxyphenyl] ethyl ketone and 25.650g (0.100mol) reactant 6-fluoro-3-(4- Piperidinyl)-1,2-benzisoxazole hydrochloride was placed in a 1000ml reaction flask, and 41.400g (0.300mol) of anhydrous potassium carbonate, 2.490g (0.015mol) of potassium iodide and 0.05% T 320.200g of the prepared solution in an aqueous solution at a temperature of 60°C, stirred and mixed, heated to 70-85°C, and reacted with stirring for 3-5 hours. Naturally cool to room temperature, then cool down to 15±5°C and keep for 1 hour. Suction filtration, wash the filter cake twice with 150ml of water, and then with 50ml of cold methanol, suction filtration to dryness, and vacuum drying at 50°C to obtain 40.00g of crude iloperidone with a yield of 93.79%. The crude product was recrystallized from methanol to obtain 37.01 g of iloperidone, with a purity of over 99.5% (HPLC normalization method), and a recrystallization yield of 92.52%.

Embodiment 3

[0037] With 26.670g (0.110mol) reactant 1-[4-(3-chloropropoxy)-3-methoxyphenyl] ethyl ketone and 25.650g (0.100mol) reactant 6-fluoro-3-(4- Piperidinyl)-1,2-benzisoxazole hydrochloride was placed in a 1000ml reaction flask, and 41.400g (0.300mol) of anhydrous potassium carbonate, 2.490g (0.015mol) of potassium iodide and 0.05% T 320.200g of the prepared solution in an aqueous solution at a temperature of 65°C, stirred and mixed, heated to 70-85°C, and reacted with stirring for 3-5 hours. Naturally cool to room temperature, then cool down to 15±5°C and keep for 1 hour. Suction filtration, wash the filter cake twice with 150ml of water, then wash with 50ml of cold methanol, suction filtration to dryness, and vacuum drying at 50°C to obtain 39.40g of crude iloperidone with a yield of 92.4%. The crude product was recrystallized from methanol to obtain 36.25 g of iloperidone, with a purity of over 99.5% (HPLC normalization method), and a recrystallization yield of 92.00%.

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Abstract

The invention provides a preparation method of a novel antipsychotic drug iloperidone, which comprises the following steps that: 6-fluoro-3-(4-piperidinyl)-1,2-benzo isoxazole hydrochloride is reacted with 1-[4-(3- chlorophenoxy)-3-methoxyphenyl]ethanone in an aqueous solution of a non-ionic surfactant by using an inorganic base as an acid binding agent and potassium iodide as a catalyst to obtain the iloperidone. The process has the advantages of high yield, high purity, good product appearance, simpleness and convenience in operation, and low cost, has no adverse impact on the environment, and is very suitable for industrial mass production.

Description

Technical field: [0001] The present invention relates to an anti-schizophrenia drug iloperidone, i.e. 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidine A preparation method of base] propoxyl]-3-methylphenyl]ethanone belongs to the field of medicine and chemical industry. Background technique: [0002] Iloperidone has a structural formula such as formula (I), and its chemical name is 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidine base] propoxy] -3-methoxyphenyl] ethanone. [0003] [0004] Iloperidon (Iloperidon) is a mixed dopamine D 2 / 5-hydroxytryptamine 5HT2A receptor blocker, for 5-hydroxytryptamine 5HT2A and dopamine D 2 、D 3 High affinity receptor for dopamine D 4 and serotonin 5HT6, 5HT7 and norepinephrine NEα 1 Moderate affinity for receptors, for 5HT1A, dopamine D 1 and histamine H 1 Receptor low affinity, no detectable affinity for cholinergic muscarinic receptors. iloperidone via dopamine D 2 、D 3 , 5-hydroxytryptamine 5HT1A and nor...

Claims

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Application Information

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IPC IPC(8): C07D413/04
Inventor 陈仲强吕敏金京龙何勤
Owner HARBIN SANLIAN PHARMA CO LTD
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