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Method for preparing iloperidone

A technology of iloperidone and piperidinyl ketone oxime, which is applied in the field of pharmacy, can solve the problems of reduced yield and high toxicity of toluene, and achieve the effects of low cost, cheap reagents and low impurity content

Active Publication Date: 2012-11-28
TIANJIN HUAJIN PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The literature also recrystallizes twice with ethanol or recrystallizes with toluene to refine crude iloperidone, the yield of recrystallization decreases twice, and toluene is more toxic. These problems need to be improved

Method used

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  • Method for preparing iloperidone
  • Method for preparing iloperidone
  • Method for preparing iloperidone

Examples

Experimental program
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Effect test

Embodiment 1

[0029]Example 1: Preparation of intermediate 2,4-difluorophenyl-4-piperidinyl ketone oxime (YPT-001)

[0030] Step 1: Add 4-(2,4-difluorobenzoyl)-piperidine hydrochloride (100g, 0.38mol) and hydroxylamine hydrochloride (100g, 1.44mol) into a 2000mL three-necked flask, add 1050mL95% ethanol, Stir, add triethylamine (88g, 0.87mol), heat to reflux for 4.5h, TLC shows that the reaction of raw materials is complete (developing solvent: DCM:MeOH=15:1 plus a little TEA). Cool to room temperature, filter with suction, wash with 500ml of ethanol, and dry under reduced pressure at 40°C to obtain about 67g of white solid with a yield of 73% and a purity of 91%.

Embodiment 2

[0031] Example 2: Preparation of intermediate 2,4-difluorophenyl-4-piperidinyl ketone oxime (YPT-001)

[0032] Step 1: Add 4-(2,4-difluorobenzoyl)-piperidine hydrochloride (15g, 0.057mol) and hydroxylamine hydrochloride (15g, 0.216mol) into a 250mL three-necked flask, add 160ml of 95% ethanol, Stir, add triethylamine (20ml, 0.144mol), heat to reflux for 3h, TLC shows that the reaction of raw materials is complete (developing solvent: DCM:MeOH=15:1 plus a little TEA). Cool to room temperature, filter with suction, wash with 80ml of ethanol, and dry to obtain 10.5g of white solid with a yield of 77% and a purity of 91%.

Embodiment 3

[0033] Example 3: Preparation of intermediate 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride (YPT-002)

[0034] Step 2: Add potassium hydroxide (135.3g, 2.41mol) and 3.5L absolute ethanol into a 20L reactor, stir, and add the crude product 2,4-difluorophenyl-(4-piperidinyl)methanone oxime (290g, 1.21mol), react at a temperature of 40°C for 2.5h, TLC shows that the reaction of the raw material is complete (developer: DCM:MeOH=15:1 plus a little TEA), remove the oil bath, cool to room temperature, filter with suction, wash with a little ethanol filter cake. The filtrate was evaporated to dryness, the residue was added with about 5L of water, extracted with dichloromethane (4.5L to 2.5L), washed once with 5L of saturated saline, once with 5L of water, and dried over anhydrous sodium sulfate. Filter and evaporate the solvent under reduced pressure to obtain 200 g (0.908 mol) of the free 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole crude product, add 2.2 L of methanol ...

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Abstract

The invention relates to a method for preparing iloperidone. The method comprises the following steps of: dissolving 4-(2,4-difluorobenzoyl)-piperidine hydrochloride and hydroxylamine hydrochloride serving as raw materials into 95 percent ethanol serving as a cheap solvent by taking excessive triethylamine as an alkali to obtain an intermediate, i.e., 2,4-difluorophenyl-4-piperidylketoxime; dissolving potassium hydroxide powder with absolute ethyl alcohol, reacting with the intermediate, purifying and salting to obtain a second intermediate, i.e., 6-fluoro-3-(4-piperidyl)-1,2-benzisoxazolehydrochloride; preparing and recrystallizing a third intermediate, i.e., 4-(3-chloropropyloxy)-3-methoxyacetophenone by taking 3-methoxyl-4-hydroxyacetophenone and 1-bromine-3-chloropropane serving raw materials; reacting the second intermediate, i.e., 6-fluoro-3-(4-piperidyl)-1,2-benzisoxazolehydrochloride with the third intermediate, i.e., 4-(3-chloropropyloxy)-3-methoxyacetophenone in a mixed solution of water and acetone under the action of potassium carbonate to obtain crude iloperidone; and refining the crude iloperidone with ethanol to obtain fine iloperidone.

Description

technical field [0001] The invention relates to a preparation method of iloperidone, a mixed dopamine D2 / 5-hydroxytryptamine 5HT2A receptor blocker, and belongs to the field of pharmacy. Background technique [0002] Iloperidone, trade name FANAPT, chemical name: 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidone Pyridyl]propoxy]-3-methoxyphenyl]ethanone, molecular formula: C24H27FN2O4, structural formula as shown in YPT-0, [0003] [0004] Iloperidone was developed by Titan and transferred to Novartis, and then transferred to Vanda Pharmaceuticals by Novartis. It was launched in the United States on May 6, 2009, and is used for the treatment of schizophrenia. Iloperidone is the first gene-targeted atypical antipsychotic for the treatment of schizophrenia. Iloperidone binds to 5-hydroxytryptamine 5HT2A and dopamine D2 and D3 receptors with high affinity (Ki values ​​are respectively 5.6, 6.3, 7.1nM), can better control the symptoms of schizophrenia. Compared wit...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D413/04
Inventor 陶秀梅汪晓平李志明苏旺程楠
Owner TIANJIN HUAJIN PHARMA
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