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Preparation method of novel brexpiprazole, aripiprazole and salts thereof

A technology of brepiprazole and aripiprazole, applied in the field of medicinal chemistry, can solve the problems of poor selectivity and affecting the purity and yield of the final product breiprazole

Inactive Publication Date: 2016-08-17
SUZHOU VIGONVITA LIFE SCIENCES CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Due to poor selectivity, when preparing 7-hydroxyl-1H-quinolin-2-one, it will be accompanied by the generation of a large amount of difficult-to-separate by-product 5-hydroxyl-1H-quinolin-2-one
This impurity will participate in the following series of reactions, thereby affecting the purity and yield of the final product brepiprazole

Method used

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  • Preparation method of novel brexpiprazole, aripiprazole and salts thereof
  • Preparation method of novel brexpiprazole, aripiprazole and salts thereof
  • Preparation method of novel brexpiprazole, aripiprazole and salts thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0188] Embodiment 1: the preparation of 7-chlorobutoxy coumarin

[0189]

[0190] 7-hydroxycoumarin (500mg, 3.09mmol), potassium carbonate (640mg, 4.64mmol), 1-bromo-4-chlorobutane (426μl, 3.71mmol) and 10ml of ethanol were dropped into the reaction flask successively, and then heated to reflux 12h. After removing ethanol, add water to dissolve potassium carbonate, filter with suction, and wash the filter cake twice with 20ml of petroleum ether. After drying, 606 mg of white product was obtained.

Embodiment 2

[0191] Embodiment 2: the preparation of compound IIa-1

[0192]

[0193] Add 7-chlorobutoxycoumarin (255mg, 1mmol), potassium carbonate (276, 2mmol), sodium iodide (150, 1mmol), 1-(benzothiophen-4-yl)piperone into the reaction flask successively Oxyzine (218mg, 1mmol) and 10ml of acetonitrile, then heated to reflux for 24h. After the acetonitrile was removed, water was added to dissolve potassium carbonate, and suction filtered. After the filter cake was slurried with 10 ml of acetonitrile, suction filtered and dried to obtain product IIa-1 (380 mg).

Embodiment 3

[0194] Embodiment 3: the preparation of brepiprazole

[0195] Compound IIa-1 was dissolved in ammonia-methanol solution, pressurized, and heated at 150°C. After the reaction, spin-dried, washed once with water and once with saturated aqueous sodium carbonate solution, and dried to obtain breiprazole.

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Abstract

The invention provides a preparation method of novel Brexpiprazole and salts thereof, aripiprazole and salts thereof, or key intermediates thereof. The method uses a starting material of 7-hydroxycoumarin or 7-hydroxy dehydrocoumarin, which is subjected to a substitution reaction, a dehydrogenation reaction and / or amination reaction. The method has the advantages of sufficient supply of easily available raw materials, low cost, high safety, simple operation, high product yield and good quality, and is suitable for enlarge production.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a preparation method of brepiprazole, aripiprazole or their salts and intermediates. Background technique [0002] Brepiprazole (Brexpiprazole, code name: OPC-34712) is a new generation of antipsychotic drugs developed by Otsuka Pharmaceutical Co., Ltd. It acts on multiple receptors, is a partial dopamine D2 receptor agonist, and a 5-HT2A receptor antagonist , α1 adrenoceptor antagonist. Currently, Phase III clinical trials are being conducted as an adjuvant treatment for major depressive disorder (MDD) in the United States and Europe; Phase III clinical trials for the treatment of schizophrenia are being conducted in the United States, Europe, and Japan; meanwhile, Phase II clinical trials for adult ADHD are also being conducted in the United States. phase clinical trials. [0003] Otsuka Pharmaceutical Co., Ltd. disclosed the preparation route of brepiprazole in...

Claims

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Application Information

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IPC IPC(8): C07D409/12C07D215/22
Inventor 沈敬山吴春晖田广辉
Owner SUZHOU VIGONVITA LIFE SCIENCES CO LTD
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