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Method for preparing aripiprazole and its intermediate

A piperazine and Chinese-style technology, applied in the field of preparation of antipsychotic drug aripiprazole, can solve the problems of long reaction time, low yield, unfavorable industrial production, etc., and achieve the effect of improving reaction efficiency

Active Publication Date: 2005-07-06
CHENGDU KANGHONG PHARMA GRP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

According to the report of CN1450056A, "the reaction time of this method is longer (4-20 hours), the yield is not high, the aftertreatment is loaded down with trivial details, and will use the bigger solvent of chloroform this toxicity, be unfavorable for industrialized production"

Method used

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  • Method for preparing aripiprazole and its intermediate
  • Method for preparing aripiprazole and its intermediate
  • Method for preparing aripiprazole and its intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0071] Stir and dissolve 100g m-aminophenol, 100g sodium bicarbonate, 400ml methanol, and 77.0ml water, and cool in an ice-salt bath. Add 96.0ml CLCH dropwise 2 CH 2 COCL, dropwise, react below 30°C for 3-4 hours, adjust the pH to 2 with concentrated hydrochloric acid, stir for 0.5 hours, add water, filter, and dry to obtain 145 g of the compound of formula (II) as white crystals. Yield 79%, melting point 130-132°C. Purity check: TLC analysis: ethyl acetate: absolute ethanol = 20:1, observed under ultraviolet light. Rf = 0.4.

[0072] IR (KBr cm -1 ): 1668.03, 1619.16, 1545.54, 1451.74, 1274.16, 1236.99, 873.87, 684.67

Embodiment 2

[0074] Add 138g of 1-(2,3-dichlorophenyl)piperazine and 1600ml of DMF to 1.4 dibromobutane for reaction, dilute with water, separate the organic layer, extract the aqueous layer with ethyl acetate, combine the organic layers, and concentrate under reduced pressure for at least amount, add acetone until the residue dissolves, add petroleum ether to precipitate, filter, and dry to obtain a brown powder, which is subjected to silica gel column chromatography to obtain 124 g of the compound of formula (III) as white needle crystals. The melting point is 120-121°C. Yield: 33.9%, purity check: TLC analysis: ethyl acetate:petroleum ether=1:2, observed under ultraviolet light. Rf = 0.7.

[0075] IR (KBr cm -1 ): 1525.04, 1494.5, 1382.31, 1199.03, 1176.57, 1059.75, 859.05, 788.04, 627.86

Embodiment 3

[0077] Add 100g of compound of formula (II), 150g of sodium iodide, and 1600ml of acetonitrile into a three-necked flask, heat, and reflux the suspension for 0.5h, then add 202.0ml of aqueous solution containing 276g of potassium carbonate, and then add 183g of compound of formula (III) , react at 60° C. for about 1 h, or TLC detects that the raw material point disappears, stop the reaction, add a large amount of water to dilute, precipitate out, filter to obtain 165 g of the compound of formula (IV) as a white powder, and the yield is 68%. Purity check: TLC analysis: ethyl acetate:petroleum ether=1:2, observed under ultraviolet light. Rf = 0.3.

[0078] IR (KBr cm -1 ): 3034.09, 1676.57, 1630.24, 1592.99, 1525.04, 1494.5, 1382.31, 1199.03, 1176.57, 1059.75, 859.05, 788.04, 627.86

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Abstract

The invention discloses a chemical synthesis method of psychotolytic medicine, especially a preparation method of aripiprazole and its intermediate. Intermediate (4) can be prepared by six different processes in the invention, and the targeted compound aripiprazole is produced from the intermediate (4) by ring-closing reaction. Compared to available method, the invention has short reaction time and high reaction efficiency.

Description

technical field [0001] The invention relates to the field of medicine, in particular to a preparation method and an intermediate of antipsychotic drug aripiprazole. Background technique [0002] The structure of aripiprazole is: [0003] [0004] It is an atypical antipsychotic used in the treatment of various acute and chronic schizophrenia and schizoaffective disorders. Developed by Japan Otsuka Pharmaceutical Company. [0005] On October 31, 1988, the Japanese Otsuka Pharmaceutical Company applied for a patent for the compound and its preparation method in Japan. In the following year, the Japanese Otsuka Pharmaceutical Company applied for patent protection in the United States, Europe, China and other places. According to the report of CN1450056A, "the reaction time of this method is longer (4-20 hours), the yield is not high, the aftertreatment is loaded down with trivial details, and will use the bigger solvent of chloroform this toxicity, be unfavorable for indus...

Claims

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Application Information

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IPC IPC(8): A61P25/00C07D215/227
Inventor 辛丕明王明新刘津爱
Owner CHENGDU KANGHONG PHARMA GRP
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