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Process for preparation of aripiprazole

An aripiprazole and piperazinyl technology is applied in the field of preparation of aripiprazole, can solve the problems of unfavorable product industrialization, reduced total yield, many side reactions, etc., and achieves easy control of intermediate quality and mild reaction conditions. , The effect of stable quality of finished products

Inactive Publication Date: 2005-01-26
重庆凯林制药有限公司 +1
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  • Description
  • Claims
  • Application Information

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Problems solved by technology

Repeated recrystallization (or column chromatography) not only greatly reduces the total yield and increases the industrial cost, but also is cumbersome to operate, which is not conducive to the industrial production of the product
[0012] This shows that the method for preparing aripiprazole reported in the EP367141 patent specification will be subject to certain restrictions on the industrialization of the product.
And the other four methods for preparing aripiprazole only described in the claims, because of involving the preparation of piperazine ring, are more unfavorable for the industrialization of products, because when carrying out the preparation of piperazine ring, the reaction temperature is higher than 220 ℃, many side reactions and extremely low yield

Method used

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  • Process for preparation of aripiprazole
  • Process for preparation of aripiprazole
  • Process for preparation of aripiprazole

Examples

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preparation example Construction

[0045] One, the preparation of compound (D)

[0046] 3-(4-bromobutoxy)nitrobenzene (E) and 1-(2,3-dichlorophenyl)-piperazine (F) or the salt that can be formed by condensation in the presence of a solvent After the reaction, 3-[4-[4-(2,3-dichlorophenyl)piperazinyl]butoxy]nitrobenzene (D) was obtained. The temperature condition of the reaction is from room temperature to 150°C, preferably 60-120°C, and the reaction is completed within a few hours to 60 hours. As for the solvent used in this reaction, it can be an ether solvent such as tetrahydrofuran, dioxane, ethylene glycol dimethyl ether; an aromatic hydrocarbon solvent such as benzene, toluene, pyridine, xylene; an alcohol solvent such as methanol, ethanol, isopropyl Alcohol; it can also be polar aprotic such as N,N-dimethylformamide, dimethyl sulfoxide, hexamethylphosphoramide, acetonitrile. Use a kind of basic reagent to help the carrying out of reaction, and said basic reagent can be potassium hydroxide, potassium carb...

example 1

[0055] Preparation of 3-[4-[4-(2,3-dichlorophenyl)piperazinyl]butoxy]nitrobenzene (D)

[0056] 5.80 g (25 mmol) of 1-(2,3-dichlorophenyl) piperazine (F), 6.89 g (25 mmol) of 3-(4-bromobutoxy) nitrobenzene (E), ), potassium carbonate 4.15g (30mmol), acetonitrile 25ml, a little potassium iodide, heated under reflux for 48 hours under stirring. After the reaction is completed, filter with suction to remove inorganic matter, wash the filtrate, then concentrate the filtrate to recover part of the organic solvent. Add 30ml of dichloromethane and 10ml of distilled water to the concentrate, separate the organic layer, extract the aqueous layer three times with 20ml of dichloromethane, combine the organic layers, and wash with water until neutral. Dry the organic layer with anhydrous sodium sulfate, remove the desiccant by suction filtration, recover the organic solvent under reduced pressure, add petroleum ether and ethyl acetate 12ml (v / v=7:3) to crystallize, filter with suction, an...

example 2-6

[0081] Example 2-6 Preparation of 3-[4-[4-(2,3-dichlorophenyl)piperazinyl]butoxy]nitrobenzene (D)

[0082] Dissolve the raw materials 1-(2,3-dichlorophenyl)piperazine (F) and 3-(4-bromobutoxy)nitrobenzene (E) in the following solvents, and use different acid-removing agents respectively, Heating and heat preservation reaction, the reaction is completed, the product is obtained after post-treatment and recrystallization, see Table 1:

[0083] Example Solvent Deacidifier Temperature (°C) Time (h) Yield (%)

[0084] 2 Tetrahydrofuran Potassium hydroxide 60 46 86.2

[0085] 3 Toluene Triethylamine 110 22 79.5

[0086] 4 Isopropanol Sodium bicarbonate 75 60 54.6

[0087] 5 N,N-Dimethylformamide Pyridine 80 42 83.4

[0088] 6 Dimethyl sulfoxide Potassium carbonate 70 27 51.3

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Abstract

The invention relates to the process for preparation of aripiprazole, wherein a compound having the general formula (A) is subject to Friedel-Crafts alkylation reaction under molten condition or at the presence of solvent and catalyst.

Description

technical field [0001] What the present invention relates to is a kind of aripiprazole namely 7-[4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy]-3,4-dihydro-2 The preparation method of (1H)-quinolinone. Background technique [0002] As we all know, aripiprazole is a quinolinone derivative, which was invented by Otsuka Corporation of Japan in 1988, and then jointly developed with Bristol-Myers Squibb Corporation of the United States. It was approved for marketing by the FDA in 2002. For the treatment of schizophrenia. [0003] Regarding the preparation of aripiprazole, five preparation methods described in the EP367141 patent are known. The specification of this patent describes one of the methods for preparing aripiprazole, the synthetic route is to use 7-hydroxyl-3,4-dihydro-quinolin-2-one (I) as raw material, and 1, 4-dibromobutane makes 7-bromobutoxy-3,4-dihydro-quinolin-2-ketone (II) after condensation reaction, (II) and 1-(2,3-dichloro Phenyl)piperazine was subjecte...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D295/088
Inventor 诸葛明邓杰叶文润沈浩
Owner 重庆凯林制药有限公司
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