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A kind of preparation method of aripiprazole

A technology for aripiprazole and intermediates, applied in the field of preparation of raw materials, can solve the problems of unsuitability for industrial production, poor material utilization rate, low purity, etc.

Active Publication Date: 2021-11-16
迪嘉药业集团股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

According to literature reports, the yield is moderate, but the purity of commercially available 4-chloro-1-butanol and 4-bromo-1-butanol is low, because it is unstable and easy to self-cyclize to generate tetrahydrofuran, and the reaction heating process is easier to cyclize. Combined, poor material utilization, not suitable for industrial production

Method used

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  • A kind of preparation method of aripiprazole
  • A kind of preparation method of aripiprazole
  • A kind of preparation method of aripiprazole

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Preparation of intermediate one

[0037] In a 250ml four-necked flask, add 113ml of dioxane, 2,3-dichlorobromobenzene (22.59g, 0.1mol), bis(dichloroethylamine) hydrochloride (17.85g, 0.1mol), sodium tert-butoxide (24.02g, 0.25mol), bis(dibenzylideneacetone)palladium (115mg, 0.2mmol), under the protection of nitrogen, stirred and raised the temperature to 101°C for 4h, and TLC monitored the complete conversion of 2,3-dichlorobromobenzene. The reaction solution was cooled to room temperature, the catalyst was recovered by filtration, and the filtrate was reduced in pressure to recover dioxane to obtain 26.35 g of Intermediate 1 with a yield of 91.8% and a purity of 97.3% by HPLC.

[0038] Preparation of intermediate two

[0039] Intermediate 1 (25.83g, 0.09mol) was dissolved in 103ml of DMF, added to a 250ml four-necked flask, added 4-amino-1-butanol (8.91g, 0.1mol), and potassium carbonate (14.90g, 0.11mol), Sodium iodide (0.67 g, 0.0045 mol) was stirred and heated to ...

Embodiment 2

[0045] Preparation of intermediate one

[0046] Add 113ml of dioxane, 2,3-dichlorobromobenzene (22.59g, 0.1mol) in a 250ml four-necked flask, bis(dichloroethylamine) hydrochloride (21.42g, 0.12mol), sodium tert-butoxide (22.10g, 0.23mol), bis(dibenzylideneacetone)palladium (28.75mg, 0.05mmol), under the protection of nitrogen, stirred and raised the temperature to 90°C for 6h, and TLC monitored the complete conversion of 2,3-dichlorobromobenzene. The reaction solution was cooled to room temperature, the catalyst was recovered by filtration, and the filtrate was reduced in pressure to recover dioxane to obtain 25.72 g of Intermediate 1 with a yield of 89.6% and a HPLC purity of 96.9%.

[0047] Preparation of intermediate two

[0048] Intermediate 1 (25.83g, 0.09mol) was dissolved in 103ml of DMF, added to a 250ml four-necked flask, added 4-amino-1-butanol (8.91g, 0.1mol), and potassium carbonate (14.90g, 0.11mol), Sodium iodide (0.67 g, 0.0045 mol) was stirred and heated to 100...

Embodiment 3

[0054] Preparation of intermediate one

[0055] Add 113ml of dioxane, 2,3-dichlorobromobenzene (22.59g, 0.1mol) in a 250ml four-necked flask, bis(dichloroethylamine) hydrochloride (21.42g, 0.12mol), sodium tert-butoxide (20.18g, 0.21mol), bis(dibenzylideneacetone)palladium (2.875g, 50mmol), under the protection of nitrogen, stirred and raised the temperature to 80°C for 9h, and TLC monitored the complete conversion of 2,3-dichlorobromobenzene. The reaction liquid was cooled to room temperature, the catalyst was recovered by filtration, and the filtrate was reduced in pressure to recover dioxane to obtain 27.13 g of Intermediate 1 with a yield of 94.5% and a HPLC purity of 97.9%. The recovered catalyst and solvent can continue to be used mechanically.

[0056] Preparation of intermediate two

[0057] Intermediate 1 (25.83g, 0.09mol) was dissolved in 103ml of DMF, added to a 250ml four-neck flask, added 4-amino-1-butanol (8.91g, 0.1mol), and sodium carbonate (11.66g, 0.11mol),...

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Abstract

The invention relates to a preparation method of aripiprazole, which belongs to the technical field of preparation of raw materials. The technical scheme of the present invention is: take 2,3-dichlorobromobenzene as the starting raw material, through coupling reaction with bis-2-chloroethylamine, 4-amino-1-butanol ring closure reaction, thionyl chloride substitution After the reaction, intermediate 3 substituted with chlorobutyl is obtained, which is then reacted with 3,4-dihydro-7-hydroxyl-2(1H)-quinolinone to generate aripiprazole. The preparation method of the present invention has great advantages in reducing the use equivalent of each material and controlling the generation of dimers, so as to better obtain the finished product of aripiprazole with higher purity.

Description

technical field [0001] The invention relates to a preparation method of aripiprazole, which belongs to the technical field of preparation of raw materials. Background technique [0002] The chemical name of aripiprazole is 7-{4-[4-(2,3-dichlorophenyl)-l-piperazinyl]butoxy}-3,4-dihydro-2(1H )-quinolinone, a third-generation atypical antipsychotic drug, was invented by Japan’s Otsuka Company in 1988, and was later jointly developed with American Bristol-Myeres Squibb Company in 2002. On November 15, 2019, it was approved by the US FDA to be marketed. The clinical indications are mainly applicable to the treatment of schizophrenia, bipolar mania, major depression (adjuvant therapy), tic disorder and manic autism. At present, it has been approved for marketing in many countries. Its chemical structural formula is as follows: [0003] [0004] Chinese patent CN1028104C discloses the preparation method of aripiprazole bulk drug, specifically as follows: [0005] [0006]...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D215/22
CPCC07D215/22
Inventor 蔡华军宫炜王兵刘云法李宝忠
Owner 迪嘉药业集团股份有限公司
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