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Preparation method of aripiprazole photodegradation impurities

An aripiprazole and photodegradation technology is applied in the field of drug synthesis and achieves the effects of high yield, easy availability of raw materials and simple operation method

Active Publication Date: 2017-05-31
REYOUNG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Aripiprazole photodegradation impurity is of great significance to the in-depth study of aripiprazole, but there is no public report on the synthetic route of this impurity in the prior art

Method used

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  • Preparation method of aripiprazole photodegradation impurities
  • Preparation method of aripiprazole photodegradation impurities

Examples

Experimental program
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Effect test

Embodiment 1

[0039] (1) Add 16.2g of 2,3-dichloroaniline into a 500mL reaction flask, add 160mL of toluene to dissolve, add 15.4g of 1-bromo-2-nitroethane while stirring, then add 0.23g of palladium acetate and 1.2g of BINAP, and reflux reaction 12h. The reaction solution was cooled to room temperature, diluted by adding 80 mL of methyl tert-butyl ether, then suction filtered and concentrated to obtain a crude product, which was then purified by 80 mL of ethyl acetate and 160 mL to obtain 18.8 g of compound IV with a yield of about 80%.

[0040] (2) Take 11.75g ​​of compound IV and put it into a 250mL reaction flask, add 30mL of water and 90mL of ethanol, add 11.2g of iron powder and 5.4g of ammonium chloride under stirring, and reflux for 4h. Then it was filtered while it was hot, solids were precipitated during the cooling down process, and filtered with suction, the resulting filter cake was beaten with 50 mL of ethanol, filtered with suction, and dried to obtain 8.7 g of compound II wi...

Embodiment 2

[0043] (1) Add 16.2g of 2,3-dichloroaniline into a 500mL reaction flask, add 160mL of dichloromethane to dissolve, add 8.9g of nitroacetaldehyde under stirring, then add 30g of sodium triacetylborohydride, reflux for 6 hours, add water Quenches the reaction. After extraction, the organic layer was taken, dried with anhydrous sodium sulfate, filtered, and rotary evaporated to obtain 19.9 g of compound IV with a yield of 85%.

[0044] (2) Add 14.1g of compound IV into a 250mL reaction flask, add 140mL of methanol, add 0.3g of 10% palladium carbon under stirring, under the condition of adding hydrogen, reflux for 8h, heat filter, and rotary steam to obtain 11.1g of compound II , the yield is about 90%.

[0045] (3) Add 6.2g of compound II and 9g of compound III into a 250mL reaction flask, add 120mL of acetonitrile, add 4.15g of potassium carbonate and 7g of sodium iodide under stirring, and reflux for 3h. Then cooled to room temperature, solids were precipitated, filtered with...

Embodiment 3

[0047] (1) Add 16.2g of 2,3-dichloroaniline into a 500mL reaction flask, add 160mL of pyridine to dissolve, add 12.4g of 2-bromoethylamine under stirring, then add 4g of fresh copper oxide and 13.8g of potassium carbonate, and reflux for 12h. The reaction solution was cooled to room temperature, then suction filtered, concentrated to obtain a crude product, and then subjected to column chromatography (eluent: dichloromethane:methanol = 8:1) to obtain 17.6 g of compound II, with a yield of about 75%.

[0048] (2) Add 6.2g of compound II and 9g of compound III into a 250mL reaction flask, add 120mL of acetonitrile, add 12.45g of potassium carbonate and 42g of sodium iodide under stirring, and reflux for 3h. Then cooled to room temperature, solids were precipitated, filtered with suction, the filter cake was added to 50 mL of water and 50 mL of methanol for slurry for 1 h, filtered with suction, and dried to obtain 11.2 g of compound I with a yield of 88%.

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Abstract

The invention relates to a preparation method of aripiprazole photodegradation impurities, and belongs to the technical field of drug synthesis. According to the preparation method, 2,3-dichlorobenzenamine is taken as a raw material, a compound II is obtained via reaction of 2,3-dichlorobenzenamine with a compound V, and a target product compound I is obtained via reaction of the compound II with a compound III; wherein A in the compound V is used for representing Cl, Br, COOH, CHO, or COCl, A' is used for representing NH2 or NO2, and n is used for representing 1 or 2. The synthesis route of the preparation method is reasonable; the raw materials are easily available; operation is convenient and simple; yield of the target product is high; and purity is high.

Description

technical field [0001] The invention relates to a preparation method of aripiprazole photodegradation impurities, belonging to the technical field of drug synthesis. Background technique [0002] Aripiprazole (Aripiprazole), the chemical name is 7-[4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy]-3,4-dihydro-2( 1H)-quinolinone, developed by Japan's Otsuka Pharmaceutical Co., Ltd., was launched in the United States in November 2002, and belongs to the third generation of atypical antipsychotic drugs. Aripiprazole is the first dopamine system stabilizer with significant efficacy on both positive and negative symptoms of schizophrenia. . Aripiprazole is used to treat schizophrenia and can significantly improve the symptoms of schizophrenia without some of the common side effects of other antipsychotic drugs, such as weight gain and involuntary muscle activity. [0003] Aripiprazole photodegradation impurities refer to impurities produced by degradation under light conditions,...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D215/22
Inventor 苗得足胡清文李乐祥于志波王海王宏光
Owner REYOUNG PHARMA
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