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Synthesis method and intermediate of brexpiprazole

A technology of epipiprazole and a synthesis method, applied in the field of pharmaceutical raw material drug synthesis, can solve problems such as unclear mechanism of action

Pending Publication Date: 2022-02-15
ZHEJIANG GUOBANG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, the exact mechanism of action of ebiprazole is not clear, it may be mediated by the partial agonist activity of 5-HT1A receptor and dopamine D2 receptor, and the antagonist activity of serotonin 5-HT2A receptor

Method used

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  • Synthesis method and intermediate of brexpiprazole
  • Synthesis method and intermediate of brexpiprazole
  • Synthesis method and intermediate of brexpiprazole

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Example 1: Synthesis of 7-(4-chlorobutoxy)-3,4-dihydro-2(1H)-quinolinone

[0037] 7-hydroxy-3,4-dihydro-2(1H)-quinolinone (200g, 1.23mol), 1-bromo-4-chlorobutane (631g, 3.68mol) and potassium carbonate (254g, 1.84mol ) into a 5L three-neck flask in DMF (800mL) for mixing and stirring, then stirred at 25°C for 30h, and the suspension gradually became thicker and thicker. Purified water (1600mL) was slowly poured into the above-mentioned 5L three-neck flask with stirring, a large amount of solids were precipitated, and the stirring was continued for 30min, followed by suction filtration, and the solids were washed with purified water. Transfer the solid obtained above to a 1L three-necked flask, add methyl tert-butyl ether (400 mL) to beat and stir for 1 h, then filter with suction, and dry the obtained solid under vacuum at 50°C to obtain an off-white solid (258 g), with a yield of about 83.6% . HPLC detection (see figure 1 ) with a purity of about 96.14% (the content...

Embodiment 2

[0040] Embodiment 2: Synthesis of 7-(4-chlorobutoxy)-quinolin-2-one

[0041] Put 7-(4-chlorobutoxy)-3,4-dihydro-2(1H)-quinolinone (150g, 0.59mol), THF (750mL) into a 1L three-necked flask, stir at room temperature and then slowly batch DDQ (161 g, 0.71 mol) was added and stirring was continued for 18 h. The above reaction solution was slowly poured into water (750 mL) for quenching, then aqueous sodium bicarbonate solution (1.57 mol / L, 750 mL) was slowly added under stirring, and stirred for 1 h. After suction filtration, the obtained solid was washed with water and dried under vacuum at 50° C. to obtain a light yellow solid (122 g) with a yield of 82.1%. HPLC detection (see figure 2 ) with a purity of about 97.43% (wherein the 7-(4-bromobutoxy)-quinolinone content is 1.67%).

[0042] Table 2: Extraction of the HPLC test result data of the intermediate of this embodiment

[0043]

Embodiment 3

[0044] Example 3: Synthesis of 1-N-tert-butoxyformyl-7-(4-chlorobutoxy)-quinolin-2-one

[0045] Mix 7-(4-chlorobutoxy)-quinolin-2-one (40.2g, 160mmol) and DMAP (1.9g, 16mmol) in dichloromethane (200mL), add dicarbonate dicarbonate dropwise under stirring at room temperature Tert-butyl ester (70.0g, 320mmol), dichloromethane (100mL) solution, followed by reaction at 35°C for 1h. The above dichloromethane reaction solution was washed with water (100ml×3), and then dried over anhydrous sodium sulfate. After filtration, dichloromethane was distilled off under reduced pressure at 35°C, and the resulting solid was stirred with methyl tert-butyl ether (400 mL) for 1 h. Filtration and washing of the solid with methyl tert-butyl ether and drying in vacuo afforded a white solid (44.9 g) in about 79.8% yield. HPLC detection (see image 3 ) with a purity of about 97.88% (the content of 1-N-tert-butoxyformyl-7-(4-bromobutoxy)-quinolin-2-one is 1.55%).

[0046] Table 3: Extraction of th...

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Abstract

The invention provides a synthesis method and an intermediate of brexpiprazole, belonging to the technical field of pharmaceutical bulk drug synthesis. According to the method, 1-tert-butoxyformyl-7-(4-halo-butoxy)-quinolin-2-one and 4-piperazine-benzothiophene hydrochloride are taken as initial raw materials, potassium carbonate is taken as an acid-binding agent, and a reflux reaction is carried out in an ethanol-water mixed solution to synthesize the tert-butoxyformyl-protected brexpiprazole. Compared with a conventional method for synthesizing brexpiprazole through a nucleophilic substitution reaction, the method disclosed by the invention has the advantages that 1-tert-butoxyformyl-7-(4-halo-butoxy)-quinolin-2-one is used as a reaction material, intramolecular and intermolecular condensation reactions caused by 7-(4-chloro-butoxy)-1H-quinolin-2-one are avoided, reaction selectivity is high, product quality is excellent, and the method is suitable for industrial production.

Description

technical field [0001] The application relates to a method for synthesizing ebiprazole and an intermediate thereof, belonging to the technical field of synthesizing pharmaceutical raw materials. Background technique [0002] The trade name of ebiprazole is Rexulti, and the chemical name is 7-(4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy)-1H-quinoline-2- Ketone, its structural formula is as shown in formula (1): [0003] [0004] Ebiprazole is a new type of atypical antipsychotic drug jointly developed by Lundbeck Pharmaceuticals of Denmark and Otsuka Pharmaceutical Co., Ltd. of Japan. It was approved for marketing by the US Food and Drug Administration on July 10, 2015. It is used as an auxiliary drug for Treatment of adults with major depressive disorder and treatment of adults with schizophrenia. Major depressive disorder is a serious mental illness that causes persistent sadness, frustration or anger and can lead to suicide in severe cases, while schizophrenia is...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D409/12C07D215/22
CPCC07D409/12C07D215/22
Inventor 白雪婷李东旭刘梓航何凤杰岳栋平李成胡德行秦欣荣姚礼高邱家军
Owner ZHEJIANG GUOBANG PHARMA
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