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A technology of ebiprazole and intermediates, applied in the new preparation field of ebiprazole, which can solve problems such as pollution, high impurities, and low yield, and achieve the effects of good selectivity, high yield, and high product purity
Active Publication Date: 2016-03-16
ANHUI HEALSTAR PHARM CO LTD
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[0021] The purpose of the present invention is to provide a new method for preparing ebiprazole, which solves the problems of high impurities, low yield and serious pollution in the existing preparation method of ebiprazole, and the raw materials of the method are easy to high yield, low price, simple operation, mild reaction conditions, and good industrial application value
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Embodiment 1
[0051] Embodiment one: the preparation of ebiprazole
[0052] a. Preparation of Intermediate II:
[0053] 150g (1.0mol) of 4-hydroxybenzothiophene, 1500ml of dry toluene, 100g (2.5mol) of 60% sodium hydride, stirred at room temperature for 5h, then added 182g (1.1mol) of 2-bromoisobutyramide, and raised the temperature to reflux. At 90-100°C, react for 6 hours, identify the end point of the reaction by TLC (developing solvent: ethyl acetate-petroleum ether = 1:1), after the reaction is completed, cool to room temperature, filter out sodium bromide, and use 1mol / L of the filtrate first Wash with sodium hydroxide solution (200ml×2), then wash with ice water (150ml×2), then wash with 100ml saturated sodium chloride solution, dry over anhydrous sodium sulfate, filter to remove the desiccant, and concentrate the filtrate to dryness to obtain a white solid Intermediate II (202g, 0.86mol), yield 86%.
[0054] 1 H—NMR (500MHz, CDCl 3 / TMS,ppm):
[0055] δ7.61–7.63(m, 1H); 7.42–7...
Embodiment 2
[0079] Embodiment two: the detection of ebiprazole
[0080] Method: use octadecylsilane bonded silica gel as filler; mobile phase A is 5 mmol / L sodium octane sulfonate solution (adjust pH 3.0 with phosphoric acid), mobile phase B is acetonitrile, and carry out linear gradient according to the following table Elution, the detection wavelength is 290nm. Flow rate 1.0mg / min
[0081]
[0082] Results: The HPLC content was 99.7%. Among the 20 known impurities of ebiprazole, only 0.04% of quinoline dimer was detected, and 0.03% of other unknown impurities were detected.
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Abstract
The invention provides a novel preparation method of brexpiprazole, belonging to the technical field of medicines and chemical synthesis, and solving the problems of more impurities, low yield and serious pollution of existing brexpiprazole preparation methods. According to the method, 4-hydroxy benzothiophene is taken as a starting material, an intermediate V is obtained by four steps of reactions, an intermediate VII is obtained from 7-hydroxy-2-quinolone by two steps of reactions, and the intermediate V and the intermediate VII are subjected to condensation to obtain the brexpiprazole meeting clinic medicinal requirements. The preparation method is easy for getting raw materials, low in price, simple in operation, and mild in reaction condition, and has good industrialized application values.
Description
technical field [0001] The invention relates to the technical field of drug synthesis technology, in particular to an organic synthesis method with simple operation, environmental protection and high yield, which is suitable for large-scale industrial production, and specifically relates to a new preparation method of ebiprazole. Background technique [0002] Brexpiprazole (brexpiprazole) is the first dopamine, partial 5-HT drug jointly developed by Otsuka Pharmaceutical and Lundbeck Pharmaceutical Company 1A Agonists and 5-HT 2A Receptor antagonist compounds, which are considered to be another blockbuster after the company's best-selling drug - aripiprazole, were launched in the United States on July 10, 2015. The trade name is Rexulti, for the treatment of adults with schizophrenia and in combination with antidepressants for the treatment of major depression in adults. [0003] Ebiprazole has a wide range of activities in multiple monoamine systems, the partial agonist a...
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