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Method for purifying brexpiprazole

A technology of ibiprazole and a purification method, which is applied in the field of ibiprazole purification, can solve the problems of high production cost, complicated operation, and low product purity, and achieve the effect of low production cost, high purity, simple and safe operation

Active Publication Date: 2018-02-09
SHANGHAI BOCIMED PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The technical problem to be solved by the present invention is to overcome the purification method of ibiprazole I in the prior art that requires column chromatography to cause complex operation, cumbersome post-treatment process, high production cost, low purity of the obtained product, and is not suitable for Defects such as industrialized production provide a kind of purification method of ibiprazole I

Method used

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  • Method for purifying brexpiprazole
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  • Method for purifying brexpiprazole

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] Embodiment 1: the preparation method of ibiprazole intermediate II

[0030]

[0031] Add 18.5kg toluene, 3.3kg 4-bromobenzo[B]thiophene, 6.67kg piperazine, 2.24kg sodium tert-butoxide, 87g palladium acetate, 144.7g 1,1'-binaphthyl-2 ,2'-bisdiphenylphosphine. The temperature of the reaction kettle is raised to 105°C-115°C, and the reaction is kept for 5-10 hours. Cool down to 15°C-25°C, add 11kg of water, stir and let it stand for stratification (2 times), concentrate the organic phase under reduced pressure to remove toluene to obtain a residue, add 21kg of methanol, cool down to 0-10°C, slowly pour into the reaction kettle Add 4 L of 6N hydrogen chloride / methanol solution dropwise, stir for 2 hours, and centrifuge and filter until dry. At 45°C-55°C, dry under normal pressure for 6-10 hours to obtain 3.1 kg of white solid ibiprazole intermediate II, with a yield of 80.0% and an HPLC purity of 98.52%.

Embodiment 2

[0032] Embodiment 2: the preparation method of ibiprazole intermediate III

[0033]

[0034] Add 25kg DMF, 3kg 7-hydroxy-2-quinolone, 7.7kg potassium carbonate dissolved in 7kg aqueous solution to a 100L glass reactor, slowly drop in 6.39kg 1-bromo-4-chlorobutane, keep the temperature at 10°C-20°C, Stir for 16 hours, and slowly drip 50kg of water into the reactor liquid. Cool to 0-10°C and stir for 2 hours, centrifuge and filter to dryness, and dry at 45°C-55°C under vacuum (-0.08-0.1MPa) for 4-10 hours to obtain 3.12kg of crude product. 20 kg of dichloromethane and 1 kg of methanol were added to this, and 30 kg of methyl tert-butyl ether was slowly added dropwise. Cool to 0-10°C and stir for 2 hours, shake filter to dryness in a centrifuge, and dry at 45°C to 55°C in a vacuum (-0.08 to -0.1MPa) for 4 to 10 hours to obtain 2.85kg of Ibiprazole intermediate III. Yield: 61.0%, HPLC purity: 97.77%.

Embodiment 3

[0035] Embodiment 3: the preparation method of Ibiprazole I crude product

[0036]

[0037] Add 42kg DMF, 3.08kg Ibiprazole Intermediate II, 4.71kg Potassium Carbonate, 2.89kg Ibipiprazole Intermediate III, and 1.7kg Sodium Iodide to a 100L glass reactor. Raise the temperature to 80°C-90°C, stir for 5-10 hours, cool down to 30°C-45°C, and add 42kg of water. Cool down to 0-10°C and stir for 2 hours. Centrifuge to filter to dryness, and dry at 45°C to 55°C under vacuum (-0.08 to -0.1MPa) for 4 to 6 hours to obtain 5.1kg of crude product with HPLC purity of 95.68%.

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Abstract

The invention discloses a method for purifying brexpiprazole. The invention provides the method for purifying brexpiprazole. The method comprises the following step: in an organic solvent, purifying abrexpiprazole crude product I, thereby obtaining brexpiprazole I, wherein the organic solvent is a mixed solvent of an aliphatic alcohol solvent, an aliphatic ether solvent and an aliphatic halogenated hydrocarbon solvent; the purity of the brexpiprazole crude product is 90-100%, including 90% but not 100%. The method disclosed by the invention is simple and safe to operate, simple in aftertreatment, high in product purity which can meet raw material medicine standards, low in production cost and applicable to industrial production.

Description

technical field [0001] The invention relates to a method for purifying ibiprazole. Background technique [0002] Ibiprazole (Brexpiprazole, I) is a serotonin-dopamine activity modulator, a partial agonist of dopamine D2 and 5-HT1A receptors, and also a 5-HT2A and norepinephrine 1B / 2C receptor, This drug is used in the treatment of schizophrenia and major depressive disorder. [0003] [0004] Comparing the clinical data of ibiprazole and aripiprazole, it is found that: PANSS value: ibiprazole is significantly better than aripiprazole; CGI-C value: ibiprazole is not inferior to aripiprazole (10mg, 30mg); the dose of ibiprazole (2mg, 4mg) is much smaller than the dose of aripiprazole (10mg, 30mg). Therefore, ibiprazole is currently one of the best drugs for the treatment of depression. [0005] The publicly reported synthetic methods of ibiprazole I under the prior art conditions are reported in patent documents CN101155804B, WO2006112464, CN 103717587A and the like. ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D409/12
CPCC07D409/12
Inventor 公绪栋陈健郭玉辉应述欢
Owner SHANGHAI BOCIMED PHARMA CO LTD
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