Brexpiprazole methyl alcohol compound, crystal form A and preparation method and application

A technology for epipiprazole methyl and alcoholate, applied in the field of epipiprazole methylate, can solve the problems of cumbersome preparation process, unsuitable for industrial production, poor crystal form solubility, etc., and achieves good sustained-release effect and high marketability Good chemical prospect and easy dissociation effect

Inactive Publication Date: 2017-05-24
SHANGHAI BOCIMED PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] The technical problem to be solved by the present invention is to provide a...

Method used

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  • Brexpiprazole methyl alcohol compound, crystal form A and preparation method and application
  • Brexpiprazole methyl alcohol compound, crystal form A and preparation method and application
  • Brexpiprazole methyl alcohol compound, crystal form A and preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0051] In a 50L reaction kettle, heat and dissolve 1.8kg of ebiprazole raw material (anhydrous substance) in 9L of dichloromethane and 1.8L of methanol, lower the temperature to 0-10°C, slowly add 18L of methanol dropwise, dropwise After completion, keep 0-10°C and stir at 120 rpm for 2 hours to crystallize, and filter to obtain a white solid filter cake. Vacuum drying (-0.08MPa--0.01MPa) at 45-55°C for 4-5 hours gave 1.68 kg of crystal form A of ebiprazole methanolate with a yield of 86.9% and a HPLC purity of 99.82%. Determination of its XRPD, DSC, DSC-TGA and infrared spectrum, its XRPD spectrum as figure 1 Shown; its DSC spectrum is shown in figure 2 shown; its DSC-TGA spectrum is as image 3 shown; its infrared spectrum is shown in Figure 4 Shown; The crystalline form A of the ebiprazole methanolate that embodiment 1 makes and reference preparation (otsukapharmaceutical.co., the ebiprazole anhydrous product that Otsuka Pharmaceutical produces) in 3% SDSpH6.8 Compari...

Embodiment 2

[0064] In a 500mL reaction bottle, heat and dissolve 18g of ebiprazole raw material (dihydrate) in 90mL of dichloromethane and 18mL of methanol, lower the temperature to 0-10°C, slowly add 180mL of methanol dropwise, after the dropwise addition , kept at 0-10° C. and stirred at a rate of 30 rpm for 2 hours to crystallize, and filtered to obtain a white solid filter cake. Vacuum (-0.08MPa--0.01MPa) drying at 45-55°C for 4-5 hours gave 16.1 g of crystal form A of ebiprazole methanolate, with a yield of 83.3% and a HPLC purity of 99.74%.

Embodiment 3

[0066] In a 500mL reaction bottle, heat and dissolve 18g of ebiprazole raw material (anhydrous substance) in 90mL of toluene and 18mL of methanol, lower the temperature to 0-10°C, slowly add 180mL of methanol dropwise, after the dropwise addition, Maintain 0-10°C and stir at 3000 rpm for 2 hours to crystallize, and filter to obtain a white solid filter cake. Vacuum drying (-0.08MPa--0.01MPa) at 45-55°C for 4-5 hours gave 16.5g of crystal form A of ebiprazole methanolate, with a yield of 85.3% and an HPLC purity of 99.89%.

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PUM

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Abstract

The invention discloses a brexpiprazole methyl alcohol compound, a crystal form A and a preparation method and application. The crystal form A of the brexpiprazole methyl alcohol compound has characteristic peaks at the positions of 3375.1 cm-1, 3064.3 cm-1, 2942.3 cm-1, 2819.0 cm-1, 1648.3 cm-1, 1625.0 cm-1, 1449.7 cm-1, 1220.8 cm-1 and 841.4 cm in an infrared absorption spectrum measured by adopting a potassium bromide pellet technique. The preparation method is safe, simple and convenient, the prepared brexpiprazole methyl alcohol compound or the crystal form A is better in solubility, makes dissociation easy so as to obtain brexpiprazole, is good in slow-release effect, suitable for drug development and wide in market prospect.

Description

technical field [0001] The invention relates to an ebiprazole methanolate, crystal form A, a preparation method and application thereof. Background technique [0002] Schizophrenia is a chronic, severe and disabling brain disorder that can cause delusions and hallucinations. According to research, about 1 million people lose their lives every year. With the rapid development of social economy, people are under increasing mental pressure from many aspects, and the incidence of mental system has been increasing. Ebiprazole (English name brexpiprazole) is the first dopamine and serotonin regulator jointly developed by Otsuka Pharmaceutical Company of Japan and Lundbeck Pharmaceutical Company of Denmark. Another heavy variety after prarazole. Based on 7 clinical II and clinical III studies that have been completed, Otsuka Pharmaceutical and Lundbeck Pharmaceutical have submitted a new drug application for epizopa to the US Food and Drug Administration (FDA) in July 2014. Thi...

Claims

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Application Information

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IPC IPC(8): C07D409/12A61K31/496A61P25/00
CPCA61P1/08A61P3/04A61P25/00A61P25/04A61P25/06A61P25/14A61P25/18A61P25/20A61P25/22A61P25/24A61P25/28A61P25/30C07B2200/13C07D409/12
Inventor 应述欢公绪栋皮红军郭玉辉陈健
Owner SHANGHAI BOCIMED PHARMA CO LTD
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