阅读说明：本技术 一种盐酸依匹哌唑新晶型及其制备方法 (Novel crystal form of brexpiprazole hydrochloride and preparation method thereof ) 是由 王洁 龚登凰 杨敏 孙文姣 巨鹏瑶 朱立峰 王玉蒙 张茜 于 2020-03-24 设计创作，主要内容包括：本发明提供一种盐酸依匹哌唑晶型S及其制备方法。本发明通过控制冰乙酸和乙醇的混合溶剂相对于依匹哌唑粗品的用量,可在常温条件下溶解依匹哌唑粗品,避免了高温滴加乙酸带来的安全隐患和健康风险。并通过控制结晶温度获得了一种粒径显著大于现有晶型的盐酸依匹哌唑新晶型S,能缩短过滤时间44％-60％,对于减小时间成本、提高生产效率非常有利,适用于工业化生产。(The invention provides an epipiprazole hydrochloride crystal form S and a preparation method thereof. According to the method, the crude product of the ipiprazole can be dissolved at normal temperature by controlling the dosage of the mixed solvent of the glacial acetic acid and the ethanol relative to the crude product of the ipiprazole, so that potential safety hazards and health risks caused by dripping acetic acid at high temperature are avoided. The novel crystal form S of the ipiprazole hydrochloride with the particle size obviously larger than that of the conventional crystal form is obtained by controlling the crystallization temperature, the filtering time can be shortened by 44-60%, the time cost is reduced, the production efficiency is improved, and the method is suitable for industrial production.)

1. A preparation method of an epipiprazole hydrochloride crystal form S comprises the following specific steps: adding crude products of the brexpiprazole into a mixed solvent of ethanol and glacial acetic acid, stirring at room temperature to dissolve the brexpiprazole, heating to the crystallization temperature of 30-45 ℃, adding hydrochloric acid until the reaction is complete, cooling to the temperature of less than or equal to 15 ℃, crystallizing, and filtering to obtain a brexpiprazole hydrochloride crystal form S;

the dosage of the mixed solvent relative to the crude product of the brexpiprazole is as follows: adding 40-50ml of ethanol and 2.5-3.5ml of glacial acetic acid into each 1g of crude brexpiprazole; preferably, the dosage of the mixed solvent relative to the crude product of the brexpiprazole is as follows: 50ml of ethanol and 2.5ml of glacial acetic acid are added into each 1g of crude brexpiprazole.

2. The crystalline form S of brexpiprazole hydrochloride prepared by the preparation method of claim 1, wherein the D90 of the crystalline form is 150-350 μm; preferably, the D90 of the crystal form is 180-310 μm.

3. Crystalline form S of ipiprazole hydrochloride according to claim 2, characterized by characteristic peaks in powder X-ray diffraction at 5.4 ± 0.2, 10.6 ± 0.2, 18.6 ± 0.2, 19.8 ± 0.2, 20.1 ± 0.2, 21.2 ± 0.2 in 2 θ (°) using Cu-K α radiation.

4. The crystalline form S of brexpiprazole hydrochloride according to claim 2, wherein the crystalline form pattern of the crystalline form is shown in figure 1.

5. The crystalline form S of brexpiprazole hydrochloride of claim 2, wherein the particle size distribution diagram of the crystalline form is shown in figure 7.

Technical Field

The patent relates to medicine preparation, in particular to a novel crystal form of brexpiprazole hydrochloride and a preparation method thereof.

Background

Brexpiprazole (Brexpiprazole, formula 1) chemically named 7- (4- (4-benzo [ b ] thiophen-4-yl-piperazin-1-yl) butoxy) -1H-quinolin-2-one is the first dopamine, part of the 5-HT1A receptor agonist and 5-HT2A receptor antagonist compound developed by tsukamur pharmaceuticals and approved for sale in the united states on day 7 and 11 of 2015 under the trade name Rexulti. The product can be used for treating adult schizophrenia, and can also be used as adjuvant medicine for treating adult major depression.

Disclosure of Invention

The invention aims to provide a novel preparation method of brexpiprazole hydrochloride, which can dissolve crude brexpiprazole at normal temperature and avoid potential safety hazard and health risk caused by dripping acetic acid at high temperature. Meanwhile, the novel crystal form S of the brexpiprazole hydrochloride is obtained unexpectedly, the crystal form has larger particle size, high yield and short time consumption of the filtering step, and is more suitable for industrial production.

The invention provides a preparation method of a new crystal form S of brexpiprazole hydrochloride, which comprises the following specific steps: adding crude products of the brexpiprazole into a mixed solvent of ethanol and glacial acetic acid, stirring at room temperature to dissolve the brexpiprazole, heating to the crystallization temperature of 30-45 ℃, adding hydrochloric acid until the reaction is complete, cooling to the temperature of less than or equal to 15 ℃, crystallizing, and filtering to obtain the brexpiprazole hydrochloride crystal form S. The dosage of the mixed solvent relative to the crude product of the brexpiprazole is as follows: adding 40-50ml of ethanol and 2.5-3.5ml of glacial acetic acid into each 1g of crude brexpiprazole. Preferably, the dosage of the mixed solvent relative to the crude product of the brexpiprazole is as follows: 50ml of ethanol and 2.5ml of glacial acetic acid are added into each 1g of crude brexpiprazole.

The invention also provides an epipiprazole crystal form hydrochloride, which is prepared by using the method. Preferably, the D90 of the crystal form is 150-350 μm. More preferably, the D90 of the crystal form is 180-310 μm.

Further, the powder X-ray diffraction measured in 2 θ (°) by Cu-K α showed characteristic peaks at 5.4. + -. 0.2, 10.6. + -. 0.2, 18.6. + -. 0.2, 19.8. + -. 0.2, 20.1. + -. 0.2, and 21.2. + -. 0.2.

Further, the crystal form pattern of the crystal form is shown in figure 1.

Further, the particle size distribution diagram of the crystal form is shown in fig. 7.

The invention achieves the following beneficial effects:

(1) the crystallization temperature is controlled within the range of 30-45 ℃, the grain diameter of the prepared crystal form S of the epipiprazole is obviously larger than that of the existing crystal form, the D90 of the crystal form S of the invention is as high as 180-310 mu m and is more than 10 times of the grain diameter of the crystal form of CN104829603A and CN104254530A in the prior art, the time of the filtration step is saved by 44-60%, the production efficiency can be obviously improved, and the large-scale production is more facilitated.

(2) According to the invention, by controlling the adding amount of ethanol and glacial acetic acid relative to the crude product of the brexpiprazole, the brexpiprazole can be dissolved at normal temperature, so that the production energy consumption is reduced, and potential safety hazard and health risk caused by dripping acetic acid at high temperature are avoided.

(3) The yield of the crystal form of the brexpiprazole hydrochloride prepared by the invention is more than 89%, and the reaction solvent is not wasted, so that the method is suitable for industrial production.

Drawings

FIG. 1 is an XRD diffraction pattern of crystalline form of brexpiprazole hydrochloride prepared in examples 2-3.

FIG. 2 is the XRD diffraction pattern data of the crystalline form of brexpiprazole hydrochloride prepared in example 2-3.

FIG. 3 is an XRD diffraction pattern of the crystalline form of brexpiprazole hydrochloride prepared in comparative example 2.

FIG. 4 is XRD diffraction pattern data of the crystalline form of brexpiprazole hydrochloride prepared in comparative example 2.

FIG. 5 is a particle size distribution diagram of example 2-1.

FIG. 6 is a particle size distribution diagram of example 2-2.

FIG. 7 is a graph showing the particle size distribution in examples 2 to 3.

FIG. 8 is a graph showing the particle size distribution in examples 2 to 4.

Detailed Description

The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or under conditions recommended by the manufacturers.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred embodiments and materials described herein are exemplary only.

The particle size testing method comprises the following steps:

particle size analyzer: mastersizer 2000.

Detection conditions are as follows: refractive index: 1.52, sample injection pressure: 2.0, dry sampling.

X-ray powder diffractometer (XRD) test method:

instrument name and model: rigaku D/MAX-2500X-ray diffractometer in Japan.

The measurement conditions were as follows: Cu/Ka₁Ray, tube pressure 40KV, tube flow 150mA, scanning range 0 ~ 60.

Preparation example 1: preparation of crude brexpiprazole

A crude product of ipiprazole was prepared as described in example 1 of CN101155804A by stirring a mixture of 90g of 7- (4-chlorobutoxy) -1H-quinolin-2-one, 100g of 1-benzo [ b ] thiophen-4-yl-piperazine hydrochloride, 140g of potassium carbonate, 60g of potassium iodide and 900m of L DMF at 80 ℃ for 2H, adding water to the reaction mixture, precipitating crystals, filtering for separation, and drying to give 130g of crude product of ipiprazole having a purity of 95.6%.