TW202315622A

TW202315622A - A crystallization process of a gnrh receptor antagonist

Info

Publication number: TW202315622A
Application number: TW111132757A
Authority: TW
Inventors: 董國梁; 陳亞; 張磊; 郭昌山
Original assignee: 大陸商江蘇恆瑞醫藥股份有限公司
Priority date: 2021-08-30
Filing date: 2022-08-30
Publication date: 2023-04-16
Also published as: WO2023030293A1; CN117769424A

Abstract

The present disclosure provides a crystallization process of a GnRH receptor antagonist. Specifically, the present disclosure provides a crystallization process of a crystal form of a compound of formula (I).

Description

一種GnRH受體拮抗劑的結晶工藝 A kind of crystallization process of GnRH receptor antagonist

本揭露關於1-(4-(7-(2,6-二氟苄基)-3-((二甲胺基)甲基)-5-(6-甲氧基噠嗪-3-基)-4,6-二羰基-4,5,6,7-四氫-2H-吡唑并[3,4-d]嘧啶-2-基)苯基)-3-甲氧基脲的晶型的結晶工藝。 The disclosure relates to 1-(4-(7-(2,6-difluorobenzyl)-3-((dimethylamino)methyl)-5-(6-methoxypyridazin-3-yl) Crystal of -4,6-dicarbonyl-4,5,6,7-tetrahydro- 2H -pyrazolo[3,4- d ]pyrimidin-2-yl)phenyl)-3-methoxyurea type of crystallization process.

***釋放激素(GnRH)也稱黃體生成素釋放激素(LHRH)，是內分泌生殖系統中的中樞調節因素。***如黃體生成素(LH)和***(FSH)的分泌和釋放，調節卵巢和黃體的正常發育，在下丘腦-垂體-性腺軸發揮重要作用。GnRH受體藉由與能夠激活磷脂醯肌醇鈣第二信使體系的G蛋白偶聯發揮其調節作用，而LH則調節性類固醇的產生，FSH調節男性***發生及女性卵泡的發育。 Gonadotropin-releasing hormone (GnRH), also known as luteinizing hormone-releasing hormone (LHRH), is a central regulatory factor in the endocrine reproductive system. The secretion and release of gonadotropins such as luteinizing hormone (LH) and follicle stimulating hormone (FSH) regulate the normal development of the ovary and corpus luteum and play an important role in the hypothalamus-pituitary-gonadal axis. GnRH receptor exerts its regulatory effect by coupling with G protein that can activate the second messenger system of phosphatidylinositol calcium, while LH regulates the production of sex steroids, and FSH regulates male spermatogenesis and female follicle development.

LH和FSH被釋放到循環中，並與卵巢或睾丸的特異性細胞上受體相結合，刺激類固醇的生成。性類固醇存在情況下，疾病例如子宮內膜異位症、子宮肌瘤和***癌等病情加重，需給予長效肽類的GnRH受體激動劑和拮抗劑進行治療控制。 LH and FSH are released into the circulation and bind to receptors on specific cells in the ovaries or testes to stimulate steroid production. In the presence of sex steroids, diseases such as endometriosis, uterine fibroids, and prostate cancer are aggravated, and long-acting peptide GnRH receptor agonists and antagonists need to be given for treatment and control.

GnRH受體激動劑介導的間接抑制腫瘤機制是藉由長期作用於下丘腦-垂體-性腺軸，導致垂體***(FSH，LH)降低，從而減少性激素的分泌而間接抑制腫瘤細胞的生長。而GnRH受體拮抗劑則直接抑制垂體***的釋放，進而抑制腫瘤細胞的生長。 The indirect tumor suppression mechanism mediated by GnRH receptor agonists is through long-term effects on the hypothalamus-pituitary-gonadal axis, resulting in the reduction of pituitary gonadotropins (FSH, LH), thereby reducing the secretion of sex hormones and indirectly inhibiting the growth of tumor cells . GnRH receptor antagonists directly inhibit the release of pituitary gonadotropins, thereby inhibiting the growth of tumor cells.

WO2015062391A1中提供了一種結構新型的高效低毒的GnRH受體拮抗劑，具有優異的效果和作用，能夠有效治療內分泌生殖系統疾病，其化學名為1-(4-(7-(2,6-二氟苄基)-3-((二甲胺基)甲基)-5-(6-甲氧基噠嗪-3-基)-4,6-二羰基-4,5,6,7-四氫-2H-吡唑并[3,4-d]嘧啶-2-基)苯基)-3-甲氧基脲，結構如下所示 WO2015062391A1 provides a novel structurally efficient and low-toxic GnRH receptor antagonist, which has excellent effects and effects, and can effectively treat endocrine reproductive system diseases. Its chemical name is 1-(4-(7-(2,6- Difluorobenzyl)-3-((dimethylamino)methyl)-5-(6-methoxypyridazin-3-yl)-4,6-dicarbonyl-4,5,6,7- Tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-2-yl)phenyl)-3-methoxyurea, the structure is shown below

WO2019020102A1公開了式(I)所示化合物的製備方法。 WO2019020102A1 discloses a preparation method of the compound represented by formula (I).

WO2018086608A1公開了式(I)所示化合物的I晶型以及製備方法，其公開了I晶型的X-射線粉末衍射圖特徵峰的角位置(2θ)，其中公開的製備I晶型的方法可用於小量製備，但當用於車間生產時存在問題。 WO2018086608A1 discloses the I crystal form of the compound represented by formula (I) and its preparation method, which discloses the angular position (2θ) of the characteristic peak of the X-ray powder diffraction pattern of the I crystal form, wherein the disclosed method for preparing the I crystal form can be used Good for small-scale preparations, but problematic when used in workshops.

本揭露提供一種製備式(I)所示化合物的晶型的方法，該方法包括式(I)所示化合物在有機溶劑A中溶解得到溶液I，將溶劑B與溶液I混合，隨後低溫析晶的步驟， The disclosure provides a method for preparing the crystal form of the compound represented by formula (I), the method comprising dissolving the compound represented by formula (I) in organic solvent A to obtain solution I, mixing solvent B with solution I, and then crystallizing at low temperature A step of,

在一些實施方案中，本揭露有機溶劑A為酮類溶劑與水的混合溶劑。在一些實施方案中，本揭露有機溶劑A為丙酮與水的混合溶劑。 In some embodiments, the organic solvent A of the present disclosure is a mixed solvent of a ketone solvent and water. In some embodiments, the organic solvent A of the present disclosure is a mixed solvent of acetone and water.

在一些實施方案中，本揭露溶劑B為水或酮類溶劑與水的混合溶劑。 In some embodiments, the solvent B of the present disclosure is water or a mixed solvent of a ketone solvent and water.

在一些實施方案中，本揭露溶劑B為水或丙酮與水的混合溶劑。 In some embodiments, the solvent B of the present disclosure is water or a mixed solvent of acetone and water.

在一些實施方案中，本揭露溶劑B為水。 In some embodiments, Solvent B of the present disclosure is water.

在一些實施方案中，本揭露溶劑B為丙酮與水的混合溶劑。 In some embodiments, the solvent B of the present disclosure is a mixed solvent of acetone and water.

在一些實施方案中，本揭露析晶的溫度不高於0℃。 In some embodiments, the crystallization temperature of the present disclosure is not higher than 0°C.

在一些實施方案中，本揭露析晶的溫度為0℃~-40℃。 In some embodiments, the crystallization temperature of the present disclosure is 0°C to -40°C.

在一些實施方案中，本揭露析晶的溫度為0℃、-1℃、-2℃、-3℃、-4℃、-5℃、-6℃、-7℃、-8℃、-9℃、-10℃、-11℃、-12℃、-13℃、-14℃、-15℃、-16℃、-17℃、-18℃、-19℃、-20℃、-2℃、-22℃、-23℃、-24℃、-25℃、-26℃、-27℃、-28℃、-29℃、-30℃、-31℃、-32℃、-33℃、-34℃、-35℃、-36℃、-37℃、-38℃、-39℃和-40℃。 In some embodiments, the crystallization temperature of the present disclosure is 0°C, -1°C, -2°C, -3°C, -4°C, -5°C, -6°C, -7°C, -8°C, -9°C ℃, -10℃, -11℃, -12℃, -13℃, -14℃, -15℃, -16℃, -17℃, -18℃, -19℃, -20℃, -2℃, -22°C, -23°C, -24°C, -25°C, -26°C, -27°C, -28°C, -29°C, -30°C, -31°C, -32°C, -33°C, -34°C °C, -35°C, -36°C, -37°C, -38°C, -39°C and -40°C.

在一些實施方案中，本揭露析晶的溫度為-10℃~-20℃。 In some embodiments, the crystallization temperature of the present disclosure is -10°C~-20°C.

在一些實施方案中，本揭露析晶的溫度為-10℃。 In some embodiments, the crystallization temperature of the present disclosure is -10°C.

在一些實施方案中，本揭露製備式(I)所示化合物的晶型的方法，包括以下步驟： In some embodiments, the present disclosure discloses a method for preparing a crystal form of a compound represented by formula (I), comprising the following steps:

1)將式(I)所示化合物在有機溶劑A中溶解得到溶液I，該有機溶劑A為丙酮與水的混合溶劑； 1) dissolving the compound represented by formula (I) in an organic solvent A to obtain a solution I, the organic solvent A being a mixed solvent of acetone and water;

2)向溶液I中加入溶劑B，該溶劑B為水或丙酮與水的混合溶劑； 2) add solvent B to solution I, and this solvent B is the mixed solvent of water or acetone and water;

3)低溫析晶，分離晶態物質即可得目標I晶型，該析晶溫度不高於0℃。 3) Low-temperature crystallization, the target crystal form I can be obtained by separating crystalline substances, and the crystallization temperature is not higher than 0°C.

在一些實施方案中，本揭露式(I)所示化合物在有機溶劑A中溶解的方式為加熱溶解。 In some embodiments, the compound represented by the formula (I) in the present disclosure is dissolved in the organic solvent A by heating.

在一些實施方案中，本揭露式(I)所示化合物在有機溶劑A中加熱溶解加熱所至的溫度為60-90℃。 In some embodiments, the compound represented by formula (I) in the present disclosure is dissolved in the organic solvent A by heating to a temperature of 60-90°C.

在一些實施方案中，本揭露式(I)所示化合物在有機溶劑A中加熱溶解加熱所至的溫度為60℃、61℃、62℃、63℃、64℃、65℃、66℃、67℃、68℃、69℃、70℃、71℃、72℃、73℃、74℃、75℃、76℃、77℃、68℃、79℃、80℃、81℃、82℃、83℃、84℃、85℃、86℃、87℃、88℃、89℃和90℃。 In some embodiments, the temperature at which the compound represented by formula (I) in the present disclosure is dissolved in organic solvent A is 60°C, 61°C, 62°C, 63°C, 64°C, 65°C, 66°C, 67°C ℃, 68℃, 69℃, 70℃, 71℃, 72℃, 73℃, 74℃, 75℃, 76℃, 77℃, 68℃, 79℃, 80℃, 81℃, 82℃, 83℃, 84°C, 85°C, 86°C, 87°C, 88°C, 89°C and 90°C.

在一些實施方案中，本揭露式(I)所示化合物在有機溶劑A中加熱溶解加熱所至的溫度為80℃。 In some embodiments, the compound represented by the formula (I) in the present disclosure is dissolved in the organic solvent A by heating to a temperature of 80°C.

在一些實施方案中，本揭露所述的方法，其進一步包括熱過濾的步驟。 In some embodiments, the method described in the present disclosure further comprises the step of thermal filtration.

在一些實施方案中，本揭露所述的方法，其進一步包括攪拌的步驟。 In some embodiments, the method described in the present disclosure further comprises the step of stirring.

在一些實施方案中，本揭露所述的方法，其中攪拌步驟的方式為機械攪拌。 In some embodiments, in the method described in the present disclosure, the method of the stirring step is mechanical stirring.

在一些實施方案中，本揭露製備式(I)所示化合物的I晶型的方法，包括以下步驟： In some embodiments, the present disclosure discloses a method for preparing the I crystal form of the compound represented by formula (I), comprising the following steps:

1)將式(I)所示化合物在有機溶劑A中加熱攪拌溶解，該有機溶劑A為丙酮與水的混合溶劑； 1) dissolving the compound represented by formula (I) in an organic solvent A with stirring and heating, and the organic solvent A is a mixed solvent of acetone and water;

2)加入溶劑B，該溶劑B為水或丙酮與水的混合溶劑； 2) adding solvent B, which is a mixed solvent of water or acetone and water;

3)低溫攪拌析晶，分離晶態物質即可得目標I晶型，析晶溫度不高於0℃。 3) Stir and crystallize at low temperature, separate the crystalline substances to obtain the target crystal form I, and the crystallization temperature is not higher than 0°C.

在一些實施方案中，本揭露所述的方法，其中該有機溶劑A為丙酮與水的混合溶劑，兩者體積比為3：1~30：1。 In some embodiments, the method described in the present disclosure, wherein the organic solvent A is a mixed solvent of acetone and water, and the volume ratio of the two is 3:1-30:1.

在一些實施方案中，本揭露所述的方法，其中該有機溶劑A為丙酮與水的混合溶劑，兩者體積比為3：1、4：1、5：1、6：1、7：1、8：1、9：1、10：1、11：1、12：1、13：1、14：1、15：1、16：1、17：1、18：1、19：1、20：1、21：1、22：1、23：1、24：1、25：1、26：1、27：1、28：1、29：1和30：1。 In some embodiments, the method described in the present disclosure, wherein the organic solvent A is a mixed solvent of acetone and water, and the volume ratio of the two is 3:1, 4:1, 5:1, 6:1, 7:1 , 8:1, 9:1, 10:1, 11:1, 12:1, 13:1, 14:1, 15:1, 16:1, 17:1, 18:1, 19:1, 20 :1, 21:1, 22:1, 23:1, 24:1, 25:1, 26:1, 27:1, 28:1, 29:1 and 30:1.

在一些實施方案中，本揭露所述的方法，其中有機溶劑A為丙酮與水的混合溶劑，兩者體積比為9：1~15：1。 In some embodiments, the method described in the present disclosure, wherein the organic solvent A is a mixed solvent of acetone and water, and the volume ratio of the two is 9:1-15:1.

在一些實施方案中，本揭露所述的方法，其中有機溶劑A為丙酮與水的混合溶劑，兩者體積比為9：1。 In some embodiments, the method described in the present disclosure, wherein the organic solvent A is a mixed solvent of acetone and water, and the volume ratio of the two is 9:1.

在一些實施方案中，本揭露所述的方法，其中溶劑B為丙酮與水的混合溶劑，兩者體積比為1：30-1：1。 In some embodiments, the method described in the present disclosure, wherein the solvent B is a mixed solvent of acetone and water, and the volume ratio of the two is 1:30-1:1.

在一些實施方案中，本揭露所述的方法，其中溶劑B為丙酮與水的混合溶劑，兩者體積比為1：30、1：29、1：28、1：27、1：26、1：25、1：24、1：23、1：22、1：21、1：20、1：19、1：18、1：17、1：16、1：15、1：14、1：13、1：12、1：11、1：10、1：9、1：8、1：7、1：6、1：5、1：4、1：3、1：2和1：1。 In some embodiments, the method described in the present disclosure, wherein solvent B is a mixed solvent of acetone and water, and the volume ratio of the two is 1:30, 1:29, 1:28, 1:27, 1:26, 1 :25, 1:24, 1:23, 1:22, 1:21, 1:20, 1:19, 1:18, 1:17, 1:16, 1:15, 1:14, 1:13 , 1:12, 1:11, 1:10, 1:9, 1:8, 1:7, 1:6, 1:5, 1:4, 1:3, 1:2 and 1:1.

在一些實施方案中，本揭露所述的方法，其中溶劑B為丙酮與水的混合溶劑，兩者體積比為1：15-1：9。 In some embodiments, the method described in the present disclosure, wherein the solvent B is a mixed solvent of acetone and water, and the volume ratio of the two is 1:15-1:9.

在一些實施方案中，本揭露所述的方法，其中溶劑B為丙酮與水的混合溶劑，兩者體積比為1：9。 In some embodiments, in the method described in the present disclosure, the solvent B is a mixed solvent of acetone and water, and the volume ratio of the two is 1:9.

在一些實施方案中，本揭露所述的方法，其中溶劑B與式(I)化合物的體積質量比為5mL/g~50mL/g。 In some embodiments, the method described in the present disclosure, wherein the volume to mass ratio of solvent B to the compound of formula (I) is 5 mL/g to 50 mL/g.

在一些實施方案中，本揭露所述的方法，其中溶劑B與式(I)化合物的體積質量比為5mL/g、6mL/g、7mL/g、8mL/g、9mL/g、10mL/g、11mL/g、12mL/g、13mL/g、14mL/g、15mL/g、16mL/g、17mL/g、18mL/g、19mL/g、20mL/g、21mL/g、22mL/g、23mL/g、24mL/g、25mL/g、26mL/g、27mL/g、28mL/g、29mL/g、30mL/g、31mL/g、32mL/g、33mL/g、34mL/g、35mL/g、36mL/g、37mL/g、38mL/g、39mL/g、40mL/g、41mL/g、42mL/g、43mL/g、44mL/g、45mL/g、46mL/g、47mL/g、48mL/g、49mL/g和50mL/g。 In some embodiments, the method described in the present disclosure, wherein the volume mass ratio of solvent B to the compound of formula (I) is 5mL/g, 6mL/g, 7mL/g, 8mL/g, 9mL/g, 10mL/g , 11mL/g, 12mL/g, 13mL/g, 14mL/g, 15mL/g, 16mL/g, 17mL/g, 18mL/g, 19mL/g, 20mL/g, 21mL/g, 22mL/g, 23mL /g, 24mL/g, 25mL/g, 26mL/g, 27mL/g, 28mL/g, 29mL/g, 30mL/g, 31mL/g, 32mL/g, 33mL/g, 34mL/g, 35mL/g , 36mL/g, 37mL/g, 38mL/g, 39mL/g, 40mL/g, 41mL/g, 42mL/g, 43mL/g, 44mL/g, 45mL/g, 46mL/g, 47mL/g, 48mL /g, 49mL/g and 50mL/g.

在一些實施方案中，本揭露所述的方法，其中溶劑B與式(I)化合物的體積質量比為10mL/g~30mL/g。 In some embodiments, the method described in the present disclosure, wherein the volume to mass ratio of solvent B to the compound of formula (I) is 10 mL/g to 30 mL/g.

在一些實施方案中，本揭露所述的方法，其中溶劑B與式(I)化合物的體積質量比為20mL/g。 In some embodiments, the method described in the present disclosure, wherein the volume to mass ratio of solvent B to the compound of formula (I) is 20 mL/g.

在一些實施方案中，本揭露所述的方法，其中有機溶劑A與式(I)所示化合物的體積質量比為10mL/g-60mL/g。 In some embodiments, the method described in the present disclosure, wherein the volume-to-mass ratio of the organic solvent A to the compound represented by formula (I) is 10 mL/g-60 mL/g.

在一些實施方案中，本揭露所述的方法，其中該有機溶劑A與式(I)所示化合物的體積質量比為10mL/g、11mL/g、12mL/g、13mL/g、14mL/g、15mL/g、16mL/g、17mL/g、18mL/g、19mL/g、20mL/g、21mL/g、22mL/g、23mL/g、24mL/g、25mL/g、26mL/g、27mL/g、28mL/g、29mL/g、30mL/g、31mL/g、32mL/g、33mL/g、34mL/g、35mL/g、36mL/g、37mL/g、38mL/g、39mL/g、40mL/g、41mL/g、 42mL/g、43mL/g、44mL/g、45mL/g、46mL/g、47mL/g、48mL/g、49mL/g、50mL/g、51mL/g、52mL/g、53mL/g、54mL/g、55mL/g、56mL/g、57mL/g、58mL/g、59mL/g和60mL/g。 In some embodiments, the method described in the present disclosure, wherein the volume mass ratio of the organic solvent A to the compound represented by formula (I) is 10mL/g, 11mL/g, 12mL/g, 13mL/g, 14mL/g , 15mL/g, 16mL/g, 17mL/g, 18mL/g, 19mL/g, 20mL/g, 21mL/g, 22mL/g, 23mL/g, 24mL/g, 25mL/g, 26mL/g, 27mL /g, 28mL/g, 29mL/g, 30mL/g, 31mL/g, 32mL/g, 33mL/g, 34mL/g, 35mL/g, 36mL/g, 37mL/g, 38mL/g, 39mL/g , 40mL/g, 41mL/g, 42mL/g, 43mL/g, 44mL/g, 45mL/g, 46mL/g, 47mL/g, 48mL/g, 49mL/g, 50mL/g, 51mL/g, 52mL/g, 53mL/g, 54mL/g g, 55 mL/g, 56 mL/g, 57 mL/g, 58 mL/g, 59 mL/g, and 60 mL/g.

在一些實施方案中，本揭露所述的方法，其中有機溶劑A與式(I)所示化合物的體積質量比為20mL/g-40mL/g。 In some embodiments, the method described in the present disclosure, wherein the volume-to-mass ratio of the organic solvent A to the compound represented by formula (I) is 20 mL/g-40 mL/g.

在一些實施方案中，本揭露所述的方法，其中有機溶劑A與式(I)所示化合物的體積質量比為30mL/g。 In some embodiments, the method described in the present disclosure, wherein the volume-to-mass ratio of the organic solvent A to the compound represented by formula (I) is 30 mL/g.

進一步地，本揭露所述的方法還包括分離晶態物質的步驟。在一些實施方案中，該分離晶態物質的步驟包括過濾、洗滌和乾燥。 Further, the method described in the present disclosure also includes the step of isolating crystalline substances. In some embodiments, the step of isolating the crystalline material comprises filtering, washing and drying.

在一些實施方案中，本揭露所述的方法，其中析晶得到的晶型的X射線粉末衍射圖基本不含有一個或多個的峰值在5.91±0.2°2θ的特徵峰。 In some embodiments, in the method described in the present disclosure, the X-ray powder diffraction pattern of the crystalline form obtained by crystallization substantially does not contain one or more characteristic peaks with peaks at 5.91±0.2°2θ.

在一些實施方案中，本揭露所述的方法，其中分離晶態物質的步驟中洗滌所用的溶劑為水或丙酮。 In some embodiments, the method described in the present disclosure, wherein the solvent used for washing in the step of isolating crystalline substances is water or acetone.

在一些實施方案中，本揭露所述的方法，其中分離晶態物質的步驟中洗滌所用的溶劑為水。 In some embodiments, the method described in the present disclosure, wherein the solvent used for washing in the step of isolating crystalline substances is water.

本揭露晶型製備方法中所用的起始原料可以是任意形式的式(I)所示化合物，具體形式包括但不限於：無定形、任意晶型等。 The starting material used in the preparation method of the disclosed crystal form can be any form of the compound represented by formula (I), and the specific form includes but not limited to: amorphous form, any crystalline form, etc.

本揭露晶型製備方法中所用的起始原料為式(I)所示化合物的無定形形式。 The starting material used in the preparation method of the disclosed crystal form is the amorphous form of the compound represented by formula (I).

本揭露晶型製備方法中所用的起始原料為式(I)所示化合物的I晶型形式。 The starting material used in the preparation method of the disclosed crystal form is the I crystal form of the compound represented by formula (I).

本揭露另一方面提供了一種式(I)所示化合物的I晶型，其可根據本揭露所述的方法製備得到。 Another aspect of the present disclosure provides a crystal form I of the compound represented by formula (I), which can be prepared according to the method described in the present disclosure.

本揭露另一方面提供了一種醫藥組成物，其由根據本揭露所述的方法製備得到的式(I)所示化合物的I晶型製備獲得。 Another aspect of the present disclosure provides a pharmaceutical composition, which is prepared from the I crystal form of the compound represented by formula (I) prepared according to the method described in the present disclosure.

本揭露另一方面提供了一種醫藥組成物的製備方法，其包括根據本揭露所述的方法製備得到的式(I)所示化合物的I晶型和和藥學上可接受的賦形劑混合的步驟。 Another aspect of the present disclosure provides a method for preparing a pharmaceutical composition, which includes the crystal form I of the compound represented by formula (I) prepared according to the method described in the present disclosure and mixed with pharmaceutically acceptable excipients step.

本揭露另一方面提供了一種醫藥組成物的製備方法，其包括根據本揭露所述的方法製備得到式(I)所示化合物的I晶型和和藥學上可接受的添加劑混合的步驟，製備得到的醫藥組成物的X射線粉末衍射圖顯示具有或不具有一個或多個的峰值在10.97±0.2°2θ的特徵峰。 Another aspect of the present disclosure provides a method for preparing a pharmaceutical composition, which includes the steps of preparing the crystal form I of the compound represented by formula (I) according to the method described in the present disclosure and mixing it with pharmaceutically acceptable additives. The X-ray powder diffraction pattern of the obtained pharmaceutical composition shows with or without one or more characteristic peaks with peaks at 10.97±0.2°2θ.

[發明詳述][Detailed description of the invention]

在本揭露的說明書和權利要求書中，除非另有說明，否則本文中使用的科學和技術名詞具有所屬技術領域具有通常知識者所通常理解的含義。然而，為了更好地理解本揭露，下面提供了部分相關術語的定義和解釋。另外，當本揭露所提供的術語的定義和解釋與所屬技術領域具有通常知識者所通常理解的含義不一致時，以本揭露所提供的術語的定義和解釋為准。 In the specification and claims of this disclosure, unless otherwise specified, scientific and technical terms used herein have the meanings commonly understood by those skilled in the art. However, for a better understanding of the present disclosure, definitions and explanations of some related terms are provided below. In addition, when the definitions and explanations of the terms provided in the present disclosure are inconsistent with the meanings commonly understood by those with ordinary knowledge in the technical field, the definitions and explanations of the terms provided in the present disclosure shall prevail.

本揭露所述的“酮類溶劑”是指羰基(-C(O)-)與兩個烴基相連的化合物，根據分子中烴基的不同，酮可分為脂肪酮、脂環酮、芳香酮、飽和酮和不飽和酮，具體實例包括但不限於：丙酮、甲基丁酮或甲基異丁酮。 The "ketone solvent" mentioned in this disclosure refers to a compound in which a carbonyl group (-C(O)-) is connected to two hydrocarbon groups. According to the different hydrocarbon groups in the molecule, ketones can be divided into aliphatic ketones, alicyclic ketones, aromatic ketones, Saturated and unsaturated ketones, specific examples include but not limited to: acetone, methyl butanone or methyl isobutyl ketone.

本揭露所述的“混合溶劑”是指一種或多種不同種類的有機溶劑按照一定比例混合而成的溶劑，或有機溶劑與水按照一定比例混合而成的溶劑。 The “mixed solvent” mentioned in this disclosure refers to a solvent obtained by mixing one or more different types of organic solvents according to a certain ratio, or a solvent obtained by mixing an organic solvent and water according to a certain ratio.

本揭露中所述乾燥溫度一般為25℃~100℃，較佳40℃~70℃，可以常壓乾燥，也可以減壓乾燥。 The drying temperature described in this disclosure is generally 25° C. to 100° C., preferably 40° C. to 70° C., and can be dried under normal pressure or reduced pressure.

本揭露所述的“X-射線粉末衍射圖譜或XRPD”是指根據布拉格公式2d sinθ=nλ(式中，λ為X射線的波長，λ=1.54056Å，衍射的級數n為任何正整數，一般取一級衍射峰，n=1)，當X射線以掠角θ(入射角的餘角，又稱為布拉格角)入射到晶體或部分晶體樣品的某一具有d點陣平面間距的原子面上時，就能滿足布拉格方程，從而測得了這組X射線粉末衍射圖。 The "X-ray powder diffraction pattern or XRPD" described in this disclosure refers to the Bragg formula 2d sinθ=nλ (where λ is the wavelength of X-rays, λ=1.54056Å, and the order n of diffraction is any positive integer, Generally, the first-order diffraction peak is taken, n=1), when X-rays are incident on an atomic plane with a d-lattice plane spacing of a crystal or a part of the crystal sample at a grazing angle θ (the complementary angle of the incident angle, also known as the Bragg angle) When it is above, the Bragg equation can be satisfied, and thus this group of X-ray powder diffraction patterns has been measured.

本揭露中所述的“差示掃描量熱分析或DSC”是指在樣品升溫或恆溫過程中，測量樣品與參考物之間的溫度差、熱流差，以表徵所有與熱效應有關的物理變化和化學變化，得到樣品的相變信息。 The "differential scanning calorimetry or DSC" mentioned in this disclosure refers to the measurement of the temperature difference and heat flow difference between the sample and the reference object during the heating or constant temperature of the sample, so as to characterize all the physical changes related to thermal effects and Chemical changes, to obtain the phase transition information of the sample.

本揭露還涉及，包括式(I)所示的化合物的I晶型，以及視需要的一種或多種藥用的賦形劑的醫藥組成物。該醫藥組成物可以製成藥學上可接受的任一劑型。例如，本揭露的I晶型或藥物製劑可以配製為片劑、膠囊劑、丸劑、顆粒劑、溶液劑、混懸劑、糖漿劑、注射劑(包括注射液、注射用無菌粉末與注射用濃溶液)、栓劑、吸入劑或噴霧劑。 The present disclosure also relates to a pharmaceutical composition comprising the crystal form I of the compound represented by formula (I), and one or more pharmaceutically acceptable excipients as needed. The pharmaceutical composition can be made into any pharmaceutically acceptable dosage form. For example, the crystal form I or pharmaceutical preparations of the present disclosure can be formulated into tablets, capsules, pills, granules, solutions, suspensions, syrups, injections (including injections, sterile powders for injections, and concentrated solutions for injections) ), suppositories, inhalants or sprays.

本揭露中所述的“基本不含有”指峰的豐度低於5%，較佳峰的豐度低於1%。本揭露中所述的“賦形劑”包括但不限於任何已經被美國食品和藥物管理局批准對於人類或家畜動物使用可接受的任何助劑、載體、賦形劑、助流劑、甜味劑、稀釋劑、防腐劑、染料/著色劑、增香劑、表面活性劑、潤濕劑、分散劑、助懸劑、穩定劑、等滲劑、溶劑或乳化劑。 "Essentially free" in this disclosure means that the abundance of peaks is less than 5%, and the abundance of preferred peaks is less than 1%. The "excipient" mentioned in this disclosure includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, or agent, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier.

[發明的有益效果][Beneficial Effects of the Invention]

與現有技術相比，本揭露的技術方案具有以下優點： Compared with the prior art, the technical solution disclosed in the present disclosure has the following advantages:

本揭露提供一種可用於車間生產1-(4-(7-(2,6-二氟苄基)-3-((二甲胺基)甲基)-5-(6-甲氧基噠嗪-3-基)-4,6-二羰基-4,5,6,7-四氫-2H-吡唑并[3,4-d]嘧啶-2-基)苯基)-3-甲氧基脲(如式(I)所示)的I晶型的製備工藝，該工藝在大規模生產過程中重現性好，解決了現有製備方法中的重現性差的問題，具有預料不到的效果。 The disclosure provides a method that can be used in workshops to produce 1-(4-(7-(2,6-difluorobenzyl)-3-((dimethylamino)methyl)-5-(6-methoxypyridazine -3-yl)-4,6-dicarbonyl-4,5,6,7-tetrahydro- 2H -pyrazolo[3,4- d ]pyrimidin-2-yl)phenyl)-3-methyl The preparation process of the I crystal form of oxyurea (as shown in formula (I)), the process has good reproducibility in the large-scale production process, solves the problem of poor reproducibility in the existing preparation methods, and has unexpected Effect.

圖1為式(I)化合物的I晶型的XRPD圖譜； Fig. 1 is the XRPD pattern of I crystal form of formula (I) compound;

圖2為式(I)化合物的I晶型的DSC圖譜； Fig. 2 is the DSC collection of illustrative plates of the I crystal form of formula (I) compound;

圖3為式(I)化合物的E晶型的XRPD圖譜； Fig. 3 is the XRPD spectrum of the E crystal form of the compound of formula (I);

圖4為式(I)化合物的E晶型和I晶型的混晶的XRPD圖譜。 Fig. 4 is an XRPD pattern of mixed crystals of Form E and Form I of the compound of formula (I).

以下將結合實施例更詳細地解釋本揭露，本揭露的實施例僅用於說明本揭露的技術方案，並非限定本揭露的實質和範圍。 The present disclosure will be explained in more detail below with reference to the embodiments. The embodiments of the present disclosure are only used to illustrate the technical solutions of the present disclosure, and do not limit the essence and scope of the present disclosure.

以下實施例中式(I)化合物參照WO2015062391A1中的方法合成得到。 In the following examples, the compound of formula (I) was synthesized according to the method in WO2015062391A1.

實施例1Example 1

1g式(I)所示化合物，30mlACE/H₂O(9：1)從室溫加熱至70℃，溶清，熱過濾，將濾液移至-10℃冷阱中，緩慢加水20ml。繼續磁力攪拌至有大量固體析出，過濾，用水洗滌濾餅，放於烘箱乾燥。得到式(I)所示化合物0.86g，收率86%，所得產品經X-射線粉末衍射圖譜和DSC圖譜確認為WO2018086608中公開的I晶型，其中I晶型的XRPD圖譜見圖1，其特徵峰位置如表1，DSC圖譜見圖2。 1g of the compound represented by formula (I), 30ml of ACE/H ₂ O (9:1) was heated from room temperature to 70°C, dissolved, hot filtered, the filtrate was transferred to a cold trap at -10°C, and 20ml of water was slowly added. Continue magnetic stirring until a large amount of solids are precipitated, filter, wash the filter cake with water, and dry in an oven. 0.86 g of the compound shown in formula (I) was obtained, with a yield of 86%. The obtained product was confirmed to be the I crystal form disclosed in WO2018086608 through the X-ray powder diffraction spectrum and the DSC spectrum, wherein the XRPD spectrum of the I crystal form is shown in FIG. 1, and The positions of characteristic peaks are shown in Table 1, and the DSC spectrum is shown in Figure 2.

表1 I晶型的XRPD譜圖的特徵峰

Table 1 Characteristic peaks of the XRPD spectrum of Form I

實施例2Example 2

1g式(I)所示化合物，30mlACE/H₂O(9：1)從室溫加熱至70℃，溶清，熱過濾，將濾液移至-10℃冷阱中，緩慢加20mlACE/H₂O(1：9)。繼續磁力攪拌至有大量固體析出，過濾，用水洗滌濾餅，放於烘箱乾燥，得到式(I)所示化合物0.7g，收率70%，所得產品經X-射線粉末衍射圖譜確認為I晶型。 1g compound represented by formula (I), 30ml ACE/H ₂ O (9:1) was heated from room temperature to 70°C, dissolved, hot filtered, the filtrate was moved to -10°C cold trap, slowly added 20ml ACE/H ₂ O(1:9). Continue magnetic stirring until a large amount of solids are precipitated, filter, wash the filter cake with water, and dry in an oven to obtain 0.7 g of the compound shown in formula (I), with a yield of 70%, and the resulting product is confirmed as crystal I by X-ray powder diffraction. type.

實施例3Example 3

20g式(I)所示化合物，600mlACE/H₂O(9：1)放於預加熱至80℃油浴鍋中，磁力攪拌至溶清，熱過濾，將濾液移至-10℃冷阱中，機械攪拌，緩慢加400ml ACE/H₂O(1：9)。繼續機械攪拌至大量固體析出，過濾，用水洗滌濾餅，放於烘箱乾燥，得到式(I)所示化合物17.5g，收率87.5%，所得產品經X-射線粉末衍射圖譜確認為I晶型。 Put 20g of the compound represented by formula (I) in 600ml ACE/H ₂ O (9:1) in an oil bath preheated to 80°C, stir magnetically until dissolved, filter hot, and transfer the filtrate to a cold trap at -10°C , with mechanical stirring, slowly add 400ml ACE/H ₂ O (1:9). Continue mechanical stirring until a large amount of solids are precipitated, filter, wash the filter cake with water, and dry in an oven to obtain 17.5 g of the compound shown in formula (I), with a yield of 87.5%, and the obtained product is confirmed as I crystal form by X-ray powder diffraction pattern .

實施例4Example 4

7.7g式(I)所示化合物，230mlACE/H₂O(9：1)放於預加熱至80℃油浴鍋中，磁力攪拌至溶清，熱過濾，將濾液移至-10℃冷阱中，機械攪拌，緩慢加170ml H₂O。繼續機械攪拌至有大量固體析出，過濾，用水洗滌濾餅，放於烘箱乾燥，得到式(I)所示化合物6.3g，收率82%，所得產品經X-射線粉末衍射圖譜確認為I晶型。 Put 7.7g of the compound represented by formula (I) in 230ml ACE/H ₂ O (9:1) in an oil bath preheated to 80°C, stir magnetically until dissolved, filter hot, and move the filtrate to a cold trap at -10°C , with mechanical stirring, slowly add 170ml of H ₂ O. Continue mechanical stirring until a large amount of solids are precipitated, filter, wash the filter cake with water, put in an oven and dry to obtain 6.3 g of the compound shown in formula (I), with a yield of 82%, and the product obtained is confirmed to be crystal I through X-ray powder diffraction. type.

實施例5Example 5

100g式(I)所示化合物，3000mlACE/H₂O(9：1)放於預加熱至80℃的水浴鍋中，機械攪拌至溶清，熱過濾，將濾液移至預降溫至-10℃的20L反應釜中，緩慢加1700ml ACE/H₂O(1：9)溶液。繼續攪拌至大量固體析出，過濾，用水洗滌濾餅，放於烘箱乾燥，得到式(I)所示化合物84.1g，收率84%，所得產品經X-射線粉末衍射圖譜確認為I晶型。 Put 100g of the compound represented by formula (I), 3000ml ACE/H ₂ O (9:1) in a water bath preheated to 80°C, mechanically stir until it dissolves, heat the filter, and move the filtrate to pre-cool to -10°C Slowly add 1700ml ACE/H ₂ O (1:9) solution to a 20L reaction kettle. Continue to stir until a large amount of solids are precipitated, filter, wash the filter cake with water, and dry in an oven to obtain 84.1 g of the compound shown in formula (I), with a yield of 84%. The resulting product is confirmed to be Form I by X-ray powder diffraction patterns.

實施例6Example 6

1000g式(I)所示化合物，30LACE/H₂O(9：1)放於預加熱至80℃的50L反應釜中，機械攪拌至溶清，熱過濾，將濾液移至預降溫至-10℃的100L反應釜中，緩慢加20L ACE/H₂O(1：9)溶液。繼續攪拌至大量固體析出，甩濾，用水洗滌濾餅，放於烘箱乾燥，得到式(I)所示化合物0.8Kg，收率80%，所得產品經X-射線粉末衍射圖譜確認為I晶型。 1000g of the compound represented by formula (I), 30LACE/H ₂ O (9:1) was placed in a 50L reaction kettle preheated to 80°C, mechanically stirred until dissolved, filtered hot, and the filtrate was transferred to a pre-cooled to -10 Slowly add 20L ACE/H ₂ O (1:9) solution to the 100L reaction kettle at ℃. Continue to stir until a large amount of solids are precipitated, shake off the filter, wash the filter cake with water, and dry in an oven to obtain 0.8Kg of the compound shown in formula (I), with a yield of 80%. The resulting product is confirmed to be I crystal form by X-ray powder diffraction pattern .

實施例7Example 7

2.5Kg式(I)所示化合物，75LACE/H₂O(9：1)放於預加熱至80℃的100L反應釜中，機械攪拌至溶清，壓濾，將濾液移至預降溫至-10℃的200L反應釜中，緩慢加50L ACE/H₂O(1：9)溶液。繼續攪拌至大量固體析出，甩濾，用水洗滌濾餅，放於烘箱乾燥，得到式(I)所示化合物2.06Kg，收率82.4%，所得產品經X-射線粉末衍射圖譜確認為I晶型。 Put 2.5Kg of the compound represented by formula (I), 75LACE/H ₂ O (9:1) in a 100L reaction kettle preheated to 80°C, mechanically stir until dissolved, press filter, and move the filtrate to a pre-cooled to - Slowly add 50L of ACE/H ₂ O (1:9) solution to a 200L reaction kettle at 10°C. Continue to stir until a large amount of solids are precipitated, shake off the filter, wash the filter cake with water, and dry in an oven to obtain 2.06Kg of the compound shown in formula (I), with a yield of 82.4%. The resulting product is confirmed as I crystal form by X-ray powder diffraction pattern .

實施例8Example 8

取1g式(I)所示化合物於100ml燒瓶中，加入30ml ACE/H₂O(9：1)溶劑，加熱至70℃溶清，熱過濾，滴加入12ml水，放於室溫下攪拌至大量固體析出，過濾，濾餅放於烘箱乾燥，得到0.7g樣品，所得產品經X-射線粉末衍射圖譜確認為CN202110363035.1中保護的晶型E，XRPD譜圖如圖3，其特徵峰位置如表2所示。 Take 1g of the compound represented by formula (I) in a 100ml flask, add 30ml of ACE/H ₂ O (9:1) solvent, heat to 70°C to dissolve, heat filter, add 12ml of water dropwise, and stir at room temperature until A large amount of solid was precipitated, filtered, and the filter cake was dried in an oven to obtain a 0.7g sample. The obtained product was confirmed to be the crystal form E protected in CN202110363035.1 by X-ray powder diffraction pattern. The XRPD pattern is shown in Figure 3, and its characteristic peak position As shown in table 2.

表2 E晶型的XRPD譜圖的特徵峰

Table 2 The characteristic peaks of the XRPD spectrum of the E crystal form

實施例9Example 9

取0.5g式(I)所示化合物於100ml燒瓶中，加入15ml ACE/H₂O(9：1)溶劑，加熱至70℃，溶清，熱過濾，濾液澄清，移至-10℃析晶。磁力攪拌至大量固體析出後過濾，濾餅放於烘箱乾燥，經檢測確定為晶型E+晶型I的混晶，XRPD譜圖如圖4。 Take 0.5g of the compound represented by formula (I) in a 100ml flask, add 15ml of ACE/H ₂ O (9:1) solvent, heat to 70°C, dissolve, heat filter, the filtrate is clear, move to -10°C for crystallization . Stir magnetically until a large amount of solids are precipitated and then filter. The filter cake is dried in an oven. It is determined to be a mixed crystal of Form E + Form I. The XRPD spectrum is shown in Figure 4.

實施例10Example 10

向100L反應釜中加入45L ACE/H2O(5：1)溶劑，加入式(I)所示化合物3Kg，開動攪拌，加熱至回流，自然冷卻至室溫，繼續攪拌3h，過濾。65±3℃鼓風乾燥10小時，得固體1.7kg，經X-射線粉末衍射圖譜檢測確定為晶型E+晶型I的混晶。 Add 45L ACE/H2O (5:1) solvent to a 100L reactor, add 3Kg of the compound represented by formula (I), start stirring, heat to reflux, cool to room temperature naturally, continue stirring for 3h, and filter. Air-dried at 65±3°C for 10 hours to obtain 1.7 kg of solid, which was determined to be a mixed crystal of Form E+Form I by X-ray powder diffraction pattern detection.

Claims

一種製備式(I)所示化合物晶型的方法，該方法包括式(I)所示化合物在有機溶劑A中溶解得到溶液I，將溶劑B與溶液I混合，隨後低溫析晶的步驟， A method for preparing a crystal form of a compound shown in formula (I), the method comprising dissolving the compound shown in formula (I) in an organic solvent A to obtain a solution I, mixing solvent B with the solution I, followed by the steps of low-temperature crystallization,

如請求項1所述的方法，其中有機溶劑A為酮類溶劑與水的混合溶劑，較佳為丙酮與水的混合溶劑。 The method according to claim 1, wherein the organic solvent A is a mixed solvent of ketone solvent and water, preferably a mixed solvent of acetone and water.

如請求項1或2所述的方法，其中溶劑B為水或酮類溶劑與水的混合溶劑。 The method as claimed in item 1 or 2, wherein the solvent B is water or a mixed solvent of ketone solvent and water.

如請求項1至3中任一項所述的方法，其中溶劑B為水。 The method as described in any one of claims 1 to 3, wherein solvent B is water.

如請求項1至3中任一項該方法，其中溶劑B為丙酮與水的混合溶劑。 The method according to any one of claims 1 to 3, wherein the solvent B is a mixed solvent of acetone and water.

如請求項1至5中任一項所述的方法，其中析晶的溫度不高於0℃，較佳0℃~-40℃，更佳-10℃~-20℃。 The method according to any one of claims 1 to 5, wherein the crystallization temperature is not higher than 0°C, preferably 0°C~-40°C, more preferably -10°C~-20°C.

如請求項1至6中任一項所述的方法，該方法包括以下步驟： The method as described in any one of claim items 1 to 6, the method comprises the following steps:

2)向溶液I中加入溶劑B，該溶劑B為水或丙酮與水的混合溶劑； 2) Add solvent B to solution I, the solvent B is a mixed solvent of water or acetone and water;

3)低溫析晶，分離晶態物質即可得目標I晶型，該析晶的溫度不高於0℃。 3) Low-temperature crystallization, the target crystal form I can be obtained by separating the crystalline substances, and the temperature of the crystallization is not higher than 0°C.

如請求項1至7中任一項所述的方法，其中式(I)所示化合物在有機溶劑A中溶解的方式為加熱溶解，較佳地，加熱溶解加熱所至的溫度為60-90℃。 The method as described in any one of claim items 1 to 7, wherein the compound represented by formula (I) is dissolved in organic solvent A by heating and dissolving, preferably, the temperature of heating and dissolving is 60-90 ℃.

如請求項8所述的方法，其進一步包括熱過濾的步驟。 The method according to claim 8, further comprising the step of thermal filtering.

如請求項1至9中任一項所述的方法，其中進一步包括攪拌的步驟；較佳為機械攪拌。 The method according to any one of claims 1 to 9, further comprising a stirring step; preferably mechanical stirring.

如請求項1至10中任一項所述的方法，其中有機溶劑A為丙酮與水的混合溶劑，兩者體積比為3：1~30：1，較佳地，兩者體積比為9：1~15：1。 The method as described in any one of claim items 1 to 10, wherein the organic solvent A is a mixed solvent of acetone and water, and the volume ratio of the two is 3:1~30:1, preferably, the volume ratio of the two is 9 :1~15:1.

如請求項1至11中任一項所述的方法，其中溶劑B為丙酮與水的混合溶劑，兩者體積比為1：30-1：1，較佳體積比為1：15-1：9。 The method as described in any one of claim items 1 to 11, wherein the solvent B is a mixed solvent of acetone and water, the volume ratio of the two is 1:30-1:1, and the preferred volume ratio is 1:15-1: 9.

如請求項1至12中任一項所述的方法，其中溶劑B與式(I)化合物的體積質量比為5mL/g~50mL/g，較佳為10mL/g~30mL/g，更佳為20mL/g。 The method as described in any one of claim items 1 to 12, wherein the volume mass ratio of solvent B to the compound of formula (I) is 5mL/g~50mL/g, preferably 10mL/g~30mL/g, more preferably It is 20mL/g.

如請求項1至13中任一項所述的方法，其中有機溶劑A與式(I)所示化合物的體積質量比為10mL/g-60mL/g，較佳為20mL/g-40mL/g，更佳為30mL/g。 The method as described in any one of claim items 1 to 13, wherein the volume mass ratio of the organic solvent A to the compound represented by formula (I) is 10mL/g-60mL/g, preferably 20mL/g-40mL/g , more preferably 30mL/g.

如請求項1至14中任一項所述的方法，其中分離晶態物質的步驟包括過濾、洗滌和乾燥。 The method according to any one of claims 1 to 14, wherein the step of isolating the crystalline material comprises filtering, washing and drying.

如請求項1至15中任一項所述的方法，其中析晶得到的晶型的X射線粉末衍射圖基本不含有一個或多個的峰值在5.91±0.2°2θ的特徵峰。 The method according to any one of claims 1 to 15, wherein the X-ray powder diffraction pattern of the crystal form obtained by crystallization basically does not contain one or more characteristic peaks with peaks at 5.91±0.2°2θ.

一種式(I)所示化合物的I晶型，其可如請求項1至16中任一項所述的方法製備得到。 A crystal form I of the compound represented by formula (I), which can be prepared by the method described in any one of claims 1 to 16.

一種醫藥組成物，其由如請求項17所述的化合物的I晶型製備獲得。 A pharmaceutical composition, which is prepared from the crystal form I of the compound described in claim 17.

一種製備如請求項18所述的醫藥組成物的方法，包括如請求項17所述的化合物的I晶型和藥學上可接受的賦形劑混合的步驟。 A method for preparing the pharmaceutical composition as described in claim 18, comprising the step of mixing the crystal form I of the compound as described in claim 17 with a pharmaceutically acceptable excipient.