WO2023030293A1 - 一种GnRH受体拮抗剂的结晶工艺 - Google Patents

一种GnRH受体拮抗剂的结晶工艺 Download PDF

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WO2023030293A1
WO2023030293A1 PCT/CN2022/115728 CN2022115728W WO2023030293A1 WO 2023030293 A1 WO2023030293 A1 WO 2023030293A1 CN 2022115728 W CN2022115728 W CN 2022115728W WO 2023030293 A1 WO2023030293 A1 WO 2023030293A1
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solvent
water
formula
present disclosure
acetone
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French (fr)
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董国梁
陈亚
张磊
郭昌山
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Jiangsu Hengrui Pharmaceutical Co Ltd
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Jiangsu Hengrui Pharmaceutical Co Ltd
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Priority to CN202280053997.XA priority Critical patent/CN117769424A/zh
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present disclosure relates to 1-(4-(7-(2,6-difluorobenzyl)-3-((dimethylamino)methyl)-5-(6-methoxypyridazin-3-yl)- Crystal form of 4,6-dicarbonyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-2-yl)phenyl)-3-methoxyurea crystallization process.
  • Gonadotropin-releasing hormone also known as luteinizing hormone-releasing hormone (LHRH)
  • LHRH luteinizing hormone-releasing hormone
  • FSH follicle stimulating hormone
  • GnRH receptor exerts its regulating 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 and FSH are released into the circulation and bind to receptors on specific cells in the ovaries or testes to stimulate steroid production.
  • 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.
  • the indirect tumor suppression mechanism mediated by GnRH receptor agonists is to indirectly inhibit the growth of tumor cells by acting on the hypothalamus-pituitary-gonad axis for a long time, resulting in the decrease of pituitary gonadotropins (FSH, LH), thereby reducing the secretion of sex hormones.
  • GnRH receptor antagonists directly inhibit the release of pituitary gonadotropins, thereby inhibiting the growth of tumor cells.
  • WO2015062391A1 provides a novel structurally efficient and low-toxic GnRH receptor antagonist, which has excellent effects and effects, and can effectively treat endocrine and 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 discloses a preparation method of the compound represented by formula (I).
  • WO2018086608A1 discloses the I crystal form of the compound represented by formula (I) and its preparation method, which discloses the angular position (2 ⁇ ) 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.
  • the present 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 crystallization step,
  • 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.
  • the solvent B of the present disclosure is water or a mixed solvent of a ketone solvent and water.
  • solvent B of the present disclosure is water or a mixed solvent of acetone and water.
  • Solvent B of the present disclosure is water.
  • solvent B of the present disclosure is a mixed solvent of acetone and water.
  • the crystallization temperature of the present disclosure is not higher than 0°C
  • the crystallization temperature of the present disclosure ranges from 0°C to -40°C.
  • 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 °C, -10°C, -11°C, -12°C, -13°C, -14°C, -15°C, -16°C, -17°C, -18°C, -19°C, -20°C, -21°C, -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.
  • the crystallization temperature of the present disclosure is -10°C to -20°C.
  • the crystallization temperature of the present disclosure is -10°C.
  • the present disclosure prepares the method for the crystalline form of the compound represented by formula (I), comprising the following steps:
  • solvent B is the mixed solvent of water or acetone and water
  • the target crystal form I can be obtained by separating crystalline substances, and the crystallization temperature is not higher than 0°C.
  • the compound represented by the formula (I) of the present disclosure is dissolved in the organic solvent A by heating.
  • 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.
  • the temperature at which the compound represented by formula (I) of the present disclosure is heated and dissolved in organic solvent A is 60°C, 61°C, 62°C, 63°C, 64°C, 65°C, 66°C, 67°C °C, 68°C, 69°C, 70°C, 71°C, 72°C, 73°C, 74°C, 75°C, 76°C, 77°C, 68°C, 79°C, 80°C, 81°C, 82°C, 83°C, 84°C, 85°C, 86°C, 87°C, 88°C, 89°C and 90°C.
  • the compound represented by formula (I) in the present disclosure is dissolved in the organic solvent A by heating to a temperature of 80°C.
  • the method described in the present disclosure further comprises the step of thermal filtration.
  • the method of the present disclosure further comprises the step of stirring.
  • the methods described in the present disclosure wherein the stirring step is performed by mechanical stirring.
  • the present disclosure prepares the method for the I crystal form of the compound represented by formula (I), comprising the following steps:
  • solvent B which is a mixed solvent of water or acetone and water
  • 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.
  • the method described in the present disclosure wherein the organic solvent A is a mixed solvent of acetone and water, 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.
  • 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.
  • 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.
  • 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.
  • solvent B is a mixed solvent of acetone and water
  • 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.
  • 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.
  • solvent B is a mixed solvent of acetone and water, and the volume ratio of the two is 1:9.
  • 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.
  • the method of 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,
  • 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.
  • 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.
  • 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.
  • 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, 46m
  • 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 20mL/g-40mL/g.
  • 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.
  • the method of the present disclosure also includes the step of isolating the crystalline material.
  • the step of isolating the crystalline material comprises filtering, washing and drying.
  • the method described in the present disclosure wherein 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°2 ⁇ .
  • the method of the present disclosure wherein the solvent used for washing in the step of isolating the crystalline material is water or acetone.
  • the method of the present disclosure wherein the solvent used for washing in the step of isolating the crystalline material is water.
  • 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.
  • the starting material used in the preparation method of the disclosed crystal form is the amorphous form of the compound represented by formula (I).
  • the starting material used in the crystal form preparation method of the present disclosure is the I crystal form of the compound represented by formula (I).
  • 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.
  • Another aspect of the present disclosure provides a pharmaceutical composition, which is prepared from the crystal form I of the compound represented by formula (I) prepared according to the method described in the present disclosure.
  • Another aspect of the present disclosure provides a preparation method of a pharmaceutical composition, which includes mixing the I crystal form of the compound represented by formula (I) prepared according to the method described in the present disclosure and a pharmaceutically acceptable excipient A step of.
  • Another aspect of the present disclosure provides a preparation method of a pharmaceutical composition, which includes the steps of preparing 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 prepared pharmaceutical composition shows with or without one or more characteristic peaks with peaks at 10.97 ⁇ 0.2°2 ⁇ .
  • keton solvent in this disclosure refers to a compound in which a carbonyl group (-C(O)-) is connected to two hydrocarbon groups.
  • 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.
  • the “mixed solvent” mentioned in the present 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.
  • the drying temperature described in the present disclosure is generally 25° C. to 100° C., preferably 40° C. to 70° C., and can be dried under normal pressure or reduced pressure.
  • Differential scanning calorimetry or DSC in this disclosure refers to measuring the temperature difference and heat flow difference between the sample and the reference object during the sample heating or constant temperature process, so as to characterize all the physical changes related to thermal effects and Chemical changes, to obtain the phase transition information of the sample.
  • the present disclosure also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the crystal form I of the compound represented by formula (I), and optionally one or more pharmaceutically acceptable excipients.
  • the pharmaceutical composition can be made into any pharmaceutically acceptable dosage form.
  • 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 injections). solution), suppositories, inhalants or sprays.
  • Essentially free in the present disclosure means that the peak abundance is less than 5%, preferably the peak abundance is less than 1%.
  • excipient 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.
  • the present disclosure provides a method that can be used in the production of 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-methoxy
  • the preparation process of the I crystal form of base urea (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.
  • Fig. 1 is the XRPD pattern of I crystal form of formula (I) compound
  • Fig. 2 is the DSC collection of illustrative plates of the I crystal form of formula (I) compound
  • Fig. 3 is the XRPD spectrum of the E crystal form of the compound of formula (I);
  • Fig. 4 is an XRPD pattern of mixed crystals of Form E and Form I of the compound of formula (I).

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Abstract

提供了一种GnRH 受体拮抗剂的结晶工艺。具体地，提供了式(I)化合物的晶型的结晶工艺。

Description

一种GnRH受体拮抗剂的结晶工艺 技术领域
本公开涉及1-(4-(7-(2,6-二氟苄基)-3-((二甲氨基)甲基)-5-(6-甲氧基哒嗪-3-基)-4,6-二羰基-4,5,6,7-四氢-2H-吡唑并[3,4-d]嘧啶-2-基)苯基)-3-甲氧基脲的晶型的结晶工艺。
背景技术
促性腺激素释放激素(GnRH)也称黄体生成素释放激素(LHRH)，是内分泌生殖系统中的中枢调节因素。促性腺激素如黄体生成素(LH)和卵泡刺激素(FSH)的分泌和释放，调节卵巢和黄体的正常发育，在下丘脑-垂体-性腺轴发挥重要作用。GnRH受体通过与能够激活磷脂酰肌醇钙第二信使体系的G蛋白偶联发挥其调节作用，而LH则调节性类固醇的产生，FSH调节男性精子发生及女性卵泡的发育。
LH和FSH被释放到循环中，并与卵巢或睾丸的特异性细胞上受体相结合，刺激类固醇的生成。性类固醇存在情况下，疾病例如子宫内膜异位症、子宫肌瘤和前列腺癌等病情加重，需给予长效肽类的GnRH受体激动剂和拮抗剂进行治疗控制。
GnRH受体激动剂介导的间接抑制肿瘤机制是通过长期作用于下丘脑-垂体-性腺轴，导致垂体促性腺激素(FSH，LH)降低，从而减少性激素的分泌而间接抑制肿瘤细胞的生长。而GnRH受体拮抗剂则直接抑制垂体促性腺激素的释放，进而抑制肿瘤细胞的生长。
WO2015062391A1中提供了一种结构新型的高效低毒的GnRH受体拮抗剂，具有优异的效果和作用，能够有效治疗内分泌生殖系统疾病，其化学名为1-(4-(7-(2,6-二氟苄基)-3-((二甲氨基)甲基)-5-(6-甲氧基哒嗪-3-基)-4,6-二羰基-4,5,6,7-四氢-2H-吡唑并[3,4-d]嘧啶-2-基)苯基)-3-甲氧基脲，结构如下所示
Figure PCTCN2022115728-appb-000001
WO2019020102A1公开了式(I)所示化合物的制备方法。
WO2018086608A1公开了式(I)所示化合物的I晶型以及制备方法，其公开了I晶型的X-射线粉末衍射图特征峰的角位置(2θ)，其中公开的制备I晶型的 方法可用于小量制备，但当用于车间生产时存在问题。
发明内容
本公开提供一种制备式(I)所示化合物的晶型的方法，所述方法包括式(I)所示化合物在有机溶剂A中溶解得到溶液I，将溶剂B与溶液I混合，随后低温析晶的步骤，
Figure PCTCN2022115728-appb-000002
在一些实施方案中，本公开有机溶剂A为酮类溶剂与水的混合溶剂。在一些实施方案中，本公开有机溶剂A为丙酮与水的混合溶剂。
在一些实施方案中，本公开溶剂B为水或酮类溶剂与水的混合溶剂。
在一些实施方案中，本公开溶剂B为水或丙酮与水的混合溶剂。
在一些实施方案中，本公开溶剂B为水。
在一些实施方案中，本公开溶剂B为丙酮与水的混合溶剂。
在一些实施方案中，本公开析晶的温度不高于0℃
在一些实施方案中，本公开析晶的温度为0℃～-40℃。
在一些实施方案中，本公开析晶的温度为0℃、-1℃、-2℃、-3℃、-4℃、-5℃、-6℃、-7℃、-8℃、-9℃、-10℃、-11℃、-12℃、-13℃、-14℃、-15℃、-16℃、-17℃、-18℃、-19℃、-20℃、-21℃、-22℃、-23℃、-24℃、-25℃、-26℃、-27℃、-28℃、-29℃、-30℃、-31℃、-32℃、-33℃、-34℃、-35℃、-36℃、-37℃、-38℃、-39℃和-40℃。
在一些实施方案中，本公开析晶的温度为-10℃～-20℃。
在一些实施方案中，本公开析晶的温度为-10℃。
在一些实施方案中，本公开制备式(I)所示化合物的晶型的方法，包括以下步骤：
1)将式(I)所示化合物在有机溶剂A中溶解得到溶液I，所述有机溶剂A为丙酮与水的混合溶剂；
2)向溶液I中加入溶剂B，所述溶剂B为水或丙酮与水的混合溶剂；
3)低温析晶，分离晶态物质即可得目标I晶型，所述析晶温度不高于0℃。
在一些实施方案中，本公开式(I)所示化合物在有机溶剂A中溶解的方式为加热溶解。
在一些实施方案中，本公开式(I)所示化合物在有机溶剂A中加热溶解加热所至的温度为60-90℃。
在一些实施方案中，本公开式(I)所示化合物在有机溶剂A中加热溶解加热所至的温度为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℃。
在一些实施方案中，本公开式(I)所示化合物在有机溶剂A中加热溶解加热所至的温度为80℃。
在一些实施方案中，本公开所述的方法，其进一步包括热过滤的步骤。
在一些实施方案中，本公开所述的方法，其进一步包括搅拌的步骤。
在一些实施方案中，本公开所述的方法，其中搅拌步骤的方式为机械搅拌。
在一些实施方案中，本公开制备式(I)所示化合物的I晶型的方法，包括以下步骤：
1)将式(I)所示化合物在有机溶剂A中加热搅拌溶解，所述有机溶剂A为丙酮与水的混合溶剂；
2)加入溶剂B，所述溶剂B为水或丙酮与水的混合溶剂；
3)低温搅拌析晶，分离晶态物质即可得目标I晶型，析晶温度不高于0℃。
在一些实施方案中，本公开所述的方法，其中所述的有机溶剂A为丙酮与水的混合溶剂，两者体积比为3:1～30:1。
在一些实施方案中，本公开所述的方法，其中所述的有机溶剂A为丙酮与水的混合溶剂，两者体积比为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。
在一些实施方案中，本公开所述的方法，其中有机溶剂A为丙酮与水的混合溶剂，两者体积比为9:1～15:1。
在一些实施方案中，本公开所述的方法，其中有机溶剂A为丙酮与水的混合溶剂，两者体积比为9:1。
在一些实施方案中，本公开所述的方法，其中溶剂B为丙酮与水的混合溶剂，两者体积比为1:30-1:1。
在一些实施方案中，本公开所述的方法，其中溶剂B为丙酮与水的混合溶剂，两者体积比为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。
在一些实施方案中，本公开所述的方法，其中溶剂B为丙酮与水的混合溶剂，两者体积比为1:15-1:9。
在一些实施方案中，本公开所述的方法，其中溶剂B为丙酮与水的混合溶 剂，两者体积比为1:9。
在一些实施方案中，本公开所述的方法，其中溶剂B与式(I)化合物的体积质量比为5mL/g～50mL/g。
在一些实施方案中，本公开所述的方法，其中溶剂B与式(I)化合物的体积质量比为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。
在一些实施方案中，本公开所述的方法，其中溶剂B与式(I)化合物的体积质量比为10mL/g～30mL/g。
在一些实施方案中，本公开所述的方法，其中溶剂B与式(I)化合物的体积质量比为20mL/g。
在一些实施方案中，本公开所述的方法，其中有机溶剂A与式(I)所示化合物的体积质量比为10mL/g-60mL/g。
在一些实施方案中，本公开所述的方法，其中所述的有机溶剂A与式(I)所示化合物的体积质量比为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。
在一些实施方案中，本公开所述的方法，其中有机溶剂A与式(I)所示化合物的体积质量比为20mL/g-40mL/g。
在一些实施方案中，本公开所述的方法，其中有机溶剂A与式(I)所示化合物的体积质量比为30mL/g。
进一步地，本公开所述的方法还包括分离晶态物质的步骤。在一些实施方案中，所述分离晶态物质的步骤包括过滤、洗涤和干燥。
在一些实施方案中，本公开所述的方法，其中析晶得到的晶型的X射线粉末衍射图基本不含有一个或多个的峰值在5.91±0.2°2θ的特征峰。
在一些实施方案中，本公开所述的方法，其中分离晶态物质的步骤中洗涤所用的溶剂为水或丙酮。
在一些实施方案中，本公开所述的方法，其中分离晶态物质的步骤中洗涤所用的溶剂为水。
本公开晶型制备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， 具体形式包括但不限于：无定形、任意晶型等。
本公开晶型制备方法中所用的起始原料为式(I)所示化合物的无定形形式。
本公开晶型制备方法中所用的起始原料为式(I)所示化合物的I晶型形式。
本公开另一方面提供了一种式(I)所示化合物的I晶型，其可根据本公开所述的方法制备得到。
本公开另一方面提供了一种药物组合物，其由根据本公开所述的方法制备得到的式(I)所示化合物的I晶型制备获得。
本公开另一方面提供了一种药物组合物的制备方法，其包括根据本公开所述的方法制备得到的式(I)所示化合物的I晶型和和药学上可接受的赋形剂混合的步骤。
本公开另一方面提供了一种药物组合物的制备方法，其包括根据本公开所述的方法制备得到式(I)所示化合物的I晶型和和药学上可接受的添加剂混合的步骤，制备得到的药物组合物的X射线粉末衍射图显示具有或不具有一个或多个的峰值在10.97±0.2°2θ的特征峰。
发明详述
在本公开的说明书和权利要求书中，除非另有说明，否则本文中使用的科学和技术名词具有本领域技术人员所通常理解的含义。然而，为了更好地理解本公开，下面提供了部分相关术语的定义和解释。另外，当本公开所提供的术语的定义和解释与本领域技术人员所通常理解的含义不一致时，以本公开所提供的术语的定义和解释为准。
本公开所述的“酮类溶剂”是指羰基(-C(O)-)与两个烃基相连的化合物，根据分子中烃基的不同，酮可分为脂肪酮、脂环酮、芳香酮、饱和酮和不饱和酮，具体实例包括但不限于：丙酮、甲基丁酮或甲基异丁酮。
本公开所述的“混合溶剂”是指一种或多种不同种类的有机溶剂按照一定比例混合而成的溶剂，或有机溶剂与水按照一定比例混合而成的溶剂。
本公开中所述干燥温度一般为25℃～100℃，优选40℃～70℃，可以常压干燥，也可以减压干燥。
本公开所述的“X-射线粉末衍射图谱或XRPD”是指根据布拉格公式2d sinθ＝nλ(式中，λ为X射线的波长，
Figure PCTCN2022115728-appb-000003
衍射的级数n为任何正整数，一般取一级衍射峰，n＝1)，当X射线以掠角θ(入射角的余角，又称为布拉格角)入射到晶体或部分晶体样品的某一具有d点阵平面间距的原子面上时，就能满足布拉格方程，从而测得了这组X射线粉末衍射图。
本公开中所述的“差示扫描量热分析或DSC”是指在样品升温或恒温过程中，测量样品与参考物之间的温度差、热流差，以表征所有与热效应有关的物理变化和化学变化，得到样品的相变信息。
本公开还涉及，包括式(I)所示的化合物的I晶型，以及任选的一种或多种 药用的赋形剂的药物组合物。所述药物组合物可以制成药学上可接受的任一剂型。例如，本公开的I晶型或药物制剂可以配制为片剂、胶囊剂、丸剂、颗粒剂、溶液剂、混悬剂、糖浆剂、注射剂(包括注射液、注射用无菌粉末与注射用浓溶液)、栓剂、吸入剂或喷雾剂。
本公开中所述的“基本不含有”指峰的丰度低于5％，优选峰的丰度低于1％。
本公开中所述的“赋形剂”包括但不限于任何已经被美国食品和药物管理局批准对于人类或家畜动物使用可接受的任何助剂、载体、赋形剂、助流剂、甜味剂、稀释剂、防腐剂、染料/着色剂、增香剂、表面活性剂、润湿剂、分散剂、助悬剂、稳定剂、等渗剂、溶剂或乳化剂。
发明的有益效果
与现有技术相比，本公开的技术方案具有以下优点：
本公开提供一种可用于车间生产1-(4-(7-(2,6-二氟苄基)-3-((二甲氨基)甲基)-5-(6-甲氧基哒嗪-3-基)-4,6-二羰基-4,5,6,7-四氢-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晶型的制备工艺，该工艺在大规模生产过程中重现性好，解决了现有制备方法中的重现性差的问题，具有预料不到的效果。
附图说明
图1为式(I)化合物的I晶型的XRPD图谱；
图2为式(I)化合物的I晶型的DSC图谱；
图3为式(I)化合物的E晶型的XRPD图谱；
图4为式(I)化合物的E晶型和I晶型的混晶的XRPD图谱。
具体实施方式
以下将结合实施例更详细地解释本公开，本公开的实施例仅用于说明本公开的技术方案，并非限定本公开的实质和范围。
以下实施例中式(I)化合物参照WO2015062391A1中的方法合成得到。
实施例1
1g式(I)所示化合物，30mlACE/H 2O(9:1)从室温加热至70℃，溶清，热过滤，将滤液移至-10℃冷阱中，缓慢加水20ml。继续磁力搅拌至有大量固体析出，过滤，用水洗涤滤饼，放于烘箱干燥。得到式(I)所示化合物0.86g，收率86％，所得产品经X-射线粉末衍射图谱和DSC图谱确认为WO2018086608中公开的I晶型，其中I晶型的XRPD图谱见图1，其特征峰位置如表1，DSC图谱见图2。
表1 I晶型的XRPD谱图的特征峰
Figure PCTCN2022115728-appb-000004
Figure PCTCN2022115728-appb-000005
实施例2
1g式(I)所示化合物，30mlACE/H 2O(9:1)从室温加热至70℃，溶清，热过滤，将滤液移至-10℃冷阱中，缓慢加20mlACE/H 2O(1:9)。继续磁力搅拌至有大量固体析出，过滤，用水洗涤滤饼，放于烘箱干燥，得到式(I)所示化合物0.7g，收率70％，所得产品经X-射线粉末衍射图谱确认为I晶型。
实施例3
20g式(I)所示化合物，600mlACE/H 2O(9:1)放于预加热至80℃油浴锅中，磁力搅拌至溶清，热过滤，将滤液移至-10℃冷阱中，机械搅拌，缓慢加400ml ACE/H 2O(1:9)。继续机械搅拌至大量固体析出，过滤，用水洗涤滤饼，放于烘箱干燥，得到式(I)所示化合物17.5g，收率87.5％，所得产品经X-射线粉末衍射图谱确认为I晶型。
实施例4
7.7g式(I)所示化合物，230mlACE/H 2O(9:1)放于预加热至80℃油浴锅中，磁力搅拌至溶清，热过滤，将滤液移至-10℃冷阱中，机械搅拌，缓慢加170ml H 2O。继续机械搅拌至有大量固体析出，过滤，用水洗涤滤饼，放于烘箱干燥，得到式(I)所示化合物6.3g，收率82％，所得产品经X-射线粉末衍射图谱确认为I晶型。
实施例5
100g式(I)所示化合物，3000mlACE/H 2O(9:1)放于预加热至80℃的水浴锅中，机械搅拌至溶清，热过滤，将滤液移至预降温至-10℃的20L反应釜中，缓慢加1700ml ACE/H 2O(1:9)溶液。继续搅拌至大量固体析出，过滤，用水洗涤滤饼，放于烘箱干燥，得到式(I)所示化合物84.1g，收率84％，所得产品经X-射线粉末衍射图谱确认为I晶型。
实施例6
1000g式(I)所示化合物，30LACE/H 2O(9:1)放于预加热至80℃的50L反应釜中，机械搅拌至溶清，热过滤，将滤液移至预降温至-10℃的100L反应釜中，缓慢加20L ACE/H 2O(1:9)溶液。继续搅拌至大量固体析出，甩滤，用水洗涤滤饼，放于烘箱干燥，得到式(I)所示化合物0.8Kg，收率80％，所得产品经X-射线粉末衍射图谱确认为I晶型。
实施例7
2.5Kg式(I)所示化合物，75LACE/H 2O(9:1)放于预加热至80℃的100L反应釜中，机械搅拌至溶清，压滤，将滤液移至预降温至-10℃的200L反应釜中，缓慢加50L ACE/H 2O(1:9)溶液。继续搅拌至大量固体析出，甩滤，用水洗涤滤饼，放于烘箱干燥，得到式(I)所示化合物2.06Kg，收率82.4％，所得产品经X-射线粉末衍射图谱确认为I晶型。
实施例8
取1g式(I)所示化合物于100ml烧瓶中，加入30ml ACE/H 2O(9:1)溶剂，加热至70℃溶清，热过滤，滴加入12ml水，放于室温下搅拌至大量固体析出，过滤，滤饼放于烘箱干燥，得到0.7g样品，所得产品经X-射线粉末衍射图谱确认为CN202110363035.1中保护的晶型E，XRPD谱图如图3，其特征峰位置如表2所示。
表2 E晶型的XRPD谱图的特征峰
Figure PCTCN2022115728-appb-000006
Figure PCTCN2022115728-appb-000007
实施例9
取0.5g式(I)所示化合物于100ml烧瓶中，加入15ml ACE/H 2O(9:1)溶剂，加热至70℃，溶清，热过滤，滤液澄清，移至-10℃析晶。磁力搅拌至大量固体析出后过滤，滤饼放于烘箱干燥，经检测确定为晶型E+晶型Ⅰ的混晶，XRPD谱图如图4。
实施例10
向100L反应釜中加入45L ACE/H2O(5:1)溶剂，加入式(I)所示化合物3Kg，开动搅拌，加热至回流，自然冷却至室温，继续搅拌3h，过滤。65±3℃鼓风干燥10小时，得固体1.7kg，经X-射线粉末衍射图谱检测确定为晶型E+晶型I的混晶。

Claims (19)

  1. 一种制备式(I)所示化合物晶型的方法，所述方法包括式(I)所示化合物在有机溶剂A中溶解得到溶液I，将溶剂B与溶液I混合，随后低温析晶的步骤，
    Figure PCTCN2022115728-appb-100001
  2. 根据权利要求1所述的方法，其中有机溶剂A为酮类溶剂与水的混合溶剂，优选为丙酮与水的混合溶剂。
  3. 根据权利要求1或2所述的方法，其中溶剂B为水或酮类溶剂与水的混合溶剂。
  4. 根据权利要求1至3中任一项所述的方法，其中溶剂B为水。
  5. 根据权利要求1至3中任一项所述的方法，其中溶剂B为丙酮与水的混合溶剂。
  6. 根据权利要求1至5中任一项所述的方法，其中析晶的温度不高于0℃，优选0℃～-40℃，更优选-10℃～-20℃。
  7. 根据权利要求1至6中任一项所述的方法，所述方法包括以下步骤：
    1)将式(I)所示化合物在有机溶剂A中溶解得到溶液I，所述有机溶剂A为丙酮与水的混合溶剂；
    2)向溶液I中加入溶剂B，所述溶剂B为水或丙酮与水的混合溶剂；
    3)低温析晶，分离晶态物质即可得目标I晶型，所述析晶的温度不高于0℃。
  8. 根据权利要求1至7中任一项所述的方法，其中式(I)所示化合物在有机溶剂A中溶解的方式为加热溶解，优选地，加热溶解加热所至的温度为60-90℃。
  9. 根据权利要求8所述的方法，其进一步包括热过滤的步骤。
  10. 根据权利要求1至9中任一项所述的方法，其中进一步包括搅拌的步骤；优选为机械搅拌。
  11. 根据权利要求1至10中任一项所述的方法，其中有机溶剂A为丙酮与水的混合溶剂，两者体积比为3:1～30:1，优选地，两者体积比为9:1～15:1。
  12. 根据权利要求1至11中任一项所述的方法，其中溶剂B为丙酮与水的混合溶剂，两者体积比为1:30-1:1，优选体积比为1:15-1:9。
  13. 根据权利要求1至12中任一项所述的方法，其中溶剂B与式(I)化合物的体积质量比为5mL/g～50mL/g，优选为10mL/g～30mL/g，更优选为20mL/g。
  14. 根据权利要求1至13中任一项所述的方法，其中有机溶剂A与式(I)所示化合物的体积质量比为10mL/g-60mL/g，优选为20mL/g-40mL/g，更优选为30mL/g。
  15. 根据权利要求1至14中任一项所述的方法，其中分离晶态物质的步骤包括过滤、洗涤和干燥。
  16. 根据权利要求1至15中任一项所述的方法，其中析晶得到的晶型的X射线粉末衍射图基本不含有一个或多个的峰值在5.91±0.2°2θ的特征峰。
  17. 一种式(I)所示化合物的I晶型，其可根据权利要求1至16中任一项所述的方法制备得到。
  18. 一种药物组合物，其由权利要求17所述的化合物的I晶型制备获得。
  19. 一种制备权利要求18所述的药物组合物的方法，包括权利要求17所述的化合物的I晶型和药学上可接受的赋形剂混合的步骤。
PCT/CN2022/115728 2021-08-30 2022-08-30 一种GnRH受体拮抗剂的结晶工艺 Ceased WO2023030293A1 (zh)

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WO2015062391A1 (zh) * 2013-10-30 2015-05-07 上海恒瑞医药有限公司 吡唑并嘧啶酮类或吡咯并三嗪酮类衍生物、其制备方法及其在医药上的应用
WO2018082687A1 (zh) * 2016-11-07 2018-05-11 江苏恒瑞医药股份有限公司 一种GnRH受体拮抗剂的多晶型及其制备方法
WO2018086608A1 (zh) * 2016-11-14 2018-05-17 江苏恒瑞医药股份有限公司 一种GnRH受体拮抗剂的结晶形式及其制备方法
WO2019020102A1 (zh) * 2017-07-28 2019-01-31 江苏恒瑞医药股份有限公司 一种嘧啶酮并杂芳基类衍生物的制备方法及其中间体

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WO2015062391A1 (zh) * 2013-10-30 2015-05-07 上海恒瑞医药有限公司 吡唑并嘧啶酮类或吡咯并三嗪酮类衍生物、其制备方法及其在医药上的应用
WO2018082687A1 (zh) * 2016-11-07 2018-05-11 江苏恒瑞医药股份有限公司 一种GnRH受体拮抗剂的多晶型及其制备方法
WO2018086608A1 (zh) * 2016-11-14 2018-05-17 江苏恒瑞医药股份有限公司 一种GnRH受体拮抗剂的结晶形式及其制备方法
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