[go: up one dir, main page]

WO2025002355A9 - 一种jak2抑制剂的晶型及制备方法 - Google Patents

一种jak2抑制剂的晶型及制备方法 Download PDF

Info

Publication number
WO2025002355A9
WO2025002355A9 PCT/CN2024/102394 CN2024102394W WO2025002355A9 WO 2025002355 A9 WO2025002355 A9 WO 2025002355A9 CN 2024102394 W CN2024102394 W CN 2024102394W WO 2025002355 A9 WO2025002355 A9 WO 2025002355A9
Authority
WO
WIPO (PCT)
Prior art keywords
solvent
compound
phenyl
formula
crystal form
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/CN2024/102394
Other languages
English (en)
French (fr)
Other versions
WO2025002355A1 (zh
Inventor
魏农农
金华
翁志洁
周峰
毕万福
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Chengdu Jinrui Foundation Biotech Co Ltd
Original Assignee
Chengdu Jinrui Foundation Biotech Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Chengdu Jinrui Foundation Biotech Co Ltd filed Critical Chengdu Jinrui Foundation Biotech Co Ltd
Publication of WO2025002355A1 publication Critical patent/WO2025002355A1/zh
Publication of WO2025002355A9 publication Critical patent/WO2025002355A9/zh
Anticipated expiration legal-status Critical
Pending legal-status Critical Current

Links

Classifications

    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present invention belongs to the field of pharmaceutical chemistry, and specifically relates to A, B, C, D crystal forms of 2- ⁇ N-[4-(4-methyl)piperazine]phenyl ⁇ amino-5,6-dihydro-7-[3-(N-tert-butyl)sulfonamido]phenyl-pyrrolo[2,3-d]pyrimidine dihydrochloride and a preparation method thereof.
  • CN110305140A describes a compound 2- ⁇ N-[4-(4-methyl)piperazine]phenyl ⁇ amino-5,6-dihydro-7-[3-(N-tert-butyl)sulfonamido]phenyl-pyrrolo[2,3-d]pyrimidine, which as a free base shows highly selective JAK2 inhibition.
  • the research content of the present invention first provides a pharmaceutically acceptable salt of 2- ⁇ N-[4-(4-methyl)piperazine]phenyl ⁇ amino-5,6-dihydro-7-[3-(N-tert-butyl)sulfonamido]phenyl-pyrrolo[2,3-d]pyrimidine, wherein the pharmaceutically acceptable salt is a conventional inorganic salt or organic salt in the art.
  • the free base refers to 2- ⁇ N-[4-(4-methyl)piperazine]phenyl ⁇ amino-5,6-dihydro-7-[3-(N-tert-butyl)sulfonamido]phenyl-pyrrolo[2,3-d]pyrimidine), which is beneficial to human absorption and the exertion of drug efficacy, and has more clinical advantages.
  • the inorganic salt is preferably dihydrochloride, sulfate, phosphate, nitrate; the organic salt is preferably methanesulfonate, citrate, oxalate, succinate.
  • the pharmaceutically acceptable salt is particularly preferably the dihydrochloride salt, which has advantages in solubility, stability and hygroscopicity over the free base and other salts.
  • the present invention further provides A, B, C, and D crystal forms of 2- ⁇ N-[4-(4-methyl)piperazine]phenyl ⁇ amino-5,6-dihydro-7-[3-(N-tert-butyl)sulfonamido]phenyl-pyrrolo[2,3-d]pyrimidine dihydrochloride and a preparation method.
  • the crystal form A of the compound of formula (1) 2- ⁇ N-[4-(4-methyl)piperazine]phenyl ⁇ amino-5,6-dihydro-7-[3-(N-tert-butyl)sulfonamido]phenyl-pyrrolo[2,3-d]pyrimidine dihydrochloride has characteristic peaks at 2 ⁇ of 5.989, 8.478, 12.288, 13.315, 16.985 and 17.476 in its X-ray powder diffraction pattern;
  • the X-ray powder diffraction pattern of the A crystal form has characteristic peaks at diffraction angles 2 ⁇ of 3.105, 5.989, 8.478, 12.288, 13.315, 16.985, 17.476, 22.174, and 24.898.
  • the X-ray powder diffraction pattern of the A crystal form has characteristic peaks at diffraction angles 2 ⁇ of 3.105, 5.989, 6.765, 8.478, 12.288, 13.315, 16.432, 16.985, 17.476, 19.370, 22.174, 24.166, 24.898, and 30.243.
  • the present invention also provides a method for preparing the crystalline form A of the compound of formula (1), the method comprising:
  • the solvent (I) is selected from at least one of water, ethanol, methanol, isopropanol, ethylene glycol, acetone, methyl tert-butyl ether, ethyl acetate, acetonitrile, tetrahydrofuran, dioxane, preferably methanol, ethanol, ethanol/water.
  • the volume (ml) of the solvent (I) is 1-60 times the weight (g) of the compound.
  • drying by heating, the drying temperature being 40°C to 100°C, preferably 50°C to 90°C.
  • the present invention provides a crystal form B of a compound of formula (1).
  • the X-ray powder diffraction spectrum of the crystal form B has characteristic peaks at diffraction angles 2 ⁇ of 5.106, 12.765, 17.879, 22.419 and 24.214.
  • the X-ray powder diffraction pattern of the B crystal form has characteristic peaks at diffraction angles 2 ⁇ of 3.452, 5.106, 5.762, 6.339, 6.911, 8.900, 11.270, 12.765, 13.914, 17.347, 20.542, 22.419, and 24.214.
  • the X-ray powder diffraction pattern of the B crystal form has characteristic peaks at diffraction angles 2 ⁇ of 3.452, 5.106, 5.762, 5.957, 6.339, 6.911, 8.900, 10.406, 11.270, 11.924, 12.765, 13.914, 14.247, 17.347, 18.476, 20.542, 22.419, and 24.214.
  • the present invention also provides a method for preparing the crystalline form B of the compound of formula (1), the method comprising:
  • the solvent (II) is selected from at least one of water, ethanol, methanol, isopropanol, and methyl tert-butyl ether, preferably methanol, ethanol/water, and methanol/methyl tert-butyl ether.
  • the volume (ml) of the solvent (II) is 1-60 times the weight (g) of the compound.
  • drying temperature is 10°C-40°C, preferably 25°C-40°C.
  • the present invention provides a crystal form C of a compound of formula (1).
  • the X-ray powder diffraction spectrum of the crystal form C has characteristic peaks at diffraction angles 2 ⁇ of 5.743, 11.931, 13.097, 15.625, 17.066 and 18.429.
  • the X-ray powder diffraction pattern of the C crystal form has characteristic peaks at diffraction angles 2 ⁇ of 5.743, 6.262, 11.931, 12.561, 13.097, 13.967, 15.625, 17.066, 18.429, 18.882, 21.432, 24.496, and 24.931.
  • the X-ray powder diffraction pattern of the C crystal form has characteristic peaks at diffraction angles 2 ⁇ of 5.743, 6.262, 6.551, 11.931, 12.561, 13.097, 13.967, 15.625, 17.066, 18.429, 18.882, 19.180, 19.639, 21.432, 23.133, 24.496, and 24.931.
  • the present invention also provides a method for preparing the crystalline form C of the compound of formula (1), the method comprising:
  • solvent (IIIa) Add the compound of formula (1) to solvent (IIIa), and slurry at room temperature or by heating, wherein the solvent (IIIa) is selected from at least one of ethanol, ethylene glycol, and acetone, preferably ethanol; or add the compound of formula (1) to solvent (IIIb), and dissolve by stirring or heating, wherein the solvent (IIIb) is selected from at least one of methanol and ethyl acetate, isopropyl acetate, or butyl acetate, preferably methanol/ethyl acetate.
  • the volume (ml) of the solvent (III) is 1-60 times the weight (g) of the compound.
  • drying temperature is 10°C-40°C, preferably 25°C-40°C.
  • the present invention provides a crystal form D of a compound of formula (1).
  • the X-ray powder diffraction spectrum of the crystal form D has characteristic peaks at diffraction angles 2 ⁇ of 6.733, 8.670, 11.931, 18.213 and 19.043.
  • the X-ray powder diffraction pattern of the D crystal form has characteristic peaks at diffraction angles 2 ⁇ of 6.733, 8.670, 11.931, 12.363, 18.213, 19.043, 23.033, and 24.813.
  • the present invention also provides a method for preparing the crystalline form D of the compound of formula (1), the method comprising:
  • drying temperature is 20°C-80°C, preferably 25°C-50°C.
  • the "X-ray powder diffraction pattern or XPRD" described in the present invention is obtained by Cu-K ⁇ ray diffraction.
  • the “differential scanning calorimetry or DSC” mentioned in the present invention refers to measuring the temperature difference and heat flow difference between a sample and a reference object during the process of heating or maintaining a constant temperature of the sample, so as to characterize all physical and chemical changes related to thermal effects and obtain the phase change information of the sample.
  • the diffraction angle 2 ⁇ described in the present invention is the Bragg angle, with the unit being degree, and the error range of the 2 ⁇ is ⁇ 0.2.
  • the beneficial effects of the present invention are as follows: the A, B, C, and D crystal forms of the compound of formula (1) provided by the present invention have more advantages in terms of stability, solubility, and formulation dissolution, are more suitable for drug development, meet the requirements of bioavailability and efficacy, can meet the medicinal requirements of production, transportation, and storage, and the production process is stable, repeatable, and controllable, and can be adapted to industrial production.
  • the four crystal forms A, B, C and D provided by the present invention can be prepared under a variety of different conditions.
  • the crystal process has good purification effect, and has the advantages of stable process and easy operation.
  • the preparation method of the crystal form is simple and low in cost.
  • FIG1 is an XPRD spectrum of the crystalline form A of the compound of formula (1);
  • FIG2 is a DSC spectrum of Form A of the compound of formula (1)
  • FIG3 is a TGA spectrum of the crystalline form A of the compound of formula (1).
  • FIG4 is an XPRD spectrum of Form B of the compound of formula (1).
  • FIG5 is a DSC spectrum of Form B of the compound of formula (1).
  • FIG6 is a TGA spectrum of Form B of the compound of formula (1).
  • FIG7 is an XPRD spectrum of Form C of the compound of formula (1).
  • FIG8 is a DSC spectrum of Form C of the compound of formula (1).
  • FIG9 is a TGA spectrum of Form C of the compound of formula (1).
  • FIG10 is an XPRD spectrum of Form D of the compound of formula (1).
  • FIG11 is a DSC spectrum of Form D of the compound of formula (1).
  • FIG12 is a TGA spectrum of the crystalline form D of the compound of formula (1).
  • XRPD is an X-ray powder diffraction test: the measurement was carried out using a Bruker D8 X-ray diffractometer in accordance with the General Rules 0451 of Part IV of the 2020 edition of the Chinese Pharmacopoeia. The test conditions were: Target: Cu; 40kv, 40mA.
  • DSC differential scanning calorimetry: the measurement was carried out using a TA Q2000 differential scanning calorimeter in accordance with the General Rules 0661 of Part IV of the 2020 edition of the Chinese Pharmacopoeia. The test conditions were: DSC: 30°C 10°C/min 300°C; TGA: 30°C 10°C/min 350°C.
  • test results show that compared with the free base, the solubility of its sulfate, dihydrochloride, oxalate, methanesulfonate and citrate in water is improved, especially the sulfate and dihydrochloride can significantly improve the solubility of the free base in water.
  • the stability of the free base and its dihydrochloride, sulfate, methanesulfonate, oxalate, and citrate was evaluated for one month at 30°C ⁇ 2°C/65%RH ⁇ 5%RH and 40°C ⁇ 2°C/75%RH ⁇ 5%RH.
  • the purity of the stability test samples was determined by HPLC to evaluate the chemical stability (HPLC method using area normalization method).
  • the compound of formula (1) (42 g) was added to a mixed solvent of 420 ml of anhydrous ethanol and 63 ml of purified water, heated and stirred to dissolve, stirred and crystallized, filtered, the filter cake was collected, and vacuum dried at 80°C to obtain the product (40 g, yield 95%).
  • the compound of formula (1) (0.3 g) was added to 9 ml of anhydrous ethanol, heated and stirred to make a slurry, stirred to crystallize, filtered, the filter cake was collected, and vacuum dried at 90°C to obtain the product (0.23 g, yield 77%), which was detected by XPRD to be Form A.
  • the compound of formula (1) (0.5 g) was added to 3 ml of anhydrous methanol, heated and stirred to dissolve, stirred and crystallized, filtered, the filter cake was collected, and vacuum dried at 60°C to obtain the product (0.21 g, yield 42%), which was detected by XPRD to be Form A.
  • X-ray powder diffraction showed that it was Form B, and its XRPD spectrum was shown in FIG4 . Its characteristic peak positions are shown in Table 6 below. There was an endothermic peak at 266.04° C. in the DSC spectrum, and the thermogravimetric analysis (TGA) showed a weight loss of 6.505% between 25° C. and 100° C.
  • the compound of formula (1) (0.5 g) was added to 3 ml of anhydrous methanol, heated and stirred to dissolve, stirred and crystallized, filtered, the filter cake was collected, and vacuum dried at 30°C to obtain the product (0.26 g, yield 52%), which was detected by XPRD to be Form B.
  • the compound of formula (1) (0.3 g) was added to a mixed solvent of 9.5 ml of anhydrous methanol and 4 ml of methyl tert-butyl ether, heated and stirred to dissolve, stirred and crystallized, filtered, the filter cake was collected, and vacuum dried at 25°C to obtain the product (0.21 g, yield 70%), which was detected by XPRD to be Form B.
  • the compound of formula (1) (0.3 g) was added to 9 ml of anhydrous ethanol, heated and stirred to make pulp, stirred to crystallize, filtered, the filter cake was collected, and vacuum dried at 30°C to obtain the product (0.25 g, yield 83%).
  • the compound of formula (1) (0.3 g) was added to a mixed solvent of 7 ml anhydrous methanol and 2.8 ml ethyl acetate, heated and stirred to dissolve, stirred and crystallized, filtered, the filter cake was collected, and vacuum dried at 40°C to obtain the product (0.26 g, yield 87%), which was detected by XPRD to be Form C.
  • X-ray powder diffraction showed that it was Form D, and its XRPD spectrum was shown in FIG10 . Its characteristic peak positions are shown in Table 8 below. There was an endothermic peak at 234.85° C. in the DSC spectrum, and the thermogravimetric analysis (TGA) showed a weight loss of 6.25% between 25° C. and 100° C.
  • Example 6 Dissolution characteristics of the crystalline dihydrochloride salt form in the formulation
  • the finished free base preparation can only reach more than 80% solubility within 120 minutes in pH1.2 hydrochloric acid medium and pH4.5 acetate buffer, and the dissolution effect in pH6.8 phosphate buffer (containing 0.05% SDS) and water medium is even worse, and the dissolution rate within 120 minutes does not exceed 20%.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

本发明属于药物化学技术领域，具体涉及2-{N-[4-(4-甲基)哌嗪]苯基}胺基-5,6-二氢-7-[3-(N-叔丁基)磺酰胺基]苯基-吡咯并[2,3-d]嘧啶二盐酸盐的A、B、C、D晶型及制备方法。本发明提供的A、B、C、D四种晶型可以通过多种不同条件制备，其结晶工艺有良好的纯化效果，且具有工艺稳定易操作等有利特点，晶型的制备方法简单，成本低廉，可以得到高纯度、溶解性佳、稳定性好的不同晶型的2-{N-[4-(4-甲基)哌嗪]苯基}胺基-5,6-二氢-7-[3-(N-叔丁基)磺酰胺基]苯基-吡咯并[2,3-d]嘧啶二盐酸盐。

Description

一种JAK2抑制剂的晶型及制备方法
本发明要求申请日为2023年6月29日的中国发明专利申请CN202310782778.1的优先权，将其整体通过引用并入本文，作为本发明披露的一部分。
技术领域
本发明属于药物化学领域，具体涉及2-{N-[4-(4-甲基)哌嗪]苯基}胺基-5,6-二氢-7-[3-(N-叔丁基)磺酰胺基]苯基-吡咯并[2,3-d]嘧啶二盐酸盐的A、B、C、D晶型及制备方法。
背景技术
CN110305140A描述了一种化合物2-{N-[4-(4-甲基)哌嗪]苯基}胺基-5,6-二氢-7-[3-(N-叔丁基)磺酰胺基]苯基-吡咯并[2,3-d]嘧啶，作为游离碱显示了高选择性JAK2抑制作用。
鉴于固体药物晶型及其稳定性对其在临床治疗中的重要性，进一步深入研究化合物2-{N-[4-(4-甲基)哌嗪]苯基}胺基-5,6-二氢-7-[3-(N-叔丁基)磺酰胺基]苯基-吡咯并[2,3-d]嘧啶二盐酸盐的多晶型，对开发适合工业生产且生物活性良好的药物具有重要意义。
发明内容
针对化合物2-{N-[4-(4-甲基)哌嗪]苯基}胺基-5,6-二氢-7-[3-(N-叔丁基)磺酰胺基]苯基-吡咯并[2,3-d]嘧啶在水中的溶解性、以及口服生物利用度等问题，本发明人经过长期努力，发现将2-{N-[4-(4-甲基)哌嗪]苯基}胺基-5,6-二氢-7-[3-(N-叔丁基)磺酰胺基]苯基-吡咯并[2,3-d]嘧啶制备成相应的可药用盐能够解决这一问题。
本发明的研究内容首先提供了2-{N-[4-(4-甲基)哌嗪]苯基}胺基-5,6-二氢-7-[3-(N-叔丁基)磺酰胺基]苯基-吡咯并[2,3-d]嘧啶的可药用盐，其中所述的可药用盐为本领域常规的无机盐或者有机盐。为了改善药物的物理化学或生物学性质，较游离碱(本发明无特别说明，游离碱均指2-{N-[4-(4-甲基)哌嗪]苯基}胺基-5,6-二氢-7-[3-(N-叔丁基)磺酰胺基]苯基-吡咯并[2,3-d]嘧啶)在体内能实现更快的溶出和释放，有利于人体的吸收和药效的发挥，更具有临床优势，进一步的，所述的无机盐优选为二盐酸盐、硫酸盐、磷酸盐、硝酸盐；所述的有机盐优选为甲磺酸盐、柠檬酸盐、草酸盐、琥珀酸盐。尤其优选可药用盐为二盐酸盐，其相对于游离碱以及其他盐，在溶解度、稳定性和引湿性方面更具有优势。
本发明进一步提供了2-{N-[4-(4-甲基)哌嗪]苯基}胺基-5,6-二氢-7-[3-(N-叔丁基)磺酰胺基]苯基-吡咯并[2,3-d]嘧啶二盐酸盐的A、B、C、D晶型及制备方法。
式(1)化合物2-{N-[4-(4-甲基)哌嗪]苯基}胺基-5,6-二氢-7-[3-(N-叔丁基)磺酰胺基]苯基-吡咯并[2,3-d]嘧啶二盐酸盐的A晶型，其X-射线粉末衍射图谱中，在2θ为5.989、8.478、12.288、13.315、16.985、17.476处有特征峰；
进一步的，所述A晶型的X-射线粉末衍射图谱，在衍射角2θ为3.105、5.989、8.478、12.288、13.315、16.985、17.476、22.174、24.898处有特征峰。
更进一步的，所述A晶型的X-射线粉末衍射图谱，在衍射角2θ为3.105、5.989、6.765、8.478、12.288、13.315、16.432、16.985、17.476、19.370、22.174、24.166、24.898、30.243处有特征峰。
本发明还提供了制备式(1)化合物的晶型A的方法，所述方法包括：
(a)将式(1)化合物加入溶剂(Ⅰ)中，搅拌溶解或加热溶解或加热打浆，所述溶剂(Ⅰ)选自水、乙醇、甲醇、异丙醇、乙二醇、丙酮、甲基叔丁基醚、乙酸乙酯、乙腈、四氢呋喃、二氧六环中的至少一种，优选甲醇、乙醇、乙醇/水。所述溶剂(Ⅰ)所用体积(ml)为化合物重量(g)的1-60倍。
(b)搅拌析晶。
(c)加热干燥，干燥温度为40℃-100℃，优选50℃-90℃。
本发明提供了式(1)化合物的晶型B，B晶型的X-射线粉末衍射图谱，在衍射角2θ为5.106、12.765、17.879、22.419、24.214处有特征峰。
进一步的，所述B晶型的X-射线粉末衍射图谱，在衍射角2θ为3.452、5.106、5.762、6.339、6.911、8.900、11.270、12.765、13.914、17.347、20.542、22.419、24.214处有特征峰。
更进一步的，所述B晶型的X-射线粉末衍射图谱，在衍射角2θ为3.452、5.106、5.762、5.957、6.339、6.911、8.900、10.406、11.270、11.924、12.765、13.914、14.247、17.347、18.476、20.542、22.419、24.214处有特征峰。
本发明还提供了制备式(1)化合物的晶型B的方法，所述方法包括：
(a)将式(1)化合物加入溶剂(Ⅱ)中，搅拌溶解或加热溶解，所述溶剂(Ⅱ)选自水、乙醇、甲醇、异丙醇、甲基叔丁基醚中的至少一种，优选甲醇、乙醇/水、甲醇/甲基叔丁基醚。所述溶剂(Ⅱ)所用体积(ml)为化合物重量(g)的1-60倍。
(b)搅拌析晶。
(c)加热干燥，干燥温度为10℃-40℃，优选25℃-40℃。
本发明提供了式(1)化合物的晶型C，C晶型的X-射线粉末衍射图谱，在衍射角2θ为5.743、11.931、13.097、15.625、17.066、18.429处有特征峰。
进一步的，所述C晶型的X-射线粉末衍射图谱，在衍射角2θ为5.743、6.262、11.931、12.561、13.097、13.967、15.625、17.066、18.429、18.882、21.432、24.496、24.931处有特征峰。
更进一步的，所述C晶型的X-射线粉末衍射图谱，在衍射角2θ为5.743、6.262、6.551、11.931、12.561、13.097、13.967、15.625、17.066、18.429、18.882、19.180、19.639、21.432、23.133、24.496、24.931处有特征峰。
本发明还提供了制备式(1)化合物的晶型C的方法，所述方法包括：
(a)将式(1)化合物加入溶剂(Ⅲa)中，室温或加热打浆，所述溶剂(Ⅲa)选自乙醇、乙二醇、丙酮中的至少一种，优选乙醇；或将式(1)化合物加入溶剂(Ⅲb)中，搅拌溶解或加热溶解，所述溶剂(Ⅲb)选自甲醇与乙酸乙酯或乙酸异丙酯或乙酸丁酯的至少一种，优选甲醇/乙酸乙酯。所述溶剂(Ⅲ)所用体积(ml)为化合物重量(g)的1-60倍。
(b)搅拌析晶。
(c)加热干燥，干燥温度为10℃-40℃，优选25℃-40℃。
本发明提供了式(1)化合物的晶型D，D晶型的X-射线粉末衍射图谱，在衍射角2θ为6.733、8.670、11.931、18.213、19.043处有特征峰。
进一步的，所述D晶型的X-射线粉末衍射图谱，在衍射角2θ为6.733、8.670、11.931、12.363、18.213、19.043、23.033、24.813处有特征峰。
本发明还提供了制备式(1)化合物的晶型D的方法，所述方法包括：
(a)将式(1)化合物加入溶剂(Ⅳ)中，搅拌溶解或加热溶解，滴加反溶剂析晶，所述溶剂(Ⅳ)选自甲醇、乙醇、乙二醇、水中的一种，优选甲醇。所述反溶剂选自乙腈。所述溶剂(Ⅳ)与乙腈的体积比为2:1-1:10，优选1:3、1:4或1:5。
(b)加热干燥，干燥温度为20℃-80℃，优选25℃-50℃。
应当理解用不同类型设备或用不同的测试条件可能给出稍微不同的熔点读数。不同晶型熔点的正确值将受化合物纯度、样品重量、加热速度、粒径和测试设备的校验和维修的影响。所提供的数值不能作为绝对值。
应当理解用不同类型设备或用不同的测试条件可能给出稍微不同的XPRD的图谱和峰值。不同晶型的图谱、峰值和各衍射峰的相对强度将受化合物纯度、样品的前处理、扫描速度、粒径和测试设备的校验和维修的影响。所提供的数值不能作为绝对值。
本发明所述的“X-射线粉末衍射图谱或XPRD”是经Cu-Kα射线衍射得到。
本发明所述的“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。
本发明所述的衍射角2θ为布拉格角，单位为度，所述2θ的误差范围是±0.2。
本发明的有益效果在于：本发明提供的式(1)化合物的A、B、C、D晶型的稳定性、溶解度、制剂溶出方面更有优势，更适合于药物开发，满足生物利用度和药效要求，能够满足生产运输储存的药用要求，生产工艺稳定、可重复可控，能够适应于工业化生产。
本发明提供的A、B、C、D四种晶型可以通过多种不同条件制备，其结晶工艺有良好的纯化效果，且具有工艺稳定易操作等有利特点，晶型的制备方法简单，成本低廉，可以得到 高纯度、溶解性佳、稳定性好的不同晶型的2-{N-[4-(4-甲基)哌嗪]苯基}胺基-5,6-二氢-7-[3-(N-叔丁基)磺酰胺基]苯基-吡咯并[2,3-d]嘧啶二盐酸盐。
附图说明
图1为式(1)化合物的晶型A的XPRD图谱；
图2为式(1)化合物的晶型A的DSC图谱；
图3为式(1)化合物的晶型A的TGA图谱；
图4为式(1)化合物的晶型B的XPRD图谱；
图5为式(1)化合物的晶型B的DSC图谱；
图6为式(1)化合物的晶型B的TGA图谱；
图7为式(1)化合物的晶型C的XPRD图谱；
图8为式(1)化合物的晶型C的DSC图谱；
图9为式(1)化合物的晶型C的TGA图谱；
图10为式(1)化合物的晶型D的XPRD图谱；
图11为式(1)化合物的晶型D的DSC图谱；
图12为式(1)化合物的晶型D的TGA图谱。
具体实施方式
以下结合实施例对本发明作进一步作具体描述，但不局限于此。
实验所用仪器的测试条件：
XRPD为X射线粉末衍射检测：测定使用Bruker D8型X射线衍射仪进行，照《中国药典》2020年版四部通则0451测定，测试条件：Target:Cu；40kv、40mA。
DSC为差示扫描量热：测定使用TA Q2000差示扫描量热仪进行，照《中国药典》2020年版四部通则0661测定，测试条件：DSC：30℃10℃/min 300℃；TGA：30℃10℃/min 350℃。
实施例1 2-{N-[4-(4-甲基)哌嗪]苯基}胺基-5,6-二氢-7-[3-(N-叔丁基)磺酰胺基]苯基-吡咯并[2,3-d]嘧啶可药用盐的相关性质
1、熔点
表1
2、溶解度
试验结果表明相对于游离碱，其硫酸盐、二盐酸盐，草酸盐、甲磺酸盐、柠檬酸盐在水中的溶解度均有所提高，尤其以硫酸盐和二盐酸盐在水中能够显著改善游离碱的溶解度。
表2不同盐型饱和溶解度(水中)测试
3、稳定性
游离碱及其五种不同种类的可药用盐在两种条件下的稳定性考察。
为了比较五种盐型与游离碱的固态稳定性，分别对游离碱及其二盐酸盐、硫酸盐、甲磺酸盐、草酸盐、柠檬酸盐在30℃±2℃/65％RH±5％RH和40℃±2℃/75％RH±5％RH条件下进行了一个月的稳定性评估。稳定性测试样品通过HPLC测定其纯度以评估化学稳定性(HPLC法采用面积归一法计算)。
表3：稳定性评估总结

结论：二盐酸盐在稳定性放置条件30℃±2℃/65％RH±5％RH和40℃±2℃/75％RH±5％RH下未发现明显的纯度降低，而游离碱及其硫酸盐、甲磺酸盐、草酸盐、柠檬酸盐在同等放置条件下均发生一定程度的纯度下降。
4、引湿性评估
参照中国药典2020年版的药物引湿性试验指导原则，针对游离碱及其五种盐型进行引湿性评估。在25℃恒温、相对湿度80％条件下，采集固体样品(游离碱和游离碱的二盐酸盐、硫酸盐、草酸盐、甲磺酸盐、柠檬酸盐)质量在24小时放置后的数据变化，引湿性评估总结见表4：
表4：引湿性评估总结
结论：从上述引湿性评估结果可以看出游离碱表现为略有引湿性，五种盐型均具有引湿性，而其中二盐酸盐和柠檬酸盐具有相对更低的引湿性，显示出更好的理化性质。
实施例2 2-{N-[4-(4-甲基)哌嗪]苯基}胺基-5,6-二氢-7-[3-(N-叔丁基)磺酰胺基]苯基-吡咯并[2,3-d]嘧啶二盐酸盐晶型的制备
1、A晶型的制备
将式(1)化合物(42g)加入到420ml无水乙醇和63ml纯化水得混合溶剂中，加热搅拌溶清，搅拌析晶，过滤，收集滤饼，80℃真空干燥得产物(40g，收率95％)。
经X-射线粉末衍射，为晶型A，其XRPD谱图如图1，其特征峰位置如下表5所示，DSC谱图中在273.68℃处有吸热峰，热重分析(TGA)在25℃-100℃之间失重2.854％。
表5 A晶型的特征峰

2、A晶型的制备
将式(1)化合物(0.3g)加入到9ml无水乙醇中，加热搅拌打浆，搅拌析晶，过滤，收集滤饼，90℃真空干燥得产物(0.23g，收率77％)，经XPRD检测为晶型A。
3、A晶型的制备
将式(1)化合物(0.5g)加入到3ml无水甲醇中，加热搅拌溶清，搅拌析晶，过滤，收集滤饼，60℃真空干燥得产物(0.21g，收率42％)，经XPRD检测为晶型A。
4、B晶型的制备
将式(1)化合物(3.66g)加入到73ml无水乙醇和4.5ml纯化水得混合溶剂中，加热搅拌溶清，搅拌析晶，过滤，收集滤饼，40℃真空干燥得产物(3.02g，收率82.5％)。
经X-射线粉末衍射，为晶型B，其XRPD谱图如图4，其特征峰位置如下表6所示，DSC谱图中在266.04℃处有吸热峰，热重分析(TGA)在25℃-100℃之间失重6.505％。
表6 B晶型的特征峰

5、B晶型的制备
将式(1)化合物(0.5g)加入到3ml无水甲醇中，加热搅拌溶清，搅拌析晶，过滤，收集滤饼，30℃真空干燥得产物(0.26g，收率52％)，经XPRD检测为晶型B。
6、B晶型的制备
将式(1)化合物(0.3g)加入到9.5ml无水甲醇和4ml甲基叔丁基醚的混合溶剂中，加热搅拌溶清，搅拌析晶，过滤，收集滤饼，25℃真空干燥得产物(0.21g，收率70％)，经XPRD检测为晶型B。
7、C晶型的制备
将式(1)化合物(0.3g)加入到9ml无水乙醇中，加热搅拌打浆，搅拌析晶，过滤，收集滤饼，30℃真空干燥得产物(0.25g，收率83％)。
经X-射线粉末衍射，为晶型C，其XRPD谱图如图7，其特征峰位置如下表7所示，DSC谱图中在274.4℃处有吸热峰，热重分析(TGA)在25℃-100℃之间失重7.307％。
表7 C晶型的特征峰

8、C晶型的制备
将式(1)化合物(0.3g)加入到7ml无水甲醇和2.8ml乙酸乙酯的混合溶剂中，加热搅拌溶清，搅拌析晶，过滤，收集滤饼，40℃真空干燥得产物(0.26g，收率87％)，经XPRD检测为晶型C。
9、D晶型的制备
将式(1)化合物(0.3g)加入到4ml无水甲醇中，搅拌溶清，滴加16ml乙腈，搅拌析晶，过滤，收集滤饼，30℃真空干燥得产物(0.17g，收率57％)。
经X-射线粉末衍射，为晶型D，其XRPD谱图如图10，其特征峰位置如下表8所示，DSC谱图中在234.85℃处有吸热峰，热重分析(TGA)在25℃-100℃之间失重6.25％。
表8 D晶型的特征峰

实施例3 A晶型、B晶型、C晶型、D晶型的稳定性试验
纯度检测按中国药典2015年版四部通则0512方法进行。

实施例4 A晶型的影响因素试验
纯度检测按中国药典2015年版四部通则0512方法进行。
实施例5 A晶型、B晶型、C晶型、D晶型的溶解度测定
按中国药典2015版四部凡例溶解度试验法，取本品置于25±2℃一定容量的溶剂中，每隔5分钟强力振摇30秒，观察30分钟内的溶解情况，结果如下：
实施例6 晶态二盐酸盐形式在制剂中的溶出特性
体外溶出试验能客观反映制剂特点，对药物在体内的溶出和释放具有重要的指导和预测作用。采用相同的处方及粉末直压工艺，其二盐酸盐晶型A制剂成品在模拟体内环境的pH1.2盐酸介质、pH4.5醋酸盐缓冲液、pH6.8磷酸盐缓冲液(含0.05％SDS)以及水介质中，均能于15分钟内达到85％以上溶出度，实现快速释放效果。而游离碱制剂成品由于原料药溶解度不佳，在pH1.2盐酸介质、pH4.5醋酸盐缓冲液中，120min内仅能达到80％以上溶出度，pH6.8磷酸盐缓冲液(含0.05％SDS)以及水介质中溶出效果更差，120min内的溶出速率均未超过20％。
以上所述仅为本发明的较佳实施例而已，并不用以限制本发明，凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。

Claims (13)

  1. 式(1)化合物2-{N-[4-(4-甲基)哌嗪]苯基}胺基-5,6-二氢-7-[3-(N-叔丁基)磺酰胺基]苯基-吡咯并[2,3-d]嘧啶二盐酸盐的A晶型，其特征在于，其X-射线粉末衍射图谱中，在2θ为5.989、8.478、12.288、13.315、16.985、17.476处有特征峰；优选的在2θ为3.105、5.989、8.478、12.288、13.315、16.985、17.476、22.174、24.898处有特征峰；优选的在2θ为3.105、5.989、6.765、8.478、12.288、13.315、16.432、16.985、17.476、19.370、22.174、24.166、24.898、30.243处有特征峰；
  2. 制备权利要求1所述的A晶型的方法，包括：
    (a)将式(1)化合物加入溶剂(Ⅰ)中，搅拌溶解或加热溶解或加热打浆，所述溶剂(Ⅰ)选自水、乙醇、甲醇、异丙醇、乙二醇、丙酮、甲基叔丁基醚、乙酸乙酯、乙腈、四氢呋喃、二氧六环中的至少一种；
    (b)搅拌析晶；
    (c)加热干燥，干燥温度为40℃-100℃。
  3. 如权利要求2所述的方法，其特征在于，步骤(a)溶剂(Ⅰ)选自甲醇、乙醇、乙醇/水，所述溶剂(Ⅰ)所用体积(ml)为式(1)化合物重量(g)的1-60倍；步骤(c)温度为50℃-90℃。
  4. 式(1)化合物2-{N-[4-(4-甲基)哌嗪]苯基}胺基-5,6-二氢-7-[3-(N-叔丁基)磺酰胺基]苯基-吡咯并[2,3-d]嘧啶二盐酸盐的B晶型，其特征在于，其X-射线粉末衍射图谱中，在2θ为5.106、12.765、17.879、22.419、24.214处有特征峰；优选的在2θ为3.452、5.106、5.762、6.339、6.911、8.900、11.270、12.765、13.914、17.347、20.542、22.419、24.214处有特征峰；优选的在2θ为3.452、5.106、5.762、5.957、6.339、6.911、8.900、10.406、11.270、11.924、12.765、13.914、14.247、17.347、18.476、20.542、22.419、24.214处有特征峰。
  5. 制备权利要求4所述的B晶型的方法，包括：
    (a)将式(1)化合物加入溶剂(Ⅱ)中，搅拌溶解或加热溶解，所述溶剂(Ⅱ)选自水、乙醇、甲醇、异丙醇、甲基叔丁基醚中的至少一种；
    (b)搅拌析晶；
    (c)加热干燥，干燥温度为10℃-40℃。
  6. 如权利要求5所述的方法，其特征在于，步骤(a)溶剂(Ⅱ)选自甲醇、乙醇/水、 甲醇/甲基叔丁基醚，所述溶剂(Ⅱ)所用体积(ml)为式(1)化合物重量(g)的1-60倍；步骤(c)温度为25℃-40℃。
  7. 式(1)化合物2-{N-[4-(4-甲基)哌嗪]苯基}胺基-5,6-二氢-7-[3-(N-叔丁基)磺酰胺基]苯基-吡咯并[2,3-d]嘧啶二盐酸盐的C晶型，其特征在于，其X-射线粉末衍射图谱中，在2θ为5.743、11.931、13.097、15.625、17.066、18.429处有特征峰；优选的在2θ为5.743、6.262、11.931、12.561、13.097、13.967、15.625、17.066、18.429、18.882、21.432、24.496、24.931处有特征峰；优选的在2θ为5.743、6.262、6.551、11.931、12.561、13.097、13.967、15.625、17.066、18.429、18.882、19.180、19.639、21.432、23.133、24.496、24.931处有特征峰。
  8. 制备权利要求7所述的C晶型的方法，包括：
    (a)将式(1)化合物加入溶剂(Ⅲa)中，室温或加热打浆，所述溶剂(Ⅲa)选自乙醇、乙二醇、丙酮中的至少一种；或将式(1)化合物加入溶剂(Ⅲb)中，搅拌溶解或加热溶解，所述溶剂(Ⅲb)选自甲醇与乙酸乙酯或乙酸异丙酯或乙酸丁酯的至少一种；
    (b)搅拌析晶；
    (c)加热干燥，干燥温度为10℃-40℃。
  9. 如权利要求8所述的方法，其特征在于，步骤(a)溶剂(Ⅲ)选自乙醇、甲醇/乙酸乙酯，所述溶剂(Ⅲ)所用体积(ml)为式(1)化合物重量(g)的1-60倍；步骤(c)温度为25℃-40℃。
  10. 式(1)化合物2-{N-[4-(4-甲基)哌嗪]苯基}胺基-5,6-二氢-7-[3-(N-叔丁基)磺酰胺基]苯基-吡咯并[2,3-d]嘧啶二盐酸盐的D晶型，其特征在于，其X-射线粉末衍射图谱中，在2θ为6.733、8.670、11.931、18.213、19.043处有特征峰；优选的在2θ为6.733、8.670、11.931、12.363、18.213、19.043、23.033、24.813处有特征峰。
  11. 制备权利要求10所述的D晶型的方法，包括：
    (a)将式(1)化合物加入溶剂(Ⅳ)中，搅拌溶解或加热溶解，滴加反溶剂析晶，所述溶剂(Ⅳ)选自甲醇、乙醇、乙二醇、水中的至少一种；所述溶剂(Ⅳ)与反溶剂的体积比为2:1-1:10；
    (b)加热干燥，干燥温度为20℃-80℃；步骤(a)所述溶剂(Ⅳ)与反溶剂的体积比为1:3、1:4或1:5；步骤(a)溶剂(Ⅳ)选自甲醇，反溶剂选自乙腈；步骤(b)温度为25℃-50℃。
  12. 化合物2-{N-[4-(4-甲基)哌嗪]苯基}胺基-5,6-二氢-7-[3-(N-叔丁基)磺酰胺基]苯基-吡咯并[2,3-d]嘧啶的盐，其特征在于所述盐选自盐酸盐、硫酸盐、磷酸盐、硝酸盐、甲磺酸盐、柠檬酸盐、草酸盐或琥珀酸盐。
  13. 如权利要求12所述的化合物2-{N-[4-(4-甲基)哌嗪]苯基}胺基-5,6-二氢-7-[3-(N-叔丁基)磺酰胺基]苯基-吡咯并[2,3-d]嘧啶的盐，其特征在于所述盐为二盐酸盐。
PCT/CN2024/102394 2023-06-29 2024-06-28 一种jak2抑制剂的晶型及制备方法 Pending WO2025002355A1 (zh)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202310782778.1A CN116813624B (zh) 2023-06-29 2023-06-29 一种jak2抑制剂的晶型及制备方法
CN202310782778.1 2023-06-29

Publications (2)

Publication Number Publication Date
WO2025002355A1 WO2025002355A1 (zh) 2025-01-02
WO2025002355A9 true WO2025002355A9 (zh) 2025-04-24

Family

ID=88125423

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2024/102394 Pending WO2025002355A1 (zh) 2023-06-29 2024-06-28 一种jak2抑制剂的晶型及制备方法

Country Status (2)

Country Link
CN (1) CN116813624B (zh)
WO (1) WO2025002355A1 (zh)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116813624B (zh) * 2023-06-29 2025-10-03 成都金瑞基业生物科技有限公司 一种jak2抑制剂的晶型及制备方法

Family Cites Families (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JO3235B1 (ar) * 2006-05-26 2018-03-08 Astex Therapeutics Ltd مركبات بيررولوبيريميدين و استعمالاتها
JP5323095B2 (ja) * 2008-02-06 2013-10-23 ノバルティス アーゲー ピロロ［２，３−ｄ］ピリミジンおよびそのチロシンキナーゼ阻害剤としての使用
US20160222014A1 (en) * 2013-09-10 2016-08-04 Asana Biosciences, Llc Compounds for regulating fak and/or src pathways
KR20190135464A (ko) * 2016-12-01 2019-12-06 압토스 바이오사이언시스 인코포레이티드 Brd4 및 jak2 이중 억제제로서의 융합된 피리미딘 및 이의 사용 방법
EP3594214A4 (en) * 2017-04-28 2020-09-30 Qilu Pharmaceutical Co., Ltd COMPOUND POLYMORPH, RELATED PREPARATION PROCESS AND USE THEREOF
CN111205290B (zh) * 2018-11-22 2021-10-08 江苏恒瑞医药股份有限公司 一种jak激酶抑制剂的结晶形式及其制备方法
CN111499642A (zh) * 2019-01-31 2020-08-07 江苏恒瑞医药股份有限公司 吡咯并[2,3-d]哒嗪-7-酮类衍生物的可药用盐、晶型及其制备方法
CN110305140B (zh) * 2019-07-30 2020-08-04 上海勋和医药科技有限公司 二氢吡咯并嘧啶类选择性jak2抑制剂
CN114929671B (zh) * 2020-01-03 2024-04-16 苏州科睿思制药有限公司 化合物i二盐酸盐的共晶及其制备方法和用途
CN116813624B (zh) * 2023-06-29 2025-10-03 成都金瑞基业生物科技有限公司 一种jak2抑制剂的晶型及制备方法

Also Published As

Publication number Publication date
CN116813624A (zh) 2023-09-29
CN116813624B (zh) 2025-10-03
WO2025002355A1 (zh) 2025-01-02

Similar Documents

Publication Publication Date Title
TWI406661B (zh) ４-甲基-ｎ-〔３-（４-甲基-咪唑-１-基）-５-三氟甲基-苯基〕-３-（４-吡啶-３-基-嘧啶-２基胺基）-苯甲醯胺之結晶型
AU2014239995B2 (en) Salt of omecamtiv mecarbil and process for preparing salt
US9895377B2 (en) Solid forms of tyrosine kinase inhibitors, process for the preparation and their pharmaceutical composition thereof
US10246437B2 (en) Crystal form of neratinib maleate and preparation method therefor
NO335103B1 (no) Forbindelse, farmasøytisk preparat inneholdende forbindelsen, anvendelse av forbindelsen samt fremgangsmåte for fremstilling derav
US20150183779A1 (en) Solid state form of vemurafenib choline salt
KR20170057441A (ko) Jak 억제제의 바이설페이트의 결정형 및 이의 제조방법
JP7314319B2 (ja) Ｃｄｋ９阻害剤の結晶多形体及びその製造方法と用途
JP2025131661A (ja) ２－（５－（４－（２－モルホリノエトキシ）フェニル）ピリジン－２－イル）－ｎ－ベンジルアセトアミドの固体形態
EP3430004B1 (en) Solid state forms of nilotinib salts
WO2021000687A1 (zh) Pac-1晶型的制备方法
WO2025002355A9 (zh) 一种jak2抑制剂的晶型及制备方法
WO2024230805A1 (zh) 一种脂蛋白化合物晶型及其制备方法
US10519150B2 (en) Salts of morpholine derivative, crystal forms thereof, processes for producing the same, pharmaceutical compositions including the same, and use thereof
BG64051B1 (bg) Нова сол
US12384784B2 (en) Polymorphs of Acalabrutinib, a Bruton's tyrosine kinase inhibitor
JP7068288B2 (ja) ４－（２－（（１ｒ，２ｒ）－２－ヒドロキシシクロヘキシルアミノ）ベンゾチアゾール－６－イルオキシ）－ｎ－メチルピコリンアミドの結晶形
JP2018518515A (ja) フェニルアミノピリミジン化合物またはその塩の多形物
JP2025530530A (ja) カレバスチン－ｐ－トルエンスルホン酸塩の結晶形及び無定形
CN111732586B (zh) 含炔基化合物盐的晶型、制备方法及应用
WO2020119772A1 (zh) 盐酸美呋哌瑞多晶型物及其制备方法
TW202216726A (zh) 八氫噻吩并喹啉化合物之琥珀酸鹽及其結晶
US20040038985A1 (en) Crystal forms of 1- [6-chloro-5-(trifluoromethly) -2-pyridinyl] piperazine hydrochloride
WO2019099761A1 (en) Solid state forms of elafibranor
WO2024169896A1 (zh) 一种苯并氮杂芳环衍生物的盐、晶型及其在医药上的应用

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 24830984

Country of ref document: EP

Kind code of ref document: A1