WO2016070697A1 - 一种jak激酶抑制剂的硫酸氢盐的结晶形式及其制备方法 - Google Patents

一种jak激酶抑制剂的硫酸氢盐的结晶形式及其制备方法 Download PDF

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WO2016070697A1
WO2016070697A1 PCT/CN2015/091527 CN2015091527W WO2016070697A1 WO 2016070697 A1 WO2016070697 A1 WO 2016070697A1 CN 2015091527 W CN2015091527 W CN 2015091527W WO 2016070697 A1 WO2016070697 A1 WO 2016070697A1
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crystal
pyrrole
hexahydrocyclopenta
methoxy
amino
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PCT/CN2015/091527
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English (en)
French (fr)
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孙飘扬
武乖利
张全良
陈永江
沈灵佳
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江苏恒瑞医药股份有限公司
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Priority to KR1020177013839A priority Critical patent/KR102522895B1/ko
Priority to RU2017118193A priority patent/RU2716260C2/ru
Priority to ES15857844T priority patent/ES2754548T3/es
Priority to JP2017518183A priority patent/JP6851572B2/ja
Priority to AU2015342444A priority patent/AU2015342444B2/en
Priority to SI201530982T priority patent/SI3216790T1/sl
Priority to BR112017007953-4A priority patent/BR112017007953B1/pt
Priority to PL15857844T priority patent/PL3216790T3/pl
Application filed by 江苏恒瑞医药股份有限公司 filed Critical 江苏恒瑞医药股份有限公司
Priority to CA2965716A priority patent/CA2965716C/en
Priority to CN201580008169.4A priority patent/CN105980390B/zh
Priority to EP15857844.3A priority patent/EP3216790B1/en
Priority to US15/522,991 priority patent/US10023577B2/en
Priority to DK15857844T priority patent/DK3216790T3/da
Priority to RS20191420A priority patent/RS59669B1/sr
Publication of WO2016070697A1 publication Critical patent/WO2016070697A1/zh
Priority to CY20191101146T priority patent/CY1122468T1/el
Priority to HRP20192030TT priority patent/HRP20192030T1/hr

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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
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
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    • 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
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    • 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

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  • the present invention relates to (3aR,5s,6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrolo[2,3- Type II crystal of d]pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide hydrogensulfate, and a preparation method and use thereof.
  • the compounds of formula (I) obtained according to the process of the invention are useful in the treatment of arthritis.
  • Tofacitinib (CP-690550) is a new oral JAK pathway inhibitor developed by Pfizer Inc. Tofacitinib is the first-in-class drug developed for the treatment of rheumatoid arthritis. Based on the structure of tofacitinib, a series of JAK kinase inhibitor compounds with in vivo and exogenous activity and high absorption have been developed, see WO2013091539.
  • the crystal form of the crystal form II has good stability, the crystal form is the most easily available and the crystal form is stable, and the preparation thereof is prepared.
  • the process is controllable and repeatable, and is more suitable for industrial production.
  • the X-ray powder diffraction pattern is represented by 8.96 (9.87), 11.80 (7.50), 13.12 (6.74), 13.53 (6.54), 13.89 (6.37), 14.42 (6.14), 14.98 (5.91), 16.52 (5.36). , 18.20 (4.87), 18.75 (4.73), 19.15 (4.63), 19.72 (4.50), 20.82 (4.26), 22.05 (4.03), 22.52 (3.95), 22.92 (3.88), 23.58 (3.77) and 27.04 (3.30) There are characteristic peaks.
  • the form of the compound of the formula (I) which can be used as a raw material is not particularly limited, and any crystal form or amorphous solid can be used, and the preparation of the compound of the formula (I) of the present invention is a type II crystal.
  • the method is:
  • a certain lower organic solvent preferably a polar organic solvent such as an alcohol, a ketone, an ester or a halogenated hydrocarbon having a small number of carbon atoms and capable of being volatilized and used as a crystallization solvent, or a mixed solution thereof; more preferably It is a recrystallization solvent of methanol, ethanol, isopropanol, ethyl acetate, acetone, dichloromethane or a mixed solution thereof.
  • a single solvent may be used for crystallization, or a mixed solvent selected from the above organic solvents may be used.
  • the method for preparing Form II crystal of the compound of formula (I) provided by the present invention comprises the steps of:
  • the organic solvent is selected from any one of an alcohol, a ketone, and an ester having a carbon number of 3 or less; or one or more of them and a carbon atom A mixed solvent of a halogenated hydrocarbon of 3 or less.
  • the organic solvent is selected from the group consisting of methanol, ethanol, isopropanol, acetone, ethyl acetate; or dichloromethane/methanol, dichloromethane/methanol/ethanol, dichloromethane/methanol/isopropanol, dichloromethane/methanol / Mixed solvent system such as ethyl acetate, dichloromethane/methanol/acetone.
  • the most preferred single solvent is methanol.
  • a preferred mixed organic solvent is a mixed solvent of dichloromethane/methanol/ethanol, and the ratio of the three is not particularly limited. In a preferred embodiment of the present invention, the volume ratio of the three is 12:3. :10.
  • the method of recrystallization is not particularly limited and can be carried out by a usual recrystallization operation method.
  • the compound of the formula (I) in any form can be slowly dissolved by heating and dissolving in an organic solvent, and after stirring, the desired crystal can be obtained by filtration and drying.
  • the crystals thus collected are usually vacuum-dried under reduced pressure at a temperature of about 30 to 100 ° C, preferably 40 to 60 ° C, to achieve the effect of removing the recrystallization solvent.
  • the crystal of the obtained compound of the formula (I) was subjected to a crystal form study by differential scanning calorimetry (DSC) and X-ray diffraction pattern measurement, and the solvent residue of the obtained crystal was examined.
  • DSC differential scanning calorimetry
  • the compound of the formula (I) prepared according to the method of the invention has no or only a low content of residual solvent, and meets the requirements of the national pharmacopoeia for the residual solvent of the pharmaceutical product, so that the crystal of the invention can be better It is used as a pharmaceutically active ingredient.
  • the type II crystal of the compound of the formula (I) prepared by the present invention has significantly better stability under high temperature and high humidity conditions than the amorphous sample, and has good crystal form stability under conditions of grinding, pressure and heat. It can meet the medicinal requirements of production, transportation and storage.
  • the production process is stable and repeatable and controllable, and can be adapted to industrial production.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) Form II, said composition further comprising at least one pharmaceutically acceptable carrier, said pharmaceutically acceptable carrier Can be selected from lactose, mannitol, microcrystalline cellulose, crosslinked carboxymethyl At least one of cellulose sodium, sodium carboxymethyl starch, hydroxypropyl methylcellulose, povidone, and magnesium stearate.
  • the content of the type II crystal in the pharmaceutical composition provided by the present invention is from 0.5 mg to 200 mg.
  • Another aspect of the invention relates to the use of a compound of formula (I) Form II crystal of the invention or a pharmaceutical composition of the invention for the manufacture of a medicament for the treatment of a disease associated with JAK kinase.
  • the disease is preferably rheumatoid and rheumatoid arthritis.
  • Figure 1 is an X-ray powder diffraction pattern of a type II crystal of a compound of formula (I) (represented by the code SHR0302 in the figure).
  • Figure 2 is a DSC spectrum of a compound of the formula II (I).
  • Figure 3 is an X-ray powder diffraction pattern of an amorphous solid of the compound of formula (I).
  • Figure 4 is a DSC chart of an amorphous solid of the compound of formula (I).
  • the insoluble material was removed by filtration, stirred for 6h, and no solids were precipitated, and 10 ml of isopropanol was added for crystallization. A large amount of white solid was precipitated, stirring was continued for 18 h, filtered, and dried to give a white solid 1.138 g, yield 92.1%.
  • the X-ray diffraction spectrum of the crystal sample is shown in Fig. 1. The crystals are about 8.96 (9.87), 11.80 (7.50), 13.12 (6.74), 13.53 (6.54), 13.89 (6.37), 14.42 (6.14), 14.98 (5.91), 16.52 (5.36), 18.20 (4.87), 18.75.
  • Example 1 The type II crystal product obtained in Example 1 and the amorphous sample prepared in Example 2 were separately placed in an open position, and examined under illumination (4,500 Lux), heating (40 ° C, 60 ° C), and high humidity (RH 75%, Stability of the sample under RH90%) conditions.
  • the sampling time was 5 days and 10 days, and the purity of HPLC was shown in Table 1.

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Abstract

本发明涉及一种JAK激酶抑制剂的硫酸氢盐的结晶形式及其制备方法。具体地，本发明涉及(3aR,5s,6aS)-N-(3-甲氧基-1,2,4-噻二唑-5-基)-5-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)六氢环戊并[c]吡咯-2(1H)-甲酰胺硫酸氢盐的II型结晶及其制备方法。所述制备方法包括将任意晶型或无定型的式(I)化合物固体在单一的有机溶剂或者它们的混合有机溶剂中结晶得到式(I)化合物的II型结晶。本发明所得到式(I)化合物的II型结晶具备良好的晶型稳定性和化学稳定性，并且所用结晶溶剂低毒低残留，可更好地用于临床治疗。

Description

一种JAK激酶抑制剂的硫酸氢盐的结晶形式及其制备方法 技术领域
本发明涉及(3aR,5s,6aS)-N-(3-甲氧基-1,2,4-噻二唑-5-基)-5-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)六氢环戊并[c]吡咯-2(1H)-甲酰胺硫酸氢盐的II型结晶及其制备方法和用途。根据本发明的方法制备获得的式(I)化合物可用于关节炎的治疗。
背景技术
关节炎是全世界最常见的慢性疾病，导致关节炎的原因很多，引起关节损伤的原因也各有不同。目前，Tofacitinib(CP-690550)是辉瑞公司研发的一种新型口服JAK通路抑制剂，Tofacitinib是开发用于类风湿性关节炎(rheumatoid arthritis)治疗的首创药物(first-in-class drug)。基于tofacitinib的结构，已开发出一系列具有体内、外活性，高吸收的JAK激酶抑制剂化合物，参见WO2013091539。根据WO2013091539中化合物筛选后并制备成盐得到了式(I)示的(3aR,5s,6aS)-N-(3-甲氧基-1,2,4-噻二唑-5-基)-5-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)六氢环戊并[c]吡咯-2(1H)-甲酰胺硫酸氢盐，其制备方法参见申请人在先提交的PCT专利申请PCT/CN2014/076794。
Figure PCTCN2015091527-appb-000001
众所周知，药用活性成分的晶型结构往往影响到该药物的化学稳定性，结晶及储存条件的不同有可能导致化合物的晶型结构的变化，有时还会伴随着产生其他形态的晶型。将式(I)化合物在甲醇中溶清后，蒸除部分溶剂，析晶可得到一种结晶，我们称之为I晶型，参见中国专利申请201410529863.8。在后续的研究中，我们惊喜的发现，该化 合物还存在另外一种晶型，该盐在多种溶剂体系中回流转晶，或者用多种溶剂成盐冲析均能得到这种晶型。在此将这种晶型定义为II晶型，经过晶型的影响因素及特殊稳定性试验，发现该II晶型晶型稳定性良好，该晶型是最易得到并且晶型稳定，其制备工艺可控可重复，更加适合于工业化生产。
发明内容
本发明的目的是提供一种JAK激酶抑制剂的硫酸氢盐(式(I)化合物)的稳定晶型以及制备和晶型的方法。
我们考察了式(I)化合物在不同结晶条件下得到的一系列结晶产物，对所得结晶产物进行了X-衍射及DSC检测，发现式(I)化合物在本发明提供的结晶条件下，可以得到一种稳定性良好的晶型，我们称其为II型结晶。本申请中的II型结晶的DSC图谱显示在218℃附近有熔融吸热峰，X-射线粉末衍射图谱如图1所示，使用Cu-Ka辐射，以2θ角度和晶面间距(d值)表示的X-射线粉末衍射图谱，其中在8.96(9.87)，11.80(7.50)，13.12(6.74)，13.53(6.54)，13.89(6.37)，14.42(6.14)，14.98(5.91)，16.52(5.36)，18.20(4.87)，18.75(4.73)，19.15(4.63)，19.72(4.50)，20.82(4.26)，22.05(4.03)，22.52(3.95)，22.92(3.88)，23.58(3.77)和27.04(3.30)有特征峰。
本发明制备II型结晶的方法中，可作为原料使用的式(I)化合物的存在形态没有特别限定，可以使用任意晶型或无定型固体，本发明的式(I)化合物II型结晶的制备方法为：
使用某些低级有机溶剂，优选含碳原子数小、同时能够挥发并可用作结晶溶剂的醇类、酮类、酯类、卤代烃等极性有机溶剂，或它们的混合溶液；更优选为甲醇、乙醇、异丙醇、乙酸乙酯、丙酮、二氯甲烷或它们的混合溶液作为重结晶溶剂。析晶时可以用单一溶剂，也可以用选自以上有机溶剂的混合溶剂。
具体的，本发明提供的制备式(I)化合物的II型结晶的方法包括以下步骤：
(1)将(3aR,5s,6aS)-N-(3-甲氧基-1,2,4-噻二唑-5-基)-5-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)六氢环戊并[c]吡咯-2(1H)-甲酰胺加入有 机溶剂，滴加浓硫酸，过滤，析晶；或者将式(I)化合物固体加热溶解于适量的有机溶剂中，冷却析晶；
(2)过滤、洗涤、干燥。
在本发明优选的实施方案中，步骤(1)中，有机溶剂选自碳原子数小于等于3的醇类、酮类、酯类的任意一种；或者其中的一种或几种与碳原子小于等于3的卤代烃的混合溶剂。进一步优选有机溶剂选自甲醇、乙醇、异丙醇、丙酮、乙酸乙酯；或二氯甲烷/甲醇、二氯甲烷/甲醇/乙醇、二氯甲烷/甲醇/异丙醇、二氯甲烷/甲醇/乙酸乙酯、二氯甲烷/甲醇/丙酮等混合溶剂体系。
进一步地，最优选的单一溶剂为甲醇。
在本发明的一个实施方案中，优选的混合有机溶剂为二氯甲烷/甲醇/乙醇的混合溶剂，三者比例没有特别限制，在本发明优选的实施方案中，三者体积比为12：3：10。
重结晶的方法没有特别限定，可以用通常的重结晶操作方法进行。例如，可以用任意形态的式(I)化合物在有机溶剂加热溶解后慢慢冷却搅拌析晶，结晶完成后，经过滤干燥，即可得到所需要的结晶。所滤取的结晶体通常在减压下，在30～100℃左右，优选40～60℃的加热条件下进行真空干燥，就能达到去除重结晶溶剂的效果。
通过差示扫描热分析(DSC)、X－衍射图谱测定，对得到的式(I)化合物的结晶体进行了晶型研究，同时对所得结晶的溶剂残留进行了检测。
按照本发明的方法制备的式(I)化合物II型结晶不含有或仅含有较低含量的残留溶剂，符合国家药典规定的有关医药产品残留溶剂的限量要求，因而本发明的结晶可以较好地作为医药活性成分使用。
经研究表明，本发明制备的式(I)化合物的II型结晶在高温、高湿的条件下稳定性显著好于无定型样品，且在研磨、压力和受热等条件下，晶型稳定性良好，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。
另一方面，本发明还提供了一种含有式(I)化合物II型结晶的药用组合物，所述组合物还包含至少一种药学上可接受的载体，所述药学上可接受的载体可以选自乳糖、甘露醇、微晶纤维素、交联羧甲基 纤维素钠、羧甲基淀粉钠、羟丙基甲基纤维素、聚维酮和硬脂酸镁中的至少一种。本发明提供的药物组合物中II型结晶的含量为0.5mg～200mg。
本发明另一方面涉及本发明的式(I)化合物II型结晶或本发明的药物组合物在制备治疗与JAK激酶有关的疾病的药物中的用途。所述疾病优选为风湿及类风湿性关节炎。
附图说明
图1是式(I)化合物(图中以代号SHR0302表示)II型结晶的X-射线粉末衍射图谱。
图2是式(I)化合物II型结晶的DSC谱图。
图3是式(I)化合物无定型固体的X-射线粉末衍射图谱。
图4是式(I)化合物无定型固体的DSC谱图。
具体实施方式
以下将结合实施例更详细地解释本发明，本发明的实施例仅用于说明本发明的技术方案，并非限定本发明的实质和范围。
实验所用的测试仪器
1、DSC谱
仪器型号：Mettler Toledo DSC 1 Staree System
吹扫气：氮气
升温速率：10.0℃/min
温度范围：40-300℃
2、X-射线衍射谱
仪器型号：D/Max-RA日本RigakuX-射线粉末衍射仪
射线：单色Cu-Kα射线(
Figure PCTCN2015091527-appb-000002
)
扫描方式：θ/2θ，扫描范围：2－40°
电压：40KV电流：40mA
实施例1
取(1.0g，2.4mmol)(3aR,5s,6aS)-N-(3-甲氧基-1,2,4-噻二唑-5-基)-5-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)六氢环戊并[c]吡咯 -2(1H)-甲酰胺加入到50ml锥形瓶中，加入12ml二氯甲烷，3ml无水甲醇，室温下搅拌，然后滴加(0.25g，2.5mmol)浓硫酸，悬浊液溶清后，过滤除去不溶物，搅拌6h，无固体析出，加10ml异丙醇冲析，有大量白色固体析出，继续搅拌18h，抽滤，干燥得白色固体1.138g，收率为92.1％。该结晶样品的X-射线衍射谱图见图1。该结晶在约8.96(9.87)，11.80(7.50)，13.12(6.74)，13.53(6.54)，13.89(6.37)，14.42(6.14)，14.98(5.91)，16.52(5.36)，18.20(4.87)，18.75(4.73)，19.15(4.63)，19.72(4.50)，20.82(4.26)，22.05(4.03)，22.52(3.95)，22.92(3.88)，23.58(3.77)和27.04(3.30)处有特征峰。DSC谱图见图2，有尖锐熔融吸热峰217.24℃，将此晶型定义为II晶型。
实施例2
取(1.0g，2.4mmol)(3aR,5s,6aS)-N-(3-甲氧基-1,2,4-噻二唑-5-基)-5-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)六氢环戊并[c]吡咯-2(1H)-甲酰胺加入到50ml锥形瓶中，加入12ml二氯甲烷，3ml无水甲醇，室温下搅拌，然后滴加(0.25g，2.5mmol)浓硫酸，悬浊液溶清后，过滤除去不溶物，滤液浓缩至干，得无定形式(I)化合物。该固体样品的X-射线衍射谱图见图3，显示无晶型特征吸收峰，DSC谱图见4。
实施例3
取(1.0g，2.4mmol)(3aR,5s,6aS)-N-(3-甲氧基-1,2,4-噻二唑-5-基)-5-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)六氢环戊并[c]吡咯-2(1H)-甲酰胺加入到50ml锥形瓶中，加入12ml二氯甲烷，3ml无水甲醇，室温下搅拌，然后滴加(0.25g，2.5mmol)浓硫酸，悬浊液溶清后，过滤除去不溶物，搅拌析晶24h，抽滤，干燥得白色固体1.15g，收率为93.2％。其X-衍射和DSC图谱经研究比对，确定产物为II晶型。
实施例4
取(1.0g，2.4mmol)(3aR,5s,6aS)-N-(3-甲氧基-1,2,4-噻二唑-5-基)-5-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)六氢环戊并[c]吡咯-2(1H)-甲酰胺加入到50ml锥形瓶中，加入12ml二氯甲烷，3ml无水甲醇，室温下搅拌，然后滴加(0.25g，2.5mmol)浓硫酸，悬浊液溶清后，过滤除去不溶物，搅拌6h，无固体析出，加10ml乙醇冲析，有大 量白色固体析出，继续搅拌18h，抽滤，干燥得白色固体1.17g，收率为94.9％。该结晶样品的X-射线衍射和DSC谱图经研究比对，确定产物为II晶型。
实施例5
取(1.0g，2.4mmol)(3aR,5s,6aS)-N-(3-甲氧基-1,2,4-噻二唑-5-基)-5-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)六氢环戊并[c]吡咯-2(1H)-甲酰胺加入到50ml锥形瓶中，加入12ml二氯甲烷，3ml无水甲醇，室温下搅拌，然后滴加(0.25g，2.5mmol)浓硫酸，悬浊液溶清后，过滤除去不溶物，搅拌6h，无固体析出，加5ml乙酸乙酯冲析，有大量白色固体析出，继续搅拌18h，抽滤，干燥得白色固体1.16g，收率为94.2％。该结晶样品的X-射线衍射和DSC谱图经研究比对，确定产物为II晶型。
实施例6
取(1.0g，2.4mmol)(3aR,5s,6aS)-N-(3-甲氧基-1,2,4-噻二唑-5-基)-5-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)六氢环戊并[c]吡咯-2(1H)-甲酰胺加入到50ml锥形瓶中，加入12ml二氯甲烷，3ml无水甲醇，室温下搅拌，然后滴加(0.25g，2.5mmol)浓硫酸，悬浊液溶清后，过滤除去不溶物，搅拌6h，无固体析出，加5ml丙酮冲析，有大量白色固体析出，继续搅拌18h，抽滤，干燥得白色固体1.14g，收率为92.3％。其X-衍射和DSC图谱经研究比对，确定产物为II晶型。
实施例7
取(1.0g，2.4mmol)(3aR,5s,6aS)-N-(3-甲氧基-1,2,4-噻二唑-5-基)-5-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)六氢环戊并[c]吡咯-2(1H)-甲酰胺加入到50ml锥形瓶中，加入12ml二氯甲烷，3ml无水甲醇，室温下搅拌，然后滴加(0.25g，2.5mmol)浓硫酸，悬浊液溶清后，过滤除去不溶物，滤液浓缩至干，得无定形式(I)化合物。将所得样品加入5ml甲醇中，加热回流20min，冷却，搅拌转晶2h，抽滤，干燥得白色固体942mg，收率为76.2％，其X-衍射和DSC图谱经研究比对，确定产物为II晶型。
实施例8
取(1.0g，2.4mmol)(3aR,5s,6aS)-N-(3-甲氧基-1,2,4-噻二唑-5- 基)-5-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)六氢环戊并[c]吡咯-2(1H)-甲酰胺，按实施例2实验方法制备得到无定形式(I)化合物。将所得样品加入5ml乙醇，加热回流溶清继续回流20min，冷却，搅拌析晶2h，抽滤，干燥得白色固体1.08g，收率为82.3％。其X-衍射和DSC图谱经研究比对，确定产物为II晶型。
实施例9
取(1.0g，2.4mmol)(3aR,5s,6aS)-N-(3-甲氧基-1,2,4-噻二唑-5-基)-5-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)六氢环戊并[c]吡咯-2(1H)-甲酰胺，按实施例2实验方法制备得到无定形式(I)化合物。将所得样品加入5ml异丙醇，加热回流溶清继续回流20min，冷却，搅拌析晶2h，抽滤，干燥得白色固体1.05g，收率为85.0％。其X-衍射和DSC图谱经研究比对，确定产物为II晶型。
实施例10
取(1.0g，2.4mmol)(3aR,5s,6aS)-N-(3-甲氧基-1,2,4-噻二唑-5-基)-5-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)六氢环戊并[c]吡咯-2(1H)-甲酰胺，按实施例2实验方法制备得到无定形式(I)化合物。将所得样品加入5ml乙酸乙酯，加热回流溶清继续回流20min，冷却，搅拌析晶2h，抽滤，干燥得白色固体1.11g，收率为90.1％。其X-衍射和DSC图谱经研究比对，确定产物为II晶型。
实施例11
取(1.0g，2.4mmol)(3aR,5s,6aS)-N-(3-甲氧基-1,2,4-噻二唑-5-基)-5-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)六氢环戊并[c]吡咯-2(1H)-甲酰胺，按实施例2实验方法制备得到无定形式(I)化合物。将所得样品加入5ml丙酮，加热回流溶清继续回流20min，冷却，搅拌析晶2h，抽滤，干燥得白色固体1.13g，收率为91.5％。其X-衍射和DSC图谱经研究比对，确定产物为II晶型。
实施例12
取(1.0g，2.4mmol)式(I)化合物(I晶型)，按中国专利申请201410529863.8中的方法所得，加入到250ml单口瓶中，加入100ml甲醇，加热回流溶清，继续回流10min，冷却，减压浓缩掉约90ml甲醇，后继续室温搅拌4h，抽滤，干燥得白色固体842mg，收率为84.2％。 该结晶样品的X-射线衍射和DSC谱图经研究比对，确定产物为II晶型。
实施例13
将实施例1所得的II型结晶产物和实施例2制得的无定型的样品分别敞口平摊放置，考察在光照(4500Lux)，加热(40℃，60℃)，高湿(RH75％，RH90％)条件下样品的稳定性。考察取样时间为5天和10天，HPLC检测纯度见表1。
表1、式(I)化合物II型结晶和无定型样品的稳定性比较
Figure PCTCN2015091527-appb-000003
稳定性考察结果表明，式(I)化合物II型结晶和无定型样品在敞口放置的条件下，经光照、高温和高湿条件下的稳定性比较发现，高湿对两者的影响不大，但是在光照、高温的条件下，II型结晶的稳定性显著好于无定型样品。
实施例14
将按实施例1方法制得的式(I)化合物II型结晶进行研磨、加热及压片处理，研究结果表明晶型稳定，详细的实验数据参见下表2。
表2.式(I)化合物II晶型特殊稳定性研究
Figure PCTCN2015091527-appb-000004

Claims (8)

  1. 一种(3aR,5s,6aS)-N-(3-甲氧基-1,2,4-噻二唑-5-基)-5-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)六氢环戊并[c]吡咯-2(1H)-甲酰胺硫酸氢盐的II型结晶，其特征在于使用Cu-Ka辐射，得到以2θ角度和晶面间距表示的X-射线粉末衍射图谱，所述结晶具有如图1所示的X-射线粉末衍射图谱，其中在约8.96(9.87)，11.80(7.50)，13.12(6.74)，13.53(6.54)，13.89(6.37)，14.42(6.14)，14.98(5.91)，16.52(5.36)，18.20(4.87)，18.75(4.73)，19.15(4.63)，19.72(4.50)，20.82(4.26)，22.05(4.03)，22.52(3.95)，22.92(3.88)，23.58(3.77)和27.04(3.30)有特征峰。
  2. 一种制备如权利要求1所述的(3aR,5s,6aS)-N-(3-甲氧基-1,2,4-噻二唑-5-基)-5-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)六氢环戊并[c]吡咯-2(1H)-甲酰胺硫酸氢盐的II型结晶的方法，所述方法包括下述步骤：
    1)将任意晶型或无定型的(3aR,5s,6aS)-N-(3-甲氧基-1,2,4-噻二唑-5-基)-5-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)六氢环戊并[c]吡咯-2(1H)-甲酰胺加入适量的有机溶剂中，滴加浓硫酸，析晶，或加入反溶剂，析晶；或者任意晶型或无定型的(3aR,5s,6aS)-N-(3-甲氧基-1,2,4-噻二唑-5-基)-5-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)六氢环戊并[c]吡咯-2(1H)-甲酰胺硫酸氢盐固体加热溶解于适量的有机溶剂中，冷却、析晶；所述有机溶剂选自碳原子数小于等于3的醇类、酮类、酯类的任意一种，或者其中的一种或几种与碳原子小于等于3的卤代烃的混合溶剂；
    2)过滤结晶并洗涤，干燥。
  3. 根据权利要求2所述的制备方法，其特征在于在步骤1)中所述的有机溶剂为甲醇、乙醇、异丙醇、丙酮、乙酸乙酯；或二氯甲烷/甲醇、二氯甲烷/甲醇/乙醇、二氯甲烷/甲醇/异丙醇、二氯甲烷/甲醇/乙酸乙酯、二氯甲烷/甲醇/丙酮；其中优选的单一溶剂为甲醇；优选的 混合溶剂为二氯甲烷/甲醇/乙醇，更优选三者体积比为12：3：10。
  4. 一种药物组合物，其含有如权利要求1所述的(3aR,5s,6aS)-N-(3-甲氧基-1,2,4-噻二唑-5-基)-5-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)六氢环戊并[c]吡咯-2(1H)-甲酰胺硫酸氢盐的II型结晶和至少一种药学上可接受的载体。
  5. 根据权利要求4所述的药物组合物，其特征在于其(3aR,5s,6aS)-N-(3-甲氧基-1,2,4-噻二唑-5-基)-5-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)六氢环戊并[c]吡咯-2(1H)-甲酰胺硫酸氢盐的II型结晶的含量为0.5mg～200mg。
  6. 根据权利要求4所述的药物组合物，其特征在于，所述药学上可接受的载体选自乳糖、甘露醇、微晶纤维素、交联羧甲基纤维素钠、羧甲基淀粉钠、羟丙基甲基纤维素、聚维酮和硬脂酸镁中的至少一种。
  7. 权利要求1所述的(3aR,5s,6aS)-N-(3-甲氧基-1,2,4-噻二唑-5-基)-5-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)六氢环戊并[c]吡咯-2(1H)-甲酰胺硫酸氢盐的II型结晶或权利要求4至6任意一项所述的药物组合物在制备治疗与JAK激酶有关的疾病的药物中的用途。
  8. 权利要求1所述的(3aR,5s,6aS)-N-(3-甲氧基-1,2,4-噻二唑-5-基)-5-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)六氢环戊并[c]吡咯-2(1H)-甲酰胺硫酸氢盐的II型结晶或权利要求4至6任意一项所述的药物组合物在制备治疗风湿及类风湿性关节炎药物中的用途。
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CN111205290A (zh) * 2018-11-22 2020-05-29 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
US10786507B2 (en) 2016-02-19 2020-09-29 Jiangsu Hengrui Medicine Co., Ltd. Pharmaceutical composition containing JAK kinase inhibitor or pharmaceutically acceptable salt thereof

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