WO2021004401A1 - 一种btk激酶抑制剂关键中间体的晶型及其制备方法 - Google Patents

一种btk激酶抑制剂关键中间体的晶型及其制备方法 Download PDF

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WO2021004401A1
WO2021004401A1 PCT/CN2020/100245 CN2020100245W WO2021004401A1 WO 2021004401 A1 WO2021004401 A1 WO 2021004401A1 CN 2020100245 W CN2020100245 W CN 2020100245W WO 2021004401 A1 WO2021004401 A1 WO 2021004401A1
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phenyl
pyrrole
cyano
tert
crystal form
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WO2021004401A9 (zh
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李超
孙鹏
田贝贝
张欣
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上海再启生物技术有限公司
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Priority to EP20837054.4A priority Critical patent/EP3892613B1/en
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Priority to US17/341,420 priority patent/US11180449B2/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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

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  • the invention relates to a crystal form of a key intermediate of a BTK kinase inhibitor and a preparation method thereof, in particular to (R)-1-(1-(tert-butoxyyl)pyrrolidin-3-yl)-3-cyano group
  • the crystal form II of -4-(4-(2,6-difluorophenoxy)phenyl)-1H-pyrrole-2-carboxylic acid ethyl ester and a preparation method thereof belong to the technical field of medicine.
  • Immune cells can usually be divided into two types: T cells and B cells.
  • the main function of B cells is to secrete various antibodies to help the body resist various foreign invasions.
  • Bruton's tyrosine protein kinase (BTK) is a member of the tyrosine protein kinase subfamily and belongs to the Tec family of kinases. It is mainly expressed in hematopoietic cells and distributed in the lymphatic system, hematopoietic and blood system.
  • Bruton tyrosine protein kinase (BTK) is a key protein kinase in the BCR signaling pathway. It can regulate the maturation and differentiation of normal B cells and is also closely related to a variety of B cell lymphoid tissue disorders. Therefore, the targeted small molecule inhibitor BTK can provide benefits for the treatment of B cell malignancies and autoimmune diseases.
  • Ibrutinib is the first-generation small molecule BTK inhibitor jointly developed by Pharmacyclics and Janssen. It was first approved by the FDA for the treatment of mantle cell lymphoma (MCL) in November 2013, and was subsequently approved in February 2014. Approved for the treatment of chronic lymphocytic leukemia (CLL). Ibrutinib can irreversibly bind to cysteine No. 481 in the ATP binding region of BTK kinase through its Michael receptor, thereby inhibiting the transmission of downstream signals by BTK and effectively controlling the growth of tumor cells. Ibrutinib transmits signals in the BCR signaling pathway and cytokine receptor signaling pathway, and mediates the migration, chemotaxis and adhesion of B cells. Preclinical studies have proved that ibrutinib can inhibit the proliferation and survival of malignant B cells.
  • PCT/US2014/061393 relates to a compound of formula II (the structural formula is as follows), namely (R)-4-amino-1-(1-(but-2-ynyl)pyrrolidin-3-yl)-3-(4 -(2,6-Difluorophenoxy)phenyl)-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one, this compound is a novel BTK kinase inhibitor, There have been improvements in kinase selectivity, clinical efficacy or indications, and safety.
  • the present invention provides a formula I: (R)-1-(1-(tert-butoxyyl)pyrrolidin-3-yl)-3-cyano-4-(4-(2,
  • the crystal form II of ethyl 6-difluorophenoxy)phenyl)-1H-pyrrole-2-carboxylate and the preparation method thereof have good stability.
  • the differential scanning calorimetry curve of the crystal form II has an endothermic peak at 95°C to 105°C.
  • the obtained crystal forms are all determined to be crystal form II, and the DSC absorption peak positions are 100.10°C and 101.20°C, respectively.
  • Crystal form is used to describe the state of existence of solid compounds, describing the composition of ions, atoms or molecules, symmetry properties and periodic arrangement of multiple parameters in the crystal.
  • Relative intensity refers to the ratio of the intensity of the first strong peak in a group of diffraction peaks belonging to a certain crystal form as the intensity of the first strong peak defined as 100%.
  • the 2 ⁇ (also called 2theta or diffraction peak) values in the X-ray powder diffraction pattern are all in degrees (°).
  • the "diffraction peak” refers to a characteristic peak that is not attributed to background noise by those skilled in the art.
  • the X-ray powder diffraction peak of the crystal form, the 2 ⁇ or diffraction peak measurement of the X-ray powder diffraction pattern has experimental errors, between one instrument and another instrument and between one sample and another sample .
  • the measurement of 2 ⁇ or diffraction peaks of X-ray powder diffraction patterns may be slightly different.
  • the experimental error or difference may be +/-0.2 units or +/-0.1 units or +/-0.05 units. Therefore, the value of the 2 ⁇ or diffraction peak cannot be regarded as absolute.
  • the differential scanning calorimetry (DSC) of the crystal form has experimental errors.
  • the position and peak of the endothermic peak may be slightly different between one instrument and another instrument and between one sample and another sample.
  • Difference, experimental error or difference value may be less than or equal to 5°C, or less than or equal to 4°C, or less than or equal to 3°C, or less than or equal to 2°C, or less than or equal to 1°C, so the peak position or peak value of the DSC endothermic peak The value of cannot be regarded as absolute.
  • Room temperature refers to a temperature of about 15°C-32°C or about 20°C-30°C or about 23°C-28°C or about 25°C.
  • the present invention also provides a method for preparing the crystal form II of the compound of formula I, which comprises the following steps:
  • the solvent is selected from any one or more of alcohols, ketones, nitriles, ethers, and esters with carbon atoms less than or equal to 4; or one or more of them and water ⁇ mixed solvents.
  • it is methanol, ethanol, isopropanol, acetone, ethyl acetate, acetonitrile, tetrahydrofuran; or ethanol/water, N,N-dimethylformamide/water, 1,4-dioxane/water.
  • a single solvent can be used for crystallization, or a mixed solvent of the above organic solvents can be used.
  • the most preferred single solvent is ethanol.
  • the method of recrystallization is not particularly limited, and it can be performed by a usual recrystallization operation method.
  • the raw material compound of formula (I) can be heated and dissolved in an organic solvent, and then slowly cooled and stirred to crystallize. After the crystallization is completed, it can be filtered and dried to obtain the desired crystal. It should be particularly noted that the filtered crystals are usually vacuum dried under reduced pressure and heating conditions of about 30-40°C to achieve the effect of removing the recrystallization solvent.
  • DSC differential scanning thermal analysis
  • XRD X-ray diffraction
  • crystal form II crystal of formula (I) prepared by the present invention has significantly better stability than type I crystal under the conditions of light and high temperature, and under the conditions of grinding and pressure, the crystal form has good stability and can meet the requirements of production
  • the requirements of transportation and storage, the production process is stable, repeatable and controllable, and can be adapted to industrial production.
  • Figure 1 is an HNMR chart of the crystal form I of the compound of formula (1) in Example 1;
  • Figure 5 is an HPLC chart of the crystal form II of the compound of formula (1) in Example 2;
  • Fig. 7 is a DSC chart of the crystal form II of the compound of formula (1) in Example 2.
  • the X-ray powder diffraction pattern has features at 2 ⁇ values of approximately 5.52, 8.62, 9.34, 11.85, 14.36, 14.52, 15.25, 17.16, 18.79, 19.02, 20.02, 20.18, 20.49, 20.79, 22.44, 23.79, 24.02, 24.29 and 28.18 Peaks and their characteristic peak positions are shown in Table 1 below.
  • the DSC spectrum is shown in Figure 4, with a sharp melting endothermic peak at 97.92°C. This crystal form is defined as crystal form II.
  • the crystal form II contains at least 97% of the crystal form II.
  • the stability inspection results show that the crystal form I and crystal form II samples are stable under light and high temperature conditions under open conditions. It is found that the crystal form II is stable under the conditions of light, high temperature and high humidity. The performance is significantly better than that of amorphous samples.
  • the type II crystals of the compound of formula (I) obtained by the method of Example 2 were subjected to grinding, heating and tableting treatments. The research results showed that the crystal form was stable. For detailed experimental data, see Table 3 below.
  • the experimental results of the influencing factors in Table 1 show that the crystal form I and crystal form II of the compound of formula (I) are placed for 10 days under the conditions of light, temperature 30°C and 40°C, high humidity 75%RH and 90%RH, the purity of the compound The change is not obvious, and the chemical stability is good; the crystal form of the sample after the influencing factor experiment is retested, the crystal form has not changed, and the physical properties are stable.

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  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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Abstract

本发明涉及一种BTK激酶抑制剂关键中间体的晶型及其制备方法，属于医药技术领域。所述晶型为(R)-1-(1-(叔丁氧酰基)吡咯烷-3-基)-3-氰基-4-(4-(2,6-二氟苯氧基)苯基)-1H-吡咯-2-甲酸乙酯晶型II。本发明所得到(R)-1-(1-(叔丁氧酰基)吡咯烷-3-基)-3-氰基-4-(4-(2,6-二氟苯氧基)苯基)-1H-吡咯-2-甲酸乙酯晶型II具备良好的化学稳定性和晶型稳定性，有利于储存和运输，同时能够将中间体高度提纯，得到纯度达99.7％以上的样品，对于BTK激酶抑制剂(R)-4-氨基-1-(1-(丁-2-炔酰基)吡咯烷-3-基)-3-(4-(2,6-二氟苯氧基)苯基)-1,6-二氢-7H-吡咯并[2,3-d]哒嗪-7-酮的质量控制具有重要的意义，并且制备工艺简单，适宜工业化的规模生产。

Description

一种BTK激酶抑制剂关键中间体的晶型及其制备方法 技术领域
本发明涉及一种BTK激酶抑制剂关键中间体的晶型及其制备方法，具体地涉及(R)-1-(1-(叔丁氧酰基)吡咯烷-3-基)-3-氰基-4-(4-(2,6-二氟苯氧基)苯基)-1H-吡咯-2-甲酸乙酯的晶型II及制备方法，属于医药技术领域。
背景技术
免疫细胞通常可以分为T细胞与B细胞两类，其中B细胞的主要职能是分泌各种抗体帮助人体抵御各种外来的侵入。Bruton酪氨酸蛋白激酶(BTK)是酪氨酸蛋白激酶亚家族的成员之一，属于Tec家族激酶，主要在造血细胞中表达，分布于淋巴系统、造血及血液系统。Bruton酪氨酸蛋白激酶(BTK)是BCR信号通路中的一个关键的蛋白激酶。能够调节正常B细胞的成熟、分化，也与多种B细胞淋巴组织失调疾病密切相关。因此，靶向小分子抑制剂BTK可对B细胞恶性肿瘤和自身免疫疾病的治疗提供效益。
依鲁替尼(Ibrutinib)是由Pharmacyclics和Janssen共同开发的第一代小分子BTK抑制剂，2013年11月被FDA首次批准用于治疗套细胞淋巴瘤(MCL)，随后2014年2月又被批准用于治疗慢性淋巴细胞白血病(CLL)。Ibrutinib可以通过其迈克尔受体与BTK激酶ATP结合区域的481号半胱氨酸不可逆地结合，进而抑制BTK对下游信号的传递，有效地控制肿瘤细胞的生长。依鲁替尼在BCR信号通路、细胞因子受体信号通路中传递信号，介导B细胞的迁移、趋化、粘附。临床前研究证明，依鲁替尼能够抑制恶性B细胞的增殖、生存。
PCT/US2014/061393涉及一种式II化合物(结构式如下)，即(R)-4-氨基-1-(1-(丁-2-炔酰基)吡咯烷-3-基)-3-(4-(2,6-二氟苯氧基)苯基)-1,6-二氢-7H-吡咯并[2,3-d]哒嗪-7-酮，该化合物为新型BTK激酶抑制剂，在激酶选择性、临床疗效或适应症以及安全性等方面均有所改善。
Figure PCTCN2020100245-appb-000001
文献报道(R)-4-氨基-1-(1-(丁-2-炔酰基)吡咯烷-3-基)-3-(4-(2,6-二氟苯氧基)苯基)-1,6-二氢-7H-吡咯并[2,3-d]哒嗪-7-酮的纯化是通过硅胶柱层析然后结晶的纯化方式实现，致使该BTK激酶抑制剂纯化方式放大困难，不利于规模化生产，作为人体用药，杂质往往会对人体产生不良影响，因此高纯度药物是药物开发的一个重要目标，然而高纯度中间体对获得高纯度的药品至关重要。
作为上述BTK激酶抑制剂(R)-4-氨基-1-(1-(丁-2-炔酰基)吡咯烷-3-基)-3-(4-(2,6-二氟苯氧基)苯基)-1,6-二氢-7H-吡咯并[2,3-d]哒嗪-7-酮的关键中间体(R)-1-(1-(叔丁氧酰基)吡咯烷-3-基)-3-氰基-4-(4-(2,6-二氟苯氧基)苯基)-1H-吡咯-2-甲酸乙酯采用柱层析手段纯化中间体成本高、效率低，不利于工业化生产，因此迫切需要开发出一种可通过结晶法纯化的、化学性质稳定的中间体，从而使得新型BTK激酶抑制剂(R)-4-氨基-1-(1-(丁-2-炔酰基)吡咯烷-3-基)-3-(4-(2,6-二氟苯氧基)苯基)-1,6-二氢-7H-吡咯并[2,3-d]哒嗪-7-酮纯化变得更加容易。同时，深入研究找到晶型纯度较高并且具备良好化学稳定性的新晶型也是非常必要的。
发明内容
为了解决上述技术问题，本发明提供一种式Ι：(R)-1-(1-(叔丁氧酰基)吡咯烷-3-基)-3-氰基-4-(4-(2,6-二氟苯氧基)苯基)-1H-吡咯-2-甲酸乙酯的晶型II及制备方法，该晶型具备良好的稳定性。
Figure PCTCN2020100245-appb-000002
研究发现：式I化合物在不同结晶条件下得到的结晶产物，对所得结晶产物进行了X-衍射及DSC检测，发现在本发明的结晶条件下，得到均为同一种稳定性良好的晶型，称其为晶型II。本申请中的晶型II结晶的DSC图谱显示在98℃附近有熔融吸热峰，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，其中2θ处特征峰包括：9.34,14.36,18.79,19.02。
进一步地，在具体实施方案中，(R)-1-(1-(叔丁氧酰基)吡咯烷-3-基)-3-氰基-4-(4-(2,6-二氟苯氧基)苯基)-1H-吡咯-2-甲酸乙酯的晶型II，其XRD图谱以2θ表示的特征峰包括：9.34,11.85,14.36,14.52,15.25,17.16,18.79,19.02,20.49,20.79,22.44和24.02。
更进一步的，在具体实施例方案中，(R)-1-(1-(叔丁氧酰基)吡咯烷-3-基)-3-氰基-4-(4-(2,6-二氟苯氧基)苯基)-1H-吡咯-2-甲酸乙酯的晶型II，其XRD图谱以2θ表示的特征峰包括：5.52,8.62,9.34,11.85,14.36,14.52,15.25,17.16,18.79,19.02,20.02,20.18,20.49,20.79,22.44,23.79,24.02,24.29和28.18。
在实施例2-4制备过程中，得到的(R)-1-(1-(叔丁氧酰基)吡咯烷-3-基)-3-氰基-4-(4-(2,6-二氟苯氧基)苯基)-1H-吡咯-2-甲酸乙酯的晶型II典型谱图为图6。
进一步地，在上述技术方案中，所述晶型II的差示扫描量热曲线在95℃-105℃处具有吸热峰。具体而言，采用研磨处理和压片处理，得到的晶型均确定为晶型II，DSC吸收峰位置分别为100.10℃和101.20℃。
术语定义:“包含”或“包括”为开放式表达，即包括本发明所指明的内容，但并不排除其它方面的内容。
“晶型”用来描述固体化合物的存在状态，描述晶体内部的离子、原子或分子组成、对称性质与周期排列规律的多种参量集合体。
“相对强度”是指将归属于某一晶型的一组衍射峰中的第一强峰的强度定义为100％时，其它峰的强度与第一强峰的强度的比值。
在本发明的上下文中，X-射线粉末衍射图中的2θ(又称2theta或衍射峰)值均以度(°)为单位。
当提及图谱和/或图中数据，“衍射峰”是指本领域的技术人员不会归属于背景噪音的一个特征峰。
所述晶型的X-射线粉末衍射峰，其X-射线粉末衍射图谱的2θ或衍射峰的量度有实验误差，在一台仪器和另一台仪器之间以及一个样品和另一个样品之间。
X-射线粉末衍射图谱的2θ或衍射峰的量度可能会略有差别，所述实验误差或差别的数值可能是+/-0.2个单位或+/-0.1个单位或+/-0.05个单位，因此所述2θ或衍射峰的数值不能视为绝对的。
所述晶型的差示扫描量热曲线(DSC)有实验误差，在一台仪器和另一台仪器 之间以及一个样品和另一个样品之间，吸热峰的位置和峰值可能会略有差别，实验误差或差别的数值可能小于等于5℃，或小于等于4℃，或小于等于3℃，或小于等于2℃，或小于等于1℃，因此所述DSC吸热峰的峰位置或峰值的数值不能视为绝对的。
在本发明上下文中，无论是否使用“大约”或“约”等字眼，所有在此公开的数字均为近似值。每一个数字的数值有可能会出现1％，2％，或5％等差异。
室温是指温度在大约15℃-32℃或大约20℃-30℃或大约23℃-28℃或大约25℃。
本发明还提供了式I化合物晶型II的制备方法，包括以下步骤：
1、将任意晶型或无定型的(R)-1-(1-(叔丁氧酰基)吡咯烷-3-基)-3-氰基-4-(4-(2,6-二氟苯氧基)苯基)-1H-吡咯-2-甲酸乙酯固体加入溶剂中，加热溶解，然后冷却析晶；
2、过滤、干燥后得到(R)-1-(1-(叔丁氧酰基)吡咯烷-3-基)-3-氰基-4-(4-(2,6-二氟苯氧基)苯基)-1H-吡咯-2-甲酸乙酯晶型II。
步骤1)中，所述溶剂选自碳原子数小于等于4的醇类、酮类、腈类、醚类、酯类的任意一种或几种；或它们中的一种或几种与水的混合溶剂。优选为甲醇、乙醇、异丙醇、丙酮、乙酸乙酯、乙腈、四氢呋喃；或乙醇/水、N,N-二甲基甲酰胺/水、1,4-二氧六环/水。
析晶时可以用单一溶剂，也可以用以上有机溶剂的混合溶剂。
进一步地，最优选的单一溶剂为乙醇。
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，可以用原料式(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。需特别说明的是，所滤取的结晶通常在减压下，在30～40℃左右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(XRD)图谱测定，对得到的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。
研究表明，本发明制备的式(I)化合物晶型II结晶在光照、高温的条件下稳定性显著好于I型晶体，且在研磨和压力等条件下，晶型稳定性良好，能够满足生 产运输储存的要求，生产工艺稳定可重复可控，能够适应于工业化生产。
附图说明
图1为实施例1式(1)化合物晶型I的HNMR图；
图2为实施例1式(1)化合物晶型I的HPLC图；
图3为实施例1式(1)化合物晶型I的XRD图；
图4为实施例1式(1)化合物晶型I的DSC图；
图5为实施例2式(1)化合物晶型II的HPLC图；
图6为实施例2式(1)化合物晶型II的XRD图；
图7为实施例2式(1)化合物晶型II的DSC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 1Staree System
吹扫气：氮气
升温速率：10.0℃/min
温度范围：20-150℃
2、X-射线衍射谱
仪器型号：Bruker D8Focus X-射线粉末衍射仪
射线：单色Cu-Kα射线(λ＝1.5406)
扫描方式：θ/2θ，扫描范围：2-40°
电压：40KV，电流：40mA
实施例1
(R)-1-(1-(叔丁氧酰基)吡咯烷-3-基)-3-氰基-4-(4-(2,6-二氟苯氧基)苯基)-1H-吡咯-2-甲酸乙酯的制备
将(R)-1-(1-(叔丁氧酰基)吡咯烷-3-基)-3-氰基-4-溴-1H-吡咯-2-甲酸乙酯(1.98g,4.8mmol)、I 2(1.60g,4.8mmol)和K 3PO 4·3H 2O(1.88g,7.2mmol)在1,4-二氧六环/水(60mL/6mL)中，采用氮气对溶液进行脱气处理后，接着氮气保护下加入 Pd 2(dba) 3(220mg,0.24mmol)和P(Cy) 3(140mg,0.48mmol)，随后升温回流反应16h。反应结束后，冷却至室温，滤出固体，浓缩滤液。残留物经硅胶色谱法(淋洗剂：二氯甲烷)纯化，减压旋蒸得到类白色固体0.57g(R)-1-(1-(叔丁氧酰基)吡咯烷-3-基)-3-氰基-4-(4-(2,6-二氟苯氧基)苯基)-1H-吡咯-2-甲酸乙酯。HPLC：99.31％，最大单杂：0.21％。 1H NMR(400MHz,DMSO-d 6):7.69(d,1H),7.61-7.66(d,2H),7.39-7.29(m,3H),7.02-7.04(d,2H),5.57-5.60(s,1H),4.35-4.30(dd,2H),3.77-3.74(m,1H),3.50-3.44(m,2H),3.40-3.44(m,1H),2.31-2.36(m,2H),1.37-1.36(s,9H),1.33-1.30(t,3H).MS(ESI)：m/z＝538[M+H] +。该固体样品X-射线衍射谱图显示无晶型特征吸收峰，谱图为图1；DSC谱图为图2，有尖锐熔融吸热峰58.7℃，据此确定产物为无定型固体I。
实施例2
取1.0g式(I)化合物(按实施例1制备的粗品)加入到25mL单口瓶中，加入2mL无水乙醇，加热回流溶清，停止加热，冷却析晶，次日抽滤，减压烘干得白色固体715mg，收率为71.5％。HPLC：99.73％，最大单杂：0.04％。该结晶样品X-射线衍射谱图见图3。X射线粉末衍射图谱在2θ值为约5.52,8.62,9.34,11.85,14.36,14.52,15.25,17.16,18.79,19.02,20.02,20.18,20.49,20.79,22.44,23.79,24.02,24.29和28.18处具有特征峰，其特征峰位置如下表1所示。DSC谱图见图4，有尖锐熔融吸热峰97.92℃，将此晶型定义为晶型II。所述晶型II至少含有97％以上晶型II。
表1、晶型II特征峰
Figure PCTCN2020100245-appb-000003
Figure PCTCN2020100245-appb-000004
实施例3
取1.0g式(I)化合物(按实施例1制备的粗品)加入到25mL单口瓶中，加入1.5mL无水乙醇，加热回流溶清，停止加热，冷却析晶，次日，抽滤，干燥得白色固体868mg，收率为86.8％。该结晶样品的X-射线衍射图谱和DSC图谱经研究对比，确定产物为晶型II。
实施例4
取1.0g式(I)化合物(按实施例1制备的粗品)加入到25mL单口瓶中，加入1mL乙醇，加热回流溶清，停止加热，冷却析晶，次日抽滤，干燥得白色固体934mg，收率为93.4％。该结晶样品的X-射线衍射图谱和DSC图谱经研究对比，确定产物为晶型II。
实施例5
将上述实施例1和2-4得到分别得到的晶型进行稳定性比较，数据如表2所示。
表2、式(I)化合物I型结晶和II型结晶的稳定性比较：
Figure PCTCN2020100245-appb-000005
Figure PCTCN2020100245-appb-000006
稳定性考察结果表明：晶型I和晶型II样品在敞口放置的条件下，经光照和高温条件下的稳定性比较发现，在光照、高温和高湿的条件下，晶型II的稳定性显著好于无定型样品。
实施例6
将按实施例2方法制得式(I)化合物的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3。
表3、式(I)化合物II型晶型特殊稳定性研究
Figure PCTCN2020100245-appb-000007
实验结论：
由表1的影响因素实验结果表明：式(I)化合物的晶型I和晶型II在光照、温度30℃和40℃、高湿75％RH和90％RH条件下放置10天，化合物纯度变化不明显，化学稳定性好；影响因素实验后的样品复测晶型，晶型未转变，物理性质稳定。

Claims (10)

  1. 一种BTK激酶抑制剂关键中间体(R)-1-(1-(叔丁氧酰基)吡咯烷-3-基)-3-氰基-4-(4-(2,6-二氟苯氧基)苯基)-1H-吡咯-2-甲酸乙酯的晶型，为晶型II，其特征在于：其粉末X-衍射图谱以2θ表示的特征峰包括：9.34,14.36,18.79,19.02。
  2. 根据权利要求1所述(R)-1-(1-(叔丁氧酰基)吡咯烷-3-基)-3-氰基-4-(4-(2,6-二氟苯氧基)苯基)-1H-吡咯-2-甲酸乙酯的晶型，其特征在于，其粉末X-衍射图谱以2θ表示的特征峰包括：9.34,11.85,14.36,14.52,15.25,17.16,18.79,19.02,20.49,20.79,22.44和24.02。
  3. 根据权利要求1所述(R)-1-(1-(叔丁氧酰基)吡咯烷-3-基)-3-氰基-4-(4-(2,6-二氟苯氧基)苯基)-1H-吡咯-2-甲酸乙酯的晶型，其特征在于，其粉末X-衍射图谱以2θ表示的特征峰包括：5.52,8.62,9.34,11.85,14.36,14.52,15.25,17.16,18.79,19.02,20.02,20.18,20.49,20.79,22.44,23.79,24.02,24.29和28.18。
  4. 根据权利要求1所述(R)-1-(1-(叔丁氧酰基)吡咯烷-3-基)-3-氰基-4-(4-(2,6-二氟苯氧基)苯基)-1H-吡咯-2-甲酸乙酯的晶型，其特征在于：其粉末X-衍射图谱如附图6所示。
  5. 根据权利要求1所述(R)-1-(1-(叔丁氧酰基)吡咯烷-3-基)-3-氰基-4-(4-(2,6-二氟苯氧基)苯基)-1H-吡咯-2-甲酸乙酯的晶型，其特征在于：所述晶型II的差示扫描量热曲线在95℃-105℃处具有吸热峰。
  6. 根据权利要求1所述(R)-1-(1-(叔丁氧酰基)吡咯烷-3-基)-3-氰基-4-(4-(2,6-二氟苯氧基)苯基)-1H-吡咯-2-甲酸乙酯的晶型，其特征在于：所述晶型II至少含有97％以上晶型II。
  7. 权利要求1-6任意一项所述(R)-1-(1-(叔丁氧酰基)吡咯烷-3-基)-3-氰基-4-(4-(2,6-二氟苯氧基)苯基)-1H-吡咯-2-甲酸乙酯的晶型的制备方法，其特征在于：将任意晶型或无定型的(R)-1-(1-(叔丁氧酰基)吡咯烷-3-基)-3-氰基-4-(4-(2,6-二氟苯氧基)苯基)-1H-吡咯-2-甲酸乙酯固体加入溶剂中，加热溶解，然后冷却析晶；过滤、干燥后得到晶型II。
  8. 根据权利要求7所述(R)-1-(1-(叔丁氧酰基)吡咯烷-3-基)-3-氰基-4-(4-(2,6-二氟苯氧基)苯基)-1H-吡咯-2-甲酸乙酯的晶型的制备方法，其特征在于：所述溶剂选自碳原子数小于等于4的醇类、酮类、腈类、醚类、酯类的任 意一种或几种；或它们中的一种或几种与水的混合溶剂。
  9. 根据权利要求8所述(R)-1-(1-(叔丁氧酰基)吡咯烷-3-基)-3-氰基-4-(4-(2,6-二氟苯氧基)苯基)-1H-吡咯-2-甲酸乙酯的晶型的制备方法，其特征在于：所述溶剂为甲醇、乙醇、异丙醇、丙酮、乙酸乙酯、乙腈、四氢呋喃、乙醇/水、N,N-二甲基甲酰胺/水、1,4-二氧六环/水。
  10. 根据权利要求9任意一项所述(R)-1-(1-(叔丁氧酰基)吡咯烷-3-基)-3-氰基-4-(4-(2,6-二氟苯氧基)苯基)-1H-吡咯-2-甲酸乙酯的晶型的制备方法，其特征在于：析晶时采用溶剂为乙醇。
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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106573001A (zh) * 2014-07-07 2017-04-19 永恒生物科技公司 作为蛋白激酶抑制剂的氨基哒嗪酮化合物
WO2017118277A1 (zh) * 2016-01-05 2017-07-13 江苏恒瑞医药股份有限公司 一种btk激酶抑制剂的结晶形式及其制备方法
CN108570036A (zh) * 2017-03-09 2018-09-25 北京赛林泰医药技术有限公司 一种btk抑制剂的多晶型物及其制备方法
WO2018210296A1 (zh) * 2017-05-18 2018-11-22 江苏恒瑞医药股份有限公司 一种ezh2抑制剂与btk抑制剂联合在制备治疗肿瘤的药物中的用途
CN110372562A (zh) * 2019-07-09 2019-10-25 上海再启生物技术有限公司 一种btk激酶抑制剂关键中间体的晶型及其制备方法

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102006060181A1 (de) 2006-12-18 2008-06-19 Bayer Materialscience Ag Verfahren zur Herstellung von Toluylendiisocyanat
DE102006061475A1 (de) 2006-12-23 2008-06-26 Evonik Degussa Gmbh Verfahren zur kontinuierlichen Herstellung von (cyclo)aliphatischen Diisocyanaten
CN107667089B (zh) 2015-06-12 2021-02-26 科思创德国股份有限公司 在气相中制备二异氰酸酯的方法
JP2021535113A (ja) * 2018-08-22 2021-12-16 江▲蘇▼恒瑞医▲薬▼股▲フン▼有限公司Jiangsu Hengrui Medicine Co., Ltd. ピロロ−アミノ−ピリダジノン化合物およびその中間体の調製方法

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106573001A (zh) * 2014-07-07 2017-04-19 永恒生物科技公司 作为蛋白激酶抑制剂的氨基哒嗪酮化合物
WO2017118277A1 (zh) * 2016-01-05 2017-07-13 江苏恒瑞医药股份有限公司 一种btk激酶抑制剂的结晶形式及其制备方法
CN108570036A (zh) * 2017-03-09 2018-09-25 北京赛林泰医药技术有限公司 一种btk抑制剂的多晶型物及其制备方法
WO2018210296A1 (zh) * 2017-05-18 2018-11-22 江苏恒瑞医药股份有限公司 一种ezh2抑制剂与btk抑制剂联合在制备治疗肿瘤的药物中的用途
CN110372562A (zh) * 2019-07-09 2019-10-25 上海再启生物技术有限公司 一种btk激酶抑制剂关键中间体的晶型及其制备方法

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
"Physical Pharmacy", 31 July 2004, CHEMICAL INDUSTRY PRESS, CN, ISBN: 7-5025-5544-7, article SU DESEN; WANG SILING; SU DESEN, EDITOR-IN-CHIEF WANG SILING: "Section 5, Preparation of Polymorphic Forms of Drugs", pages: 1 - 18, XP009527987 *
See also references of EP3892613A4

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