WO2019057201A1 - 一种雌激素受体抑制剂的晶型及其制备方法 - Google Patents

一种雌激素受体抑制剂的晶型及其制备方法 Download PDF

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WO2019057201A1
WO2019057201A1 PCT/CN2018/107324 CN2018107324W WO2019057201A1 WO 2019057201 A1 WO2019057201 A1 WO 2019057201A1 CN 2018107324 W CN2018107324 W CN 2018107324W WO 2019057201 A1 WO2019057201 A1 WO 2019057201A1
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solvent
compound
formula
crystal form
preparation
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贺辉君
陆剑宇
李卫东
施沈一
陈志娟
丁照中
胡利红
王铁林
董加强
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罗欣生物科技（上海）有限公司
山东罗欣药业集团股份有限公司
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Priority to CN201880054052.3A priority Critical patent/CN111032627B/zh
Priority to US16/648,943 priority patent/US11034653B2/en
Publication of WO2019057201A1 publication Critical patent/WO2019057201A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • 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

Definitions

  • the invention discloses a crystal form of an estrogen receptor inhibitor and a preparation method thereof, and specifically discloses a crystal form of the compound of the formula (I) and a preparation method thereof, and further comprises the crystal form being prepared for treating breast cancer.
  • the application of the drug is a crystal form of an estrogen receptor inhibitor and a preparation method thereof, and specifically discloses a crystal form of the compound of the formula (I) and a preparation method thereof, and further comprises the crystal form being prepared for treating breast cancer. The application of the drug.
  • breast cancer has become the second highest incidence of cancer in the world and the highest incidence of cancer among women.
  • the role of the estrogen-estrogen receptor signaling pathway in the development of breast cancer has been identified; and the estrogen receptor (ER) has also developed into the most important biomarker for breast cancer.
  • ER estrogen receptor
  • breast cancer can be divided into estrogen receptor-positive breast cancer and estrogen receptor-negative breast cancer. Among them, estrogen receptor-positive breast cancer accounts for more than 70% of the total number of breast cancer patients. .
  • Endocrine Therapy which targets the estrogen-estrogen receptor signaling pathway in breast cancer cells, has the least harmful effect and has been used as the first choice for the treatment of estrogen receptor-positive breast cancer.
  • Endocrine therapy mainly includes the following three treatment methods: ovarian suppression therapy, aromatase inhibitor (AI), and selective estrogen receptor modulator (SERM). Ovarian suppression therapy is less effective than the other two treatments because of poor efficacy.
  • aromatase inhibitors first generation, second generation
  • the problem of chemical enzyme inhibitors has been widely used.
  • letrozole has been used as a first-line drug for the treatment of estrogen receptor-positive breast cancer.
  • the selective estrogen receptor modulator (SERM) acts directly on the estrogen receptor to block this signaling pathway, with a significant therapeutic effect and a long history of application.
  • tamoxifen is the most representative selective estrogen receptor modulator.
  • As a first-line drug recommended for its priority tamoxifen has shown significant clinical efficacy in the prevention and treatment of estrogen receptor-positive breast cancer.
  • estrogen Receptor-positive breast cancers are also becoming more prominent in their resistance to aromatase inhibitors and selective estrogen receptor modulators.
  • aromatase inhibitors estrogen receptors can produce corresponding mutations.
  • the mutated estrogen receptor itself maintains an agonistic conformation in the absence of estrogen, allowing it to continue to function as a receptor to promote breast cancer cell proliferation.
  • the resistance mechanism of breast cancer cells to the selective estrogen receptor modulator tamoxifen is more complicated.
  • breast cancer cells can compensate for the loss of function of estrogen receptor activation domain-2 (AF-2) by tamoxifen by activating estrogen receptor activation domain-1 (AF-1) function.
  • breast cancer cells can adapt to the conformation of the estrogen receptor after binding to tamoxifen by regulating the structure or concentration of estrogen receptor coactivator, so that estrogen receptor function is restored, thereby causing drug resistance.
  • Selective estrogen receptor down-regulator has unique advantages in the treatment of breast cancer resistant to both hormones.
  • selective estrogen receptor down-regulation antagonizes estrogen receptor function, which can greatly accelerate the ubiquitination and degradation of estrogen receptors in breast cancer cells (normal or variant), completely blocking estrogen/estrogen
  • the receptor signaling pathway aims to inhibit the growth and proliferation of normal or drug-resistant breast cancer cells.
  • selective estrogen receptor down-regulation can effectively inhibit the proliferation of hormone-resistant breast cancer cells.
  • Fulvestrant has shown good results in the treatment of hormone-resistant breast cancer, demonstrating the unique advantages of selective estrogen receptor down-regulation.
  • fulvestrant itself has many problems.
  • fulvestrant exhibits zero oral bioavailability because of its poor PK properties; meanwhile, fulvestrant has a higher blood clearance rate. For both of these reasons, this drug can only be administered by intramuscular injection. However, due to its strong lipophilic structure, intramuscularly administered fulvestrant also has serious problems in tissue distribution; its clinical manifestation is that only about 50% of breast cancer patients who use fulvestrant show clinical response. . Therefore, the development of selective estrogen receptor downregulation with oral bioavailability is a much needed medical need.
  • WO2012037411A2 reports the oral selective estrogen receptor down-regulation ARN-810, a phase II trial of this molecule for the treatment of ER-positive breast cancer. According to reports [J. Med. Chem. 2015, 58 (12), 4888-4904], the important pharmacophore of this molecule is the carbazole structure on the left side of the molecule, and the nitrogen atom in the carbazole structure acts as a hydrogen bond acceptor. Estrogen receptor binding.
  • the present invention provides a crystalline form of the compound of formula (I) having an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2 theta angles: 9.921 ⁇ 0.2 °, 11.949 ⁇ 0.2 °, 14.895 ⁇ 0.2 °, 16.753 ⁇ 0.2 °, 19.713 ⁇ 0.2°, 20.9 ⁇ 0.2°, 22.45 ⁇ 0.2°, 23.78 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the above Form A has characteristic diffraction peaks at the following 2 theta angles: 9.921 ⁇ 0.2 °, 10.751 ⁇ 0.2 °, 11.949 ⁇ 0.2 °, 14.169 ⁇ 0.2 °, 14.895 ⁇ 0.2°, 16.753 ⁇ 0.2°, 19.713 ⁇ 0.2°, 20.268 ⁇ 0.2°, 20.9 ⁇ 0.2°, 22.45 ⁇ 0.2°, 23.78 ⁇ 0.2°, 24.39 ⁇ 0.2°.
  • the XRPD pattern analysis data of the above A crystal form is shown in Table 1.
  • the A crystalline form has a differential scanning calorimetry curve having an endothermic peak at 195.45 °C ⁇ 3 °C.
  • the above-described Form A crystal has a differential scanning calorimetry curve as shown in FIG.
  • the above-mentioned Form A crystal has a thermogravimetric analysis curve having a weight loss of 0.1919% ⁇ 0.2% at 191.73 ⁇ 3°C.
  • thermogravimetric analysis curve of the above A crystal form is shown in FIG.
  • the method for preparing the above A crystal form includes
  • the solvent is selected from the group consisting of methanol, ethanol or isopropanol.
  • the method for preparing the above A crystal form includes
  • the solvent is selected from the group consisting of a mixed solvent of methanol and water.
  • the method for preparing the above A crystal form includes
  • the solvent is selected from the group consisting of a mixed solvent of ethanol and water.
  • the method for preparing the above A crystal form includes
  • the solvent is selected from a mixed solvent of isopropyl alcohol and water.
  • the volume ratio of methanol to water in the mixed solvent is from 1 to 4:1.
  • the volume ratio of methanol to water in the mixed solvent is 1:1.
  • the present invention also provides the use of the above crystalline form A or the crystalline form obtained by the above method for the preparation of a medicament for the treatment of breast cancer.
  • the X-ray powder diffraction pattern of the above-mentioned Form A crystal before sampling (0 days) under 40 degrees, 75% RH conditions is shown in FIG.
  • the XRPD pattern analysis data of the above A crystal form before sampling (0 days) under the conditions of 40 degrees and 75% RH is shown in Table 2.
  • the X-ray powder diffraction pattern of the A crystal form before sampling (10 days) under 40 degrees, 75% RH conditions is shown in FIG.
  • the XRPD pattern analysis data of the above A crystal form before sampling (10 days) under the conditions of 40 degrees and 75% RH is shown in Table 3.
  • the X-ray powder diffraction pattern of the above A crystal form before sampling (31 days) under 40 degrees, 75% RH conditions is shown in FIG.
  • the XRPD pattern analysis data of the above A crystal form before sampling (31 days) under the conditions of 40 degrees and 75% RH is shown in Table 4.
  • the invention also provides the use of the above crystalline form A in the preparation of a medicament for the treatment of breast cancer.
  • the compound of the invention does not contain crystal water or a crystallization solvent, has good stability, and has almost no hygroscopicity, and has a good promising prospect.
  • intermediate compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, combinations thereof with other chemical synthesis methods, and those skilled in the art.
  • Well-known equivalents, preferred embodiments include, but are not limited to, embodiments of the invention.
  • the present invention employs the following abbreviations: min for minutes; rt for room temperature; THF for tetrahydrofuran; NMP for N-methylpyrrolidone; MeSO 3 H for methanesulfonic acid; DME for ethylene glycol dimethyl ether; DCM for dichloro Methane; Xphos stands for 2-biscyclohexylphosphino-2'4'6'-triisopropylbiphenyl; EtOAc stands for ethyl acetate; MeOH stands for methanol; acetate stands for acetone; 2-Me-THF stands for 2-methyltetrahydrofuran; IPA stands for isopropyl alcohol; RH stands for relative humidity.
  • Test method Approximately 10-20 mg samples were used for XRPD detection.
  • Test method Take the sample (about 1mg) and put it in the DSC aluminum pot for testing. Under the condition of 50mL/min N 2 , the temperature is 10°C/min.
  • the sample is heated from 30 ° C to 300 ° C.
  • Test method Take the sample (2 ⁇ 5mg) in a TGA platinum pot for testing, heating the sample from 30 ° C (room temperature) to 300 ° C or weight loss at a heating rate of 10 ° C / min under 25 mL / min N 2 conditions 20%.
  • Test conditions Samples (10-15 mg) were placed in a DVS sample pan for testing.
  • the hygroscopicity evaluation is classified as follows:
  • Humidity classification Wet weight gain* deliquescence Absorb sufficient water to form a liquid Very hygroscopic ⁇ W% ⁇ 15% Humidity 15%> ⁇ W% ⁇ 2% Slightly hygroscopic 2%> ⁇ W% ⁇ 0.2% No or almost no hygroscopicity ⁇ W% ⁇ 0.2%
  • Figure 1 is an XRPD spectrum of Cu-K ⁇ radiation of the crystalline form of Compound A of formula (I).
  • Figure 2 is a DSC chart of the crystalline form of Compound A of formula (I).
  • Figure 3 is a TGA spectrum of the crystalline form of Compound A of formula (I).
  • Figure 4 is a DVS spectrum of the crystalline form of Compound A of formula (I).
  • the square dot line indicates the desorption process curve, and the diamond dot solid line indicates the adsorption curve.
  • Figure 5 is an XRPD spectrum of Cu-K ⁇ radiation before the sampling (day 0) of the compound A of the formula (I) at 40 °, 75% RH.
  • Figure 6 is an XRPD spectrum of Cu-K ⁇ radiation before the sampling (10 days) of the compound A of the formula (I) at 40 °, 75% RH.
  • Figure 7 is an XRPD spectrum of Cu-K ⁇ radiation before the sampling (31 days) of the compound A of the formula (I) at 40 °, 75% RH.
  • Step A Slowly add n-butyl lithium (2.5 M, 428.40 mL, 1.05 eq) at -75 ° C under a nitrogen atmosphere (1 hour) to 1 (100.00 g, 1.02 mol, 140.85 mL, 1.00 eq. In a solution of tetrahydrofuran (500 mL). The reaction solution was stirred at 0 ° C for 10 minutes and then the temperature was lowered to -75 ° C, then hexamethylphosphoric acid triamine (201.06 g, 1.12 mol, 197.12 mL, 1.10 eq) was added (one hour).
  • PE: EA 100:1
  • Step C To a solution of 6 (35.00 g, 298.76 mmol, 1.00 eq) in 400 mL dichloromethane, dimethylaminopyridine (3.65 g, 29.88 mmol, 0.10 eq) and Boc 2 O (68.46 g, 313.70 mmol, 72.07) mL, 1.05 eq).
  • the reaction solution was reacted at 20 ° C for 12 hours and then washed twice with 400 ml of ammonium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered and evaporated
  • Step D Lithium diisopropylamide (2M, 75.95 mL, 1.10 eq) was slowly added dropwise to a solution of 7 (30.00 g, 138.08 mmol, 1.00 eq) in tetrahydrofuran (400 mL) at -75 ° C under nitrogen. .
  • bromine cyanide 55.40 g, 523.04 mmol, 38.47 mL, 3.79 eq
  • the mixture was heated to 15 ° C for 12 hours, 400 ml of water was added, and the organic phase was separated by 300.
  • the organic layer was dried over anhydrous sodium sulfate and filtered to give a crude material.
  • Step E To a solution of 8 (39.00 g, 131.69 mmol, 1.00 eq) in 300 mL of N,N-dimethylacetamide, cesium carbonate (85.81 g, 263.38 mmol, 2.00 eq), cuprous iodide (1.25 g, 6.58 mmol, 0.05 eq), palladium acetate (1.48 g, 6.58 mmol, 0.05 eq) and 1,1'-bis(diphenylphosphino)ferrocene (3.65 g, 6.58 mmol, 0.05 eq), then protected with nitrogen 2 (33.26 g, 263.38 mmol, 2.00 eq) was added.
  • Step G To a solution of 5 (3.00 g, 17.73 mmol, 1.00 eq) in 30 ml of dimethyltetrahydrofuran was added bispinacol borate (4.50 g, 17.73 mmol, 1.00 eq.) and tetras(triphenylphosphine). Platinum (1.10 g, 886.50 umol, 0.05 eq). The reaction solution was reacted at 70 ° C for 5 hours under nitrogen atmosphere, and then cooled to room temperature. The 6 in the reaction mixture was directly used for the next reaction without purification.
  • Step H To a solution of 10 (7.50 g, 17.72 mmol, 1.00 eq) of 70 ml of dimethyltetrahydrofuran and 3 ml of aqueous solution of cesium carbonate (11.55 g, 35.44 mmol, 2.00 eq), compound 5 (4.28 g) at 0 ° C , 14.18 mmol, 0.80 eq) and bis(triphenylphosphine)palladium dichloride (622.02 mg, 886.00 umol, 0.05 eq). The reaction solution was reacted at 15 ° C for 12 hours under nitrogen atmosphere, and the reaction solution was used in the next step without purification.
  • Step J To a mixed solution of 13 (4.50 g, 5.57 mmol, 1.00 eq) of 30 ml of methanol, 30 ml of tetrahydrofuran and 10 ml of water, lithium hydroxide (1.33 g, 55.73 mmol, 10.00 eq) was added. The reaction solution was reacted at 35 ° C for 1 hour, then 30 ml of water was added, then the pH was adjusted to 5 with 1 M hydrochloric acid solution, extracted twice with 50 ml of ethyl acetate, and the combined organic layer was washed twice with 60 ml of water. . The organic layer was dried over anhydrous sodium sulfate and filtered and evaporated The crude product was isolated by preparative HPLC (carboxylic acid).
  • Step K Compound 14 (150.00 mg, 336.39 umol, 1.00 eq) and N-chlorosuccinimide (53.90 mg, 403.67 umol, 1.20 eq) were dissolved in 5 ml of acetonitrile. The reaction solution was stirred at 15 ° C for 6 hours under protection. After the reaction is completed, the reaction solution is concentrated, and the formic acid system is prepared and isolated to obtain the product I.
  • the crystal form of the compound of the formula (I) has a wetting weight gain of 0.1687% at 25 ° C / 80% RH, and has almost no hygroscopicity.
  • Example 4 Solid state stability test of compound A of formula (I) under high humidity and light conditions
  • the crystalline form of Compound A of formula (I) (2 parts each of 10 mg for the relevant substance analysis and 1 part of the appropriate amount for crystal form stability test) was placed on the bottom of the glass vial and spread into a thin layer. Samples placed under high humidity conditions are sealed with aluminum foil paper, and small holes are placed on the aluminum foil paper to ensure that the sample can be in full contact with ambient air. Samples are taken on the 10th day; the sample placed under the light condition is exposed, and the sample is placed. Exposed to the light source, irradiated with sufficient energy and sampled for detection. The test results were compared with the initial test results of 0 days.
  • Example 5 Long-term crystal form stability test of compound A of formula (I) under high temperature and high humidity conditions
  • Compound A crystal form was examined and placed at 40 ° C, 75% RH and samples were taken at different time points (10 days, 31 days) to detect XRPD.
  • the crystal form of Compound A was stored in a refrigerator at -20 ° C as a control.
  • the XRPD results are shown in Figures 5, 6, and 7.

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Abstract

一种雌激素受体抑制剂的晶型及其制备方法，具体公开了式(I)化合物的A晶型及其制备方法，还包括所述晶型在制备用于治疗乳腺癌的药物中的应用。

Description

一种雌激素受体抑制剂的晶型及其制备方法
本申请主张如下优先权：
申请号201710874782.5，申请日2017年9月25日。
技术领域
本发明公开了一种雌激素受体抑制剂的晶型及其制备方法，具体公开了式(I)化合物的A晶型及其制备方法，还包括所述晶型在制备用于治疗乳腺癌的药物中的应用。
背景技术
根据WHO统计，乳腺癌已成为全球发病率第二高的癌症，也是女性中发病率最高的癌症。经过多年的研究，已经确定了雌激素-雌激素受体信号通路在乳腺癌发展中的作用；而雌激素受体(ER)也已经发展成了乳腺癌最重要的生物标记物。以雌激素受体表达为判别指标，乳腺癌可以划分为雌激素受体阳性乳腺癌及雌激素受体阴性乳腺癌；其中，雌激素受体阳性的乳腺癌占乳腺癌患者总数的70％以上。
针对乳腺癌细胞内雌激素-雌激素受体信号通路的内分泌疗法(Endocrine Therapy，ET)因其危害性最小，疗效显著，已经成为治疗雌激素受体阳性乳腺癌的首选疗法。内分泌疗法主要包含以下三种治疗方法：卵巢抑制疗法，芳香化酶抑制剂(Aromatase inhibitor,AI)，选择性雌激素受体调节剂(Selective estrogen receptor modulator,SERM)。卵巢抑制疗法因为疗效不理想，患者满意度低而应用较其他两种疗法少。早期的芳香化酶抑制剂(第一代，第二代)靶点选择性低，毒副作用大；经过多年的研究，第三代芳香化酶抑制剂大大提高了其选择性，解决了早期芳香化酶抑制剂的问题而得到了广泛的应用。其中，来曲唑等已作为一线药物用于治疗雌激素受体阳性乳腺癌。选择性雌激素受体调节剂(SERM)直接作用于雌激素受体以阻断此信号通路，疗效显著，应用历史较长。其中，他莫昔芬是最具有代表性的选择性雌激素受体调节剂。作为优先推荐使用的一线药物，他莫昔芬用于预防和治疗雌激素受体阳性乳腺癌表现出显著的临床疗效。
尽管芳香化酶抑制剂来曲唑以及选择性雌激素受体调节剂他莫昔芬在治疗雌激素受体阳性乳腺癌方面表现了良好的疗效，但是，随着两类药物的应用，雌激素受体阳性乳腺癌针对芳香化酶抑制剂以及选择性雌激素受体调节剂的耐药性问题也表现的越来越突出。大量的研究表明，乳腺癌对上述两种荷尔蒙疗法的耐药机理是不完全相同的。对于芳香化酶抑制剂，雌激素受体可产生相应的变异。变异后的雌激素受体可在无雌激素存在的条件下本身保持激动的构象，使得其继续发挥受体功能以促进乳腺癌细胞增殖。乳腺癌细胞对于选择性雌激素受体调节剂他莫昔芬的耐药机理较为复杂多样。首先，乳腺癌细胞可通过激活雌激素受体激活功能区-1(AF-1)功能来补偿因他莫昔芬导致的雌激素受体激活功能区-2(AF-2)的功能缺失。同时，乳腺癌细胞可通过调节雌激素受体共激活因子结构或者浓度来适应与他莫昔芬结合后的雌激素受体的构象，使得雌激素受体功能恢复，从而引起耐药。
在治疗耐上述两种荷尔蒙疗法的乳腺癌上，选择性雌激素受体下调剂(Selective estrogen receptor down-regulator,SERD)体现出了特有的优越性。机理上，选择性雌激素受体下调剂拮抗雌激素受体功能，可大大加速乳腺癌细胞内(正常的或者变异的)雌激素受体的泛素化降解，彻底阻断雌激素/雌激素受体信号通路，达到抑制正常的或者耐药性乳腺癌细胞生长增殖的目的。研究表明，选择性雌激素受体下调剂可有效抑制耐荷尔蒙的乳腺癌细胞的增殖。作为唯一上市的选择性雌激素受体下调剂氟维司群 (Fulvestrant)在治疗耐荷尔蒙疗法的乳腺癌上表现出了良好的效果，验证了选择性雌激素受体下调剂的独特优势。但是，氟维司群本身存在很多问题。首先，因为其PK性质很差，氟维司群表现出了零口服生物利用度；同时，氟维司群又有较高的血液清除率。由于以上两种原因，这个药物只能通过肌肉注射给药。但是，因为其强亲酯性结构，肌肉注射给药的氟维司群在组织分布上也存在严重问题；其临床变现为只有约50％应用氟维司群的乳腺癌患者表现出了临床响应。因此，研发有口服生物利用度的选择性雌激素受体下调剂是亟需的医疗需求。
WO2012037411A2报道了口服型的选择性雌激素受体下调剂ARN-810，这个分子治疗ER阳性乳腺癌的临床II期试验正在进行中。据报道[J.Med.Chem.2015,58(12),4888-4904],该分子的重要药效团为分子左侧的吲唑结构，吲唑结构内的氮原子作为氢键受体与雌激素受体结合。
Figure PCTCN2018107324-appb-000001
发明内容
本发明提供式(I)化合物的A晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：9.921±0.2°，11.949±0.2°，14.895±0.2°，16.753±0.2°，19.713±0.2°，20.9±0.2°，22.45±0.2°，23.78±0.2°。
Figure PCTCN2018107324-appb-000002
在本发明的一些方案中，上述A晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：9.921±0.2°，10.751±0.2°，11.949±0.2°，14.169±0.2°，14.895±0.2°，16.753±0.2°，19.713±0.2°，20.268±0.2°，20.9±0.2°，22.45±0.2°，23.78±0.2°，24.39±0.2°。
在本发明的一些方案中，上述A晶型的X射线粉末衍射图谱如图1所示。
在本发明的一些方案中，上述A晶型的XRPD图谱解析数据如表1所示。
表1
Figure PCTCN2018107324-appb-000003
在本发明的一些方案中，上述A晶型，其差示扫描量热曲线在195.45℃±3℃处具有吸热峰。
在本发明的一些方案中，上述A晶型，其差示扫描量热曲线图谱如图2所示。
在本发明的一些方案中，上述A晶型，其热重分析曲线在191.73±3℃时失重达0.1919％±0.2％。
在本发明的一些方案中，上述A晶型，其热重分析曲线图谱如图3所示。
在本发明的一些方案中，上述A晶型的制备方法，包括
(a)将式(I)化合物加入溶剂中，搅拌、加热、回流，溶解后自然冷却至10℃～25℃；
(b)过滤，滤饼用溶剂洗涤；
(c)50℃真空干燥；
其中，所述溶剂选自：甲醇、乙醇或异丙醇。
在本发明的一些方案中，上述A晶型的制备方法，包括
(a)将式(I)化合物加入溶剂中，搅拌、加热、回流，溶解后自然冷却至10℃～25℃；
(b)过滤，滤饼用溶剂洗涤；
(c)50℃真空干燥；
其中，所述溶剂者选自甲醇与水的混合溶剂。
在本发明的一些方案中，上述A晶型的制备方法，包括
(a)将式(I)化合物加入溶剂中，搅拌、加热、回流，溶解后自然冷却至10℃～25℃；
(b)过滤，滤饼用溶剂洗涤；
(c)50℃真空干燥；
其中，所述溶剂者选自乙醇与水的混合溶剂。
在本发明的一些方案中，上述A晶型的制备方法，包括
(a)将式(I)化合物加入溶剂中，搅拌、加热、回流，溶解后自然冷却至10℃～25℃C；
(b)过滤，滤饼用溶剂洗涤；
(c)50℃真空干燥；
其中，所述溶剂者选自异丙醇和水的混合溶剂。
在本发明的一些方案中，上述述混合溶剂中甲醇与水的体积比为1～4:1。
在本发明的一些方案中，上述混合溶剂中甲醇与水的体积比为1:1。
本发明还提供上述的A晶型或上述的方法制得的晶型在制备用于治疗乳腺癌的药物中的应用。
在本发明的一些方案中，上述A晶型在40度，75％RH条件下放样取样前(0天)的X射线粉末衍射图谱如图5所示。
在本发明的一些方案中，上述A晶型在40度，75％RH条件下放样取样前(0天)的XRPD图谱解析数据如表2所示。
表2 40℃，75％RH条件下0天
Figure PCTCN2018107324-appb-000004
Figure PCTCN2018107324-appb-000005
在本发明的一些方案中，上述A晶型在40度，75％RH条件下放样取样前(10天)的X射线粉末衍射图谱如图6所示。
在本发明的一些方案中，上述A晶型在40度，75％RH条件下放样取样前(10天)的XRPD图谱解析数据如表3所示。
表3 40℃，75％RH条件下10天
Figure PCTCN2018107324-appb-000006
在本发明的一些方案中，上述A晶型在40度，75％RH条件下放样取样前(31天)的X射线粉末衍射图谱如图7所示。
在本发明的一些方案中，上述A晶型在40度，75％RH条件下放样取样前(31天)的XRPD图谱解析数据如表4所示。
表4 40℃，75％RH条件下31天
Figure PCTCN2018107324-appb-000007
在本发明还提供上述A晶型在制备用于治疗乳腺癌的药物中的应用。
技术效果
本发明化合物不含结晶水或结晶溶剂，稳定性较好，且几乎无引湿性，具有良好的成药前景。
定义和说明
除非另有说明，本文所用的下列术语和短语旨在含有下列含义。一个特定的短语或术语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文出现商品名时，旨在指代其对应的商品或其活性成分。
本发明的中间体化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同 替换方式，优选的实施方式包括但不限于本发明的实施例。
本发明具体实施方式的化学反应是在合适的溶剂中完成的，所述的溶剂须适合于本发明的化学变化及其所需的试剂和物料。为了获得本发明的化合物，有时需要本领域技术人员在已有实施方式的基础上对合成步骤或者反应流程进行修改或选择。
下面会通过实施例具体描述本发明，这些实施例并不意味着对本发明的任何限制。
本发明所使用的所有溶剂是市售的，无需进一步纯化即可使用。
本发明采用下述缩略词：min代表分钟；r.t.代表室温；THF代表四氢呋喃；NMP代表N-甲基吡咯烷酮；MeSO 3H代表甲烷磺酸；DME代表乙二醇二甲醚；DCM代表二氯甲烷；Xphos代表2-双环己基膦-2’4’6’-三异丙基联苯；EtOAc代表乙酸乙酯；MeOH代表甲醇；acetone代表丙酮；2-Me-THF代表2-甲基四氢呋喃；IPA代表异丙醇；RH代表相对湿度。
化合物经手工或者
Figure PCTCN2018107324-appb-000008
软件命名，市售化合物采用供应商目录名称。
粉末X-射线衍射(X-ray powder diffractometer,XRPD)
仪器型号：布鲁克D8advance X-射线衍射仪
测试方法：大约10～20mg样品用于XRPD检测。
详细的XRPD参数如下：
光管：Cu,kα,
Figure PCTCN2018107324-appb-000009
光管电压：40kV，光管电流：40mA
发散狭缝：0.60mm
探测器狭缝：10.50mm
防散射狭缝：7.10mm
扫描范围：4-40deg
步径：0.02deg
步长：0.12秒
样品盘转速：15rpm
差热分析(Differential Scanning Calorimeter,DSC)
仪器型号：TA Q2000差示扫描量热仪
测试方法：取样品(约1mg)置于DSC铝锅内进行测试，在50mL/min N 2条件下，以10℃/min的升
温速率，加热样品从30℃到300℃。
热重分析(Thermal Gravimetric Analyzer,TGA)
仪器型号：TA Q5000热重分析仪
测试方法：取样品(2～5mg)置于TGA铂金锅内进行测试，在25mL/min N 2条件下，以10℃/min的升温速率，加热样品从30℃(室温)到300℃或失重20％。
动态蒸汽吸附分析(Dynamic Vapor Sorption,DVS)
仪器型号：SMS DVS Advantage动态蒸汽吸附仪
测试条件：取样品(10～15mg)置于DVS样品盘内进行测试。
详细的DVS参数如下：
温度：25℃
平衡：dm/dt＝0.01％/min(最短：10min，最长：180min)
干燥：0％RH下干燥120min
RH(％)测试梯级：10％
RH(％)测试梯级范围：0％-90％-0％
引湿性评价分类如下：
引湿性分类 引湿增重*
潮解 吸收足量水分形成液体
极具引湿性 ΔW％≥15％
有引湿性 15％>ΔW％≥2％
略有引湿性 2％>ΔW％≥0.2％
无或几乎无引湿性 ΔW％<0.2％
*在25±1℃和80±2％RH下的引湿增重(ΔW％)
高效液相色谱仪(High Performance Liquid Chromatograph,HPLC)
Figure PCTCN2018107324-appb-000010
恒温恒湿箱(40C/75％RH)
生产厂家：Binder
设备型号：KBF-240
附图说明
图1为式(I)化合物A晶型的Cu-Kα辐射的XRPD谱图。
图2为式(I)化合物A晶型的DSC谱图。
图3为式(I)化合物A晶型的TGA谱图。
图4为式(I)化合物A晶型的DVS谱图。正方形点标线表示解吸附过程曲线，菱形点标实线表示吸附曲线。
图5为式(I)化合物A晶型在40度，75％RH条件下放样取样前(0天)的Cu-Kα辐射的XRPD谱图。
图6为式(I)化合物A晶型在40度，75％RH条件下放样取样前(10天)的Cu-Kα辐射的XRPD谱图。
图7为式(I)化合物A晶型在40度，75％RH条件下放样取样前(31天)的Cu-Kα辐射的XRPD谱图。
具体实施方式
为了更好的理解本发明的内容，下面结合具体实施例来做进一步的说明，但具体的实施方式并不是对本发明的内容所做的限制。
实施例1：式(I)化合物的制备
Figure PCTCN2018107324-appb-000011
Figure PCTCN2018107324-appb-000012
步骤A：在-75℃和氮气保护下，将正丁基锂(2.5M,428.40mL,1.05eq)缓慢滴加(用时1个小时)到1(100.00g,1.02mol,140.85mL,1.00eq)的四氢呋喃(500mL)溶液中。反应液升到0℃搅拌10分钟后再将温度降低到-75℃，然后加入六甲基磷酰三胺(201.06g,1.12mol,197.12mL,1.10eq)(用时1个小时)。反应液在-75℃搅拌一个小时后加入碘乙烷(198.86g,1.27mol,101.98mL,1.25eq)(用时一个小时)，然后升温至20℃下反应10个小时后加入400毫升水，分液后有机相用400毫升水洗三次，无水硫酸钠干燥，过滤后通过蒸馏分离得到产品2.
步骤B：向3(10.00g,43.10mmol,1.00eq)的100毫升乙腈溶液中加入磷酰基乙酸三乙酯4(11.60g,51.72mmol,10.26mL,1.20eq)和氯化锂(3.65g,86.20mmol,1.77mL,2.00eq)，在0℃和氮气保护下，逐滴的加入DBU(8.53g,56.03mmol,8.45mL,1.30eq)的乙腈溶液(用时30分钟)，反应液在15℃下反应1个小时后加入100毫升水，分液后水相再用70毫升二氯甲烷萃取两次。联合的有机层用无水硫酸钠干燥，过滤后浓缩得到粗品。粗品通过硅胶柱层析分离(PE:EA＝100:1-30:1)得到产品5。
步骤C：向6(35.00g,298.76mmol,1.00eq)的400毫升二氯甲烷溶液中加入二甲氨基吡啶(3.65g,29.88mmol,0.10eq)和Boc 2O(68.46g,313.70mmol,72.07mL,1.05eq)。反应液在20℃下反应12个小时后用400毫升氯化铵溶液萃洗两次。有机层用无水硫酸钠干燥，过滤后浓缩得产品7。
步骤D：在-75℃和氮气保护下，将二异丙基氨基锂(2M,75.95mL,1.10eq)缓慢滴加到7(30.00g,138.08mmol,1.00eq)的四氢呋喃(400mL)溶液中。反应液在-75℃搅拌30分钟后加入溴氰(55.40g,523.04mmol,38.47mL,3.79eq)，然后升温至15℃下反应12个小时，加入400毫升水，分液后有机相用300毫升水洗三次，有机层用无水硫酸钠干燥，过滤后得到粗品。粗品通过硅胶柱层层析(PE:EA＝1:0-50:1)分离得到产品8。
步骤E：向8(39.00g,131.69mmol,1.00eq)的300毫升N,N二甲基乙酰胺溶液中加入碳酸铯(85.81g,263.38mmol,2.00eq)，碘化亚铜(1.25g,6.58mmol,0.05eq)，醋酸钯(1.48g,6.58mmol,0.05eq)和1,1’-双(二苯基膦)二茂铁(3.65g,6.58mmol,0.05eq)，然后在氮气保护下加入2(33.26g,263.38mmol,2.00eq)。反应液在80℃下反应12个小时后加入1L乙酸乙酯和1L水，过滤后分液，有机层用1L水萃洗3次。有机层用无水硫酸钠干燥，过滤后浓缩得到粗品。粗品通过硅胶柱层析分离(PE:EA＝1:0-30:1)得到产品9。
步骤F：向9(27.00g,100.25mmol,1.00eq)的300毫升甲醇和15mL水溶液中加入碳酸钾(69.27g,501.25mmol,5.00eq)。反应液在70℃下反应12个小时后过滤浓缩，加入300毫升乙酸乙酯后用300毫升水萃洗2次。有机层用无水硫酸钠干燥，过滤后浓缩得到粗品。粗品通过硅胶柱层析(PE:EA＝100:1-30:1)分离得到产品10。
步骤G：向5(3.00g,17.73mmol,1.00eq)的30毫升二甲基四氢呋喃溶液中加入双频哪醇硼酸酯 (4.50g,17.73mmol,1.00eq)和四(三苯基磷)铂(1.10g,886.50umol,0.05eq)。反应液在70℃和氮气保护下反应5个小时后冷却到室温，反应液中的6无需纯化直接用于下一步反应。
步骤H：在0℃下向10(7.50g,17.72mmol,1.00eq)的70毫升二甲基四氢呋喃和3毫升水溶液中加入碳酸铯(11.55g,35.44mmol,2.00eq)，化合物5(4.28g,14.18mmol,0.80eq)和二(三苯基磷)二氯化钯(622.02mg,886.00umol,0.05eq)。反应液在15℃和氮气保护下反应12个小时，反应液中11无需纯化直接用于下一步反应。
步骤I：向11(8.30g,17.61mmol,1.00eq)的100毫升二甲基四氢呋喃溶液中加入2-氯-4-氟碘苯(9.03g,35.22mmol,2.00eq)，氢氧化钾溶液(4M,22.01mL,5.00eq)和二(三苯基磷)二氯化钯(617.94mg,880.50umol,0.05eq)。反应液在70℃和氮气保护下反应12个小时后用硅藻土过滤，滤液用100毫升饱和食盐水萃洗2次。有机层用无水硫酸钠干燥，过滤后浓缩得到粗品。粗品通过硅胶柱层析(PE:EA＝40:1-10:1)分离得到产品13。
步骤J：向13(4.50g,5.57mmol,1.00eq)的30毫升甲醇，30毫升四氢呋喃和10毫升水的混合溶液中加入氢氧化锂(1.33g,55.73mmol,10.00eq)。反应液在35℃下反应1个小时后加入30毫升水，然后用1M的盐酸溶液调节pH到5，再用50毫升乙酸乙酯萃取两次，联合的有机层用60毫升水萃洗两次。有机层用无水硫酸钠干燥，过滤后浓缩得到粗品。粗品通过制备HPLC(甲酸体系)分离得到14。
步骤K：将化合物14(150.00mg,336.39umol,1.00eq)和N-氯代琥珀亚酰胺(53.90mg,403.67umol,1.20eq)溶于5毫升乙腈中。反应液在15℃但其保护下搅拌6小时。反应完全后反应液浓缩后甲酸体系制备分离得到产品I。
1H NMR(400MHz,DMSO-d 6)11.51(s,1H),7.50(d,J＝8.0Hz,1H),7.47-7.37(m,5H),7.29(dd,J＝6.4,8.4Hz,1H),7.22-7.09(m,3H),7.01(d,J＝8.4Hz,2H),6.41(d,J＝16.4Hz,1H),2.49-2.36(m,2H),0.89(t,J＝7.6Hz,3H)
实施例2：式(I)化合物A晶型的制备
式(I)化合物(5.0g，10.35mmol)在100mL甲醇和水的混合液(体积比，甲醇：水＝4:1)中搅拌加热至回流至固体完全溶解，自然冷却至15℃，过滤，滤饼用10mL甲醇和水的混合液(体积比，甲醇：水＝4:1)洗涤，50℃真空干燥，得到式(I)化合物A晶型。
式(I)化合物(5.0g，10.35mmol)在20mL甲醇和水的混合液(体积比，甲醇：水＝1:1)中搅拌加热至回流12小时，自然冷却至15℃，过滤，滤饼用2mL甲醇和水的混合液(体积比，甲醇：水＝1:1)洗涤，50℃真空干燥，得到式(I)化合物A晶型。
实施例3：式(I)化合物A晶型的吸湿性研究
实验材料：
SMS DVS Advantage动态蒸汽吸附仪
实验方法：
取式(I)化合物A晶型适量置于DVS样品盘内进行DVS分析。
实验结果：
式(I)化合物A晶型的DVS谱图如图4所示，△W＝0.1687％。
实验结论：
式(I)化合物A晶型在在25 ℃/80％RH下游离酸晶型III引湿增重0.1687％，几乎无引湿性。
实施例4：式(I)化合物A晶型高湿及光照条件下的固体稳定性试验
实验目的：
考察式(I)化合物A晶型在高湿(室温/相对湿度92.5％，敞口)及光照(1ICH，总照度＝1.2×10 6Lux·hr/近紫外＝200w·hr/m 2，敞口)条件下的稳定性。
试验方法：
取式(I)化合物A晶型(2份各10mg用于有关物质分析，1份适量用于晶型稳定性检测)置于玻璃样品瓶的底部，摊成薄薄一层。高湿条件下放置的样品用铝箔纸封瓶口，并在铝箔纸上扎些小孔，保证样品能与环境空气充分接触，第10天取样检测；光照条件下放置的样品敞口，将样品暴露在光源下，照射足够的能量后取样检测。检测结果与0天的初始检测结果进行比较。
试验结果：见下表5、表6。
表5式(I)化合物A晶型的固体稳定性试验
试验条件 时间点 晶型(XRPD)
- 0天 A晶型
高湿(室温/相对湿度92.5％，敞口) 10天 A晶型
光照(1ICH，敞口) - A晶型
表6式(I)化合物A晶型的固体稳定性试验HPLC分析结果
Figure PCTCN2018107324-appb-000013
实验结论：式(I)化合物A晶型在高湿及光照条件下稳定。
实施例5：式(I)化合物A晶型高温高湿条件下的长期晶型稳定性试验
考察化合物A晶型在40℃，75％RH条件下放置并在不同的时间点(10天，31天)取样检测XRPD。化合物A晶型保存于-20℃的冰箱内作为对照品。XRPD结果见图5、图6、图7。
实验结论：式(I)化合物A晶型在长时间高温高湿条件下稳定。

Claims (14)

  1. 式(I)化合物的A晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：9.921±0.2°，11.949±0.2°，14.895±0.2°，16.753±0.2°，19.713±0.2°，20.9±0.2°，22.45±0.2°，23.78±0.2°。
    Figure PCTCN2018107324-appb-100001
  2. 根据权利要求1所述的A晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：9.921±0.2°，10.751±0.2°，11.949±0.2°，14.169±0.2°，14.895±0.2°，16.753±0.2°，19.713±0.2°，20.268±0.2°，20.9±0.2°，22.45±0.2°，23.78±0.2°，24.39±0.2°。
  3. 根据权利要求2所述的A晶型，其X射线粉末衍射图谱如说明书图1所示。
  4. 根据权利要求1～3任意一项所述的A晶型，其差示扫描量热曲线在195.45℃±3℃处具有吸热峰。
  5. 根据权利要求4所述的A晶型，其差示扫描量热曲线图谱如说明书图2所示。
  6. 根据权利要求1～3任意一项所述的A晶型，其热重分析曲线在191.73±3℃时失重达0.1919％±0.2％。
  7. 根据权利要求6所述的A晶型，其热重分析曲线图谱如说明书图3所示。
  8. 式(I)化合物的A晶型的制备方法，包括
    (a)将式(I)化合物加入溶剂中，搅拌、加热、回流，溶解后自然冷却至10℃～25℃；
    (b)过滤，滤饼用溶剂洗涤；
    (c)50℃真空干燥；
    其中，所述溶剂选自：甲醇、乙醇或异丙醇。
  9. 式(I)化合物的A晶型的制备方法，包括
    (a)将式(I)化合物加入溶剂中，搅拌、加热、回流，溶解后自然冷却至10℃～25℃；
    (b)过滤，滤饼用溶剂洗涤；
    (c)50℃真空干燥；
    其中，所述溶剂者选自甲醇与水的混合溶剂。
  10. 式(I)化合物的A晶型的制备方法，包括
    (a)将式(I)化合物加入溶剂中，搅拌、加热、回流，溶解后自然冷却至10℃～25℃；
    (b)过滤，滤饼用溶剂洗涤；
    (c)50℃真空干燥；
    其中，所述溶剂者选自乙醇与水的混合溶剂。
  11. 式(I)化合物的A晶型的制备方法，包括
    (a)将式(I)化合物加入溶剂中，搅拌、加热、回流，溶解后自然冷却至10℃～25℃；
    (b)过滤，滤饼用溶剂洗涤；
    (c)50℃真空干燥；
    其中，所述溶剂者选自异丙醇和水的混合溶剂。
  12. 根据权利要求9所述的方法，其中，所述混合溶剂中甲醇与水的体积比为1～4:1。
  13. 根据权利要求12所述的方法，其中，所述混合溶剂中甲醇与水的体积比为1:1。
  14. 权利要求1～7任意一项所述的A晶型或权利要求8～13任意一项所述的方法制得的晶型在制备用于治疗乳腺癌的药物中的应用。
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