WO2020147852A9 - 抗抑郁药物sage-217的晶型及其制备方法 - Google Patents

抗抑郁药物sage-217的晶型及其制备方法 Download PDF

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WO2020147852A9
WO2020147852A9 PCT/CN2020/072924 CN2020072924W WO2020147852A9 WO 2020147852 A9 WO2020147852 A9 WO 2020147852A9 CN 2020072924 W CN2020072924 W CN 2020072924W WO 2020147852 A9 WO2020147852 A9 WO 2020147852A9
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crystal form
sage
compound
xrpd
ray powder
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PCT/CN2020/072924
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French (fr)
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WO2020147852A1 (zh
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王鹏
李丕旭
陈嗣平
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苏州鹏旭医药科技有限公司
浙江易众化工有限公司
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Priority to EP20741441.8A priority Critical patent/EP3912985A4/en
Priority to JP2021541735A priority patent/JP2022521568A/ja
Priority to US17/424,179 priority patent/US20220235094A1/en
Publication of WO2020147852A1 publication Critical patent/WO2020147852A1/zh
Publication of WO2020147852A9 publication Critical patent/WO2020147852A9/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • C07J43/003—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton not condensed
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • 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 the field of chemical medicine, in particular to the crystal form of the antidepressant drug SAGE-217 and a preparation method thereof.
  • SAGE-217 is a drug candidate for the treatment of symptoms such as postpartum depression and major depression.
  • Existing antidepressant drugs as a single treatment often have limitations.
  • SAGE-217 is a new generation of GABA receptor modulating drugs, optimized for the selectivity of synaptic and extra-synaptic GABA receptors and the pharmacokinetic characteristics of daily oral administration.
  • the GABA system is the main inhibitory signal pathway of the brain and central nervous system, and is of great significance for regulating the function of the central nervous system. The regulation of GABA receptors has obvious therapeutic effects.
  • SAGE-217 compound is shown in formula I, and its chemical name is 1-(2-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethyl ten Hexahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile.
  • polymorphs A, C, and K described in the patent application are anhydrous crystals, crystals B, F, N, O, and P are solvates, and crystals L, M, H, I, and J are metastable. , Crystal Forms D and E are not clearly described.
  • the polymorphic form of a compound refers to the state of matter in which there are two or more different crystal forms in the compound. Polymorphism is widespread in organic compounds. Solvates are an important state of matter in polymorphism. Different crystal forms of the same compound have significant differences in solubility, melting point, density, stability, etc., which affect the stability and uniformity of the compound to varying degrees. Different crystal forms have obvious differences in the purification ability of the compound through crystallization in the purification process of the compound. Therefore, comprehensive and systematic polymorphic screening and selection of the most suitable crystalline form in the research and development of pharmaceutical processes are one of the important research contents that cannot be ignored.
  • the purpose of this application is to provide a new crystal form of SAGE-217 and its preparation method.
  • this application relates to crystal form 04, crystal form 06, crystal form D-1 and crystal form D-2 of SAGE-217, which are mainly characterized by X-ray powder diffraction (“XRPD”) data
  • XRPD X-ray powder diffraction
  • DSC differential scanning calorimetry
  • TGA thermogravimetric analysis
  • EVA evolved gas analysis
  • the present invention also provides a method for preparing crystalline SAGE-217 through a crystallization method.
  • the SAGE-217 raw material used therein can be prepared by any suitable method, including synthetic methods known in the art.
  • a solution adopted in this application is: a crystal form 04 of SAGE-217, and its X-ray powder diffraction pattern at 2theta values is 11.6 ⁇ 0.2°, 13.5 ⁇ 0.2°, 16.2 ⁇ 0.2°, 16.5 ⁇ 0.2° and 23.2 There is a characteristic peak at ⁇ 0.2°.
  • its X-ray powder diffraction pattern has characteristic peaks at 2theta values of 6.8 ⁇ 0.2°, 14.7 ⁇ 0.2°, 18.7 ⁇ 0.2°, 19.2 ⁇ 0.2° and 21.3 ⁇ 0.2°.
  • the X-ray powder diffraction pattern (peak position) of the crystal form 04 is basically consistent with FIG. 1.
  • the present invention also provides highly crystalline SAGE-217 crystal form 04 that may be affected by the phenomenon of preferential orientation, as shown in the exemplary XRPD patterns of C and D in FIG. 1. Since the phenomenon of preferential orientation is known to significantly change the relative intensity of some peaks in the XRPD pattern, for the crystal form 04 crystalline powder with a high degree of orientation, if it is not properly processed before the measurement, the 2theta value in the XRPD pattern can be observed to be 19.4 ⁇ The peak intensity of 0.2°, 20.3 ⁇ 0.2°, 27.2 ⁇ 0.2° and 34.1 ⁇ 0.2° increased significantly.
  • this application provides a method for preparing SAGE-217 crystal form 04 from a solution of ethyl formate or formic acid mixed with alcohol, dichloromethane or acetonitrile by cooling or evaporative crystallization.
  • the crystalline SAGE-217 crystal form 04 can be prepared by the methods reported in Examples 1-5.
  • the crystal form 04 can be prepared by cooling or evaporating crystallization after the mixed solvent of formic acid ester or formic acid and alcohol is completely dissolved.
  • the chemical and physical stability of solvates is relatively poor.
  • the chemical stability of crystal form 04 is good, the purity is basically unchanged, and the crystal form remains.
  • the crystal form 04 remains stable in the exposed powder state for one day, and the crystal form stability is greater than seven days when stored in a sealed vial at 25°C/45%RH. Under the accelerated stability test conditions of 25°C/60% humidity and 40°C/75% humidity, the crystal form can be stored stably without change for one month.
  • crystal form 04 has no hygroscopicity. More importantly, compared with the previously reported crystal form K, crystal form 04 has better mechanical stress stability, that is, better mechanical processing performance. This will be of great significance for the application of crystal form 04 in formulations.
  • the crystalline form 04 of SAGE-217 is also characterized by having the DSC curve shown in A in Fig. 2 and the TGA curve shown in A in Fig. 3, wherein the DSC curve is shown at 120°C to 160°C. There is a broad endothermic peak at °C (starting at 113.9 °C), and melting of the sample occurs when the temperature is higher than 173.3 °C (starting at 167.5 °C).
  • the TGA curve shows a 12.4% weight loss between 85-190°C.
  • the EGA spectrum confirmed the release of formic acid and ethyl formate. It is speculated to be a 1:1 formic acid solvate. The bound formic acid should be derived from the degradation of the formate solvent. .
  • the crystalline form 04 of SAGE-217 is also characterized by having the DSC curve shown in B in FIG. 2 and the TGA curve shown in B in FIG. 3, wherein the DSC curve is shown at 100°C to 180°C. °C has a broad endothermic peak.
  • the TGA curve shows a weight loss of 13.5% between 60°C and 190°C.
  • the EGA spectrum confirmed the release of formic acid and ethyl formate. It is speculated that it is a 1:1 formic acid solvate. The bound formic acid should be derived from the degradation of the formate solvent.
  • the crystalline form 04 of SAGE-217 is characterized by having the DSC curve shown in C in FIG. 2 and the TGA curve shown in C in FIG. 3, wherein the DSC curve is shown at 110.5°C (initial The broad endothermic peak at 98.5°C), the gentler endothermic peak at 147°C (starting at 144°C) and the sharp endothermic peak at 155.5°C (starting at 152.5°C). Above 208.8°C (starting at 205.7°C), sample melting occurs.
  • the TGA curve showed that three different and continuous weight loss between 70-185°C were 1.9%, 1.6% and 6.3%, respectively.
  • the EGA spectrum confirmed that formic acid was released. It was detected in EGA that the released formic acid accounted for 9.8% of the total weight of the sample.
  • the molar ratio of SAGE-217 to formic acid was 1:0.97, indicating that a 1:1 formic acid solvate was formed.
  • the second solution adopted by this application is: a SAGE-217 crystal form 06, whose X-ray powder diffraction pattern at 2theta values is 8.7 ⁇ 0.2°, 10.0 ⁇ 0.2°, 13.2 ⁇ 0.2°, 15.0 ⁇ 0.2°, 15.8 There are characteristic peaks at ⁇ 0.2° and 17.3 ⁇ 0.2°.
  • its X-ray powder diffraction pattern has characteristic peaks at 2theta values of 5.0 ⁇ 0.2°, 5.5 ⁇ 0.2°, 19.4 ⁇ 0.2°, 20.0 ⁇ 0.2° and 21.9 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of SAGE-217 crystal form 06 is basically the same as that of FIG. 4.
  • the present application provides a method for preparing SAGE-217 crystal form 06 by cooling or evaporative crystallization using nitromethane as a solvent.
  • crystalline SAGE-217 crystal form 06 can be prepared by crystallization by the method reported in Examples 6-7.
  • Form 06 remains stable in the exposed powder state for 16 hours, and has a stability of more than seven days when stored in a sealed vial at 25°C/45% RH.
  • the crystalline form 06 of SAGE-217 is characterized by having the DSC curve shown in FIG. 5 and the TGA curve shown in FIG. 6.
  • the DSC curve of crystal form 06 shows that there are two endothermic peaks at a temperature lower than 240°C: one at 93.2°C is formed due to the endothermic release of the solvent, and the other is formed at T 209.4°C due to the endothermic heat of melting.
  • TGA showed that the first weight loss was due to the release of water, which was 0.6% from 25°C to 95°C; the second weight loss was 2.1%, which was consistent with the release of nitromethane detected by EGA.
  • the calculated molar ratio of SAGE-217 to nitromethane is 1:0.14, indicating that the captured solvent may form a non-stoichiometric solvate. The compound will degrade above 220°C.
  • the third solution adopted by this application is: a SAGE-217 crystal form D-1, whose X-ray powder diffraction pattern at 2theta values is 7.2 ⁇ 0.2°, 8.6 ⁇ 0.2°, 13.3 ⁇ 0.2°, 19.6 ⁇ 0.2° There are characteristic peaks at 23.0 ⁇ 0.2°.
  • its X-ray powder diffraction pattern has characteristic peaks at 2theta values of 7.9 ⁇ 0.2°, 10.6 ⁇ 0.2°, 15.7 ⁇ 0.2°, 16.3 ⁇ 0.2°, 21.3 ⁇ 0.2° and 21.6 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of SAGE-217 crystal form D-1 is basically the same as that of FIG. 7.
  • this application provides a method for preparing crystalline SAGE-217 crystal form D-1 by cooling or evaporation using 4-methyl-2-pentanone as a solvent.
  • crystalline SAGE-217 crystal form D-1 can be prepared by crystallization by the method reported in Examples 8-10.
  • Form D-1 can be prepared by evaporation and crystallization of 4-methyl-2-pentanone solution. Crystallized by evaporation of 4-methyl-2-pentanone solution at room temperature to 40°C under reduced pressure. The crystal form D-1 remains stable in the exposed powder state for 18 hours, and the crystal form stability is greater than seven days when stored in a sealed vial at 25°C/45%RH. After 9 months of storage at a temperature of 0-8°C, the chemical stability is good and the crystal form is maintained.
  • the crystalline form D-1 of SAGE-217 is characterized in accordance with the DSC curve shown in FIG. 8 and the TGA curve shown in FIG. 9.
  • the DSC curve of the crystal form D-1 shows that there are three endothermic peaks, among which the two endothermic peaks at 93°C and 99.6°C are the endotherms caused by the release of the solvent.
  • the endothermic peak at 209.2°C is due to the endotherm caused by melting.
  • TGA showed two consecutive weight loss, one was 3.2% between 85°C and 110°C, and the other was 7.8% between 110°C and 145°C, which was comparable to the 4-methyl-2-pentanone detected by EGA. Release unanimously.
  • the total weight loss was 11%, and the molar ratio of SAGE-217 to 4-methyl-2-pentanone was 1:0.5 by calculation, indicating the formation of a hemisolvate.
  • the compound degrades above 300°C.
  • the present invention also provides a SAGE-217 crystal form D-2, the X-ray powder diffraction pattern of the 2theta value is 7.3 ⁇ 0.2°, 8.6 ⁇ 0.2°, 13.4 ⁇ 0.2°, 19.7 ⁇ 0.2° and 23.3 ⁇ 0.2° With characteristic peaks.
  • its X-ray powder diffraction pattern has characteristic peaks at 2theta values of 7.8 ⁇ 0.2°, 10.6 ⁇ 0.2°, 15.5 ⁇ 0.2°, 16.4 ⁇ 0.2°, 19.0 ⁇ 0.2° and 21.3 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of SAGE-217 crystalline form D-2 is basically the same as that of FIG. 10.
  • this application provides a method for preparing crystalline SAGE-217 crystal form D-2 by evaporation using a mixture of isobutyl acetate and ketone as a solvent.
  • crystalline SAGE-217 crystalline form D-2 can be prepared by crystallization by the methods reported in Examples 11-12.
  • the crystal form D-2 can be prepared from 4-methyl-2-pentanone/isobutyl acetate mixed solvent by cooling or evaporative crystallization.
  • the crystal form D-2 remains stable in the exposed powder state for 18 hours, and the crystal form stability is greater than seven days when stored in a sealed vial at 25°C/45%RH. It has good chemical stability during storage for 9 months at a temperature of 0-8°C.
  • the crystalline form D-2 of SAGE-217 is characterized in that it has the DSC curve shown in FIG. 11 and the TGA curve shown in FIG. 12.
  • the DSC curve of crystal form D-2 shows that there are two endothermic peaks, which are 92.4°C due to the release of solvent and 209.4°C due to melting.
  • the TGA curve shows that the weight loss between 85°C and 150°C is 11.5%, which is consistent with the release of isobutyl acetate detected by EGA.
  • the calculated molar ratio of SAGE-217 to isobutyl acetate is 1:0.5, indicating the formation of a hemisolvate. The compound degrades above 220°C.
  • the crystalline form D-1 and crystalline form D-2 of SAGE-217 are separated from the solvent system (tetrahydrofuran/water) in the patent WO2018039378A1 to obtain the XRPD pattern of the crystalline form D sample for labeling comparison, and it is considered that the three are different crystalline forms.
  • the crystal forms D-1 and D-2 described in the present invention have significantly different shift signals relative to the crystal form D in the diffraction pattern, confirming that they are different crystal forms .
  • crystal form D-1 and crystal form D-2 are the hemisolvate crystal forms of 4-methyl-2-pentanone and isobutyl acetate, respectively, and the solvent used for crystal form D There is no 4-methyl-2-pentanone or isobutyl acetate in the system.
  • the SAGE-217 crystals of crystal form D-1 and crystal form D-2 provided by the present invention show better stability than crystal form D separated according to the solvent system reported in WO2018039378A1.
  • this application also relates to SAGE-217 crystal form 01, crystal form 02, crystal form 03, crystal form 05, crystal form 07, crystal form 08 and crystal form 09. They can be prepared by crystallization by the method reported in Examples 18-24, respectively.
  • the SAGE-217 crystal forms of SAGE-217 crystal form 01, crystal form 02, crystal form 03, crystal form 05, crystal form 07, crystal form 08, and crystal form 09 provided by this application are characterized in Figs. 14-20 The reported XRPD pattern.
  • the crystal form has relatively low stability and tends to transform into a more stable crystal-free form.
  • this application provides more new crystal forms of SAGE-217, which provides more choices for drug development.
  • crystal form 04, crystal form 06, crystal form D-1, crystal form D-2, etc. also have very good stability.
  • crystal form 04 also has significantly improved mechanical stability than existing crystal forms. .
  • Figure 1 is the XRPD pattern of the crystal form 04 of compound I, where A is the XRPD pattern of the crystal form 04 obtained in Example 1, B is the XPRD pattern of the crystal form 04 obtained in Example 2, and C and D are obtained in Examples 4 and 5.
  • DSC chart of the crystal form 04 of compound I, where A is the DSC chart of the crystal form 04 obtained in Example 1, B is the DSC chart of the crystal form 04 obtained in Example 2, and C is the crystal form 04 obtained in Example 4. DSC chart;
  • Figure 3 is the TGA diagram and heat flow curve of the crystalline form 04 of compound I, where A is the TGA diagram (top) and the heat flow curve (bottom) of the crystalline form 04 obtained in Example 1, and B is the TGA of the crystalline form 04 obtained in Example 2 Figure (top) and heat flow curve (bottom), C is the TGA diagram (top) and heat flow curve (bottom) of crystal form 04 obtained in Example 4;
  • Figure 4 is the XRPD pattern of the crystalline form 06 of compound I;
  • Figure 5 is a DSC chart of crystalline form 06 of compound I;
  • Figure 6 shows the TGA diagram (top) and heat flow curve (bottom) of the crystalline form 06 of compound I;
  • Figure 7 is an XRPD diagram of the crystalline form D-1 of compound I;
  • Figure 8 is a DSC chart of the crystalline form D-1 of Compound I.
  • Figure 9 shows the TGA diagram (top) and heat flow curve (bottom) of the crystalline form D-1 of compound I;
  • Figure 10 is an XRPD diagram of the crystalline form D-2 of compound I;
  • Figure 11 is a DSC chart of the crystalline form D-2 of Compound I;
  • Figure 12 shows the TGA diagram (top) and heat flow curve (bottom) of the crystalline form D-2 of Compound I;
  • Figure 13 is an XRPD comparison diagram of the crystal forms D-1 and D-2 of compound I and the crystal form D reported in WO2018039378A1;
  • Figure 14 is the XRPD pattern of the crystalline form 01 of compound I;
  • Figure 15 is the XRPD pattern of the crystalline form 02 of compound I;
  • Figure 16 is the XRPD pattern of the crystalline form 03 of compound I;
  • Figure 17 is the XRPD pattern of the crystalline form 05 of compound I;
  • Figure 18 is the XRPD pattern of the crystalline form 07 of compound I;
  • Figure 19 is the XRPD pattern of the crystalline form 08 of compound I;
  • Figure 20 is the XRPD pattern of the crystalline form 09 of compound I;
  • Fig. 21 is a DVS diagram of crystalline form 04 of compound I;
  • Figure 22 is the XRPD diagram of Form 04 before and after applying 2 tons of mechanical pressure
  • Figure 23 is the XRPD diagram of the patented crystal form K of WO 2018/039378 A1 before and after 2 tons of mechanical pressure is applied.
  • test method is usually implemented according to conventional conditions or conditions recommended by the manufacturer; the compound I is prepared by the patent WO2014169833 method.
  • the X-ray powder diffraction pattern of the present invention is collected on a Rigaku Miniflex 600X diffraction powder diffractometer.
  • the differential scanning calorimetry (DSC) chart of the present invention was collected on a Mettler-Toledo DSC1.
  • the method parameters of Differential Scanning Calorimetry (DSC) are as follows:
  • Scan range 25 ⁇ 250°C; Scan rate: 10°C/min
  • thermogravimetric analysis (TGA) graph of the present invention is collected on Mettler Toledo TGA/DSC1 (Mettler Toledo DSC1).
  • thermogravimetric analysis TGA
  • Scan range 25 ⁇ 320°C; Scan rate: 10°C/min
  • Example 10 Repeat the operation of Example 9
  • the sample of crystal form 04 prepared in Example 1 was placed on a microbalance pan in a sealed sample chamber, and then exposed to different relative humidity.
  • the relative humidity ranged from 0% or 40% to 90%. Change in 10% increments.
  • the sample is balanced when dm/dt is less than 0.002% within 10 minutes. Record the mass of the dried sample and the equilibrium mass at each humidity level. The weight change is plotted against relative humidity, which is the moisture adsorption isotherm of the sample. See Figure 15 for the results.
  • moisture-absorbing weight gain is not less than 15%
  • moisture absorption moisture absorption and weight gain are less than 15% but not less than 2%
  • weight gain is less than 2% but not less than 0.2%
  • Example 14 Stability of Form 04 under Different Temperature and Humidity Conditions
  • the crystal form D-1 prepared in Example 8 was placed at 2-8° C., and after 9 months of standing, the crystal form was taken out and evaluated. The result showed that the crystal form did not change.
  • the purity results of high performance liquid chromatography are as follows As shown in the table. The results show that the crystal form 06 has good chemical stability.
  • the crystal form D-2 prepared by the present invention was placed at 2-8°C for 9 months, and the purity was determined by high performance liquid chromatography before and after storage to evaluate the chemical stability.
  • the purity results of the high performance liquid chromatography are as follows Shown. It has good chemical stability during storage for 9 months at a temperature of 0-8°C.
  • Example 17 Crystal Form 04 Thermodynamic Solubility and Mechanical Pressure Stability Test:
  • Thermodynamic solubility test the solid powder is added to water to a saturated solution, and then the suspension is stirred for 24 hours under magnetic stirring at 25°C. After completion, it was filtered with a 0.20 ⁇ m filter and analyzed by HPLC. Tests are carried out in parallel, and the average of each group of tests is taken twice.
  • thermodynamic dissolution results are recorded in the table above. Based on the results of these samples, the thermodynamic solubility is calculated.
  • the value of crystal form 04 is 437.5ng/mL and the value of crystal form K is 398.0ng/mL.
  • the thermodynamic solubility of the two is within the error range, and the results are basically the same.

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Abstract

本申请涉及抗抑郁药物SAGE-217的晶型04、晶型06、晶型D-1、晶型D-2及其制备方法和包含其的药物组合物。晶型04的XRPD在2theta值为11.6±0.2°,13.5±0.2°,16.2±0.2°,16.5±0.2°和23.2±0.2°处具有特征峰；晶型06的XRPD在2theta值为8.7士0.20,10.0±0.2°,13.2±0.2°,15.0±0.2°,15.8±0.2°和17.3±0.2°处具有特征峰；晶型D-1的XRPD在2theta值为7.2±0.2°,8.6±0.2°,13.3±0.2°,19.6士0.20芽口23.0±0.2°处具有特征峰；晶型D-2的XRPD在2theta值为7.3±0.2°,8.6±0.2°,13.4±0.2°,19.7士0.2。和23.3士0.2。处具有特征峰。本申请提供的新晶型，具有非常好的稳定性，为药物开发提供给了更多选择。

Description

抗抑郁药物SAGE-217的晶型及其制备方法 技术领域
本发明涉及化学医药领域，具体涉及有关抗抑郁药物SAGE-217的晶型及其制备方法。
背景技术
SAGE-217是治疗产后抑郁症、重度抑郁症等症状的候选药物。现有抗抑郁药物作为单一手段进行治疗往往存在局限性。SAGE-217是作为新一代的GABA受体调节药物，针对突触和突触外GABA受体的选择性以及每日口服给药的药代动力学特征进行了优化。GABA系统是大脑和中枢神经系统的主要抑制信号通路，对调节中枢神经系统功能具有重要意义。针对GABA受体的调节有比较明显的治疗效果。
SAGE-217化合物结构如式I所示，化学名称为1-(2-((3R,5R,8R,9R,10S,13S,14S,17S)-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-氧代乙基)-1H-吡唑-4-腈。
Figure PCTCN2020072924-appb-000001
国际专利申请WO2018039378A1描述了SAGE-217的结晶晶型A，B，C，D，E，F，H，I，J，K，L，M，N，O和P，以及制备多晶型的方法。
该专利申请中描述的多晶型A，C和K为无水晶型，晶型B，F，N，O，P为溶剂合物，晶型L，M，H，I，J为亚稳态，晶型D和E则未见明确的描述。
化合物的多晶型是指在化合物物中存在有两种或两种以上不同晶型的物质状态。多晶型现象在有机化合物中广泛存在。溶剂合物是多晶型现象中一类重要的物质状态。同一化合物的不同晶型在溶解度、熔点、密度、稳定性等方面有显著的差异，从而不同程度的影响化合物的稳定性、均一性。不同的晶型在化合物的纯化过程中通过结晶对化合物的提纯能力有着明显的不同。因此，药物工艺研发中进行全面系统的多晶型筛选，选择最合适开发的晶型，是不可忽视的重要研究内容之一。
发明内容
本申请的目的是提供SAGE-217的新晶型及其制备方法。
在特定的实施方案中，本申请涉及SAGE-217的晶型04，晶型06，晶型D-1和晶型D-2，这些晶型主要由X射线粉末衍射(“XRPD”)数据表征，同时还可参考差示扫描量热法(“DSC”)，热重量分析(“TGA”)与演化气体分析(“EGA”)等相关数据表征。
本发明还提供了一种通过结晶方法制备结晶SAGE-217的方法。其中所使用的SAGE-217原料可以通过任何合适的方法制备，包括本领域已知的合成方法。
本申请采取的一种方案是：一种SAGE-217的晶型04，其X射线粉末衍射图在2theta值为11.6±0.2°，13.5±0.2°，16.2±0.2°，16.5±0.2°和23.2±0.2°处具有特征峰。
更进一步的，其X射线粉末衍射图在2theta值为6.8±0.2°，14.7±0.2°，18.7±0.2°，19.2±0.2°和21.3±0.2°处具有特征峰。
在根据本申请的一些具体实施方式中，所述晶型04的X射线粉末衍射图(峰位置)与图1基本一致。
本发明还提供了可能受择优取向现象影响的高度结晶的SAGE-217晶型04，如图1中C和D的示例性XRPD图谱。由于已知择优取向现象会明显改变XRPD图中一些峰的相对强度，对于取向度高的晶型04结晶粉末，如果测量之前未经适当处理，则可观察到XRPD图谱中的2theta值为19.4±0.2°，20.3±0.2°，27.2±0.2°和34.1±0.2°的峰强度明显上升。
另一方面，本申请提供了一种通过从甲酸乙酯或甲酸与醇，二氯甲烷或乙腈混合的溶液中降温或蒸发结晶制备SAGE-217晶型04的方法。
在一个具体的实施方案中，结晶SAGE-217晶型04可以通过实施例1～5中报道的方法制备。
晶型04可以通过甲酸酯或甲酸及醇类的混合溶剂溶解完全后，降温或蒸发结晶的方式制备。通常情况下，溶剂合物的化学和物理稳定性相对较差。我们意外地发现，在0-8℃温度下9个月存储过程，晶型04化学稳定性良好，纯度基本未发生变化，晶型保持。晶型04在暴露的粉末状态保持一天仍然晶型稳定，在25℃/45％RH下在密封的小瓶中储存状态有大于七天的晶型稳定性。在加速稳定性测试条件25℃/60％湿度和40℃/75％湿度下，晶型可以稳定的保存一个月不发生变化。晶型04的DVS曲线显示，晶型04没有吸湿性。更为重要的是，与已见报道的晶型K相比较，晶型04有更好的机械应力稳定性，即机械加工性能更好。这对于晶型04在制剂中的应用，将有重要意义。
在一个具体的实施方案中，SAGE-217的晶体晶型04的特征还在于具有图2中A所示的DSC曲线和图3中A所示的TGA曲线，其中DSC曲线显示在120℃～160℃(起始于113.9℃)有宽吸热峰，高于173.3℃(在167.5℃开始)则发生样品熔化。TGA曲线显示在85-190℃之间有12.4％的失重，EGA光谱证实有甲酸和甲酸乙酯释放，推测为1:1的甲酸溶剂合物，所结合甲酸应来源于甲酸酯溶剂的降解。
在一个具体的实施方案中，SAGE-217的晶体晶型04的特征还在于具有图2中B所示的DSC曲线和图3中B所示的TGA曲线，其中DSC曲线显示在100℃～180℃有宽吸热峰。TGA曲线显示60～190℃之间有13.5％的失重，EGA光谱证实有甲酸和甲酸乙酯释放，推测为1:1的甲酸溶剂合物，所结合甲酸应来源于甲酸酯溶剂的降解。
在一个具体的实施方案中，SAGE-217的晶体晶型04的特征在于具有图2中C所示的DSC曲线和图3中C所示的TGA曲线，其中DSC曲线显示在110.5℃(起始于98.5℃)的宽吸热峰，在147℃(在144℃开始)的较为平缓的吸热峰和在155.5℃的尖锐吸热峰(起始于152.5℃)。高于208.8℃(在205.7℃开始)，发生样品熔化。TGA曲线显示70-185℃之间的三种不同且连续的失重分别为1.9％，1.6％和6.3％，EGA光谱证实有甲酸被释放出来。在EGA中检测到释放出甲酸占样品总重量的9.8％。通过计算得出SAGE-217与甲酸的摩尔比为1：0.97，表明形成1：1的甲酸溶剂合物。
本申请采取的第二种方案是：一种SAGE-217晶型06，其X射线粉末衍射图在 2theta值为8.7±0.2°，10.0±0.2°，13.2±0.2°，15.0±0.2°，15.8±0.2°和17.3±0.2°处具有特征峰。
更进一步的，其X射线粉末衍射图在2theta值为5.0±0.2°，5.5±0.2°，19.4±0.2°，20.0±0.2°和21.9±0.2°处具有特征峰。
在一些具体实施方式中，SAGE-217晶型06的X射线粉末衍射图与图4基本一致。
在另一方面，本申请提供了使用硝基甲烷作为溶剂通过降温或蒸发结晶制备SAGE-217晶型06的方法。
在一个具体的实施方案中，结晶SAGE-217晶型06可以通过实施例6～7中报道的方法通过结晶制备。
晶型06在暴露的粉末状态保持16小时仍然稳定，在25℃/45％RH在密封的小瓶中储存状态有大于七天的稳定性。
在一个具体的实施方案中，SAGE-217的晶体晶型06的特征在于具有图5中所示的DSC曲线和图6所示的TGA曲线。晶型06的DSC曲线表明存在两个温度低于240℃的吸热峰：一个在93.2℃，是由于溶剂释放吸热形成，而另一个在T为209.4℃，是由于熔化吸热形成。TGA显示，第一次失重是由于水释放，从25℃到95℃为0.6％；第二次失重为2.1％，与EGA检测到的硝基甲烷释放一致。通过计算得出SAGE-217与硝基甲烷的摩尔比)为1：0.14，表明捕获的溶剂可能形成非化学计量比的溶剂合物。化合物高于220℃会发生降解。
本申请采取的第三种方案是：一种SAGE-217晶型D-1，其X射线粉末衍射图在2theta值为7.2±0.2°，8.6±0.2°，13.3±0.2°，19.6±0.2°和23.0±0.2°处具有特征峰。
更进一步的，其X射线粉末衍射图在2theta值为7.9±0.2°，10.6±0.2°，15.7±0.2°，16.3±0.2°，21.3±0.2°和21.6±0.2°处具有特征峰。
在一些具体实施方式中，SAGE-217晶型D-1的X射线粉末衍射图与图7基本一致。
另一方面，本申请提供了使用4-甲基-2-戊酮作为溶剂通过降温或蒸发制备结晶SAGE-217晶型D-1的方法。
在一个实施方案中，结晶SAGE-217晶型D-1可以通过实施例8～10中报道的方法通过结晶制备。
晶型D-1可以通过4-甲基-2-戊酮溶液蒸发结晶制备。通过4-甲基-2-戊酮溶液在室温至40℃减压蒸发结晶。晶型D-1在暴露的粉末状态保持18小时仍然保持晶型稳定，在25℃/45％RH在密封的小瓶中储存状态有大于七天的晶型稳定性。在0-8℃温度下9个月存储过程，化学稳定性良好，晶型保持。
在一个具体的实施方案中，SAGE-217的晶型D-1的特征在于根据图8中所示的DSC曲线和图9所示的TGA曲线。晶型D-1的DSC曲线表明存在三个吸热峰，其中93℃和99.6℃二个吸热峰是由溶剂释放引起的吸热。209.2℃的吸热峰是由于熔化引起的吸热。TGA显示两个连续的失重，一个在85℃-110℃之间为3.2％，另一个在110℃-145℃之间为7.8％，与EGA检测到的4-甲基-2-戊酮的释放一致。总失重为11％，通过计算得出SAGE-217与4-甲基-2-戊酮的摩尔比为1：0.5，表明形成半溶剂化物。化合物在300℃以上发生降解。
本发明还提供一种SAGE-217晶型D-2，其X射线粉末衍射图在2theta值为7.3±0.2°，8.6±0.2°，13.4±0.2°，19.7±0.2°和23.3±0.2°处具有特征峰。
更进一步的，其X射线粉末衍射图在2theta值为7.8±0.2°，10.6±0.2°，15.5±0.2°，16.4±0.2°，19.0±0.2°和21.3±0.2°处具有特征峰。
在一些具体实施方式中，SAGE-217晶型D-2的X射线粉末衍射图与图10基本一致。
另一方面，本申请提供了使用乙酸异丁酯与酮混合物作为溶剂通过蒸发制备结晶SAGE-217晶型D-2的方法。
在一些实施方案中，结晶SAGE-217晶型D-2可以通过实施例11～12中报道的方法通过结晶制备。
晶型D-2可以从由4-甲基-2-戊酮/乙酸异丁酯的混合溶剂中降温或蒸发结晶制备。晶型D-2在暴露的粉末状态保持18小时仍然晶型稳定，在25℃/45％RH在密封的小瓶中储存状态有大于七天的晶型稳定性。在0-8℃温度下9个月存储过程，化学稳定性良好。
在一个具体的实施方案中，SAGE-217的晶型D-2的特征在于其具有图11中所示的DSC曲线和图12所示的TGA曲线。晶型D-2的DSC曲线表明存在两个吸热峰，分别为92.4℃由于溶剂释放产生吸热和209.4℃由于熔化吸热。TGA曲线显示在85℃-150℃之间的失重为11.5％，与EGA检测到的乙酸异丁酯的释放一致。通过计算得出SAGE-217与乙酸异丁酯的摩尔比为1：0.5，表明形成半溶剂合物。化合物在220℃以上发生降解。
将SAGE-217的晶型D-1和晶型D-2与专利WO2018039378A1中的溶剂体系(四氢呋喃/水)分离得到晶型D样品的XRPD图谱进行标记对比，认为三者是不同的晶型。如图13中报道的XRPD图谱比较所示，本发明中描述的晶型D-1和D-2在衍射图中相对于晶型D有明显不同的移位信号，证实其为不同的晶型。此外，基于EGA数据，晶型D-1和晶型D-2分别是4-甲基-2-戊酮和乙酸异丁酯的半溶剂合物晶型，而得到晶型D所使用的溶剂体系并不存在4-甲基-2-戊酮或乙酸异丁酯。
在另一个具体实施方案中，本发明提供的晶型D-1和晶型D-2的SAGE-217结晶相对于根据WO2018039378A1中报道的溶剂体系分离的晶型D显示出更好的稳定性。
此外，本申请还涉及SAGE-217晶型01，晶型02，晶型03，晶型05，晶型07，晶型08和晶型09。它们分别可以通过实施例18-24中报道的方法通过结晶制备。本申请提供的SAGE-217晶型01，晶型02，晶型03，晶型05，晶型07，晶型08和晶型09的SAGE-217结晶晶型，其特征在于图14～20中报道的XRPD图谱。其中所述晶型稳定性相对较低并且倾向于转化成更稳定的无水晶型。
与现有技术相比，本申请提供了更多SAGE-217的新晶型，为药物开发提供给了更多选择。新晶型中，晶型04，晶型06，晶型D-1，晶型D-2等还具有非常好的稳定性，其中晶型04还具有比现有晶型明显提升的机械稳定性。
附图说明
图1为化合物I的晶型04的XRPD图，其中A为实施例1所得晶型04的XRPD图，B为实施例2所得晶型04的XPRD图，C和D为实施例4，5所得晶型04的XRPD图；
图2为化合物I的晶型04的DSC图，其中A为实施例1所得晶型04的DSC图，B为实施例2所得晶型04的DSC图，C为实施例4所得晶型04的DSC图；
图3为化合物I的晶型04的TGA图和热流曲线，其中A为实施例1所得晶型04的TGA图(上)和热流曲线(下)，B为实施例2所得晶型04的TGA图(上)和热流曲线(下)，C为实施例4所得晶型04的TGA图(上)和热流曲线(下)；
图4为化合物I的晶型06的XRPD图；
图5为化合物I的晶型06的DSC图；
图6为化合物I的晶型06的TGA图(上)和热流曲线(下)；
图7为化合物I的晶型D-1的XRPD图；
图8为化合物I的晶型D-1的DSC图；
图9为化合物I的晶型D-1的TGA图(上)和热流曲线(下)；
图10为化合物I的晶型D-2的XRPD图；
图11为化合物I的晶型D-2的DSC图；
图12为化合物I的晶型D-2的TGA图(上)和热流曲线(下)；
图13为化合物I的晶型D-1、D-2与WO2018039378A1所报道晶型D的XRPD对比图；
图14为化合物I的晶型01的XRPD图；
图15为化合物I的晶型02的XRPD图；
图16为化合物I的晶型03的XRPD图；
图17为化合物I的晶型05的XRPD图；
图18为化合物I的晶型07的XRPD图；
图19为化合物I的晶型08的XRPD图；
图20为化合物I的晶型09的XRPD图；
图21为化合物I的晶型04的DVS图；
图22为晶型04施加2吨机械压力前后XRPD图；
图23为WO 2018/039378 A1的专利晶型K施加2吨机械压力前后XRPD图。
具体实施方式
以下将通过具体实施例进一步阐述本发明，但并不用于限制本发明的保护范围。本领域技术人员可在权利要求范围内对制备方法和使用仪器作出改进，这些改进也应视为本发明的保护范围。因此，本发明专利的保护范围应以所附权利要求为准。
下述实施例中，所述的试验方法通常按照常规条件或制造厂商建议的条件实施；所述化合物I通过专利WO2014169833方法制备。
本发明中所用到的缩写的解释如下：
XRPD：X射线粉末衍射
DSC：差示扫描量热分析
TGA：热重分析
本发明所述的X射线粉末衍射图在Rigaku Miniflex 600X衍射粉末衍射仪上采集。
XRPD扫描参数初始位置[°2Th.]:3；结束位置[°2Th.]:40；扫描步长:0.01°；扫描速度10°/min；铜阳极
Figure PCTCN2020072924-appb-000002
电压:15mA；电流：40kV。
本发明所述差示扫描量热分析(DSC)图在梅特勒-托莱多DSC1上采集。差示扫描量热分析(DSC)的方法参数如下：
扫描范围：25～250℃；扫描速率：10℃/min
保护气体：氮气
本发明所述热重分析(TGA)图在梅特勒-托莱多TGA/DSC1(Mettler Toledo DSC1)上采集。
热重分析(TGA)的方法参数如下：
扫描范围：25～320℃；扫描速率：10℃/min
保护气体：氮气
下面通过实施例来描述本申请的实施方式，本领域的技术人员应当认识到，这些具体的实施例仅表明为了达到本申请的目的而选择的实施技术方案，并不是对技术方案的限制。根据本申请的教导，结合现有技术对本申请技术方案的改进是显然的，均属于本申请保护的范围。
实施例1：制备Sage-217晶型04
配制10mg/mL的Sage-217甲酸乙酯溶液，将此溶液在25℃下搅拌60min，使之溶解完全，用有机滤头(25mm/0.45μm)过滤溶液，所得滤液于10℃条件下静置，过滤得到白色固体，其XRPD图谱如图1中谱线A所示，相应的XRPD数据如下表：
Figure PCTCN2020072924-appb-000003
实施例2(重复实施例1操作)
配制10mg/mL的Sage-217甲酸乙酯溶液，将此溶液在25℃下搅拌60min，使之溶解完全，用有机滤头(25mm/0.45μm)过滤溶液，所得滤液于10℃条件下静置，过滤得到白色固体，其XRPD图谱如图1中谱线B所示。
实施例3 制备Sage-217晶型04
配制25mg/mL的Sage-217甲酸乙酯溶液，将此溶液在25℃下搅拌6h，使之溶解完全，用有机滤头(25mm/0.45μm)过滤溶液，所得滤液于25℃条件下静置，过滤得到白色固体，其XRPD图谱与图1A一致。
实施例4 制备Sage-217晶型04
配制10mg/mL的Sage-217甲酸/异丁醇(1/1,v/v)溶液，将此溶液在25℃下搅拌60min，使之溶解完全，用有机滤头(25mm/0.45μm)过滤溶液，所得滤液于25℃条件下减压析晶，过滤得到白色固体，其XRPD图谱如图1中谱线C所示。
实施例5 制备Sage-217晶型04
配制10mg/mL的Sage-217甲酸/异丁醇(1/1,v/v)溶液，将此溶液在25℃下搅拌60min，使之溶解完全，用有机滤头(25mm/0.45μm)过滤溶液，所得滤液于40℃条件下减压析晶，过滤得到白色固体，其XRPD图谱如图1中谱线D所示。
实施例6 制备Sage-217晶型06
配制10mg/mL的Sage-217硝基甲烷溶液，将此溶液在25℃下搅拌60min，使之溶解完全，用有机滤头(25mm/0.45μm)过滤溶液，所得滤液于25℃条件下减压析晶，过滤得到白色固体，其XRPD图谱如图4所示，相应的XRPD数据如下：
Figure PCTCN2020072924-appb-000004
实施例7 制备Sage-217晶型06
配制10mg/mL的Sage-217硝基甲烷溶液，将此溶液在25℃下搅拌60min，使 之溶解完全，用有机滤头(25mm/0.45μm)过滤溶液，所得滤液于40℃条件下减压析晶，过滤得到白色固体，其XRPD图谱与图4一致。
实施例8 制备Sage-217晶型D-1
配制10mg/mL的Sage-217 4-甲基-2-戊酮溶液，将此溶液在25℃下搅拌60min，使之溶解完全，用有机滤头(25mm/0.45μm)过滤溶液，所得滤液于25℃条件下减压析晶，过滤得到白色固体，其XRPD图谱如图7所示，相应XRPD数据如下：
Figure PCTCN2020072924-appb-000005
实施例9 制备Sage-217晶型D-1
配制10mg/mL的Sage-217 4-甲基-2-戊酮溶液，将此溶液在25℃下搅拌60min，使之溶解完全，用有机滤头(25mm/0.45μm)过滤溶液，所得滤液于40℃条件下减压析晶，过滤得到白色固体，其XRPD图谱与图7一致。
实施例10 重复实施例9操作
配制10mg/mL的Sage-217 4-甲基-2-戊酮溶液，将此溶液在25℃下搅拌60min，使之溶解完全，用有机滤头(25mm/0.45μm)过滤溶液，所得滤液于40℃条件下减压析晶，过滤得到白色固体，其XRPD图谱与图7一致。
实施例11 制备Sage-217晶型D-2
配制10mg/mL的Sage-217 4-甲基-2-戊酮/乙酸异丁酯(1/1,v/v)溶液，将此溶液在25℃下搅拌60min，使之溶解完全，用有机滤头(25mm/0.45μm)过滤溶液，所得滤液于25℃条件下减压析晶，过滤得到白色固体，其XRPD图谱如图10所示，相应XRPD数据如下：
Figure PCTCN2020072924-appb-000006
Figure PCTCN2020072924-appb-000007
实施例12 制备Sage-217晶型D-2
配制10mg/mL的Sage-217 4-甲基-2-戊酮/乙酸异丁酯(1/1,v/v)溶液，将此溶液在25℃下搅拌60min，使之溶解完全，用有机滤头(25mm/0.45μm)过滤溶液，所得滤液于40℃条件下减压析晶，过滤得到白色固体，其XRPD图谱与图10一致。
实施例13 Sage-217晶型04的DVS测试
将实施例1制备的晶型04的样品放置在处于密封样品室里的微量天平盘上，随后暴露在不同的相对湿度下，相对湿度的变化范围为0％或40％至90％，相对湿度以10％的增量变化。在每一个湿度水平下，10分钟内当dm/dt小于0.002％时，样品则平衡。记录干燥样品的质量与每个湿度水平下的平衡质量，重量变化对相对湿度作图，即为样品的水分吸附等温线。结果参见图15。
由图21可见，晶型04在25℃条件下，当相对湿度从40％到90％变化时，晶型04吸收水量为0.06％，表明晶型04无或几乎无引湿性。
关于引湿性特征描述与引湿性增重的界定(中国药典2010年版附录XIX J药物引湿性试验指导原则，实验条件：25±1℃，80％相对湿度)：
潮解：吸收足量水分形成液体
极具引湿性：引湿增重不小于15％
有引湿性：引湿增重小于15％但不小于2％
略有引湿性：引湿增重小于2％但不小于0.2％
无或几乎无引湿性：引湿增重小于0.2％。
实施例14:不同温度和湿度条件下晶型04稳定性
取实施例1制备的晶型04样品，分别放置于25℃/60％湿度和40℃/75％湿度 下，放置1个月；放置于2-8℃下，放置9个月；放置结束后，将上述样品取出并测试晶型，结果如下表所示。
温度 25℃ 40℃ 2-8℃(冰箱中)
相对湿度 60％ 75％ /
保存时间 1个月 1个月 9个月
晶型 晶型04 晶型04 晶型04
取本发明的晶型04的样品放置于2-8℃下，放置9个月，并在放置前后利用高效液相色谱法进行纯度测定以评估化学稳定性，高效液相色谱法纯度结果如下表所示。结果表明晶型04化学稳定性良好。
Figure PCTCN2020072924-appb-000008
实施例15:晶型D-1的稳定性实验
将实施例8制备的晶型D-1放置于2-8℃下，放置9个月后，取出并评估晶型，结果表明晶型没有发生改变。取本发明制备的晶型D-1放置于2-8℃下，放置9个月，并在放置前后利用高效液相色谱法进行纯度测定以评估化学稳定性，高效液相色谱法纯度结果如下表所示。结果表明晶型06化学稳定性良好。
Figure PCTCN2020072924-appb-000009
实施例16:晶型D-2的稳定性实验
将本发明制备晶型D-2放置于2-8℃下，放置9个月，并在放置前后利用高效液相色谱法进行纯度测定以评估化学稳定性，高效液相色谱法纯度结果如下表所示。在0-8℃温度下9个月存储过程，化学稳定性良好。
Figure PCTCN2020072924-appb-000010
实施例17:晶型04热力学溶解度和机械耐压稳定性测试：
热力学溶解度测试：将固体粉末加入水中至饱和溶液，接下来将该悬浮液在25℃磁力搅拌下搅拌24小时。完成后将其用0.20μm过滤器过滤并通过HPLC分析。平行进行试验，每组验测试两次取均值。
Figure PCTCN2020072924-appb-000011
在上表中记录了热力学溶解结果。根据这些样品的结果计算得出热力学溶解度，晶型04的值为437.5ng/mL，晶型K的值为398.0ng/mL，两者的热力学溶解度在误差范围之内，结果基本一致。
进一步对本申请的晶型04和WO 2018/039378 A1中的报道晶型K的机械稳定性进行评估，对100mg样品施加2吨机械压力，将回收的片剂轻轻磨碎并通过XRPD测试。
晶型04的XRPD测试显示其没有明显的变化(图22)，而对于WO 2018/039378A1中的报道晶型K，观察到其结晶度略有下降(图23)。从一个侧面说明本申请的晶型04的物理稳定性优于晶型K。
实施例18：制备Sage-217晶型01
配制10mg/mL的Sage-217对二甲苯溶液，将此溶液由75℃冷却至25℃，搅拌析晶，过滤得到固体，测试XRPD，其XRPD图谱如图14所示，相应XRPD数据如下。实际中发现该晶型稳定性相对前述的晶型04、晶型06、晶型D-1、晶型D-2较差。
Figure PCTCN2020072924-appb-000012
实施例19：制备Sage-217晶型02
配制10mg/mL的Sage-217的乙二胺溶液，将此溶液在搅拌下由50℃冷却至 25℃，搅拌析晶，过滤得到固体烘干测试XRPD，其XRPD图谱如图15所示，相应XRPD数据如下。实际中发现该晶型稳定性相对前述的晶型04、晶型06、晶型D-1、晶型D-2较差。
Figure PCTCN2020072924-appb-000013
实施例20：制备Sage-217晶型03
配制10mg/mL的Sage-217碳酸二乙酯溶液，将此溶液由75℃冷却至25℃搅拌析晶，过滤得到固体测试XRPD，其XRPD图谱如图16所示，相应XRPD数据如下。实际中发现该晶型稳定性相对前述的晶型04、晶型06、晶型D-1、晶型D-2较差。
Figure PCTCN2020072924-appb-000014
Figure PCTCN2020072924-appb-000015
实施例21：制备Sage-217晶型05
配制10mg/mL的Sage-217乙二醇二甲醚浆液，将此浆液在25℃搅拌15天，过滤得到固体测试XRPD，其XRPD图谱如图17所示，相应XRPD数据如下。实际中发现该晶型稳定性相对前述的晶型04、晶型06、晶型D-1、晶型D-2较差。
Figure PCTCN2020072924-appb-000016
实施例22：制备Sage-217晶型07
配制10mg/mL的Sage-217甲苯溶液，将此溶液由75℃冷却至10℃，搅拌析晶，过滤得到固体测试XRPD，其XRPD图谱如图18所示，相应XRPD数据如下。实际中发现该晶型稳定性相对前述的晶型04、晶型06、晶型D-1、晶型D-2较差。
Figure PCTCN2020072924-appb-000017
Figure PCTCN2020072924-appb-000018
实施例23：制备Sage-217晶型08
配制10mg/mL的Sage-217甲苯溶液，将此溶液由75℃快速冷却至10℃以下，搅拌析晶，过滤得到固体测试XRPD，其XRPD图谱如图19所示。相应XRPD数据如下。
Figure PCTCN2020072924-appb-000019
Figure PCTCN2020072924-appb-000020
实施例24：制备Sage-217晶型09
配制10mg/mL的Sage-217乙腈溶液，将此溶液由50℃冷却至25℃，搅拌析晶，过滤得到固体测试XRPD，其XRPD图谱如图20所示，相应XRPD数据如下。实际中发现该晶型稳定性相对前述的晶型04、晶型06、晶型D-1、晶型D-2较差。
Figure PCTCN2020072924-appb-000021
本申请包括但不限于以上实施例，凡是在本申请精神的原则下进行的任何等同替代或局部改进，都将视为在本申请的保护范围之内。

Claims (12)

  1. 一种化合物SAGE-217的晶型04，化合物SAGE-217的化学名称为1-(2-((3R,5R,8R,9R,10S,13S,14S,17S)-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-氧代乙基)-1H-吡唑-4-腈，其特征在于，其X射线粉末衍射图在2theta值为11.6°±0.2°,13.5°±0.2°，16.2°±0.2°,16.5°±0.2°和23.2°±0.2°处具有特征峰。
  2. 根据权利要求1所述的晶型04，其特征还在于，其X射线粉末衍射图在2theta值为6.8°±0.2°,14.7°±0.2°,18.7°±0.2°，19.2°±0.2°和21.3°±0.2°处具有特征峰。
  3. 根据权利要求1所述的晶型04，其特征在于，其X射线粉末衍射图与图1基本一致。
  4. 根据权利要求1所述的晶型04，其特征在于，所述晶型04是化合物SAGE-217的甲酸溶剂合物。
  5. 一种如权利要求1至4中任一项权利要求所述的化合物SAGE-217的晶型04的制备方法，其特征在于，包括将SAGE-217在甲酸酯或甲酸和有机溶剂的混合体系中结晶得到晶型04。
  6. 根据权利要求5所述的制备方法，其特征在于，所述甲酸酯的酯基选自含碳数C1-C10的基团，所述有机溶剂选自含碳数C1-C10的醇类溶剂、二氯甲烷及乙腈。
  7. 一种化合物SAGE-217的晶型06，化合物SAGE-217的化学名称为1-(2-((3R,5R,8R,9R,10S,13S,14S,17S)-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-氧代乙基)-1H-吡唑-4-腈，其特征在于，其X射线粉末衍射图在2theta值为8.7±0.2°，10.0±0.2°，13.2±0.2°，15.0±0.2°，15.8±0.2°和17.3±0.2°处具有特征峰。
  8. 根据权利要求7所述的晶型06，其特征还在于，其X射线粉末衍射图在2theta值为5.0±0.2°，5.5±0.2°，19.4±0.2°，20.0±0.2°和21.9±0.2°处具有特征峰。
  9. 根据权利要求7所述的晶型06，其特征在于，其X射线粉末衍射图与图4基本一致。
  10. 一种如权利要求7至9中任一项权利要求所述的化合物SAGE-217的晶型06的制备方法，其特征在于，包括将SAGE-217在硝基甲烷体系中结晶得到晶型06。
  11. 一种化合物SAGE-217的晶型D-1，化合物SAGE-217的化学名称为1-(2-((3R,5R,8R,9R,10S,13S,14S,17S)-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-氧代乙基)-1H-吡唑-4-腈，其特征在于，其X射线粉末衍射图在2theta值为7.2±0.2°，8.6±0.2°，13.3±0.2°，19.6±0.2°和23.0±0.2°处具有特征峰。
  12. 根据权利要求11所述的晶型D-1，其特征还在于，其X射线粉末衍射图在2theta值为7.9±0.2°，10.6±0.2°，15.7±0.2°，16.3±0.2°，21.3±0.2°和21.6±0.2°处具有特征峰。
PCT/CN2020/072924 2019-01-20 2020-01-19 抗抑郁药物sage-217的晶型及其制备方法 WO2020147852A1 (zh)

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