CN102887936A - Crystal forms of 2-cyano-3,12-dioxoolean-1,9(11)-diene-28-oic acid methyl ester - Google Patents

Crystal forms of 2-cyano-3,12-dioxoolean-1,9(11)-diene-28-oic acid methyl ester Download PDF

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CN102887936A
CN102887936A CN2012104086159A CN201210408615A CN102887936A CN 102887936 A CN102887936 A CN 102887936A CN 2012104086159 A CN2012104086159 A CN 2012104086159A CN 201210408615 A CN201210408615 A CN 201210408615A CN 102887936 A CN102887936 A CN 102887936A
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diene
cyano
dioxo
olean
methyl
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CN2012104086159A
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Chinese (zh)
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杨朝惠
高岳君
张晓宇
汪建明
张炎锋
陈敏华
王鹏
李丕旭
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苏州晶云药物科技有限公司
苏州鹏旭医药科技有限公司
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Priority to CN2012104086159A priority Critical patent/CN102887936A/en
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07JSTEROIDS
    • C07J63/00Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms
    • C07J63/008Expansion of ring D by one atom, e.g. D homo steroids
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07BGENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13Crystalline forms, e.g. polymorphs

Abstract

The invention relates to the field of pharmaceutical chemistry, and particularly relates to several crystal forms of 2-cyano-3,12-dioxoolean-1,9(11)-diene-28-oic acid methyl ester suitable for medicament development. The invention is characterized in that the crystal forms are methylbenzene solvate, semi-dioxane solvate and semi-tetrahydrofuran solvate of 2-cyano-3,12-dioxoolean-1,9(11)-diene-28-oic acid methyl ester. The several crystal forms have favorable solubility and stability, contain no toxicity and are suitable for being prepared into medicaments.

Description

2-氰基-3,12- 二氧代齐墩果-1,9 (11) - 二烯-28-酸甲酯晶型 2-cyano-3,12-dioxo-olean-1,9 (11) - diene -28- methyl ester Form

技术领域 FIELD

[0001] 本发明涉及药物化学领域,具体涉及2-氰基-3,12- 二氧代齐墩果_1,9 (11)- 二烯-28-酸甲酯的适应药物开发的几种晶型。 [0001] The present invention relates to pharmaceutical chemistry, specifically relates to 3,12-dioxo-olean _1,9 (11) 2-cyano - adaptation of several drug development diene -28- methyl polymorphs.

背景技术 Background technique

[0002] 三萜的生物合成主要是在植物内由角鲨烯的环化生成,它作为原料药时生物活性相对较弱。 [0002] triterpene biosynthesis mainly generated by the cyclization of squalene in a plant, which as a biologically active drug substance is relatively weak. 因此科学家们寻求合成类似物来增强效力。 So the scientists seek to enhance the effectiveness of synthetic analogs. 2-氰基-3,12-二氧代齐墩果-1,9(11)-二烯-28-酸甲酯就是其中一种具有良好的抗炎,分化和抗增殖效果,具备药物开发潜力的药物分子。 2-cyano-3,12-dioxo-olean-1,9 (11) - diene -28- methyl ester is one having a good anti-inflammatory, anti-proliferative and differentiation effects, drug development comprising potential drug molecules. 其结构式如下: The structural formula is as follows:

[0003] [0003]

O O

[0004] 目前,专利US8088824B2报道了2_氰基_3,12-二氧代齐墩果_1,9 (11)- 二烯-28-酸甲酯的无水晶型、无定形、半苯溶剂合物和二甲醇溶剂合物。 [0004] Currently, patent US8088824B2 reported 2_ cyano _3,12- _1,9-dioxo-olean (11) - diene-methyl -28- anhydrous crystalline form, amorphous, semi-benzene solvates and solvates dimethanol. 但是无水晶型存在溶解度差,生物利用度低的问题。 However, there is no difference in solubility, low bioavailability crystal type of issue. 而无定形又热力学不稳定,在有晶种诱导或较高温度和湿度环境中有转变成其他晶型的潜在风险。 While amorphous and thermodynamically unstable, there is the potential risk of another crystalline form into the seed or induction of elevated temperature and humidity in the environment. 半苯溶剂合物中苯属于一类溶剂,对人体的毒性很大,且不能在人体内降解,不适合进行药物开发。 Semiquinones benzene solvate belongs to a class of solvents, toxic to the human body is large, and can not be degraded in the human body, is not suitable for drug development. 二甲醇合物晶型不稳定,容易部分或者全部脱去甲醇,转变成其他晶型,经验证二甲醇合物在密闭环境中放置7天后全部转变为无水晶型。 Dimethanol compound unstable polymorph easily off some or all of the methanol, is converted into another crystalline form, proven dimethanol compound for 7 days in a closed environment, complete conversion of the anhydrous crystalline form.

[0005] 此外,科学文献(Acta Cryst. (2002) · C58, 0199-0200)中还报道了一种它的一水 [0005] In addition, the scientific literature (Acta Cryst. (2002) · C58, 0199-0200) also reported a one of its water

一甲醇合物,这个晶型同样不稳定,容易脱去水或者甲醇,发生晶型转变。 A compound of methanol, the same crystal form is unstable, readily removable with water or methanol, crystal transformation occurs.

[0006] 因此寻找溶解度好,生物利用度高,稳定,无毒或者低毒的2-氰基-3,12-二氧代齐墩果-I,9 (11)- 二烯-28-酸甲酯新晶型十分必要。 [0006] Thus looking good solubility and high bioavailability, stability, low toxicity or non-toxic 2-cyano-3,12-dioxo-olean -I, 9 (11) - diene-28-oic acid methyl new crystal form is necessary.

发明内容 SUMMARY

[0007] 本发明公开了一类2-氰基-3,12- 二氧代齐墩果-1,9 (11)- 二烯_28_酸甲酯的溶剂合物,为晶型I、II、III。 [0007] The present invention discloses a class of 2-cyano-3,12-dioxo-olean-1,9 (11) - diene _28_ methyl ester solvate, crystalline form I, II, III. 它们不仅溶解度好、稳定性好且无毒,更适合于制备成药物。 They not only good solubility, stability and non-toxic, more suitable for the preparation of a pharmaceutical.

[0008] 本发明公开了2-氰基-3,12-二氧代齐墩果-1,9(11)-二烯-28-酸甲酯的晶型I,其X 射线粉末衍射图在光谱d-间距9. 65,7. 58,7. 18,6. 29,6. 06,5. 47,5. 21,4. 77 和3. 07埃(同A)具有特征峰。 [0008] The present invention discloses 2-cyano-3,12-dioxo-olean-1,9 (11) - diene -28- Form I of methyl, an X-ray powder diffraction pattern 9. spectrum d- spacing 65,7. 58,7. 18,6. 29,6. 06,5. 47,5. 21,4. 77 and 3.07 angstroms (with A) has characteristic peaks. 其X射线粉末衍射图如图I。 An X-ray powder diffraction pattern as shown in FIG I. [0009] 晶型I为2-氰基-3,12- 二氧代齐墩果-1,9 (11)- 二烯_28_酸甲酯的甲苯溶剂合物,加热至180° C时失重为7.2%。 Diene _28_ methyl toluene solvate was heated to 180 ° C - [0009] Form I is 2-cyano-3,12-dioxo-olean-1,9 (11) weight loss of 7.2%. 其热重分析图如图2。 Which thermogravimetric analysis is shown in Figure 2.

[0010] 晶型I的差示扫描量热分析图在接近117°c处有吸热峰,焓值为25. 87J/g,加热至215° C时有一熔化峰,焓值为34. 88J/g。 Has a melting peak at [0010] Differential scanning calorimetry analysis of crystalline Form I of FIG endothermic peak near 117 ° c, the enthalpy value of 25. 87J / g, was heated to 215 ° C, an enthalpy value 34. 88J / g. 如图3。 3.

[0011] 本发明的晶型I可用如下方法制备:将2-氰基-3,12-二氧代齐墩果-1,9(11)-二烯-28-酸甲酯溶解在甲苯溶液中,经过挥发,得到白色固体即为甲苯溶剂合物。 [0011] Form I of the present invention can be prepared as follows: 2-cyano-3,12-dioxo-olean-1,9 (11) - diene were dissolved in a toluene solution of methyl -28- , after evaporation, to give a white solid, a toluene solvate.

[0012] 本发明还公开了2-氰基-3,12- 二氧代齐墩果_1,9 (11)- 二烯_28_酸甲酯的另一种晶型,即晶型II。 [0012] The present invention also discloses a 2-cyano-3,12-dioxo-olean _1,9 (11) - diene _28_ methyl ester another crystalline form, Form II i.e. . 其X射线粉末衍射图在光谱d-间距10. 01,7. 09,6. 84,6. 23,5. 29,5. 20,5. 10,4. 84,和4. 61埃具有特征峰。 X-ray powder diffraction pattern having characteristic spectral d- spacing 10. 01,7. 09,6. 84,6. 23,5. 29,5. 20,5. 10,4. 84 and 4.61 Å peak. 如图4。 4.

[0013] 晶型II为2-氰基-3,12-二氧代齐墩果-1,9(11)-二烯-28-酸甲酯的半二氧六环溶剂合物,加热至195° C时失重为8. 05%。 [0013] Form II is a 2-cyano-3,12-dioxo-olean-1,9 (11) - half-dioxane solvate diene -28- methyl, heated to weight loss of 8.05% when 195 ° C. 其热重分析图如图5。 Which thermogravimetric analysis is shown in Figure 5.

[0014] 晶型II的差示扫描量热分析图在接近150° C处有吸热峰,焓值为58. 10J/g,加热至221 °C时有一熔化峰,焓值为51. 74J/g,如图6。 [0014] The differential scanning calorimetry analysis of crystalline Form II of FIG endothermic peak near 150 ° C, the enthalpy value of 58. 10J / g, a melting peak when heated to 221 ° C, an enthalpy value 51. 74J / g, as shown in FIG 6.

[0015] 晶型II可用如下方法制备:将2_氰基-3,12_ 二氧代齐墩果-1,9(11) -二烯-28-酸甲酯溶解在I,4- 二氧六环和水的混合溶液中,室温混悬搅拌,得到的白色固体即得。 [0015] Form II prepared following methods are available: the -3,12_ 2_ cyano-1,9-dioxo-olean (11) - diene -28- methyl ester was dissolved in I, 4- dioxo six ring and a mixed solution of water, stirred suspension at room temperature, the resulting white solid to obtain.

[0016] 本发明还公开了2-氰基-3,12- 二氧代齐墩果_1,9 (11)- 二烯_28_酸甲酯的第三种晶型,即晶型III。 [0016] The present invention also discloses a 2-cyano-3,12-dioxo-olean _1,9 (11) - diene _28_ methyl third polymorph, Form III i.e. . 其X射线粉末衍射图在光谱d-间距10. 00,7. 14,6. 80,6. 65,6. 10,5. 62,5. 29,4. 88,和4. 50埃具有特征峰。 An X-ray powder diffraction pattern spectrum of d- spacing 10. 00,7. 14,6. 80,6. 65,6. 10,5. 62,5. 29,4. 88, 4.50 Å and having the features peak. 如图8。 8.

[0017] 晶型III是2-氰基-3,12-二氧代齐墩果-1,9(11)-二烯-28-酸甲酯的半四氢呋喃溶剂合物,在加热至149° C时失重为6. 86%。 [0017] Form III is 2-cyano-3,12-dioxo-olean-1,9 (11) - diene semi-tetrahydrofuran solvate -28- methyl, heated to 149 ° weight loss of 6.86% when C. 半四氢呋喃溶剂合物脱溶剂后的理论失重为6.70%。 After solvent removal Theory half tetrahydrofuran solvate weight loss was 6.70%. 如图9。 9.

[0018] 晶型III的差示扫描量热分析图在接近136° C时处有吸热峰,焓值为57. 30J/g,加热至221° C时有一熔化峰,焓值为57. 71J/g。 Has a melting peak at [0018] Differential scanning calorimetry analysis of crystalline Form III in FIG endothermic peak at near 136 ° C, an enthalpy value of 57. 30J / g, was heated to 221 ° C, the enthalpy value of 57. 71J / g. 如图10。 10.

[0019] 晶型III可用如下方法制备:将2_氰基_3,12- 二氧代齐墩果-1,9 (11) - 二烯-28-酸甲酯溶解在四氢呋喃溶液中,将其与反溶剂正庚烷一起冷藏,经过反向反溶剂添加法将2-氰基-3,12- 二氧代齐墩果-1,9(11)- 二烯-28-酸甲酯的四氢呋喃溶液滴加到正庚烷中,然后混悬搅拌,即得。 [0019] Form III was prepared following methods are available: the _3,12- 2_ cyano-1,9-dioxo-olean (11) - diene -28- methyl ester was dissolved in tetrahydrofuran solution, with refrigerated anti-solvent n-heptane, after reverse antisolvent method 2-cyano-3,12-dioxo-olean-1,9 (11) - diene-methyl -28- tetrahydrofuran was added dropwise n-heptane, and then suspended with stirring, ie.

[0020] 本发明通过用甲苯、二氧六环和四氢呋喃作为溶剂重结晶,得到的溶剂合物具有毒性较小,稳定性好的优点,在室温密闭放置I个月晶型不发生改变,其稳定性试验的结果通过晶型储存前后的X射线粉末衍射图对比可见,见图12、13、14。 [0020] The present invention is by treatment with toluene, dioxane and tetrahydrofuran as a solvent and recrystallized solvate obtained with less toxicity, good stability, is placed in a closed room months polymorph I is not changed, which the results of the stability test by X-ray powder diffraction pattern of the polymorph stored before and after comparison can be seen, Figure 12, 13. 由图可见本发明的晶型 FIG crystalline form of the present invention can be seen

1、11和III密闭放置I个月后晶型不发生改变,说明本发明的三种晶型比较稳定。 1,11 sealed and placed Form III is not changed after I month, three kinds of crystal forms described in the present invention is relatively stable. 图12中下面的图为新制备的晶型I,上面的图为密闭放置I个月之后的晶型I。 Form I in the graph of FIG. 12 below freshly prepared, is placed above the sealed graph polymorph I. months after I 图13中上面的图为新制备的晶型II,下面的图为密闭放置I个月之后的晶型II。 Form II in FIG. 13 upper graph freshly prepared, placed in a sealed bottom portion shows the polymorph II after I month. 图14中上面的图为新制备的晶型III,下面的图为密闭放置I个月之后的晶型III。 Form III in FIG. 14 upper graph freshly prepared, placed in a sealed bottom portion shows the Form III after I month.

[0021] 本发明的晶型I、II、III制备中操作简单,溶剂用量少且无毒,生产成本低,在工业化方面具有明显优势。 Simple Form I, II, III prepared in operation [0021] of the present invention, less solvent and non-toxic, low production costs, it has obvious advantages in terms of industrialization.

附图说明[0022] 图I是晶型I的X射线粉末衍射图。 BRIEF DESCRIPTION [0022] Figure I is a X-ray powder diffraction pattern of Form I.

[0023] 图2是晶型I的热重分析图。 [0023] FIG 2 is a thermogravimetric analysis of Form I Fig.

[0024] 图3是晶型I的差示扫描量热分析图。 [0024] FIG. 3 is a differential scanning calorimetry thermogram of Form I.

[0025] 图4是晶型II的X射线粉末衍射图。 [0025] FIG. 4 is a polymorph II of the X-ray powder diffraction pattern.

[0026] 图5是晶型II的热重分析图。 [0026] FIG. 5 is a polymorph II of FIG thermogravimetric analysis.

[0027] 图6是晶型II的差示扫描量热分析图。 [0027] FIG. 6 is a crystalline form II of a differential scanning calorimetry thermogram.

[0028] 图7是晶型II的液态核磁图。 [0028] FIG. 7 is a liquid crystal Form II NMR FIG.

[0029] 图8是晶型III的X射线粉末衍射图。 [0029] FIG. 8 is an X-ray powder diffraction pattern of Form III.

[0030] 图9是晶型III的热重分析图。 [0030] FIG. 9 is a thermogravimetric analysis of Form III Fig.

[0031] 图10是晶型III的差示扫描量热分析图。 [0031] FIG. 10 is a differential scanning calorimetry thermogram of Form III.

[0032] 图11是晶型III的液态核磁图。 [0032] FIG. 11 is a liquid state NMR of Form III Fig.

[0033] 图12是晶型I的稳定性考察X射线粉末衍射图。 [0033] FIG 12 is an X-ray powder diffraction Stability of Form I Fig.

[0034] 图13是晶型II的稳定性考察X射线粉末衍射图。 [0034] FIG. 13 is the stability of Form II The X-ray powder diffraction pattern.

[0035] 图14是晶型III的稳定性考察X射线粉末衍射图。 [0035] FIG 14 is an X-ray powder diffraction stability of Form III of FIG.

具体实施方式 Detailed ways

[0036] 实施例I [0036] Example I

[0037] 取50mg 2_氰基_3,12-二氧代齐墩果_1,9 (11) - 二烯-28-酸甲酯溶解在500 μ L甲苯中,放置于通风橱中快速挥发,I天后即得到甲苯溶剂合物即晶型I 53. Smg0 [0037] Take 50mg 2_ cyano-dioxo-olean _3,12- _1,9 (11) - diene -28- methyl ester dissolved in 500 μ L of toluene, placed in a fume hood fast volatile, I days to obtain toluene solvate Form I 53. Smg0 i.e.

[0038] X射线粉末衍射图见图I。 [0038] X-ray powder diffraction pattern shown in Figure I. 热重分析图见图2。 Thermogravimetric analysis is shown in Figure 2. 差不扫描量热分析图见图3。 Differential scanning calorimetry is not shown in Figure 3.

[0039] 实施例2 [0039] Example 2

[0040] 将200mg的2_氰基_3,12- 二氧代齐墩果_1,9 (11) - 二烯-28-酸甲酯溶解在Iml体积比4 : I的1,4_ 二氧六环和水的混合溶液中,经过室温混悬搅拌24小时,得到的白色固体146mg。 [0040] The 2_ 200mg of cyano-dioxo-olean _3,12- _1,9 (11) - diene -28- methyl ester was dissolved in Iml volume ratio of 4: I, two 1,4_ six ring oxygen mixed solution of water and, after stirring at room temperature was suspended for 24 hours to give a white solid 146mg. 纯度为99. 48%。 Purity 99.48%. 白色固体即为晶型II,也是半1,4_ 二氧六环溶剂合物。 As a white solid, a crystal form II, is semi-1,4_ dioxane solvate.

[0041] X射线粉末衍射图见图4。 [0041] X-ray powder diffraction pattern shown in Figure 4. 热重分析谱图见图5。 TGA spectrum shown in Figure 5. 差不扫描量热分析图见图6。 Differential scanning calorimetry is not shown in Figure 6. 液态核磁图见图7。 Liquid NMR shown in Figure 7.

[0042] 实施例3 [0042] Example 3

[0043] 将16. 9mg的2_氰基_3,12-二氧代齐墩果_1,9 (11) - 二烯_28_酸甲酯溶解在 [0043] 16. 9mg of the cyano 2_ dioxo-olean _3,12- _1,9 (11) - diene _28_ acid methyl ester was dissolved in

0.2ml的四氢呋喃溶液中,将其与4. Oml的反溶剂正庚烷一起放置于_22° C中冷藏I小时,经过反向反溶剂添加法将2-氰基-3,12- 二氧代齐墩果-1,9(11)-二烯-28-酸甲酯的四氢呋喃溶液缓慢滴加到正庚烷中,然后混悬搅拌24小时,得到的白色固体11. 4mg.纯度99. 25%。 0.2ml of tetrahydrofuran, which was 4. Oml with heptane antisolvent placed in a refrigerated _22 ° C with I h, after reverse antisolvent 2-cyano-3,12-dioxo method Generation oleanolic-1,9 (11) - diene -28- methyl tetrahydrofuran was slowly added dropwise n-heptane, and then stirred for 24 hours was suspended, and the resulting white solid was 11. 4mg purity 99. 25%. 白色固体即为晶型III,也即半四氢呋喃溶剂合物。 As a white solid, a Form III, i.e. semi-tetrahydrofuran solvate.

[0044] X射线粉末衍射图见图8。 [0044] X-ray powder diffraction pattern shown in Figure 8. 热重分析图见图9。 Thermogravimetric analysis is shown in Figure 9. 差不扫描量热分析图见图10。 Differential scanning calorimetry is not shown in Figure 10. 液态核磁图见图11。 Liquid NMR shown in Figure 11.

Claims (10)

1. 一种2-氰基-3,12- 二氧代齐墩果-1,9 (11) - 二烯-28-酸甲酯的晶型I,其特征是:其X 射线粉末衍射图在光谱d-间距9. 65,7. 58,7. 18,6. 29,6. 06,5. 47,5. 21,4. 77 和3. 07埃具有特征峰。 A 2-cyano-3,12-dioxo-olean-1,9 (11) - diene-methyl -28- Form I, characterized by: an X-ray powder diffraction pattern 9. in the spectrum d- spacing 65,7. 58,7. 18,6. 29,6. 06,5. 47,5. 21,4. 77 and 3.07 angstroms with characteristic peaks.
2.权利要求I的晶型I,其为2-氰基-3,12- 二氧代齐墩果-1,9 (11) - 二烯-28-酸甲酯的甲苯溶剂合物,加热至180° C时失重为7.2%。 I 2. I crystalline form of claim 1, which is 2-cyano-3,12-dioxo-olean-1,9 (11) - diene -28- methyl toluene solvate is heated when weight loss of 7.2% to 180 ° C.
3.权利要求I的晶型I,其差示扫描量热分析图在接近117° C处有吸热峰。 I 3. The crystalline form as claimed in claim I, which is a differential scanning calorimetry thermogram endothermic peak at near 117 ° C.
4. 一种2-氰基-3,12- 二氧代齐墩果-1,9(11)- 二烯-28-酸甲酯的晶型II,其特征是:其X射线粉末衍射图在光谱d-间距10. 01,7. 09,6. 84,6. 23,5. 29,5. 20,5. 10,4. 84,和4. 61埃具有特征峰。 4. A 2-cyano-3,12-dioxo-olean-1,9 (11) - diene -28- methyl Form II, characterized by: an X-ray powder diffraction pattern spectrum having characteristic peaks at d- spacing 10. 01,7. 09,6. 84,6. 23,5. 29,5. 20,5. 10,4. 84, and 4.61 angstroms.
5.权利要求4的晶型II,其为2-氰基-3,12- 二氧代齐墩果-I,9(11) - 二烯-28-酸甲酯的半二氧六环溶剂合物,加热至195° C失重为8. 05%。 Half-dioxane solvent diene -28- methyl - polymorph II 4 of 9 (11) according to claim 1, which is 2-cyano-3,12-dioxo-olean -I, composition, was heated to 195 ° C a weight loss of 8.05%.
6.权利要求4的晶型II,其差示扫描量热分析图在接近150° C处有吸热峰。 Form II 4 in which a differential scanning calorimetry thermogram endothermic peak near 150 ° C at a claim.
7. —种2-氰基-3,12- 二氧代齐墩果-1,9 (11)- 二烯_28_酸甲酯的晶型III,其特征是:其X射线粉末衍射图在光谱d-间距10. 00,7. 14,6. 80,6. 65,6. 10,5. 62,5. 29,4. 88,和4. 50埃具有特征峰。 7. - kind of 2-cyano-3,12-dioxo-olean-1,9 (11) - diene _28_ methyl Form III, characterized in that: an X-ray powder diffraction pattern 10. the spectral d- spacing 00,7. 14,6. 80,6. 65,6. 10,5. 62,5. 29,4. 88, and 4.50 angstroms with characteristic peaks.
8.权利要求7的晶型III,其是2-氰基-3,12- 二氧代齐墩果-1,9(11)- 二烯-28-酸甲酯的半四氢呋喃溶剂合物,在加热至149° C时失重为6. 86%。 Form III 7 of claim 1, which is 2-cyano-3,12-dioxo-olean-1,9 (11) - diene semi-tetrahydrofuran solvate -28- methyl, when heated to 149 ° C a weight loss of 6.86%.
9.权利要求7的晶型III,其差示扫描量热分析图在接近136° C时处有吸热峰。 Form III 7 in which a differential scanning calorimetry thermogram at near 136 ° C endothermic peak as claimed in claim 9,.
10.权利要求7的晶型III的制备方法,包括:将2-氰基-3,12- 二氧代齐墩果-1,9 (II) - 二烯-28-酸甲酯溶解在四氢呋喃溶液中,将其与反溶剂正庚烷一起冷藏,经过反向反溶剂添加法将2-氰基-3,12- 二氧代齐墩果-1,9 (11)- 二烯-28-酸甲酯的四氢呋喃溶液滴加到正庚烷中,然后混悬搅拌,即得。 10. A method of preparing Form III of claim 7, comprising: 2-cyano-3,12-dioxo-olean -1,9 (II) - diene -28- methyl ester was dissolved in tetrahydrofuran solution, which was chilled with heptane antisolvent, France over the reverse antisolvent 2-cyano-3,12-dioxo-olean-1,9 (11) - diene -28- was added dropwise to a tetrahydrofuran solution of methyl n-heptane, and then suspended with stirring, ie.
CN2012104086159A 2012-10-24 2012-10-24 Crystal forms of 2-cyano-3,12-dioxoolean-1,9(11)-diene-28-oic acid methyl ester CN102887936A (en)

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US9278912B2 (en) 2012-09-10 2016-03-08 Reata Pharmaceuticals, Inc. C13-hydroxy derivatives of oleanolic acid and methods of use thereof
US9556222B2 (en) 2012-06-15 2017-01-31 Reata Pharmaceuticals, Inc. A-ring epoxidized triterpenoid-based anti-inflammation modulators and methods of use thereof
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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10093614B2 (en) 2008-04-18 2018-10-09 Reata Pharmaceuticals, Inc. Antioxidant Inflamation modulators: oleanolic acid derivatives with amino and other modifications at C-17
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US9278912B2 (en) 2012-09-10 2016-03-08 Reata Pharmaceuticals, Inc. C13-hydroxy derivatives of oleanolic acid and methods of use thereof
US9593074B2 (en) 2012-09-10 2017-03-14 Reata Pharmaceuticals, Inc. C17-alkanediyl and alkenediyl derivatives of oleanolic acid and methods of use thereof
WO2019014412A1 (en) 2017-07-13 2019-01-17 Pliva Hrvatska D.O.O. New crystalline polymorphs of bardoxolone methyl

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