WO2017092702A1 - Crystal form ii of obeticholic acid, preparation method and usage thereof - Google Patents
Crystal form ii of obeticholic acid, preparation method and usage thereof Download PDFInfo
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- WO2017092702A1 WO2017092702A1 PCT/CN2016/108283 CN2016108283W WO2017092702A1 WO 2017092702 A1 WO2017092702 A1 WO 2017092702A1 CN 2016108283 W CN2016108283 W CN 2016108283W WO 2017092702 A1 WO2017092702 A1 WO 2017092702A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
- C07J9/005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane containing a carboxylic function directly attached or attached by a chain containing only carbon atoms to the cyclopenta[a]hydrophenanthrene skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
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- 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 belongs to the field of chemical synthesis, and in particular, the invention relates to a crystal form II of cholestyric acid and a preparation method and use thereof.
- Obecholic acid is a highly active farnesoid X receptor (FXR) agonist developed by Intercept Pharmaceuticals, Inc., and was the first in 20 years to develop a primary treatment.
- Drugs for biliary cirrhosis and nonalcoholic fatty liver disease In 2014, Intercept Pharmaceuticals Inc. announced that Phase III clinical trials of nonalcoholic steatohepatitis (NASH) have achieved the primary clinical endpoint. The study of primary biliary cirrhosis is currently in Phase III clinical trials.
- FXR farnesoid X receptor
- the present invention aims to solve at least to some extent one of the technical problems in the related art, or at least to some extent, to provide a useful commercial choice. To this end, it is an object of the present invention to provide a new crystalline form of oleic acid with high purity, low impurity, stableness and uniformity.
- the invention provides a crystalline form II of oleic acid.
- 2 ⁇ is 4.9° ⁇ 0.2°, 5.3 ⁇ 0.2°, 6.3° ⁇ 0.2°, 7.2° ⁇ 0.2°, 7.7° ⁇ 0.2°, 8.9° ⁇ 0.2°, 9.9° ⁇ 0.2°, 10.6° ⁇ 0.2°, 11.0° ⁇ 0.2°, 12.4° ⁇ 0.2°, 12.6° ⁇ 0.2°, 14.9° ⁇ 0.2°, 15.3° ⁇ 0.2°, 15.9° ⁇ 0.2°, 16.5° ⁇ 0.2°, 16.7° ⁇ 0.2°, 18.0° ⁇ 0.2°, 19.0° ⁇ 0.2°, 20.6° ⁇ 0.2°, 21.0° Characteristic peaks at ⁇ 0.2° and 24.7° ⁇ 0.2°.
- the crystal form II of the present invention has high purity, low impurity, at least 99.5% by weight of oleic acid, and is stable and uniform, and can be effectively used for preventing or treating primary bile. Spontaneous cirrhosis or nonalcoholic fatty liver disease.
- X-ray powder diffraction studies have been widely used to elucidate molecular structure, crystallization and polymorphism, using Philips APD equipped with a 3 KW X-ray generator (CuK ⁇ 1 radiation) and a NaI (Ti) flash detector.
- the powder X-ray (XRD) was recorded on a Model 3720 powder diffractometer and measured from 3 to 45° (2 ⁇ ). Among them, the sample is kept at ambient temperature during the measurement.
- the oleic acid crystal form II may further have the following additional technical features:
- the crystal form II of oleic acid has an X-ray powder diffraction pattern as shown in FIG.
- the oleic acid crystal form II sample shows an endothermic peak at about 96.4 ° C in a DSC (TGA) (STA449 F3 Synchronous Thermal Analyzer - German Benz Instruments Manufacturing Co., Ltd.) chart.
- the above crystal form of oleic acid contains at least 99.5% by weight of oleic acid represented by Formula I, whereby the purity of the oligocholic acid II crystal form can be further improved.
- the invention provides the use of the above-described crystalline form II of olbecholic acid of the invention for the preparation of a medicament for the prevention or treatment of primary biliary cirrhosis and non- Alcoholic fatty liver disease. As a result, the drug treatment is better.
- the invention provides a process for the preparation of the crystal form II of the above embodiment, which comprises the steps of: (1) 3 ⁇ ,7 ⁇ -dihydroxy-6 ⁇ -alkyl -5?-cholic acid crude mixed with the first organic solvent and dissolved by heating to obtain a first mixture containing 3?,7?-dihydroxy-6?-alkyl-5?-cholanoic acid and a first organic solvent; a seed crystal is added to the first mixture, and is cooled to carry out crystallization to obtain a second mixture containing 3 ⁇ ,7 ⁇ -dihydroxy-6 ⁇ -alkyl-5 ⁇ -cholanoic acid, filtered, and the filter cake is used.
- the first organic solvent is washed, and the solid is collected to obtain a solid of 3 ⁇ ,7 ⁇ -dihydroxy-6 ⁇ -alkyl-5 ⁇ -cholanoic acid; (3) a second organic solvent is added to the collected solid, and heated and stirred to obtain 3 ⁇ ,7 ⁇ -dihydroxy-6 ⁇ -alkyl-5 ⁇ -cholanoic acid and a second organic solvent a third mixture; (4) subjecting the third mixture to temperature crystallization to obtain a fourth mixture containing crystals of 3 ⁇ ,7 ⁇ -dihydroxy-6 ⁇ -alkyl-5 ⁇ -cholanoic acid; (5) The mixture was filtered, and the filter cake was washed with the second organic solvent, followed by vacuum drying to obtain the crystal form II of the cholestyric acid.
- the method for preparing the crystal form II of oleic acid of the invention has the advantages of simple preparation process, mild reaction condition, high product yield, low production efficiency, low production cost, safety and environmental protection, and is beneficial to the oyster Industrialized large-scale production of acid crystal products.
- the first organic solvent is at least one selected from the group consisting of methanol, ethanol, isopropanol, ethyl acetate, tetrahydrofuran, acetone, tert-butyl methyl ether, methyl tetrahydrofuran, butyl acetate, and propyl acetate.
- the crude 3 ⁇ ,7 ⁇ -dihydroxy-6 ⁇ -alkyl-5 ⁇ -cholanoic acid can be sufficiently dissolved.
- the second organic solvent is at least one selected from the group consisting of acetone, methyl tert-butyl ether, n-hexane, n-heptane, most preferably n-heptane.
- a crude 3 ⁇ ,7 ⁇ -dihydroxy-6 ⁇ -alkyl-5 ⁇ -cholanoic acid is mixed with the first organic solvent in a mass of 1/2.5 to 1/5.
- the volume ratio is preferably 1/3 to 1/4 mass-volume ratio.
- the second organic solvent is added to the collected solids in a ratio of 1/4 to 1/6 by mass, preferably 1/4 to 1/5 by mass. .
- the collected solid can be sufficiently dissolved and the beating is sufficiently dispersed.
- the temperature is raised to 30 to 100 ° C, preferably 45 to 60 ° C, to effect the heating and dissolution.
- the crude 3 ⁇ ,7 ⁇ -dihydroxy-6 ⁇ -alkyl-5 ⁇ -cholanoic acid can be sufficiently dissolved, and the beating is sufficiently dispersed.
- the temperature is raised to 30 to 100 ° C, preferably 45 to 60 ° C, to effect the heating and dissolution.
- the collected solid can be sufficiently dissolved and the beating is sufficiently dispersed.
- the temperature is lowered to 0 to 40 ° C, preferably 0 to 20 ° C, more preferably 0 to 10 ° C to carry out the temperature-lowering crystallization.
- the product can be obtained in high yield and high purity.
- the vacuum drying is carried out at a temperature of 40 to 70 ° C, preferably 50 to 60 ° C.
- the solvent residue can be effectively dried and removed, and at the same time, high-temperature melting and crystal transformation does not occur.
- the oleic acid crystal form II of the present invention and the preparation method thereof have at least one of the following points:
- the present invention obtains a novel crystal form of oleic acid, and shows that it is a new crystalline compound which has not been reported in the literature by XRD data, and the compound can be stably existed and can be used as a preparation of amorphous bae The precursor of the acid product.
- the crystal form II of the present invention has high purity, low impurity, stability and uniformity.
- the method for preparing the crystal form II of oleic acid of the invention has the advantages of simple preparation process, mild reaction condition, high product yield, safety and environmental protection, and is favorable for the industrialized large-scale production of the oyster cholic acid crystal type product.
- the obtained crystal can be precipitated from the system with high purity, can effectively remove impurities during the reaction, improve production efficiency, and reduce production cost.
- the olbecholic acid crystalline form II of the present invention can be effectively used for the prevention or treatment of primary biliary cirrhosis and nonalcoholic fatty liver disease.
- Example 1 is a high performance liquid chromatogram of crystal form II of oleic acid according to Example 1 of the present invention
- Example 2 is a DSC-TGA chart of crystal form II of oleic acid according to Example 1 of the present invention
- Example 4 is an X-ray powder diffraction pattern of crystal form II of oleic acid according to Example 1 of the present invention.
- the general method for preparing oleic acid mainly comprises the following steps:
- Another organic solvent is added to the solid, stirred at a temperature, cooled and crystallized, filtered, washed with a filter cake, and dried at a controlled temperature to obtain a crystal form of oleic acid.
- the crystal form II of oleic acid is prepared according to the following procedure:
- the obtained products are about 4.9 ° ⁇ 0.2 °, 5.3 ⁇ 0.2 °, 6.3 ° ⁇ 0.2 °, 7.2 ° ⁇ 0.2 °, 7.7 ° ⁇ 0.2 °, 8.9 ° ⁇ 0.2 °, 9.9 ° ⁇ 0.2°, 10.6° ⁇ 0.2°, 11.0° ⁇ 0.2°, 12.4° ⁇ 0.2°, 12.6° ⁇ 0.2°, 14.9° ⁇ 0.2°, 15.3° ⁇ 0.2°, 15.9° ⁇ 0.2°, 16.5° ⁇ 0.2 Key absorption peaks at °, 16.7 ° ⁇ 0.2 °, 18.0 ° ⁇ 0.2 °, 19.0 ° ⁇ 0.2 °, 20.6 ° ⁇ 0.2 °, 21.0 ° ⁇ 0.2 ° and 24.7 ° ⁇ 0.2 ° (2 ⁇ ), indeed
- the cholesteric crystal form II has an X-ray powder diffraction pattern as shown in FIG.
- the crystal form II of oleic acid is prepared according to the following procedure:
- the crystal form II of oleic acid is prepared according to the following procedure:
- the wet product prepared above was taken, 500 ml of n-heptane was added, and the mixture was heated to 50 ° C and stirred for 12 hours. The mixture was cooled to 10 ° C for 5 h, filtered, and the filter cake was washed with 60 ml of n-heptane. It was then dried under vacuum at 55 ° C for 4 h. Finally, 83.0 g of product was obtained. It was confirmed by HPLC, DSC-TGA pattern, NMR hydrogen spectrum and XRD (X-ray powder diffraction pattern) that the obtained product was a crystal form II compound of oleic acid.
- the wet product prepared above was taken, and a volume of 16 ml of ethyl acetate was added thereto, and the mixture was heated to 50 ° C and stirred for 12 hours.
- the mixture was cooled to 10 ° C for 5 h, filtered, and the filter cake was washed with 5 ml of ethyl acetate. It was then dried under vacuum at 55 ° C for 4 h. 2.8 g of a compound in the molten state of oleic acid was obtained, and the residual solvent was as high as about 12%, and it was not sufficiently dried.
- the wet product prepared above was taken, and a volume of 16 ml of butyl acetate was added thereto, and the mixture was heated to 50 ° C and stirred for 12 hours.
- the mixture was cooled to 10 ° C for 5 h, filtered, and the filter cake was washed with 5 ml of butyl acetate. It was then dried under vacuum at 80 ° C for 4 h. 2.5 g of a compound in the molten state of oleic acid was obtained.
- Example 1 Comparing Comparative Example 1 and Comparative Example 2 with Example 1, it was found that the sample obtained from the comparative example was not easy to dry, the solvent was difficult to remove, and the sample was easily melted when the temperature was too high during vacuum drying, and Example 1
- the illustrated method of the present invention does not have these disadvantages, and is capable of efficiently obtaining a high purity, single heterogeneous, stable, and uniform oleic acid II crystal form compound.
- the crystal form II of the present invention is a crystalline powder having uniform particle size, high purity and good stability, and can be used for treating primary biliary cirrhosis and nonalcoholic fatty liver disease.
- the method for preparing the crystal form II of oleic acid of the invention has the advantages of simple preparation process, mild reaction condition, high product yield, safety and environmental protection, and is favorable for the industrialized large-scale production of the oyster cholic acid crystal type product.
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Abstract
Description
优先权信息Priority information
本申请请求2015年12月1日向中国国家知识产权局提交的、专利申请号为201510870285.9的专利申请的优先权和权益，并且通过参照将其全文并入此处。Priority is claimed on Japanese Patent Application No. 201510870285.9, the entire disclosure of which is incorporated herein by reference in its entirety in its entirety in its entirety in
本发明属于化学合成领域，具体而言，本发明涉及奥贝胆酸晶型Ⅱ及其制备方法和用途。The invention belongs to the field of chemical synthesis, and in particular, the invention relates to a crystal form II of cholestyric acid and a preparation method and use thereof.
奥贝胆酸(OCA，式I所示化合物)是由美国Intercept制药公司研发的一种高活性的法尼醇X受体(FXR)激动剂，是二十年来首个研发用于治疗原发性胆汁性肝硬化和非酒精性脂肪性肝病的药物。2014年美国Intercept制药公司宣布奥贝胆酸治疗非酒精性脂肪肝炎(nonalcoholic steatohepatitis，NASH)的Ⅲ期临床实验达到主要临床终点，治疗原发性胆汁性肝硬化的研究目前处于三期临床。Obecholic acid (OCA, a compound of formula I) is a highly active farnesoid X receptor (FXR) agonist developed by Intercept Pharmaceuticals, Inc., and was the first in 20 years to develop a primary treatment. Drugs for biliary cirrhosis and nonalcoholic fatty liver disease. In 2014, Intercept Pharmaceuticals Inc. announced that Phase III clinical trials of nonalcoholic steatohepatitis (NASH) have achieved the primary clinical endpoint. The study of primary biliary cirrhosis is currently in Phase III clinical trials.
然而，目前纯度高、单杂少、稳定、均一的奥贝胆酸晶型，仍有待研究。However, the current high purity, single-poor, stable, and uniform crystal form of oleic acid remains to be studied.
发明内容Summary of the invention
本发明旨在至少在一定程度上解决相关技术中的技术问题之一，或至少在一定程度提供一种有用的商业选择。为此，本发明的一个目的在于提出一种纯度高、单杂少、稳定、均一的奥贝胆酸新晶型。The present invention aims to solve at least to some extent one of the technical problems in the related art, or at least to some extent, to provide a useful commercial choice. To this end, it is an object of the present invention to provide a new crystalline form of oleic acid with high purity, low impurity, stableness and uniformity.
在本发明的一个方面，本发明提出了一种奥贝胆酸晶型Ⅱ。根据本发明的实施例，在所述奥贝胆酸晶型Ⅱ的X射线粉末衍射图中，2θ在4.9°±0.2°、5.3±0.2°、6.3°±0.2°、7.2°±0.2°、7.7°±0.2°、8.9°±0.2°、9.9°±0.2°、10.6°±0.2°、11.0°±0.2°、12.4°±0.2°、12.6°±0.2°、 14.9°±0.2°、15.3°±0.2°、15.9°±0.2°、16.5°±0.2°、16.7°±0.2°、18.0°±0.2°、19.0°±0.2°、20.6°±0.2°、21.0°±0.2°和24.7°±0.2°处具有特征峰。发明人惊奇地发现，本发明的奥贝胆酸晶型Ⅱ纯度高、单杂少、含有至少99.5％重量的奥贝胆酸，并且稳定、均一，能够有效用于预防或治疗原发性胆汁性肝硬化或非酒精性脂肪性肝病。In one aspect of the invention, the invention provides a crystalline form II of oleic acid. According to an embodiment of the present invention, in the X-ray powder diffraction pattern of the crystal form II of the oleic acid, 2θ is 4.9°±0.2°, 5.3±0.2°, 6.3°±0.2°, 7.2°±0.2°, 7.7°±0.2°, 8.9°±0.2°, 9.9°±0.2°, 10.6°±0.2°, 11.0°±0.2°, 12.4°±0.2°, 12.6°±0.2°, 14.9°±0.2°, 15.3°±0.2°, 15.9°±0.2°, 16.5°±0.2°, 16.7°±0.2°, 18.0°±0.2°, 19.0°±0.2°, 20.6°±0.2°, 21.0° Characteristic peaks at ±0.2° and 24.7°±0.2°. The inventors have surprisingly found that the crystal form II of the present invention has high purity, low impurity, at least 99.5% by weight of oleic acid, and is stable and uniform, and can be effectively used for preventing or treating primary bile. Spontaneous cirrhosis or nonalcoholic fatty liver disease.
需要说明的是，X-射线粉末衍射研究已广泛用于阐明分子结构、结晶和多晶型现象，用装有3KW X-射线发生器(CuKα1放射)和NaI(Ti)闪射检测器的Philips APD 3720型粉末衍射仪记录粉末X-射线(XRD)，从3～45°(2θ)进行测定即可。其中，测定中使样品保持在环境温度。It should be noted that X-ray powder diffraction studies have been widely used to elucidate molecular structure, crystallization and polymorphism, using Philips APD equipped with a 3 KW X-ray generator (CuKα1 radiation) and a NaI (Ti) flash detector. The powder X-ray (XRD) was recorded on a Model 3720 powder diffractometer and measured from 3 to 45° (2θ). Among them, the sample is kept at ambient temperature during the measurement.
另外，根据本发明的实施例，所述奥贝胆酸晶型Ⅱ还可以具有如下附加的技术特征：In addition, according to an embodiment of the present invention, the oleic acid crystal form II may further have the following additional technical features:
根据本发明的实施例，所述奥贝胆酸晶型Ⅱ具有如图4所示的X射线粉末衍射图谱。According to an embodiment of the invention, the crystal form II of oleic acid has an X-ray powder diffraction pattern as shown in FIG.
根据本发明的实施例，所述奥贝胆酸晶型Ⅱ样品在DSC(TGA)(STA449F3同步热分析仪—德国耐驰仪器制造有限公司)图中显示其在96.4℃左右有吸热峰。According to an embodiment of the present invention, the oleic acid crystal form II sample shows an endothermic peak at about 96.4 ° C in a DSC (TGA) (STA449 F3 Synchronous Thermal Analyzer - German Benz Instruments Manufacturing Co., Ltd.) chart.
根据本发明的实施例，上述奥贝胆酸的Ⅱ晶型含有至少99.5％重量的式I所示的奥贝胆酸，由此可以进一步提高奥贝胆酸Ⅱ晶型的纯度。According to an embodiment of the present invention, the above crystal form of oleic acid contains at least 99.5% by weight of oleic acid represented by Formula I, whereby the purity of the oligocholic acid II crystal form can be further improved.
在本发明的第二方面，本发明提出了前面所述的本发明的奥贝胆酸晶型Ⅱ在制备药物中的用途，所述药物用于预防或治疗原发性胆汁性肝硬化和非酒精性脂肪性肝病。由此，药物治疗效果更好。In a second aspect of the invention, the invention provides the use of the above-described crystalline form II of olbecholic acid of the invention for the preparation of a medicament for the prevention or treatment of primary biliary cirrhosis and non- Alcoholic fatty liver disease. As a result, the drug treatment is better.
在本发明的第三方面，本发明提出了一种制备上述实施例的奥贝胆酸晶型Ⅱ的方法，该方法包括以下步骤：(1)将3α,7α-二羟基-6α-烷基-5β-胆烷酸粗品与第一有机溶剂混合，并加热溶解，以便获得含有3α,7α-二羟基-6α-烷基-5β-胆烷酸和第一有机溶剂的第一混合物；(2)向所述第一混合物中加入晶种，并降温进行析晶，以便获得含3α,7α-二羟基-6α-烷基-5β-胆烷酸第二混合物，过滤，并将滤饼用所述第一有机溶剂洗涤，收集固体，以便获得3α,7α-二羟基-6α-烷基-5β-胆烷酸固体；(3)向收集的固体中加入第二有机溶剂，并加热搅拌，得到3α,7α-二羟基-6α-烷基-5β-胆烷酸和第二有机溶剂的第 三混合物；(4)将所述第三混合物进行降温析晶，以便获得含有3α,7α-二羟基-6α-烷基-5β-胆烷酸晶体的第四混合物；(5)将所述第四混合物过滤，用所述第二有机溶剂将滤饼进行洗涤，然后进行真空干燥，以便获得所述奥贝胆酸晶型Ⅱ。In a third aspect of the invention, the invention provides a process for the preparation of the crystal form II of the above embodiment, which comprises the steps of: (1) 3α,7α-dihydroxy-6α-alkyl -5?-cholic acid crude mixed with the first organic solvent and dissolved by heating to obtain a first mixture containing 3?,7?-dihydroxy-6?-alkyl-5?-cholanoic acid and a first organic solvent; a seed crystal is added to the first mixture, and is cooled to carry out crystallization to obtain a second mixture containing 3α,7α-dihydroxy-6α-alkyl-5β-cholanoic acid, filtered, and the filter cake is used. The first organic solvent is washed, and the solid is collected to obtain a solid of 3α,7α-dihydroxy-6α-alkyl-5β-cholanoic acid; (3) a second organic solvent is added to the collected solid, and heated and stirred to obtain 3α,7α-dihydroxy-6α-alkyl-5β-cholanoic acid and a second organic solvent a third mixture; (4) subjecting the third mixture to temperature crystallization to obtain a fourth mixture containing crystals of 3α,7α-dihydroxy-6α-alkyl-5β-cholanoic acid; (5) The mixture was filtered, and the filter cake was washed with the second organic solvent, followed by vacuum drying to obtain the crystal form II of the cholestyric acid.
根据本发明的实施例，本发明的制备奥贝胆酸晶型Ⅱ的方法，制备工艺简洁，反应条件温和，产品收率高，生产效率稿，生产成本低，安全环保，有利于奥贝胆酸晶型产品的工业化大生产。According to an embodiment of the present invention, the method for preparing the crystal form II of oleic acid of the invention has the advantages of simple preparation process, mild reaction condition, high product yield, low production efficiency, low production cost, safety and environmental protection, and is beneficial to the oyster Industrialized large-scale production of acid crystal products.
另外，根据本发明上述实施例的方法还可以具有如下附加的技术特征：In addition, the method according to the above-described embodiments of the present invention may further have the following additional technical features:
根据本发明的实施例，所述第一有机溶剂为选自甲醇、乙醇、异丙醇、乙酸乙酯、四氢呋喃、丙酮、叔丁基甲醚、甲基四氢呋喃、乙酸丁酯、乙酸丙酯的至少一种，优选乙酸乙酯、乙酸丁酯、乙酸丙酯的至少一种。由此，3α,7α-二羟基-6α-烷基-5β-胆烷酸粗品可以充分溶解。According to an embodiment of the present invention, the first organic solvent is at least one selected from the group consisting of methanol, ethanol, isopropanol, ethyl acetate, tetrahydrofuran, acetone, tert-butyl methyl ether, methyl tetrahydrofuran, butyl acetate, and propyl acetate. For example, at least one of ethyl acetate, butyl acetate, and propyl acetate is preferred. Thus, the crude 3α,7α-dihydroxy-6α-alkyl-5β-cholanoic acid can be sufficiently dissolved.
根据本发明的实施例，所述第二有机溶剂为选自丙酮、甲基叔丁基醚、正己烷、正庚烷的至少一种，最优选正庚烷。由此，可以充分打浆，分散固体，同时除去第一溶剂影响。According to an embodiment of the invention, the second organic solvent is at least one selected from the group consisting of acetone, methyl tert-butyl ether, n-hexane, n-heptane, most preferably n-heptane. Thereby, the pulp can be sufficiently beaten to disperse the solid while removing the influence of the first solvent.
根据本发明的实施例，在步骤(1)中，将3α,7α-二羟基-6α-烷基-5β-胆烷酸粗品与所述第一有机溶剂混合按照1/2.5～1/5质量体积比，优选1/3～1/4质量体积比混合。由此，可以充分溶解3α,7α-二羟基-6α-烷基-5β-胆烷酸粗品，并充分分散打浆。According to an embodiment of the present invention, in step (1), a crude 3α,7α-dihydroxy-6α-alkyl-5β-cholanoic acid is mixed with the first organic solvent in a mass of 1/2.5 to 1/5. The volume ratio is preferably 1/3 to 1/4 mass-volume ratio. Thereby, the crude 3α,7α-dihydroxy-6α-alkyl-5β-cholanoic acid can be sufficiently dissolved, and the beating is sufficiently dispersed.
根据本发明的实施例，在步骤(3)中，按照1/4～1/6质量体积比，优选1/4～1/5质量体积比，向收集的固体中加入所述第二有机溶剂。由此，可以充分溶解收集的固体，并充分分散打浆。According to an embodiment of the present invention, in the step (3), the second organic solvent is added to the collected solids in a ratio of 1/4 to 1/6 by mass, preferably 1/4 to 1/5 by mass. . Thereby, the collected solid can be sufficiently dissolved and the beating is sufficiently dispersed.
根据本发明的实施例，在步骤(1)中，升温至30～100℃，优选45～60℃，以进行所述加热溶解。由此，可以充分溶解3α,7α-二羟基-6α-烷基-5β-胆烷酸粗品，并充分分散打浆。According to an embodiment of the present invention, in the step (1), the temperature is raised to 30 to 100 ° C, preferably 45 to 60 ° C, to effect the heating and dissolution. Thereby, the crude 3α,7α-dihydroxy-6α-alkyl-5β-cholanoic acid can be sufficiently dissolved, and the beating is sufficiently dispersed.
根据本发明的实施例，在步骤(3)中，升温至30～100℃，优选45～60℃，以进行所述加热溶解。由此，可以充分溶解收集的固体，并充分分散打浆。According to an embodiment of the present invention, in the step (3), the temperature is raised to 30 to 100 ° C, preferably 45 to 60 ° C, to effect the heating and dissolution. Thereby, the collected solid can be sufficiently dissolved and the beating is sufficiently dispersed.
根据本发明的实施例，在步骤(4)中，降温至0～40℃，优选0～20℃，更优选0～10℃，以进行所述降温析晶。由此，可以高收率、高纯度地获得产物。According to an embodiment of the present invention, in the step (4), the temperature is lowered to 0 to 40 ° C, preferably 0 to 20 ° C, more preferably 0 to 10 ° C to carry out the temperature-lowering crystallization. Thereby, the product can be obtained in high yield and high purity.
根据本发明的实施例，于40～70℃，优选50～60℃的温度下进行所述真空干燥。由此可以有效干燥和除去溶剂残留，同时有不会出现高温熔化转晶。According to an embodiment of the invention, the vacuum drying is carried out at a temperature of 40 to 70 ° C, preferably 50 to 60 ° C. Thereby, the solvent residue can be effectively dried and removed, and at the same time, high-temperature melting and crystal transformation does not occur.
与现有技术相比，本发明的奥贝胆酸晶型Ⅱ及其制备方法具有下列有点的至少之一： Compared with the prior art, the oleic acid crystal form II of the present invention and the preparation method thereof have at least one of the following points:
1、本发明制备获得了一种新的奥贝胆酸晶型，并且经过XRD数据显示其为没有文献报道过的新晶型化合物，该化合物能够稳定存在，并且可以作为制备无定型奥贝胆酸产品的前体。1. The present invention obtains a novel crystal form of oleic acid, and shows that it is a new crystalline compound which has not been reported in the literature by XRD data, and the compound can be stably existed and can be used as a preparation of amorphous aussie The precursor of the acid product.
2、本发明的奥贝胆酸晶型Ⅱ，纯度高、单杂少、稳定、均一。2. The crystal form II of the present invention has high purity, low impurity, stability and uniformity.
3、本发明的制备奥贝胆酸晶型Ⅱ的方法，制备工艺简洁，反应条件温和，产品收率高，安全环保，有利于奥贝胆酸晶型产品的工业化大生产。所得晶体能以高纯度从体系中析出，可以有效地去除反应过程中的杂质，提高了生产效率，降低了生产成本。3. The method for preparing the crystal form II of oleic acid of the invention has the advantages of simple preparation process, mild reaction condition, high product yield, safety and environmental protection, and is favorable for the industrialized large-scale production of the oyster cholic acid crystal type product. The obtained crystal can be precipitated from the system with high purity, can effectively remove impurities during the reaction, improve production efficiency, and reduce production cost.
4、本发明的奥贝胆酸晶型Ⅱ可以有效用于预防或治疗原发性胆汁性肝硬化和非酒精性脂肪性肝病。4. The olbecholic acid crystalline form II of the present invention can be effectively used for the prevention or treatment of primary biliary cirrhosis and nonalcoholic fatty liver disease.
本发明附加方面和优点将在下面的描述中部分给出，部分将从下面的描述中变得明显，或通过本发明的实践了解到。The additional aspects and advantages of the invention will be set forth in part in the description which follows.
本发明的上述和/或附加的方面和优点从结合下面附图对实施例的描述中将变得明显和容易理解，其中：The above and/or additional aspects and advantages of the present invention will become apparent and readily understood from
图1为根据本发明实施例1的奥贝胆酸晶型Ⅱ的高效液相图谱；1 is a high performance liquid chromatogram of crystal form II of oleic acid according to Example 1 of the present invention;
图2为根据本发明实施例1的奥贝胆酸晶型Ⅱ的DSC-TGA图；2 is a DSC-TGA chart of crystal form II of oleic acid according to Example 1 of the present invention;
图3为根据本发明实施例1的奥贝胆酸晶型Ⅱ的NMR氢谱；3 is an NMR hydrogen spectrum of crystal form II of oleic acid according to Example 1 of the present invention;
图4为根据本发明实施例1的奥贝胆酸晶型Ⅱ的X射线粉末衍射图。4 is an X-ray powder diffraction pattern of crystal form II of oleic acid according to Example 1 of the present invention.
发明详细描述Detailed description of the invention
下面详细描述本发明的实施例，需要说明的是下面描述的实施例是示例性的，仅用于解释本发明，而不能理解为对本发明的限制。另外，如果没有明确说明，在下面的实施例中所采用的所有试剂均为市场上可以购得的，或者可以按照文本或已知的方法合成的，对于没有列出的反应条件，也均为本领域技术人员容易获得的。The embodiments of the present invention are described in detail below, and the embodiments described below are intended to be illustrative only and not to limit the invention. In addition, all reagents used in the following examples are commercially available if not explicitly stated, or may be synthesized according to text or known methods, and for the reaction conditions not listed, It is readily available to those skilled in the art.
一般方法General method
在下列实施例中，制备奥贝胆酸的一般方法主要包括以下步骤：In the following examples, the general method for preparing oleic acid mainly comprises the following steps:
称取3α,7α-二羟基-6α-烷基-5β-胆烷酸粗品，加入有机溶剂加热溶解，加入晶种降温析晶，过滤得到固体；Weigh 3α,7α-dihydroxy-6α-alkyl-5β-cholanoic acid crude, add to the organic solvent to heat and dissolve, add seed crystals to cool and crystallize, and filter to obtain a solid;
向固体加入另一有机溶剂，升温搅拌，降温析晶，过滤，滤饼洗涤，控制温度干燥得到奥贝胆酸Ⅱ晶型。 Another organic solvent is added to the solid, stirred at a temperature, cooled and crystallized, filtered, washed with a filter cake, and dried at a controlled temperature to obtain a crystal form of oleic acid.
实施例1奥贝胆酸晶型Ⅱ的制备Example 1 Preparation of Obicholic Acid Crystal Form II
根据本发明的制备奥贝胆酸晶型Ⅱ的方法，按照以下步骤制备奥贝胆酸晶型Ⅱ：According to the method for preparing the crystal form II of oleic acid according to the present invention, the crystal form II of oleic acid is prepared according to the following procedure:
(1)：3α,7α-二羟基-6α-烷基-5β-胆烷酸湿品的制备(1): Preparation of 3α,7α-dihydroxy-6α-alkyl-5β-cholanoic acid wet product
取4.0g 3α,7α-二羟基-6α-烷基-5β-胆烷酸，加入16ml乙酸丁酯，加热至50℃搅拌溶解，降温至10℃冷却析晶2h，过滤，滤饼用5ml乙酸丁酯洗涤，得到湿品3α,7α-二羟基-6α-烷基-5β-胆烷酸。Take 4.0g of 3α,7α-dihydroxy-6α-alkyl-5β-cholanoic acid, add 16ml of butyl acetate, heat to 50 ° C and stir to dissolve, cool down to 10 ° C, cool and crystallize for 2h, filter, filter cake with 5ml acetic acid The butyl ester was washed to obtain a wet 3α,7α-dihydroxy-6α-alkyl-5β-cholanoic acid.
(2)：奥贝胆酸晶型Ⅱ的制备(2): Preparation of oleic acid crystal form II
取上述制备的湿品，加入16ml正庚烷，加热至50℃搅拌12h。降温至10℃析晶5h，过滤，滤饼用5ml正庚烷洗涤。然后在55℃条件下真空干燥4h。最终得到3.0g产物。HPLC分析纯度为99.8％(高效液相图谱如图1所示)。经DSC-TGA图谱分析(结果如图2所示)可知，该产物在96.4℃左右融化。The wet product prepared above was taken, 16 ml of n-heptane was added, and the mixture was heated to 50 ° C and stirred for 12 hours. The mixture was cooled to 10 ° C for 5 h, filtered, and the filter cake was washed with 5 ml of n-heptane. It was then dried under vacuum at 55 ° C for 4 h. Finally, 3.0 g of product was obtained. HPLC analysis showed a purity of 99.8% (high performance liquid chromatogram as shown in Figure 1). The DSC-TGA pattern analysis (results shown in Figure 2) showed that the product melted around 96.4 °C.
该产物的NMR氢谱如图3所示，且1H-NMR(400MHz,DMSO-d6)：δ0.61(s,1H),0.81-0.93(m,9H),2.12-2.23(m,2H),3.13(m,1H),3.50(brs,1H),4.06-4.07(d,1H),4.3(d,1H),11.97(s,1H)，。The NMR hydrogen spectrum of this product is shown in Figure 3, and 1 H-NMR (400 MHz, DMSO-d6): δ 0.61 (s, 1H), 0.81 - 0.93 (m, 9H), 2.12 - 2.23 (m, 2H) ), 3.13 (m, 1H), 3.50 (brs, 1H), 4.06-4.07 (d, 1H), 4.3 (d, 1H), 11.97 (s, 1H).
进一步，经XRD分析，所制得的产物在约4.9°±0.2°、5.3±0.2°、6.3°±0.2°、7.2°±0.2°、7.7°±0.2°、8.9°±0.2°、9.9°±0.2°、10.6°±0.2°、11.0°±0.2°、12.4°±0.2°、12.6°±0.2°、14.9°±0.2°、15.3°±0.2°、15.9°±0.2°、16.5°±0.2°、16.7°±0.2°、18.0°±0.2°、19.0°±0.2°、20.6°±0.2°、21.0°±0.2°和24.7°±0.2°(2θ)处有关键的吸收峰，确为奥贝胆酸晶型Ⅱ，其X射线粉末衍射图如图4所示。Further, by XRD analysis, the obtained products are about 4.9 ° ± 0.2 °, 5.3 ± 0.2 °, 6.3 ° ± 0.2 °, 7.2 ° ± 0.2 °, 7.7 ° ± 0.2 °, 8.9 ° ± 0.2 °, 9.9 ° ±0.2°, 10.6°±0.2°, 11.0°±0.2°, 12.4°±0.2°, 12.6°±0.2°, 14.9°±0.2°, 15.3°±0.2°, 15.9°±0.2°, 16.5°±0.2 Key absorption peaks at °, 16.7 ° ± 0.2 °, 18.0 ° ± 0.2 °, 19.0 ° ± 0.2 °, 20.6 ° ± 0.2 °, 21.0 ° ± 0.2 ° and 24.7 ° ± 0.2 ° (2θ), indeed The cholesteric crystal form II has an X-ray powder diffraction pattern as shown in FIG.
由此，确定制备得到3.0g奥贝胆酸晶型Ⅱ化合物。Thus, it was confirmed that 3.0 g of the compound of the form II of cholestyramine was prepared.
实施例2奥贝胆酸晶型Ⅱ的制备Example 2 Preparation of Obicholic Acid Crystal Form II
根据本发明的制备奥贝胆酸晶型Ⅱ的方法，按照以下步骤制备奥贝胆酸晶型Ⅱ：According to the method for preparing the crystal form II of oleic acid according to the present invention, the crystal form II of oleic acid is prepared according to the following procedure:
(1)：3α,7α-二羟基-6α-烷基-5β-胆烷酸湿品的制备(1): Preparation of 3α,7α-dihydroxy-6α-alkyl-5β-cholanoic acid wet product
取4.0g 3α,7α-二羟基-6α-烷基-5β-胆烷酸，加入13.4ml乙酸丁酯，加热至50℃搅拌溶解，降温至10℃冷却析晶2h，过滤，滤饼用5ml乙酸丁酯洗涤，得到湿品3α,7α-二羟基-6α-烷基-5β-胆烷酸。Take 4.0g of 3α,7α-dihydroxy-6α-alkyl-5β-cholanoic acid, add 13.4ml of butyl acetate, heat to 50 ° C and stir to dissolve, cool down to 10 ° C, cool and crystallize for 2h, filter, filter cake with 5ml Washing with butyl acetate gave wet 3α,7α-dihydroxy-6α-alkyl-5β-cholanoic acid.
(2)：奥贝胆酸晶型Ⅱ的制备(2): Preparation of oleic acid crystal form II
取上述制备的湿品，加入18ml正庚烷，加热至50℃搅拌12h。降温至10℃析晶5h，过滤，滤饼用5ml正庚烷洗涤。然后在55℃条件下真空干燥4h。最终得到3.2g产物。HPLC分析纯度为99.8％ The wet product prepared above was taken, 18 ml of n-heptane was added, and the mixture was heated to 50 ° C and stirred for 12 hours. The mixture was cooled to 10 ° C for 5 h, filtered, and the filter cake was washed with 5 ml of n-heptane. It was then dried under vacuum at 55 ° C for 4 h. Finally, 3.2 g of product was obtained. HPLC analysis purity was 99.8%
实施例3奥贝胆酸晶型Ⅱ的制备Example 3 Preparation of Obicholic Acid Crystal Form II
根据本发明的制备奥贝胆酸晶型Ⅱ的方法，按照以下步骤制备奥贝胆酸晶型Ⅱ：According to the method for preparing the crystal form II of oleic acid according to the present invention, the crystal form II of oleic acid is prepared according to the following procedure:
(1)：3α,7α-二羟基-6α-烷基-5β-胆烷酸湿品的制备(1): Preparation of 3α,7α-dihydroxy-6α-alkyl-5β-cholanoic acid wet product
取100g 3α,7α-二羟基-6α-烷基-5β-胆烷酸，加入300ml乙酸丁酯，加热至50℃搅拌溶解。降温至10℃冷却析晶2h。过滤，滤饼用20ml乙酸丁酯洗涤，得到湿品3α,7α-二羟基-6α-烷基-5β-胆烷酸。100 g of 3α,7α-dihydroxy-6α-alkyl-5β-cholanoic acid was taken, 300 ml of butyl acetate was added, and the mixture was heated to 50 ° C and stirred to dissolve. Cool down to 10 ° C and cool the crystallization for 2 h. After filtration, the filter cake was washed with 20 ml of butyl acetate to give wet 3?,7?-dihydroxy-6?-alkyl-5?-cholanoic acid.
(2)：奥贝胆酸晶型Ⅱ的制备(2): Preparation of oleic acid crystal form II
取上述制备的湿品，加入500ml正庚烷，加热至50℃搅拌12h。降温至10℃析晶5h，过滤，滤饼用60ml正庚烷洗涤。然后在55℃条件下真空干燥4h。最终得到83.0g产物。经HPLC、DSC-TGA图谱、NMR氢谱、XRD(X射线粉末衍射图)分析确认，所得产物即为奥贝胆酸晶型Ⅱ化合物.The wet product prepared above was taken, 500 ml of n-heptane was added, and the mixture was heated to 50 ° C and stirred for 12 hours. The mixture was cooled to 10 ° C for 5 h, filtered, and the filter cake was washed with 60 ml of n-heptane. It was then dried under vacuum at 55 ° C for 4 h. Finally, 83.0 g of product was obtained. It was confirmed by HPLC, DSC-TGA pattern, NMR hydrogen spectrum and XRD (X-ray powder diffraction pattern) that the obtained product was a crystal form II compound of oleic acid.
对比例1Comparative example 1
参照实施例1的方法，按照以下步骤制备奥贝胆酸：Referring to the method of Example 1, the preparation of oleic acid was carried out as follows:
取4.0g 3α,7α-二羟基-6α-烷基-5β-胆烷酸，加入16ml乙酸丁酯，加热至50℃搅拌溶解，降温至10℃冷却析晶2h，过滤，滤饼用5ml乙酸丁酯洗涤，得到湿品3α,7α-二羟基-6α-烷基-5β-胆烷酸。Take 4.0g of 3α,7α-dihydroxy-6α-alkyl-5β-cholanoic acid, add 16ml of butyl acetate, heat to 50 ° C and stir to dissolve, cool down to 10 ° C, cool and crystallize for 2h, filter, filter cake with 5ml acetic acid The butyl ester was washed to obtain a wet 3α,7α-dihydroxy-6α-alkyl-5β-cholanoic acid.
取上述制备的湿品，加入16ml体积乙酸乙酯，加热至50℃搅拌12h。降温至10℃析晶5h，过滤，滤饼用5ml乙酸乙酯洗涤。然后在55℃条件下真空干燥4h。得到奥贝胆酸熔融状态化合物2.8g，残留溶剂高达12％左右，无法充分干燥。The wet product prepared above was taken, and a volume of 16 ml of ethyl acetate was added thereto, and the mixture was heated to 50 ° C and stirred for 12 hours. The mixture was cooled to 10 ° C for 5 h, filtered, and the filter cake was washed with 5 ml of ethyl acetate. It was then dried under vacuum at 55 ° C for 4 h. 2.8 g of a compound in the molten state of oleic acid was obtained, and the residual solvent was as high as about 12%, and it was not sufficiently dried.
对比例2Comparative example 2
参照实施例1的方法，按照以下步骤制备奥贝胆酸：Referring to the method of Example 1, the preparation of oleic acid was carried out as follows:
取4.0g 3α,7α-二羟基-6α-烷基-5β-胆烷酸，加入16ml乙酸丁酯，加热至50℃搅拌溶解，降温至10℃冷却析晶2h，过滤，滤饼用5ml乙酸丁酯洗涤，得到湿品3α,7α-二羟基-6α-烷基-5β-胆烷酸。Take 4.0g of 3α,7α-dihydroxy-6α-alkyl-5β-cholanoic acid, add 16ml of butyl acetate, heat to 50 ° C and stir to dissolve, cool down to 10 ° C, cool and crystallize for 2h, filter, filter cake with 5ml acetic acid The butyl ester was washed to obtain a wet 3α,7α-dihydroxy-6α-alkyl-5β-cholanoic acid.
取上述制备的湿品，加入16ml体积乙酸丁酯，加热至50℃搅拌12h。降温至10℃析晶5h，过滤，滤饼分别用5ml乙酸丁酯洗涤。然后在80℃条件下真空干燥4h。得到奥贝胆酸熔融状态化合物2.5g。 The wet product prepared above was taken, and a volume of 16 ml of butyl acetate was added thereto, and the mixture was heated to 50 ° C and stirred for 12 hours. The mixture was cooled to 10 ° C for 5 h, filtered, and the filter cake was washed with 5 ml of butyl acetate. It was then dried under vacuum at 80 ° C for 4 h. 2.5 g of a compound in the molten state of oleic acid was obtained.
将对比例1、对比例2与实施例1进行比较发现，对比例获得的奥贝胆酸样品不易干燥，溶剂难除，并且真空干燥时温度过高样品易于变成熔融状态，而实施例1所示的本发明的方法没有这些缺点，且能够高效获得纯度高、单杂小、稳定、均一的奥贝胆酸Ⅱ晶型化合物。Comparing Comparative Example 1 and Comparative Example 2 with Example 1, it was found that the sample obtained from the comparative example was not easy to dry, the solvent was difficult to remove, and the sample was easily melted when the temperature was too high during vacuum drying, and Example 1 The illustrated method of the present invention does not have these disadvantages, and is capable of efficiently obtaining a high purity, single heterogeneous, stable, and uniform oleic acid II crystal form compound.
本发明的奥贝胆酸晶型Ⅱ呈颗粒大小均一的结晶性粉末，纯度高，稳定性较好，能够用于治疗原发性胆汁性肝硬化和非酒精性脂肪性肝病。本发明的制备奥贝胆酸晶型Ⅱ的方法，制备工艺简洁，反应条件温和，产品收率高，安全环保，有利于奥贝胆酸晶型产品的工业化大生产。The crystal form II of the present invention is a crystalline powder having uniform particle size, high purity and good stability, and can be used for treating primary biliary cirrhosis and nonalcoholic fatty liver disease. The method for preparing the crystal form II of oleic acid of the invention has the advantages of simple preparation process, mild reaction condition, high product yield, safety and environmental protection, and is favorable for the industrialized large-scale production of the oyster cholic acid crystal type product.
尽管本发明的具体实施方式已经得到详细的描述，本领域技术人员将会理解。根据已经公开的所有教导，可以对那些细节进行各种修改和替换，这些改变均在本发明的保护范围之内。本发明的全部范围由所附权利要求及其任何等同物给出。Although specific embodiments of the invention have been described in detail, those skilled in the art will understand. Various modifications and alterations of the details are possible in light of the teachings of the invention. The full scope of the invention is given by the appended claims and any equivalents thereof.
在本说明书的描述中，参考术语“一个实施例”、“一些实施例”、“示意性实施例”、“示例”、“具体示例”、或“一些示例”等的描述意指结合该实施例或示例描述的具体特征、结构、材料或者特点包含于本发明的至少一个实施例或示例中。在本说明书中，对上述术语的示意性表述不一定指的是相同的实施例或示例。而且，描述的具体特征、结构、材料或者特点可以在任何的一个或多个实施例或示例中以合适的方式结合。 In the description of the present specification, the description with reference to the terms "one embodiment", "some embodiments", "illustrative embodiment", "example", "specific example", or "some examples", etc. Particular features, structures, materials or features described in the examples or examples are included in at least one embodiment or example of the invention. In the present specification, the schematic representation of the above terms does not necessarily mean the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in a suitable manner in any one or more embodiments or examples.
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| EP3248983A4 (en) * | 2014-12-30 | 2017-12-13 | Crystal Pharmatech Co. Ltd. | Crystal form a of obeticholic acid and preparation method therefor |
| WO2019106043A1 (en) | 2017-11-29 | 2019-06-06 | Hexal Ag | Pharmaceutical composition comprising obeticholic acid |
| WO2019197962A1 (en) * | 2018-04-09 | 2019-10-17 | Biophore India Pharmaceuticals Pvt. Ltd | Crystalline forms of (3α, 5β, 6α, 7α)-6-ethyl-3, 7-dihydroxycholan-24-oic acid (obeticholic acid) and processes thereof |
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| CN109280071A (en) * | 2017-07-19 | 2019-01-29 | 东莞东阳光药物研发有限公司 | Crystal form of obeticholic acid and preparation method thereof |
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| WO2013192097A1 (en) * | 2012-06-19 | 2013-12-27 | Intercept Pharmaceuticals, Inc. | Preparation, uses and solid forms of obeticholic acid |
| CN105801653A (en) * | 2014-12-30 | 2016-07-27 | 苏州晶云药物科技有限公司 | Crystal form A of obeticholic acid, and preparation method thereof |
| CN105859814A (en) * | 2015-01-23 | 2016-08-17 | 江苏奥赛康药业股份有限公司 | Obeticholic acid compound and pharmaceutical composition thereof |
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| WO2019106043A1 (en) | 2017-11-29 | 2019-06-06 | Hexal Ag | Pharmaceutical composition comprising obeticholic acid |
| WO2019197962A1 (en) * | 2018-04-09 | 2019-10-17 | Biophore India Pharmaceuticals Pvt. Ltd | Crystalline forms of (3α, 5β, 6α, 7α)-6-ethyl-3, 7-dihydroxycholan-24-oic acid (obeticholic acid) and processes thereof |
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