WO2017092703A1 - 制备无定型奥贝胆酸的方法 - Google Patents

制备无定型奥贝胆酸的方法 Download PDF

Info

Publication number
WO2017092703A1
WO2017092703A1 PCT/CN2016/108285 CN2016108285W WO2017092703A1 WO 2017092703 A1 WO2017092703 A1 WO 2017092703A1 CN 2016108285 W CN2016108285 W CN 2016108285W WO 2017092703 A1 WO2017092703 A1 WO 2017092703A1
Authority
WO
WIPO (PCT)
Prior art keywords
oleic acid
solution
mixture
acid
temperature
Prior art date
Application number
PCT/CN2016/108285
Other languages
English (en)
French (fr)
Inventor
秦志平
王火箭
冷正文
钱丽娜
崔健
Original Assignee
中美华世通生物医药科技（武汉）有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 中美华世通生物医药科技（武汉）有限公司 filed Critical 中美华世通生物医药科技（武汉）有限公司
Publication of WO2017092703A1 publication Critical patent/WO2017092703A1/zh

Links

Images

Classifications

    • 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

Definitions

  • the present invention is in the field of chemical synthesis, and in particular, the present invention relates to a process for preparing amorphous oleic acid.
  • 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
  • an object of the present invention is to provide a method for preparing amorphous oleic acid, which has mild reaction conditions and simple process, and can efficiently obtain a high-purity, dispersed powdered oleic acid amorphous product.
  • the obtained amorphous oleic acid can be effectively used for the prevention or treatment of primary biliary cirrhosis and nonalcoholic fatty liver disease.
  • the present invention provides a method for preparing amorphous oleic acid, which comprises: (1) contacting a raw material of oleic acid with an alkaline solution to obtain a cholestyric acid containing a first mixture; (2) arranging the acidic solution and maintaining the acidic solution at a predetermined temperature; (3) adding the first mixture to the acidic solution to obtain a second mixture; (4) The second mixture is subjected to precipitation precipitation, the solid is separated, and the separated solid is vacuum dried to obtain the amorphous oleic acid.
  • the inventors have surprisingly found that the method has mild reaction conditions, simple process, and high purity and dispersion.
  • a good powdered oleic acid amorphous product, the resulting amorphous oleic acid can be effectively used for the prevention or treatment of primary biliary cirrhosis and non-alcoholic fatty liver disease.
  • the method for preparing amorphous oleic acid may further have the following additional technical features:
  • the oleic acid raw material is oligocholic acid crystalline form II.
  • the high-purity, dispersed amorphous oleic acid of the present invention can be obtained.
  • the 2 ⁇ is 4.9° ⁇ 0.2°, 5.3 ⁇ 0.2°, 6.3° ⁇ 0.2°, 7.2° ⁇ 0.2.
  • the oleic acid form II has an X-ray powder diffraction pattern as shown in FIG.
  • X-ray powder diffraction studies have been widely used to elucidate molecular structure, crystallization and polymorphism, using Philips APD3720 equipped with a 3KW X-ray generator (CuK ⁇ 1 radiation) and a NaI (Ti) flash detector.
  • the powder X-ray (XRD) was recorded by a powder diffractometer, and it was measured from 3 to 45 (2 ⁇ ). Among them, the sample was kept at ambient temperature during the measurement.
  • the oleic acid crystal form II sample exhibits an endothermic peak of about 96.4 ° C in a DSC (TGA) (STA449 F3 Synchronous Thermal Analyzer - German Benz Instruments Manufacturing Co., Ltd.) chart.
  • the alkaline solution is at least one selected from the group consisting of sodium hydroxide solution and potassium hydroxide solution, preferably a sodium hydroxide solution.
  • the sodium salt formed with oleic acid can be sufficiently completely dissolved into the aqueous phase system.
  • the concentration of the alkaline solution is from 1.0 to 2.0% by weight, preferably from 1.2 to 1.5% by weight. This makes it possible to completely form a salt and not to cause a side reaction due to an excessively high concentration.
  • the oleic acid raw material is contacted with the alkaline solution at a temperature of 20 to 30 ° C, preferably 25 to 30 ° C.
  • the system can be fully dissolved and subsequent temperature control can be facilitated.
  • the oleic acid raw material is contacted with the alkaline solution in a weight ratio of 1:10 to 1.5:10. Thereby, the system can be sufficiently dissolved.
  • the acidic solution inorganic acid aqueous solution preferably at least one of concentrated aqueous solutions of hydrochloric acid, sulfuric acid, and phosphoric acid, more preferably concentrated aqueous hydrochloric acid.
  • the first mixture containing oleic acid can be sufficiently dissolved and mixed.
  • the concentration of the acidic solution is from 0.5 to 1.5% by weight, preferably from 0.5 to 0.8% by weight.
  • the acid can be sufficiently neutralized to precipitate a solid.
  • the predetermined temperature is 30 to 50 ° C, preferably 40 to 50 ° C.
  • the reaction in the step (3), at a temperature of 40 to 60 ° C, preferably 40 to 50 ° C
  • the first mixture is added dropwise to the acidic solution.
  • the reaction can be made sufficient, and the system can be sufficiently dispersed.
  • the first mixture is added dropwise to the acidic solution at a mass ratio of 7:20 to 15:20. Thereby, the reaction can be made sufficient.
  • the second mixture in the step (4), is cooled to 10 to 30 ° C, preferably 20 to 30 ° C, in order to effect precipitation crystallization.
  • the yield can be effectively improved and the purity of the precipitated crystal can be controlled.
  • the vacuum drying is carried out at a temperature of 40 to 60 ° C, preferably 40 to 50 ° C.
  • the applicant has found through trial and error research that the above method of the present invention can not only efficiently produce amorphous cholestyric acid, but also obtain a high-purity, dispersed powder state amorphous Aobe. cholic acid.
  • Example 1 is an X-ray powder diffraction pattern of crystal form II of oleic acid according to Example 1 of the present invention
  • Example 2 is a HPLC high performance liquid chromatogram of amorphous oleic acid according to Example 4 of the present invention
  • Figure 3 is an X-ray powder diffraction pattern of an acid amorphous austemper according to Example 4 of the present invention.
  • the 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° ⁇ 0.2°, and 24.7° ⁇ 0.2 There is a characteristic peak at °.
  • amorphous oleic acid is synthesized according to the following steps:
  • the first mixture containing the oleic acid of step (1) is rapidly added dropwise to the aqueous hydrochloric acid solution prepared in the step (2) while stirring, and the mixture is thoroughly stirred during the addition, and the temperature of the control system is 40 ° C to precipitate a large amount of white solid. .
  • the temperature was lowered to about 20 ° C, and washed by filtration to obtain a filter cake. Then, the filter cake was dried in a vacuum drying oven at 40 ° C for 20 hours to obtain 0.74 g of a well-dispersed powdered oleic acid with a yield of 91.4%. .
  • amorphous oleic acid is synthesized according to the following steps:
  • the first mixture containing the oleic acid of step (1) is rapidly added dropwise to the aqueous hydrochloric acid solution prepared in the step (2) while stirring, and the mixture is thoroughly stirred during the addition, and the temperature of the control system is 45 ° C to precipitate a large amount of white solid. .
  • the temperature was lowered to about 20 ° C, and washed by filtration to obtain a filter cake. Then, the filter cake was dried in a vacuum drying oven at 45 ° C for 20 hours to obtain 13.8 g of a well-dispersed powdered oleic acid with a yield of 91.3%. .
  • amorphous oleic acid is synthesized according to the following steps:
  • the first mixture containing the oleic acid of step (1) was quickly added dropwise to the aqueous hydrochloric acid solution prepared in the step (2) while stirring, and the mixture was thoroughly stirred during the addition, and the temperature of the system was controlled at 50 ° C to precipitate a large amount of white solid. After heating and stirring for 1 hour, the temperature was lowered to about 25 ° C, and washed by filtration to obtain a filter cake. Then, the filter cake was dried in a vacuum drying oven at 50 ° C for 20 hours to obtain 0.70 kg of a well-dispersed powdered oleic acid with a yield of 92.1%. . The purity was 99.9% by HPLC and the HPLC high performance liquid chromatogram is shown in Figure 2.
  • X-ray analysis confirmed that the crystal form was amorphous, and the X-ray powder diffraction pattern of the amorphous form of oleic acid was as shown in FIG.
  • the alkaline solution containing the oleic acid obtained in the step (1) is rapidly added dropwise to the aqueous hydrochloric acid solution prepared in the step (2) under stirring, and the mixture is thoroughly stirred during the addition, and the temperature of the system is controlled at 30 ° C to 35 ° C. A large amount of white solid precipitated. After heating and stirring for 2 hours, the temperature was lowered to about 20 ° C, and washed by filtration. The filter cake was dried in a vacuum drying oven at 45 ° C for 12 h to obtain 0.66 g of a bulk solid, that is, solid oleic acid, which was poor in properties and poor in dispersion. Agglomeration, and the solid oleic acid yield was only 80.9%.
  • the comparative multiple tests show that the present invention can efficiently produce a high-purity, dispersed powdery amorphous bis-cholic acid product by controlling the optimized reaction temperature and relevant experimental conditions at each step.
  • the method for preparing amorphous oleic acid of the invention has mild reaction conditions and simple process, and can efficiently obtain a high-purity, dispersed powder-form amorphous cholestyric acid product.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Steroid Compounds (AREA)

Abstract

提供了制备无定型奥贝胆酸的方法。其中，该方法包括：(1)将奥贝胆酸原料与碱性溶液接触，以便获得含有奥贝胆酸的第一混合物；(2)配置酸性溶液并使所述酸性溶液保持预定温度；(3)将所述第一混合物滴加至所述酸性溶液中，以便获得第二混合物；(4)将所述第二混合物进行降温沉淀，分离固体，并对所分离的固体进行真空干燥，以便获得所述无定型奥贝胆酸。

Description

制备无定型奥贝胆酸的方法
优先权信息
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201510870311.8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。
技术领域
本发明属于化学合成领域，具体而言，本发明涉及制备无定型奥贝胆酸的方法。
背景技术
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。
Figure PCTCN2016108285-appb-000001
然而，目前制备奥贝胆酸产品的方法，仍有待改进。
发明内容
本发明旨在至少在一定程度上解决上述技术问题之一或至少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了一种制备无定型奥贝胆酸的方法，该方法反应条件温和，工艺简单，能高效得到高纯度、分散好的粉末状奥贝胆酸无定型产品，所得的无定型奥贝胆酸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。
根据本发明的第一方面，本发明提出了一种制备无定型奥贝胆酸的方法，该方法包括：(1)将奥贝胆酸原料与碱性溶液接触，以便获得含有奥贝胆酸的第一混合物；(2)配置酸性溶液并使所述酸性溶液保持预定温度；(3)将所述第一混合物滴加至所述酸性溶液中，以便获得第二混合物；(4)将所述第二混合物进行降温沉淀，分离固体，并对所分离的固体进行真空干燥，以便获得所述无定型奥贝胆酸。
发明人惊奇地发现，该方法反应条件温和，工艺简单，能高效得到高纯度、分散 好的粉末状奥贝胆酸无定型产品，所得的无定型奥贝胆酸可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。
另外，根据本发明的实施例，所述制备无定型奥贝胆酸的方法还可以具有如下附加的技术特征：
根据本发明的实施例，所述奥贝胆酸原料为奥贝胆酸晶型Ⅱ。由此可以获得本发明所述的高纯度、分散好的无定型奥贝胆酸。
根据本发明的具体实施例，在所述奥贝胆酸晶型Ⅱ的X射线粉末衍射图中，其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。
根据本发明的具体实施例，奥贝胆酸晶型Ⅱ具有如图1所示的X射线粉末衍射图谱。
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 APD3720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，测定中样品保持在环境温度。
根据本发明的具体实施例，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96.4℃左右吸热峰。
根据本发明的实施例，所述碱性溶液为选自氢氧化钠溶液和氢氧化钾溶液中的至少一种，优选为氢氧化钠溶液。由此，可以与奥贝胆酸形成钠盐充分完全地溶解到水相体系中。
根据本发明的实施例，所述碱性溶液的浓度为1.0～2.0重量％，优选为1.2～1.5重量％。由此可以完全成盐且不至于浓度过高引起副反应。
根据本发明的实施例，在步骤(1)中，于20～30℃，优选25～30℃的温度下将所述奥贝胆酸原料与所述碱性溶液接触。由此，可以使体系充分溶解以及方便后续温度控制。
根据本发明的实施例，按照1:10～1.5:10的重量比，将所述奥贝胆酸原料与所述碱性溶液接触。由此，可以使体系充分溶解。
根据本发明的实施例，所述酸性溶液无机酸水溶液，优选浓盐酸、硫酸、磷酸的水溶液中的至少一种，更优选浓盐酸水溶液。由此，可以使含有奥贝胆酸的第一混合物充分溶解混合。
根据本发明的实施例，所述酸性溶液的浓度为0.5～1.5重量％，优选为0.5～0.8重量％。由此可以充分中和成酸析出固体。
根据本发明的实施例，在步骤(2)中，所述预定温度为30～50℃，优选40～50℃。
根据本发明的实施例，在步骤(3)中，于40～60℃，优选40～50℃的温度下将 所述第一混合物滴加至所述酸性溶液中。由此，可以使反应充分，同时可以使体系分散充分。
根据本发明的实施例，按照7:20～15:20的质量比，将所述第一混合物滴加至所述酸性溶液中。由此，可以使反应充分。
根据本发明的实施例，在步骤(4)中，将所述第二混合物降温至10～30℃，优选20～30℃，以便实现沉淀析晶。由此可以有效提高收率和控制析出晶体的纯度。
根据本发明的实施例，在步骤(4)中，于40～60℃，优选40～50℃的温度下进行所述真空干燥。由此，可以有效干燥，同时不影响产物纯度和性状。
根据本发明的具体实施例，申请人经反复试验研究发现，采用本发明的上述方法不仅可以高效地制备得到无定型奥贝胆酸，并且能获得高纯度、分散好的粉末状态无定型奥贝胆酸。
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。
附图说明
本发明的上述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：
图1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；
图2为根据本发明实施例4的无定型奥贝胆酸的HPLC高效液相图谱；
图3为根据本发明实施例4的酸无定型奥贝胆的X射线粉末衍射图。
发明详细描述
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。
实施例1制备奥贝胆酸晶型Ⅱ
按照下述步骤制备奥贝胆酸晶型Ⅱ：
取40.0g 3α,7α-二羟基-6α-烷基-5β-胆烷酸，加入120ml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50ml乙酸丁酯洗涤，得到湿品3α,7α-二羟基-6α-烷基-5β-胆烷酸。取上述制备的湿品，加入200ml体积正庚烷，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30.0g奥贝胆酸晶型Ⅱ化合物。经XRD分析判断为晶型Ⅱ。其中，奥贝胆酸晶型Ⅱ的X射线粉末衍射图如图1所示。
晶型Ⅱ的X射线粉末衍射图中，其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。
实施例2无定型奥贝胆酸的合成
根据本发明的制备无定型奥贝胆酸的方法，按照以下步骤合成无定型奥贝胆酸：
(1)奥贝胆酸碱性溶液的制备
称取12.0g纯化水和0.35g 50％氢氧化钠水溶液充分混合，搅拌下加入0.82g实施例1制备获得的奥贝胆酸晶型Ⅱ，略升温，继续搅拌溶解，控制温度在25℃，以便获得含有奥贝胆酸的第一混合物。
(2)酸性溶液的制备
室温下向洁净反应釜中加入36.5g纯化水，再加入0.5g 37％的浓盐酸，搅拌均匀，升温并控制温度为40℃，以便获得盐酸水溶液。
(3)无定型奥贝胆酸的制备
搅拌下，将步骤(1)的含有奥贝胆酸的第一混合物快速滴加到步骤(2)制备好的盐酸水溶液中，加入过程中充分搅拌，控制体系温度为40℃，析出大量白色固体。继续保温搅拌2h后降温至20℃左右，过滤洗涤，得到滤饼，然后将滤饼在真空干燥箱中40℃干燥20h，得到0.74g分散较好的粉末状奥贝胆酸，收率91.4％。
实施例3无定型奥贝胆酸的合成
根据本发明的制备无定型奥贝胆酸的方法，按照以下步骤合成无定型奥贝胆酸：
(1)奥贝胆酸碱性溶液的制备
称取130.0g纯化水和3.5g 50％氢氧化钠水溶液充分混合，搅拌下加入15.0g实施例1制备获得的奥贝胆酸晶型Ⅱ，略升温，继续搅拌溶解，控制温度在27℃，以便获得含有奥贝胆酸的第一混合物。
(2)酸性溶液的制备
室温下向洁净反应釜中加入300.0g纯化水，再加入5.0g 37％的浓盐酸，搅拌均匀，升温并控制温度为45℃，以便获得盐酸水溶液。
(3)无定型奥贝胆酸的制备
搅拌下，将步骤(1)的含有奥贝胆酸的第一混合物快速滴加到步骤(2)制备好的盐酸水溶液中，加入过程中充分搅拌，控制体系温度为45℃，析出大量白色固体。继续保温搅拌2h后降温至20℃左右，过滤洗涤，得到滤饼，然后将滤饼在真空干燥箱中45℃干燥20h，得到13.8g分散较好的粉末状奥贝胆酸，收率91.3％。
实施例4无定型奥贝胆酸的合成
根据本发明的制备无定型奥贝胆酸的方法，按照以下步骤合成无定型奥贝胆酸：
(1)奥贝胆酸碱性液的制备
称取7.43kg纯化水和0.17kg 50％氢氧化钠水溶液充分混合，搅拌下加入0.76kg实施例1制备获得的奥贝胆酸晶型Ⅱ，略升温，继续搅拌溶解，控制温度在30℃，以便获得含有奥贝胆酸的第一混合物。
(2)酸性溶液的制备
室温下向洁净反应釜中加入11.4kg纯化水，再加入0.25kg 37％的浓盐酸，搅拌均匀，升温并控制温度为50℃左右，以便获得盐酸水溶液。
(3)无定型奥贝胆酸的制备
搅拌下，将步骤(1)的含有奥贝胆酸的第一混合物快速滴加到步骤(2)制备好的盐酸水溶液中，加入过程中充分搅拌，控制体系温度50℃，析出大量白色固体。继续保温搅拌1h后降温至25℃左右，过滤洗涤，得到滤饼，然后将滤饼在真空干燥箱中50℃干燥20h，得到0.70kg分散较好的粉末状奥贝胆酸，收率92.1％。经HPLC检测，纯度为99.9％，HPLC高效液相图谱如图2所示。经XRD分析判断晶型为无定型，奥贝胆酸无定型的X射线粉末衍射图如图3所示。
对比例1
参照实施例2的方法，按照以下步骤合成无定型奥贝胆酸：
(1)奥贝胆酸碱性溶液的制备
室温下称取12.0g纯化水和0.35g 50％氢氧化钠水溶液充分混合，搅拌下加入0.82g实施例1制备获得的奥贝胆酸晶型Ⅱ，继续搅拌溶解，以便获得含有奥贝胆酸的碱性溶液。
(2)酸性溶液的制备
室温下向洁净反应釜中加入36.5g纯化水，再加入0.5g 37％的浓盐酸，搅拌均匀，控制温度为常温，以便获得盐酸水溶液。
(3)无定型奥贝胆酸的制备
搅拌下，将步骤(1)获得的含有奥贝胆酸的碱性溶液快速滴加到步骤(2)制备好的盐酸水溶液中，加入过程中充分搅拌，体系温度控制在30℃～35℃，析出大量白色固体。继续保温搅拌2h后降温至20℃左右，过滤洗涤，得到滤饼在真空干燥箱中45℃干燥12h，得到0.66g块状固体，即固体奥贝胆酸，其性状差，分散不好，容易结块，且此固体奥贝胆酸收率仅80.9％。
此外，对比多次试验显示，本发明通过控制每步的优化反应温度和相关实验条件能高效制得高纯度、分散好的粉末状无定型奥贝胆酸产品。
工业实用性
本发明的制备无定型奥贝胆酸的方法，反应条件温和，工艺简单，能高效得到高纯度、分散好的粉末状无定型奥贝胆酸产品。
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。
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。

Claims (9)

  1. 一种制备无定型奥贝胆酸的方法，其特征在于，包括：
    (1)将奥贝胆酸原料与碱性溶液接触，以便获得含有奥贝胆酸的第一混合物；
    (2)配置酸性溶液并使所述酸性溶液保持预定温度；
    (3)将所述第一混合物滴加至所述酸性溶液中，以便获得第二混合物；
    (4)将所述第二混合物进行降温沉淀，分离固体，并对所分离的固体进行真空干燥，以便获得所述无定型奥贝胆酸。
  2. 根据权利要求1所述的方法，其特征在于，所述奥贝胆酸原料为奥贝胆酸晶型Ⅱ，
    任选的，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，
    任选的，在所述奥贝胆酸晶型Ⅱ的DSC分析中，所述奥贝胆酸晶型Ⅱ在96.4℃有吸热峰。
  3. 根据权利要求1所述的方法，其特征在于，所述碱性溶液为选自氢氧化钠溶液和氢氧化钾溶液中的至少一种，优选为氢氧化钠溶液。
  4. 根据权利要求3所述的方法，其特征在于，所述碱性溶液的浓度为1.0～2.0重量％，优选为1.2～1.5重量％。
  5. 根据权利要求1所述的方法，其特征在于，在步骤(1)中，于20～30℃，优选25～30℃的温度下将所述奥贝胆酸原料与所述碱性溶液接触，
    任选地，按照1:10～1.5:10的重量比，将所述奥贝胆酸原料与所述碱性溶液接触。
  6. 根据权利要求1所述的方法，其特征在于，所述酸性溶液为无机酸水溶液，优选浓盐酸、硫酸、磷酸的水溶液中的至少一种，更优选浓盐酸水溶液。
  7. 根据权利要求6所述的方法，其特征在于，所述酸性溶液的浓度为0.5～1.5重量％，优选为0.5～0.8重量％。
  8. 根据权利要求1所述的方法，其特征在于，在步骤(2)中，所述预定温度为30～50℃，优选40～50℃，
    任选的，在步骤(3)中，于40～60℃，优选40～50℃的温度下将所述第一混合物滴加至所述酸性溶液中，
    任选地，按照7:20～15:20的质量比，将所述第一混合物滴加至所述酸性溶液中。
  9. 根据权利要求1所述的方法，其特征在于，在步骤(4)中，将所述第二混合物降温至10～30℃，优选20～30℃，以便实现沉淀，
    任选的，在步骤(4)中，于40～60℃，优选40～50℃的温度下进行所述真空干燥。
PCT/CN2016/108285 2015-12-01 2016-12-01 制备无定型奥贝胆酸的方法 WO2017092703A1 (zh)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201510870311.8 2015-12-01
CN201510870311.8A CN106810587A (zh) 2015-12-01 2015-12-01 制备无定型奥贝胆酸的方法

Publications (1)

Publication Number Publication Date
WO2017092703A1 true WO2017092703A1 (zh) 2017-06-08

Family

ID=58796327

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2016/108285 WO2017092703A1 (zh) 2015-12-01 2016-12-01 制备无定型奥贝胆酸的方法

Country Status (2)

Country Link
CN (1) CN106810587A (zh)
WO (1) WO2017092703A1 (zh)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3248983A4 (en) * 2014-12-30 2017-12-13 Crystal Pharmatech Co. Ltd. Crystal form a of obeticholic acid and preparation method therefor

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109535216B (zh) * 2017-09-22 2022-09-16 上海汇伦医药股份有限公司 一种无定型奥贝胆酸的制备方法及无定型奥贝胆酸
CN107674107B (zh) * 2017-09-30 2020-09-15 上海博志研新药物技术有限公司 一种奥贝胆酸的精制方法
CN109535217B (zh) * 2018-11-13 2020-04-14 丽珠集团新北江制药股份有限公司 一种奥贝胆酸的精制方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013192097A1 (en) * 2012-06-19 2013-12-27 Intercept Pharmaceuticals, Inc. Preparation, uses and solid forms of obeticholic acid
CN105085597A (zh) * 2015-08-28 2015-11-25 成都百裕科技制药有限公司 一种无定型奥贝胆酸的制备方法

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1568706A1 (en) * 2004-02-26 2005-08-31 Intercept Pharmaceuticals, Inc. Novel steroid agonist for FXR

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013192097A1 (en) * 2012-06-19 2013-12-27 Intercept Pharmaceuticals, Inc. Preparation, uses and solid forms of obeticholic acid
CN105085597A (zh) * 2015-08-28 2015-11-25 成都百裕科技制药有限公司 一种无定型奥贝胆酸的制备方法

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3248983A4 (en) * 2014-12-30 2017-12-13 Crystal Pharmatech Co. Ltd. Crystal form a of obeticholic acid and preparation method therefor

Also Published As

Publication number Publication date
CN106810587A (zh) 2017-06-09

Similar Documents

Publication Publication Date Title
WO2017092703A1 (zh) 制备无定型奥贝胆酸的方法
US8217061B2 (en) Polymorphs of sorafenib tosylate and sorafenib hemi-tosylate, and processes for preparation thereof
TWI765913B (zh) 結晶型的考布曲鈣（ｃａｌｃｏｂｕｔｒｏｌ）及其製備方法
WO2016107289A1 (zh) 制备索非布韦晶型6的方法
WO2017092702A1 (zh) 奥贝胆酸晶型ⅱ及其制备方法和用途
WO2018120923A1 (zh) 1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸的制备方法
WO2012022240A1 (zh) 一种厄洛替尼碱的新晶型及其制备方法
JP5519201B2 (ja) ２−（３−シアノ−４−イソブチルオキシフェニル）−４−メチル−５−チアゾールカルボン酸の結晶多形体の製造方法
JP2018522945A (ja) ビラスチンの結晶形態及びそれらの調製方法
WO2017131218A1 (ja) アジルサルタン及びその製造方法
CN105517992B (zh) 新型结晶性芳烷基胺化合物及其制造方法
EP2342204A1 (en) Novel polymorph of moxifloxacin hydrochloride
CN102070625A (zh) 一种伊潘立酮的结晶方法
CN110526897B (zh) 制备吡虫啉多晶型的方法
WO2013013595A1 (zh) 一种17α-乙酰氧基-11β-(4-N,N-二甲氨基苯基)-19-去甲孕甾-4,9-二烯-3,20-二酮的结晶物及其制备方法
JP4208976B2 (ja) ｄ４ Ｔ多形フォームＩ方法
TWI496789B (zh) 表柔比星（ｅｐｉｒｕｂｉｃｉｎ）鹽酸鹽之結晶
JP2020517674A (ja) ボルチオキセチンＨＢｒ α型を製造するための方法
JP2018080125A (ja) インドリン化合物のβ型結晶の製造方法
WO2013013594A1 (zh) 一种17α-乙酰氧基-11β-(4-N,N-二甲氨基苯基)-19-去甲孕甾-4,9-二烯-3,20-二酮的无定形物及其制备方法
WO2010108417A1 (zh) 阿昔洛韦2/3水合物的制备方法
JPWO2009119395A1 (ja) ２−アミノ−２−［２−［４−（３−ベンジルオキシフェニルチオ）−２−クロロフェニル］エチル］−１，３−プロパンジオール塩酸塩の結晶化方法
EP1685099A1 (en) Crystalline forms of 1,24(s)-dihiyproxy vitamin d2
WO2019037591A1 (zh) 盐酸美法仑晶型及其制备方法与应用
JP6663232B2 (ja) 新規結晶構造を有するアジルサルタン及びその製造方法

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 16870013

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 16870013

Country of ref document: EP

Kind code of ref document: A1