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WO2018010651A1 - 一种奥贝胆酸及其中间体的制备方法 - Google Patents

一种奥贝胆酸及其中间体的制备方法 Download PDF

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WO2018010651A1
WO2018010651A1 PCT/CN2017/092554 CN2017092554W WO2018010651A1 WO 2018010651 A1 WO2018010651 A1 WO 2018010651A1 CN 2017092554 W CN2017092554 W CN 2017092554W WO 2018010651 A1 WO2018010651 A1 WO 2018010651A1
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hydrogen
borohydride
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张顺吉
王生
刘路
田伟伟
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Jiangsu Hengrui Medicine Co Ltd
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Jiangsu Hengrui Medicine Co Ltd
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Priority to CA3027761A priority patent/CA3027761A1/en
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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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention relates to a preparation method of oleic acid and an intermediate thereof.
  • Obicholic acid (as shown in formula I), chemical name 6 ⁇ -ethyl-3 ⁇ , 7 ⁇ -dihydroxy-5 ⁇ -cholanoic acid, is a semi-synthetic chenodeoxycholic acid derivative used to treat the portal vein Hypertension and liver disease, including primary biliary cirrhosis, bile acid diarrhea, nonalcoholic steatohepatitis.
  • Obecholic acid acts by activating FXR receptors, a nuclear receptor that is expressed primarily in the liver, intestines, and kidneys. It regulates the expression of genes involved in bile acids, fats, and glucose metabolism, and regulates immune response. Activation of FXR inhibits bile acid synthesis and prevents toxic reactions caused by excessive accumulation of bile acids.
  • WO2002072598 discloses for the first time the preparation method of oleic acid (as shown below), which is obtained by direct alkylation of compound XIV with iodoethane under strong basic conditions to obtain compound XV, which is obtained by reduction and carboxyl deprotection of compound XV.
  • Abecholic acid due to the poor selectivity and low yield of direct alkylation with iodoethane, it is difficult to achieve amplification synthesis in this synthesis process.
  • WO2006122977 has improved the above synthesis process (as shown below) by converting compound VIII into a silicon-based protected enol compound IX, compound IX and acetaldehyde are condensed and dehydrated to obtain compound X, and compound X is first hydrolyzed to obtain XI. Further, the compound XII is obtained by hydrogenation reduction of palladium carbon under basic conditions, and the compound XII is reduced by a carbonyl group to obtain oleic acid. Although the synthesis process can achieve amplification synthesis, the yield of the hydrogenation reduction step is low, resulting in a low yield of the final product.
  • WO2016045480 discloses a novel synthesis method of oleic acid by finally protecting the hydroxyl group of the compound (XIa) and then hydrogenating the reaction to finally obtain oleic acid.
  • the yield of the synthesis process is increased, the reaction has difficulty in the amplification process, the reaction yield is lowered, the impurities are generated, and the separation and purification are difficult, resulting in the presence of a part of impurities in the final product oleic acid which cannot be removed, and the purification is difficult.
  • the invention provides a process for the preparation of a compound of formula V, which comprises preparing a compound V by hydrogenation of a compound of formula VI in the presence of an acidic material and a catalyst,
  • R 1 is hydrogen or a carboxy protecting group, preferably hydrogen or C 1-10 alkyl, more preferably hydrogen, methyl or ethyl;
  • R 2 is C 1-5 alkyl, preferably methyl;
  • R 3 It is a hydrogen or hydroxy protecting group, preferably hydrogen or methoxymethyl.
  • the acidic material may be a protic acid or a Lewis acid, preferably an organic or inorganic acid, more preferably a C 1-5 alkyl acid, most preferably acetic acid or formic acid.
  • the catalyst may be a catalyst commonly used in catalytic hydrogenation, preferably palladium carbon, PtO 2 or Raney nickel. The hydrogenation reaction is preferably carried out at a pressure between 1 and 3 atmospheres.
  • Another aspect of the present invention provides a process for the preparation of oleic acid comprising the above-described step of preparing a compound of formula V wherein R 2 is a methyl group.
  • R 1 is a carboxy protecting group, preferably a methyl or ethyl group; and R 3 is hydrogen;
  • R 1 is hydrogen and R 3 is hydrogen.
  • R 1 is a carboxy protecting group and R 3 is hydrogen
  • the 3 ⁇ -hydroxy group of compound V can be further protected to a compound of formula IV wherein R 5 is a hydroxy protecting group, preferably a methoxymethyl group.
  • the compound of formula IV can be further hydrolyzed under basic conditions to give a compound of formula III.
  • the compound of formula III can be further reduced by a reducing agent to give a compound of formula II, wherein the reducing agent is preferably a borohydride, more preferably sodium borohydride.
  • the compound of formula II can be further dehydroxylated to give the oleic acid.
  • the method of preparation further comprises the step of heat treating a compound selected from the group consisting of compounds V, IV, III, the heat treatment comprising heating the compound under basic conditions, preferably at a temperature of from 95 to 105 °C.
  • the heat treatment step may be carried out after any one of the steps of preparing the compound V, IV or III, and the heat treatment method is a method disclosed in the prior art, that is, heating the product under alkaline conditions, specifically, reacting The product is heated under the alkaline condition at a temperature of 95-105 ° C for an hour to make the 6- ⁇ -ethyl epimerization to 6- ⁇ -ethyl.
  • the reaction in this step is stable, the conversion rate is high, and the yield is basically more than 90 percent.
  • the compound of formula V may be further reduced by a reducing agent to obtain oleic acid, optionally further comprising the step of heat treating the compound of formula V, wherein the reducing agent is preferably a borohydride, more preferably Sodium borohydride, the heat treatment comprising heating the compound under alkaline conditions, preferably at a temperature of from 95 to 105 °C.
  • the reducing agent is preferably a borohydride, more preferably Sodium borohydride
  • Another aspect of the invention also provides a method for preparing oleic acid, comprising the steps of:
  • a compound of the formula VIb is hydrogenated in the presence of an acidic material and a catalyst to produce a compound of the formula Vb;
  • R 4 is a carboxy protecting group, preferably a methyl or ethyl group
  • R 5 is a hydroxy protecting group, preferably a methoxymethyl group
  • the acidic medium is preferably formic acid or acetic acid
  • the catalyst is preferably palladium carbon
  • the borohydride The material is preferably sodium borohydride, and the heat treatment comprises heating the product under basic conditions, preferably at a temperature of from 95 to 105 °C.
  • Another aspect of the invention also provides a method for preparing oleic acid, comprising the steps of:
  • the acidic medium is preferably formic acid or acetic acid;
  • the catalyst is preferably palladium carbon;
  • the borohydride boron hydrogen Sodium the heat treatment comprising heating the compound of formula IIc under basic conditions, preferably at a temperature of from 95 to 105 °C.
  • a bond Configuration is not specified, ie key Can be or Or both with Two configurations.
  • the hydroxy protecting group of the present invention is a suitable group for hydroxy protection known in the art, see the hydroxy protecting group in the literature ("Protective Groups in Organic Synthesis", 5 Th Ed. TW Greene & P. GM Wuts).
  • the hydroxy protecting group may be a (C 1-10 alkyl or aryl) 3 silane group, for example: triethylsilyl, triisopropylsilyl, tert-butyldimethyl Silyl, tert-butyldiphenylsilyl, etc.; may be a C 1-10 alkyl or substituted alkyl group, preferably an alkoxy or aryl substituted alkyl group, more preferably a C 1-6 alkoxy substituted C a 1-6 alkyl or phenyl substituted C 1-6 alkyl group, most preferably a C 1-4 alkoxy substituted C 1-4 alkyl group, for example: methyl, tert-butyl,
  • Carboxylic acid protecting group is a suitable group for carboxylic acid protection known in the art, see the carboxylic acid protecting group in the literature ("Protective Groups in Organic Synthesis", 5 Th Ed. TW Greene & P. GM Wuts), As an example, preferably, the carboxylic acid protecting group may be a substituted or unsubstituted C 1-10 linear or branched alkyl group, a substituted or unsubstituted C 2-10 linear or branched alkenyl group.
  • alkynyl substituted or unsubstituted C 3-8 cyclic alkyl, substituted or unsubstituted C 5-10 aryl or heteroaryl, or (C 1-8 alkyl or aryl) 3 silane
  • a straight or branched alkyl group of C 1-6 is preferred, and a linear or branched alkyl group of C 1-4 is more preferred.
  • Alkyl means a saturated aliphatic hydrocarbon group, including straight chain and branched chain groups of 1 to 20 carbon atoms. Preference is given to alkyl groups having 1 to 10 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl or pentyl groups and the like. More preferred are lower alkyl groups having 1 to 6 carbon atoms such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl or tert-butyl, pentyl, heptyl and the like.
  • the alkyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from alkoxy, halogen, hydroxy, nitro, cyano, cycloalkyl, Heterocyclic group, aryl group, heteroaryl group, carbonyl group.
  • the compound IIa (4.4 kg) was dissolved in 50 liters of tetrahydrofuran, cooled to 0 ° C, 40 liters of 4N aqueous hydrochloric acid solution was added, the temperature was raised to 20 ° C, and the reaction was carried out for 8 hours, and 40 liters of ethyl acetate was added thereto, and the extract was concentrated and analyzed. Crystallization, filtration and drying gave 3.8 kg of oleic acid in a yield of 95% and HPLC purity of 98.4%.
  • Example 3 According to the method of Example 3 in WO2016045480, the compound IId (1.96 kg) was dissolved in 20 L of tetrahydrofuran, the reaction solution was cooled to 0 ° C, 15 liters of 4N aqueous hydrochloric acid solution was added, and the mixture was heated to 20 to 30 ° C for 8 hours, and TLC showed impurities. The reaction mixture was concentrated under reduced pressure. The residue was evaporated. The yield was 58%, and the HPLC purity was 89.6%.

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  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
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  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

本发明涉及一种奥贝胆酸及其中间体的制备方法。具体而言，本发明涉及一种如式V所示的化合物的制备方法，包括通过如式VI所示的化合物在酸性物质和催化剂的存在下加氢反应制得化合物V，以及通过化合物V制备奥贝胆酸的方法。该方法具有反应条件温和，收率高，副产物少，操作简便，适合大规模生产等优点。

Description

一种奥贝胆酸及其中间体的制备方法 技术领域
本发明涉及一种奥贝胆酸及其中间体的制备方法。
背景技术
奥贝胆酸(如式I所示)，化学名为6α-乙基-3α,7α-二羟基-5β-胆烷酸，是一种半合成鹅去氧胆酸衍生物，用于治疗门静脉血压过高以及肝脏疾病，包括原发性胆汁性肝硬化、胆汁酸腹泻、非酒精性脂肪性肝炎。奥贝胆酸是通过激活FXR受体发挥作用，FXR是一种核受体，主要在肝脏、肠、肾脏中表达，它能够调节与胆汁酸、脂肪和糖代谢相关基因的表达，还能调节免疫反应。激活FXR能够抑制胆汁酸合成，预防胆汁酸过度积累导致的毒性反应。
Figure PCTCN2017092554-appb-000001
WO2002072598首次公开了奥贝胆酸的制备方法(如下所示)，该方法通过化合物XIV在强碱性条件下用碘乙烷直接烷基化得到化合物XV，化合物XV经过还原和羧基脱保护制得奥贝胆酸。但由于用碘乙烷直接烷基化的选择性差和收率过低，该合成过程很难实现放大合成。
Figure PCTCN2017092554-appb-000002
WO2006122977对以上合成工艺进行了改进(如下所示)，该方法通过把化合物VIII转化为硅基保护的烯醇化合物IX，化合物IX与乙醛缩合脱水后得到化合物X，化合物X先水解得到XI，再经过在碱性条件下钯碳加氢还原得到化合物XII，化合物XII经过羰基还原后制得奥贝胆酸。该合成工艺虽然可以实现放大合成，但氢化还原步骤收率偏低，导致终产品收率偏低。
Figure PCTCN2017092554-appb-000003
WO2016045480公开了一种新的奥贝胆酸的合成方法，通过对化合物(XIa)的羟基进行保护，再氢化反应，最终得到奥贝胆酸。该合成工艺虽然收率提高，但反应在放大过程中存在困难，反应收率降低，生成杂质较多，分离纯化难度大，导致终产品奥贝胆酸存在无法除去的部分杂质，纯化困难。
Figure PCTCN2017092554-appb-000004
因此，急需一种收率高、杂质少且能够工业化生产的奥贝胆酸的合成工艺来克服现有技术的不足。
发明内容
本发明一方面提供了一种如式V所示的化合物的制备方法，包括通过如式VI所示的化合物在酸性物质和催化剂的存在下加氢反应制得化合物V，
Figure PCTCN2017092554-appb-000005
其中，R1为氢或羧基保护基，优选为氢或C1-10烷基，更优选为氢、甲基或乙基；R2为C1-5烷基，优选为甲基；R3为氢或羟基保护基，优选为氢或甲氧基甲基。
所述酸性物质可以是质子酸或者路易斯酸，优选有机酸或无机酸，更优选C1-5烷基酸，最优选乙酸或甲酸。所述催化剂可以是催化氢化反应常用的催化剂，优选为钯碳、PtO2或兰尼镍。氢化反应优选在1和3个大气压之间的压力下进行。
本发明另一方面提供了一种奥贝胆酸的制备方法，包括上述制备如式V所示的化合物的步骤，其中R2为甲基。
在此步反应中，优选地，R1为羧基保护基，优选甲基或乙基；R3为氢；
另一优选地，R1为氢，R3为氢。
当R1为羧基保护基，R3为氢时，还可进一步将化合物V的3α-羟基保护得式IV化合物，其中，R5为羟基保护基，优选甲氧基甲基。
Figure PCTCN2017092554-appb-000006
式IV化合物可进一步地在碱性条件下水解得式III化合物。
Figure PCTCN2017092554-appb-000007
式III化合物可进一步地经过还原剂还原得式II化合物，其中还原剂优选硼氢化物，更优选硼氢化钠。
Figure PCTCN2017092554-appb-000008
式II化合物可进一步地脱羟基保护基最终得到奥贝胆酸。
Figure PCTCN2017092554-appb-000009
任选地，制备方法还包括热处理选自化合物V、IV、III的化合物的步骤，所述热处理包括在碱性条件下加热所述化合物，加热温度优选95-105℃。所述热处理步骤可在制备化合物V、IV或III的步骤中的任意一个步骤后进行，热处理方法为现有技术中公开的方法，即在碱性条件下加热所述产物，具体的为将反应产物在碱性条件下以95-105℃的温度加热体系数小时使得6-β-乙基差向异构化为6-α-乙基，该步骤反应稳定，转化率高，产率基本在90％以上。
当R1为氢，R3为氢时，式V化合物还可进一步经过还原剂还原得奥贝胆酸，任选地还包括热处理式V化合物的步骤，其中还原剂优选硼氢化物，更优选硼氢化钠，所述热处理包括在碱性条件下加热所述化合物，加热温度优选95-105℃。
本发明另一方面还提供了一种奥贝胆酸的制备方法，包括如下步骤：
Figure PCTCN2017092554-appb-000010
1)式VIb化合物在酸性物质和催化剂的存在下加氢反应制得式Vb化合物；
2)将式Vb化合物的3α-羟基保护得式IVb化合物；
3)式IVb化合物在碱性条件下水解，以及任选地热处理反应产物得式IIIb化合物；
4)式IIIb化合物经过硼氢化物还原得式IIb化合物；
5)式IIb化合物脱羟基保护基得到奥贝胆酸，
其中，R4为羧基保护基，优选甲基或乙基；R5为羟基保护基，优选甲氧基甲基；所述酸性介质优选甲酸或乙酸；所述催化剂优选钯碳；所述硼氢化物优选硼氢化钠，所述热处理包括在碱性条件下加热所述产物，加热温度优选95-105℃。
本发明另一方面还提供了一种奥贝胆酸的制备方法，包括如下步骤：
Figure PCTCN2017092554-appb-000011
1)式IIIc化合物在酸性物质和催化剂的存在下加氢反应得式IIc化合物；
2)任选地热处理式IIc化合物；
3)式IIc化合物经过硼氢化物还原得到奥贝胆酸，
其中，所述酸性介质优选甲酸或乙酸；所述催化剂优选钯碳；所述硼氢化物硼氢 化钠，所述热处理包括在碱性条件下加热所述式IIc化合物，加热温度优选95-105℃。
本发明所述化合物的化学结构中，键
Figure PCTCN2017092554-appb-000012
并未指定构型，即键
Figure PCTCN2017092554-appb-000013
可以为
Figure PCTCN2017092554-appb-000014
或
Figure PCTCN2017092554-appb-000015
或者同时包含
Figure PCTCN2017092554-appb-000016
和
Figure PCTCN2017092554-appb-000017
两种构型。
本发明所述的奥贝胆酸及其中间体的制备方法中，由于催化氢化反应在酸性条件下进行，不仅反应收率提高，产物纯度也大幅提高，同时反应在放大后也能保持很好的反应效果。在随后将中间体的3α-羟基进行保护，有效地降低了反应副产物的生成，提高了产物纯度，使得终产品纯化难度大大降低，提高了工业生产的效率。
本发明的羟基保护基是本领域已知的适当的用于羟基保护的基团，参见文献(“Protective Groups in Organic Synthesis”，5Th Ed.T.W.Greene&P.G.M.Wuts)中的羟基保护基团。作为示例，优选地，所述的羟基保护基可以是(C1-10烷基或芳基)3硅烷基，例如：三乙基硅基，三异丙基硅基，叔丁基二甲基硅基，叔丁基二苯基硅基等；可以是C1-10烷基或取代烷基，优选烷氧基或芳基取代的烷基，更优选C1-6烷氧基取代的C1-6烷基或苯基取代的C1-6烷基，最优选C1-4烷氧基取代的C1-4烷基，例如：甲基，叔丁基，烯丙基，苄基，甲氧基甲基(MOM)，乙氧基乙基，2-四氢吡喃基(THP)等；可以是(C1-10烷基或芳香基)酰基，例如：甲酰基，乙酰基，苯甲酰基等；可以是(C1-6烷基或C6-10芳基)磺酰基；也可以是(C1-6烷氧基或C6-10芳基氧基)羰基。
“羧酸保护基”是本领域已知的适当的用于羧酸保护的基团，参见文献(“Protective Groups in Organic Synthesis”，5Th Ed.T.W.Greene&P.G.M.Wuts)中的羧酸保护基团，作为示例，优选地，所述的羧酸保护基可以是取代或非取代的C1-10的直链或支链烷基、取代或非取代的C2-10的直链或支链烯基或炔基、取代或非取代的C3-8的环状烷基、取代或非取代的C5-10的芳基或杂芳基、或(C1-8烷基或芳基)3硅烷基；优选C1-6的直链或支链烷基，更优选C1-4的直链或支链烷基。
“烷基”指饱和的脂族烃基团，包括1至20个碳原子的直链和支链基团。优选含有1至10个碳原子的烷基，例如甲基、乙基、丙基、2-丙基、正丁基、异丁基、叔丁基或戊基等。更优选的是含有1至6个碳原子的低级烷基，例如甲基、乙基、丙基、2-丙基、正丁基、异丁基或叔丁基、戊基、庚基等。烷基可以是取代的或未取代的，当被取代时，取代基优选为一个或多个以下基团，独立地选自烷氧基、卤素、羟基、硝基、氰基、环烷基、杂环基、芳基、杂芳基、羰基。
实施例中所涉及的化合物的结构式如下
Figure PCTCN2017092554-appb-000018
Figure PCTCN2017092554-appb-000019
具体实施方式
以下将结合具体实例详细地解释本发明，使得本专业技术人员更全面地理解本发明具体实例仅用于说明本发明的技术方案，并不以任何方式限定本发明。
实施例1：制备化合物Va
将化合物VIa(6千克，根据WO2006122977中的方法制得)溶于乙酸(48升)中，加入钯碳(0.5千克,10wt％)在氢气(1.5大气压)和20℃下反应16小 时，过滤，浓缩后的残余液用乙酸乙酯(50升)稀释，依次用水、饱和碳酸氢钠水溶液和饱和食盐水洗1次，无水硫酸钠干燥后过滤，浓缩得到5.8千克化合物Va，产率96％，HPLC纯度为97.2％。
1HNMR(400MHz,MeOD)δ4.14-4.07(m,2H),3.54-3.44(m,1H),2.71-2.46(m,1H),2.41-2.32(m,1H),2.28-2.19(m,1H),2.17-0.78(m,36H),0.74-0.68(m,3H).
实施例2：制备化合物IVa
将化合物Va(5.8千克)溶于二氯甲烷(50升)中，加入二异丙基乙基胺(5.6升)，滴加溴甲基甲醚1.4升，室温反应16～20小时，依次用稀盐酸、饱和碳酸氢钠水溶液和饱和食盐水洗1次，无水硫酸钠干燥后过滤，浓缩得到5.8千克化合物IVa，产率91％，HPLC纯度为95.5％。
1HNMR(400MHz,MeOD)δ4.60-4.54(m,2H),4.08-4.00(m,2H),3.47-3.36(m,1H),3.25(s,3H),2.64-2.40(m,1H),2.34-2.25(m,1H),2.22-2.11(m,1H),2.10-0.72(m,36H),0.67-0.60(m,3H).
实施例3：制备化合物IIIa
将化合物IVa(5.8千克)溶于40升甲醇中，冷却到0℃，加入30％氢氧化钠溶液10升，升温至90～100℃反应15h，加稀盐酸调节至弱酸性，浓缩后加50升乙酸乙酯，饱和食盐水洗1次，干燥后浓缩得到5千克化合物IIIa，产率91％，HPLC纯度为95.8％。
1HNMR(400MHz,MeOD)δ4.64-4.60(m,2H),3.50-3.40(m,1H),3.31(s,3H),2.86-2.80(dd,1H),2.53-2.47(dd,1H),2.39-2.29(m,1H),2.25-2.10(m,2H),2.06-0.77(m,31H),0.71(s,3H).
实施例4：制备化合物IIa
将化合物IIIa(5千克)溶于60升乙醇中，冷却到0℃，加入400克硼氢化钠，升温到20℃，反应8小时，缓慢滴加1M盐酸直至pH＝6，固体析出，过滤，固体用水洗涤，干燥后得到4.4千克化合物IIa，产率88％，HPLC纯度为96％。
1HNMR(400MHz,MeOD)δ4.65(s,2H),3.66(m,1H),3.36-2.27(m,4H),2.38-2.30(m,1H),2.24-2.16(m,1H),2.03-0.87(m,34H),0.70(s,3H).
实施例5：制备奥贝胆酸
将化合物IIa(4.4千克)溶于50升四氢呋喃中，冷却到0℃，加入40升4N盐酸水溶液，升温到20℃，反应8小时，加40升乙酸乙酯萃取，萃取液经浓缩后，析晶，过滤，干燥得到3.8千克奥贝胆酸，产率95％，HPLC纯度为98.4％。
1HNMR(400MHz,DMSO-d)δ11.95(s,1H),4.32-4.28(d,1H),4.07-4.02(d,1H), 3.52-3.47(m,1H),3.18-3.07(m,1H),2.28-2.18(m,1H),2.15-2.05(m,1H),1.94-0.79(m,34H),0.61(s,3H).
实施例6：制备化合物XII
Figure PCTCN2017092554-appb-000020
将化合物XI(1千克，根据WO2006122977中的方法制得)溶于乙酸(10升)中，加入钯碳(100克,10wt％)在氢气(1.5大气压)和20℃下反应16h，过滤，浓缩后的残余液用乙酸乙酯(10升)稀释，依次用水、饱和碳酸氢钠水溶液和饱和食盐水洗1次，无水硫酸钠干燥后过滤，减压浓缩后溶于10升甲醇中，冷却到0℃，加入30％氢氧化钠溶液3升，升温至90～100℃反应15h，加稀盐酸调节至弱酸性，浓缩后加10升乙酸乙酯，饱和食盐水洗1次，浓缩后用乙酸丁酯重结晶得到850克化合物XII，产率85％，HPLC纯度为98.1％。
实施例7：制备奥贝胆酸
将化合物XII(850克)溶于10升乙醇中，冷却到0℃，加入80克硼氢化钠，升温到20℃，反应8小时，缓慢滴加1M盐酸直至pH＝6，固体析出，过滤，固体用水洗涤，再用乙酸丁酯重结晶，得到700克奥贝胆酸，产率82％，HPLC纯度为98％。
对比例1
Figure PCTCN2017092554-appb-000021
根据WO2016045480中实施例2的方法，将化合物IVd(3kg)溶于乙醇(25升) 中，加入钯碳(300g,10wt％)，和2.2kg 30％氢氧化钠水溶液，在氢气(1.5大气压)和20℃下反应20h，过滤，减压浓缩后母液用2N盐酸中和，乙酸乙酯萃取，减压浓缩，柱层析分离(二氯甲烷：甲醇＝30：1)得到2.05kg化合物IIId，产率72％，纯度80.5％。
Figure PCTCN2017092554-appb-000022
根据WO2016045480中实施例3的方法，将化合物IIId(2.05kg)溶于25L无水乙醇中，加入170g硼氢化钠，升温至20℃下反应10h。缓慢滴加磷酸调节pH＝6，减压浓缩，乙酸乙酯萃取，浓缩有机相得1.96kg化合物IId，产率95％。
Figure PCTCN2017092554-appb-000023
根据WO2016045480中实施例3的方法，将化合物IId(1.96kg)溶于20L四氢呋喃中，反应液冷却至0℃，加入15升4N盐酸水溶液，升温至20～30℃后反应8小时，TLC显示杂质较多；反应液减压浓缩，剩余物乙酸乙酯萃取，再次减压浓缩，柱层析分离(二氯甲烷：甲醇：乙酸乙酯＝30：1：1)，得奥贝胆酸1.25kg，收率58％，HPLC纯度为89.6％。
由于已根据其特殊的实施方案描述了本发明，某些修饰和等价变化对于精通此领域的技术人员是显而易见的且包括在本发明的范围内。

Claims (13)

  1. 一种如式V所示的化合物的制备方法，包括通过如式VI所示的化合物在酸性物质和催化剂的存在下加氢反应制得化合物V的步骤，
    Figure PCTCN2017092554-appb-100001
    其中，R1为氢或羧基保护基；R2为C1-5烷基；R3为氢或羟基保护基。
  2. 根据权利要求1所述的制备方法，其特征在于，R1为氢或C1-10烷基，优选为氢、甲基或乙基。
  3. 根据权利要求1所述的制备方法，其特征在于，R2为甲基。
  4. 根据权利要求1所述的制备方法，其特征在于，R3为氢或甲氧基甲基。
  5. 根据权利要求1所述的制备方法，其特征在于，所述酸性物质选自有机酸或无机酸，优选C1-5烷基酸，更优选乙酸或甲酸。
  6. 根据权利要求1所述的制备方法，其特征在于，所述催化剂为钯碳、PtO2或兰尼镍。
  7. 一种奥贝胆酸的制备方法，其特征在于包括根据权利要求1～6所述的制备如式V所示的化合物的步骤，其中R2为甲基。
  8. 根据权利要求7所述的制备方法，其特征在于，R1为羧基保护基，优选甲基或乙基；R3为氢。
  9. 根据权利要求8所述的制备方法，其特征在于，还包括将式V化合物的3α-羟基保护得式IV化合物的步骤，其中，R5为羟基保护基，优选甲氧基甲基，
    Figure PCTCN2017092554-appb-100002
    还包括式IV化合物在碱性条件下水解得式III化合物的步骤，
    Figure PCTCN2017092554-appb-100003
    还包括式III化合物经过还原剂还原得式II化合物的步骤，所述还原剂优选硼氢化物，更优选硼氢化钠，
    Figure PCTCN2017092554-appb-100004
    还包括式II化合物脱羟基保护基得到奥贝胆酸的步骤，
    Figure PCTCN2017092554-appb-100005
    以及，任选地包括热处理选自化合物V、IV、III的化合物的步骤，所述热处理包 括在碱性条件下加热所述化合物，加热温度优选95-105℃。
  10. 根据权利要求7所述的制备方法，其特征在于，R1为氢，R3为氢。
  11. 根据权利要求10所述的制备方法，其特征在于，还包括式V化合物经过还原剂还原得奥贝胆酸的步骤，还包括任选地热处理式V化合物的步骤，其中还原剂优选硼氢化物，更优选硼氢化钠，所述热处理包括在碱性条件下加热所述化合物，加热温度优选95-105℃。
  12. 一种奥贝胆酸的制备方法，包括如下步骤：
    Figure PCTCN2017092554-appb-100006
    1)式VIb化合物在酸性物质和催化剂的存在下加氢反应制得式Vb化合物；
    2)将式Vb化合物的3α-羟基保护得式IVb化合物；
    3)式IVb化合物在碱性条件下水解，以及任选地热处理反应产物得式IIIb化合物；
    4)式IIIb化合物经过硼氢化物还原得式IIb化合物；
    5)式IIb化合物脱羟基保护基得到奥贝胆酸，
    其中，R4为羧基保护基，优选甲基或乙基；R5为羟基保护基，优选甲氧基甲基；所述酸性介质优选甲酸或乙酸；所述催化剂优选钯碳；所述硼氢化物优选硼氢化钠，所述热处理包括在碱性条件下加热所述产物，加热温度优选95-105℃。
  13. 一种奥贝胆酸的制备方法，包括如下步骤：
    Figure PCTCN2017092554-appb-100007
    1)式IIIc化合物在酸性物质和催化剂的存在下加氢反应得式IIc化合物；
    2)任选地热处理式IIc化合物；
    3)式IIc化合物经过硼氢化物还原得到奥贝胆酸，
    其中，所述酸性介质优选甲酸或乙酸；所述催化剂优选钯碳；所述硼氢化物优选硼氢化钠，所述热处理包括在碱性条件下加热所述式IIc化合物，加热温度优选95-105℃。
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019145977A1 (en) * 2018-01-25 2019-08-01 Msn Laboratories Private Limited, R&D Center PROCESS FOR THE PREPARATION OF 3α,7α-DIHYDROXY6α-ETHYL-5β-CHOLAN-24-OIC ACID
CN112898369A (zh) * 2019-12-04 2021-06-04 博瑞生物医药（苏州）股份有限公司 用于制备奥贝胆酸的方法

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111285914B (zh) * 2018-12-10 2023-02-17 江西青峰药业有限公司 一种奥贝胆酸的制备方法

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006122977A2 (en) * 2005-05-19 2006-11-23 Erregierre S.P.A. PROCESS FOR PREPARING 3α(β)-7α(β)-DIHYDROXY-6α(β)-ALKYL-5β-CHOLANIC ACID
WO2016045480A1 (zh) * 2014-09-28 2016-03-31 上海源力生物技术有限公司 一种奥贝胆酸的制备方法
CN105669811A (zh) * 2014-11-17 2016-06-15 正大天晴药业集团股份有限公司 新的7-酮-6β-烷基胆烷酸衍生物在制备奥贝胆酸以及其在医药领域的用途
CN106008639A (zh) * 2016-03-11 2016-10-12 深圳市塔吉瑞生物医药有限公司 用于预防或治疗fxr-介导疾病的胆烷酸化合物
WO2016173524A1 (zh) * 2015-04-29 2016-11-03 正大天晴药业集团股份有限公司 鹅去氧胆酸衍生物
WO2016173493A1 (en) * 2015-04-28 2016-11-03 Shanghai De Novo Pharmatech Co. Ltd. Sulfonylaminocarbonyl derivative, pharmaceutical composition and uses thereof

Family Cites Families (2)

* 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
CN104672290B (zh) * 2015-01-05 2017-06-06 北京普禄德医药科技有限公司 一种用于预防或治疗fxr‑介导的疾病的药物及其制备方法和用途

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006122977A2 (en) * 2005-05-19 2006-11-23 Erregierre S.P.A. PROCESS FOR PREPARING 3α(β)-7α(β)-DIHYDROXY-6α(β)-ALKYL-5β-CHOLANIC ACID
WO2016045480A1 (zh) * 2014-09-28 2016-03-31 上海源力生物技术有限公司 一种奥贝胆酸的制备方法
CN105669811A (zh) * 2014-11-17 2016-06-15 正大天晴药业集团股份有限公司 新的7-酮-6β-烷基胆烷酸衍生物在制备奥贝胆酸以及其在医药领域的用途
WO2016173493A1 (en) * 2015-04-28 2016-11-03 Shanghai De Novo Pharmatech Co. Ltd. Sulfonylaminocarbonyl derivative, pharmaceutical composition and uses thereof
WO2016173524A1 (zh) * 2015-04-29 2016-11-03 正大天晴药业集团股份有限公司 鹅去氧胆酸衍生物
CN106008639A (zh) * 2016-03-11 2016-10-12 深圳市塔吉瑞生物医药有限公司 用于预防或治疗fxr-介导疾病的胆烷酸化合物

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CLAUDIO, D' AMORE: "Design, Synthesis, and Biological Evaluation of Po- tent Dual Agonists of Nuclear and Membrane Bile Acid Receptors", J. MED. CHEM., 4 January 2014 (2014-01-04), XP055165457 *
HE, YAN: "Application of Catalytic Hydrogenation in Organic Synthesis", NATURAL SCIENCE JOURNAL OF HARBIN NORMAL UNIVERSITY, vol. 21, no. 05, 31 December 2005 (2005-12-31) *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019145977A1 (en) * 2018-01-25 2019-08-01 Msn Laboratories Private Limited, R&D Center PROCESS FOR THE PREPARATION OF 3α,7α-DIHYDROXY6α-ETHYL-5β-CHOLAN-24-OIC ACID
US11434256B2 (en) 2018-01-25 2022-09-06 Msn Laboratories Private Limited, R&D Center Process for the preparation of 3α,7α-dihydroxy-6α-ethyl-5β-cholan-24-oic acid
CN112898369A (zh) * 2019-12-04 2021-06-04 博瑞生物医药（苏州）股份有限公司 用于制备奥贝胆酸的方法
CN112898369B (zh) * 2019-12-04 2024-09-17 博瑞生物医药（苏州）股份有限公司 用于制备奥贝胆酸的方法

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