WO2016165496A1 - 一种制备去氧胆酸的方法 - Google Patents

一种制备去氧胆酸的方法 Download PDF

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WO2016165496A1
WO2016165496A1 PCT/CN2016/074662 CN2016074662W WO2016165496A1 WO 2016165496 A1 WO2016165496 A1 WO 2016165496A1 CN 2016074662 W CN2016074662 W CN 2016074662W WO 2016165496 A1 WO2016165496 A1 WO 2016165496A1
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compound
formula
benzoyloxy
reacting
conditions
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PCT/CN2016/074662
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English (en)
French (fr)
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林成刚
桂力
陈盼
王致轩
管童伟
殷媛媛
陆玉玲
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诺瑞特国际药业股份有限公司
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Priority to US15/566,097 priority Critical patent/US10160782B2/en
Priority to EP16779471.8A priority patent/EP3284748A4/en
Priority to JP2018505512A priority patent/JP2018512066A/ja
Publication of WO2016165496A1 publication Critical patent/WO2016165496A1/zh
Priority to US16/184,399 priority patent/US20190077826A1/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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
    • C07J1/0003—Androstane derivatives
    • C07J1/0011—Androstane derivatives substituted in position 17 by a keto group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J13/00—Normal steroids containing carbon, hydrogen, halogen or oxygen having a carbon-to-carbon double bond from or to position 17
    • C07J13/007—Normal steroids containing carbon, hydrogen, halogen or oxygen having a carbon-to-carbon double bond from or to position 17 with double bond in position 17 (20)
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J21/00—Normal steroids containing carbon, hydrogen, halogen or oxygen having an oxygen-containing hetero ring spiro-condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • C07J21/005—Ketals
    • C07J21/008—Ketals at position 17

Definitions

  • the present invention relates to the field of pharmaceutical organic synthesis, and in particular to a novel method for preparing deoxycholic acid or an ester thereof, or a pharmaceutically acceptable salt thereof, and an intermediate thereof.
  • the invention provides a method for chemically synthesizing deoxycholic acid, which not only has high yield and high purity, but also is suitable for quality control and is convenient for industrial production.
  • the present invention provides a method of preparing deoxycholic acid or an ester thereof or a pharmaceutically acceptable salt thereof:
  • the method includes,
  • the Lewis acid in item g) is EtAlCl 2 .
  • the hydrogenation conditions in item h) comprise a pd/C or PtO 2 catalyst.
  • the oxidizing conditions in item i) comprise tert-butyl peroxide and pyridinium chlorochromate.
  • the hydrogenation conditions in item j) comprise a pd/C or PtO 2 catalyst.
  • the reducing agent in item k) is LiAl(OtBu) 3 H.
  • the deprotection and hydrolysis conditions in item l) comprise a compound of formula 6 with an alkali gold metal hydroxide, a base.
  • the gold metal alkoxide, the alkaline earth metal hydroxide, the alkaline earth metal alkoxide, or a mixture thereof is reacted.
  • the hydrolysis conditions include acid treatment to obtain deoxycholic acid. In other aspects, the acid treatment is omitted to obtain the corresponding salt.
  • the alkali gold metal hydroxide is NaOH.
  • the salt of deoxycholic acid can be prepared by reaction with an alkaline earth metal alkoxide or hydroxide.
  • Salts of deoxycholic acid include sodium, potassium, or lithium salts.
  • an intermediate compound selected from the group consisting of:
  • deoxycholic acid or an ester thereof or a pharmaceutically acceptable salt thereof in the present invention is prepared by the following method:
  • the method includes:
  • Compound 1 of the invention is prepared by the following method:
  • Compound 1.4 of the invention is prepared by the following method:
  • the compound of formula 1.3 is reacted with H 2 to form a compound of formula 1.4 using N-methylpyrrolidone as solvent and 10% pd/C as a catalyst at room temperature.
  • Lewis acid in the present invention means an electron pair acceptor. These include, but are not limited to, EtAlCl 2 , aluminum chloride, ferric chloride, boron trifluoride, antimony pentachloride, and triflate of the lanthanide.
  • hydrophilic agent refers to an agent that can provide hydrogen to a molecule.
  • triphenylethylphosphonium bromide (41.6 g, 112 mmol) was dissolved in 150 mL of tetrahydrofuran, and potassium t-butoxide (12.6 g, 112 mmol) was added to the suspension at 20-30 ° C.
  • the reaction solution was orange.
  • the mixture was stirred at room temperature for 1 hour, and 100 ml of a solution of compound 1.6 (20 g, 51 mmol) in tetrahydrofuran was added dropwise, and the mixture was stirred for 20 minutes, and reacted at room temperature for 2 hours.
  • TLC showed complete conversion of the starting material, and the reaction mixture was poured into 400 mL of ice water and added.
  • the mixture was extracted with methyl tert-butyl ether (50 mL) ⁇ 2, and the organic layer was washed with saturated brine (40 mL).
  • the solvent was removed under reduced pressure to leave a volume of about 40 mL, 200 mL of isopropanol was added, and tetrahydrofuran was removed under reduced pressure.
  • 100 mL of solvent a large amount of solids were precipitated, 20 ml of water was added dropwise thereto, and the crystallized liquid was cooled to 0-5 ° C, stirred and crystallized for 1 hour, filtered to obtain white needle crystals, and blast-dried compound 1 at 40-50 ° C. (17.5 g, yield 85%).
  • reaction solution was slowly added to an ice-water mixture (4400 g, 20 V) under stirring, and the mixture was separated, and the organic phases were combined.
  • the organic phase was washed successively with 1 mol/L hydrochloric acid (2200 ml, 10 V) and 10% sodium chloride solution (2200 ml, 10V).
  • isopropyl alcohol (1320 ml, 6V) was added, and distillation under reduced pressure was continued until the density of the distilled liquid was close to that of isopropanol.
  • the temperature of the reaction mixture of the compound 3 and acetonitrile obtained in Example 8 was adjusted to 45 to 50 ° C, and after adding cuprous iodide (309 g, 1624 mmol), TBHP (70%) (783 g, 6089 mmol) was added, and stirring was continued for 24 hours.
  • the compound 3 (1.2%) ⁇ 2% (area normalization method) was monitored by HPLC, and the reaction was stopped.
  • the temperature of the reaction system was lowered to 15 to 25 ° C, then ethyl acetate (5.0 L, 5 V) was added, and a saturated sodium sulfite solution (5.0 L, 5 V) was added dropwise, stirred, filtered, and the filtrate was added to a saturated sodium chloride solution (3.0 L, 3V) Stir, separate the liquid, combine the organic phases, remove some of the solvent under reduced pressure, and keep the volume of the system at about 13L.
  • the organic phase system for controlling the above solvent removal was controlled at a temperature of 20 to 30 ° C, and pyridinium chlorochromate (481 g, 2233 mmol) was added in portions, and the compound 4a ⁇ 2% (area normalization method) was monitored by HPLC to stop the reaction.
  • Ethyl acetate (5.0 L, 5 V) was added, and the insoluble material was removed by filtration.
  • the filtrate was added to a saturated sodium sulfite solution (5.0 L, 5 V) and a saturated sodium chloride solution (3.0 L, 3 V).
  • the organic phase was washed once with a sodium chloride solution (3.0 L, 3 V) and the organic solvent was evaporated from vacuo.
  • the Pd/C was recovered by filtration, and the solvent was removed under reduced pressure.
  • the solvent was dissolved in ethyl acetate (6.0 L, 10 V), and the temperature of the system was controlled at 20 to 30 ° C.
  • Pyridinium chlorochromate (76.4 g, 355 mmol) was added in portions, and stirring was continued. After 12 hours, the HPLC showed that the enol compound and the hydroxy compound were less than 1%, filtered through a bed of celite, and the filtrate was washed with water, and the organic phase was combined. The organic phase was evaporated under reduced pressure and dissolved in tetrahydrofuran (6.0 L, 10 V) to give a solution. .
  • the solution was added to a 10 L clean dry autoclave, the previously recovered Pd/C was added, the system hydrogen pressure was maintained at 1.5 MPa, the temperature was 55-65 ° C, the reaction was carried out for 24 hours, and the compound 4 ⁇ 1% by HPLC was monitored. 85%.
  • the Pd/C was recovered by filtration, and the solvent was evaporated under reduced pressure.
  • the solvent was dissolved in ethyl acetate (6.0 L, 10 V), and the temperature of the system was controlled at 20 to 30 ° C.
  • Pyridinium chlorochromate 158 g, 734 mmol
  • HPLC shows enol compound and hydroxyl
  • the compound was less than 1%, filtered through a bed of celite, and the filtrate was washed with water, and the organic phase was combined.
  • the organic phase was evaporated under reduced pressure and dissolved in tetrahydrofuran (6.0 L, 10 V) to give a solution.
  • the solution was added to a 10 L clean dry autoclave, the previously recovered Pd/C was added, the system hydrogen pressure was maintained at 1.5 MPa, the temperature was 55-65 ° C, the reaction was carried out for 24 hours, and the compound 4 ⁇ 1% by HPLC was monitored. 92%.
  • the reaction system was filtered through a 0.22 ⁇ m organic filter to remove Pd/C, activated carbon (60 g, 10% wt) was added, and the mixture was heated under reflux for 30 min.
  • the activated carbon was removed by filtration through a 0.22 ⁇ m organic filter.
  • the filtrate was evaporated under reduced pressure and dichloromethane (1800 ml) was added. , 3V) and methanol (4800ml, 8V).
  • the methylene chloride was removed under reduced pressure, and a white solid was precipitated, and the crystals were cooled and crystallized.
  • a compound (5 g, 170 g, 334 mmol), tetrahydrofuran (1020 ml, 6 V) was added to a 3000 ml three-neck round bottom flask, and stirred to dissolve.
  • the temperature of the system was controlled at -5 to 5 ° C, and a 1 mol/L solution of tri-tert-butoxyaluminum hydride in tetrahydrofuran (501 mL, 501 mmol) was added dropwise. After the dropwise addition was completed, stirring was continued at -5 to 5 ° C for 24 hours.
  • the compound 5 (aera) was monitored by HPLC to stop the reaction.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Steroid Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

本发明公开了一种制备去氧胆酸或其酯或其药学可接受盐的方法，所述化合物可用于去除脂肪沉积。

Description

一种制备去氧胆酸的方法 技术领域
本发明涉及医药有机合成领域，具体地，涉及一种制备去氧胆酸或其酯、或其药学可接受盐，及其中间体的新方法。
背景技术
快速去除脂肪是古老的理想，有文献报道，将去氧胆酸注射至体内脂肪沉积部位时，具有脂肪去除的特性。目前去氧胆酸主要来源于动物躯体，虽然成本相对较低，但存在可能含有动物病原体和其它有害因子的危险。
为了实现去氧胆酸去除脂肪的全部潜力，解决动物来源产品带来的问题。本发明提供了一种以化学方式合成去氧胆酸的方法，不仅所得产品的收率高、纯度高，还适用于质量控制，便于工业化生产。
发明内容
本发明提供了一种制备去氧胆酸或其酯或其药学可接受盐的方法：
Figure PCTCN2016074662-appb-000001
所述方法包括，
g)在路易斯酸存在下使式1化合物与丙烯酸甲酯反应形成式2化合物
Figure PCTCN2016074662-appb-000002
h)在氢化条件下使式2化合物与H2反应形成式3化合物
Figure PCTCN2016074662-appb-000003
i)使式3化合物与氧化剂反应形成式4化合物
Figure PCTCN2016074662-appb-000004
j)在氢化条件下使式4化合物与H2反应形成式5化合物
Figure PCTCN2016074662-appb-000005
k)使式5化合物与还原剂反应形成式6化合物
Figure PCTCN2016074662-appb-000006
和
l)使式6化合物暴露于去保护条件下形成其酯，并且任选地暴露于适宜水解条件下形成去氧胆酸或其药学上可接受的盐。
在一实施例中，g)项中的路易斯酸是EtAlCl2。
在一实施例中，h)项中的氢化条件包含pd/C或PtO2催化剂。
在一实施例中，i)项中的氧化条件包含过氧化叔丁醇和氯铬酸吡啶盐。
在一实施例中，j)项中的氢化条件包含pd/C或PtO2催化剂。
在一实施例中，k)项中的还原剂是LiAl(OtBu)3H。
在一实施例中，l)项中的去保护和水解条件包含使式6化合物与碱金金属氢氧化物、碱 金金属醇盐、碱土金属氢氧化物、碱土金属醇盐、或其混合物反应。在某些方面，水解条件包括酸处理以获得去氧胆酸。在其他方面中，省略酸处理以获得相应的盐。
在一实施例中，所述碱金金属氢氧化物是NaOH。
在一实施例中，去氧胆酸的盐可通过与碱土金属醇盐或氢氧化物反应来制备。去氧胆酸的盐包括钠、钾、或锂盐。
在一实施例中，提供选自由以下组成的群组的中间体化合物：
(Z)-3α-苯甲酰氧基-5β-孕甾-9(11)，17(20)-二烯(1)；
(E)-3α-苯甲酰氧基-5β-胆-9(11)，16,-二烯-24-酸甲酯(2)；
3α-苯甲酰氧基-5β-胆-9(11)-烯-24-酸甲酯(3)；
3α-苯甲酰氧基-5β-胆-9(11)-烯-12-酮-24-酸甲酯(4)；
3α-苯甲酰氧基-5β-胆烷-12-酮-24-酸甲酯(5)；
3α-苯甲酰氧基-5β-胆-9(11)-烯-12-羟基-24-酸甲酯(5a)；
3α-苯甲酰氧基-5β-胆烷-12β-羟基-24-酸甲酯(5b)；和
3α-苯甲酰氧基-5β-胆烷-12α-羟基-24-酸甲酯(6)。
在一优选实施例中，本发明中去氧胆酸或其酯或其药学可接受盐由以下方法制备：
所述方法包括：
g)在路易斯酸存在下使式1化合物与丙烯酸甲酯反应形成式2化合物
Figure PCTCN2016074662-appb-000007
h)在氢化条件下使式2化合物与H2反应形成式3化合物
Figure PCTCN2016074662-appb-000008
i)使式3化合物与氧化剂反应形成式4化合物，HPLC监测化合物3(1.2％)<2％(面积归一化法)，停止反应，淬灭，处理反应。随后加入氯铬酸吡啶盐，氧化反应过程中生成的化合物4a获得化合物4
Figure PCTCN2016074662-appb-000009
j)在氢化条件下使式4化合物与H2反应形成式5化合物，停止反应，加入氯铬酸吡啶盐，分别氧化反应过程中生成的化合物5a和化合物5b，由此获得的化合物4在氢化条件下，继续与H2反应得到化合物5，这样循环操作提高化合物5的收率
Figure PCTCN2016074662-appb-000010
k)使式5化合物与还原剂反应形成式6化合物
Figure PCTCN2016074662-appb-000011
l)使式6化合物暴露于去保护条件下形成其酯，并且任选地暴露于适宜水解条件下形成去氧胆酸或其药学上可接受的盐，所述适宜水解条件为NaOH溶液。
在一实施例中，本发明中的化合物1由以下方法制备：
Figure PCTCN2016074662-appb-000012
在一实施例中，本发明的化合物1.4由以下方法制备：
室温下，以N-甲基吡咯烷酮为溶剂、10％pd/C为催化剂，将式1.3化合物与H2反应生成式1.4化合物
Figure PCTCN2016074662-appb-000013
本发明中术语“路易斯酸”是指电子对受体。包括但不限于EtAlCl2、氯化铝、氯化铁、三氟化硼、五氯化铌以及镧系元素的三氟甲磺酸盐。
术语“氢化剂”是指可向分子提供氢的试剂。
具体实施方式
下面通过非限定性实施例来对本发明进行说明，应当理解为，此处描述的优选实施例仅用于说明和解释本发明，并不用于限定本发明。
实施例1：化合物1.2的合成
5L三口瓶中加入二氯甲烷(2.0L，8V)和化合物1.1(250.0g，826.5mmol)，搅拌加热至溶解。向反应液中滴加浓硫酸(124.0g，1240.0mmol,98％)，加热反应液至回流，搅拌4h停止反应。
待反应液冷却后，将其缓慢倒入1L冰水中，搅拌5min，随后滴加饱和碳酸钠溶液调PH值至7～8。静止分液，水相以CH2Cl2(200mL，0.8V)萃取两次，合并有机相；有机相以水(500mL，2V)、饱和食盐水(500mL，2V)洗涤并以无水硫酸钠干燥。干燥后过滤得到有机相，旋蒸除去有机相得粗品。向粗品中加乙酸乙酯(375mL，1.5V)，室温下打浆洗涤12h过滤，以乙酸乙酯(50mL，0.2V)洗涤滤饼，抽干，20-40℃真空干燥得化合物1.2(211.0g，收率89.7％)。
1H-NMR(400MHz,CDCl3)δ:5.76(s,1H),5.64-5.45(m,1H),2.70-2.33(m,6H),2.23-2.02(m,7H),1.72-1.56(m,1H),1.57-1.45(m,1H),1.36(s,3H),1.27-1.08(m,1H),0.89(s,3H).
实施例2：化合物1.3的合成
将化合物1.2(200.0g，703.3mmol)、乙二醇(261.9g，4.22mol)、一水合对甲苯磺酸(6.7g，35.2mmol)和甲苯(2.0L，10V)置于3L单口瓶中，安装分水器及冷凝管，搅拌加热至回流反应2h。
冷却后，将反应液倒入水(800mL，4V)中，分液，水相以乙酸乙酯：四氢呋喃＝5:1(200mL，1V)萃取，合并有机相，有机相以水(300mL，1.5V)、饱和食盐水(300mL，1.5V)洗涤，无水硫酸钠干燥，干燥后过滤得有机相，旋蒸除去溶剂得粗品。粗品以乙酸乙酯(1.0L，5V)加热溶解，随后加入正庚烷(400mL，2V)降至室温搅拌析晶1h，抽滤，以乙酸乙酯：正庚烷＝2.5:1(150mL，0.75V)洗涤滤饼，抽干，20-30℃真空干燥得化合物1.3(196.2g，收率85.0％)。
1H-NMR(400MHz,CDCl3)δ:5.75(s,1H),5.54(d,J＝5.8Hz,1H),3.93(m,2H),3.88(m,2H),
2.64-2.30(m,6H),2.26-1.97(m,7H),1.87(m,1H),1.73-1.65(m,1H),1.35(s,3H),1.11(m,1H),0.86(s,3H).
实施例3：化合物1.4的合成
化合物1.3(150.0g,456.8mmol)、钯炭(15.0g,10％)、N-甲基吡咯烷酮(1.5L，10V)置于加压反应釜中，氢气置换，在40-60psi、150rpm的条件下室温搅拌6h。
加入乙酸乙酯(750mL，5V)，过滤除去钯炭，加水(750mL，5V)，水相以乙酸乙酯(300mL，2V)萃取两次，合并有机相，有机相以水(450mL，3V)、饱和食盐水(450mL，3V)洗涤后，用无水硫酸钠干燥，过滤获得有机相，旋蒸除去溶剂得化合物1.4(135.8g，收率90.0％)。
经过TLC和ELSD检测，全部是5β构型的化合物1.4，未发现5α构型的结构。
1H-NMR(400MHz,CDCl3)δ:5.44(d,J＝5.6Hz,1H),3.94-3.92(m,4H),2.50-2.40(m,2H),2.17(m,2H),2.14-1.95(m,7H),1.86-1.69(m,4H),1.49(m,4H),1.10(s,3H),0.99-0.87(m,1H),0.81(s,3H).
实施例4：化合物1.5的合成
将化合物1.4(130.0g,393.4mmol)、四氢呋喃(1.3L，10V)投入2L三口瓶，氮气保护下搅拌溶解，降温至-5至5℃，滴加LiAl(OtBu)3H(786.8mL,786.8mmol,1.0M)，室温搅拌30min。滴加7％对甲苯磺酸(260mL，2V)，室温搅拌6h。加水(520mL，4V)，以乙酸乙酯(520mL，4V)萃取，合并有机相，有机相以水(520mL，4V)、饱和食盐水(390mL，3V)洗涤并以无水硫酸钠干燥，过滤获得有机相，旋蒸除去溶剂的粗品；粗品以丙酮：正庚烷＝1:8(390mL，3V)室温打浆洗涤1h，抽干，20℃化合物1.5(107.8g，收率95.0％)。
1H-NMR(400MHz,CDCl3)δ:5.42(d,J＝5.6Hz,1H),3.73-3.60(m,1H),2.46(m,1H),2.23-1.98(m,7H),1.80-1.70(m,2H),1.57-1.36(m,7H),1.33-1.13(m,3H),1.09(s,3H),0.82(s,3H).
实施例5：化合物1.6的合成
化合物1.5(30.0g,104mmol)、DMAP(1.22g，10mmol)及三乙胺(30.4g，300mmol)溶于300mL二氯甲烷中，室温下向其中滴加苯甲酰氯(28.1g，200mmol)，滴完完毕，升温至回流，反应10小时，TLC显示反应完全，停止反应。冷却反应液至室温，补加200mL二氯甲烷，100mL水洗涤反应液一次，2N HCl(150mL)洗涤有机相一次，饱和食盐水(100mL)洗涤 有机相一次，减压脱除溶剂得油状物，300mL丙酮溶解油状物，向其中缓慢滴加50mL水，渐有固体析出，冷却至0-5℃搅拌2-4小时，抽滤得白色粉末固体化合物1.6(38.2g，收率95％)。
1H-NMR(400MHz,CDCl3)δ:8.05(dd,J＝8.2,1.0Hz,2H),7.55(m,1H),7.45(m,2H),5.49(d,J＝5.6Hz,1H),5.08-4.93(m,2H),2.49(m,1H),2.32-1.99(m,7H),1.95-1.85(m,1H),1.84-1.51(m,7H),1.48-1.20(m,3H),1.15(s,3H),0.85(s,3H).
实施例6：化合物1的合成
氮气保护下，三苯基乙基溴化膦(41.6g，112mmol)溶于150mL四氢呋喃，20-30℃下向混悬液中加入叔丁醇钾(12.6g，112mmol)，反应液即呈橘红色，室温搅拌1小时，滴加100毫升溶有化合物1.6(20g，51mmol)的四氢呋喃溶液，20分钟滴完，室温反应2小时，TLC显示原料完全转化，将反应液倾倒至400mL冰水中，加入甲基叔丁基醚(50mL)×2分液萃取，饱和食盐水(40mL)洗涤有机层，减压脱除溶剂，留约40mL体积，加入200mL异丙醇，减压脱除四氢呋喃，留约100mL溶剂时，已有大量固体析出，向其中滴加20毫升水，冷却结晶液至0-5℃，搅拌析晶1小时，过滤得白色针状结晶，40-50℃鼓风干燥的化合物1(17.5g，收率85％)。
1H-NMR(400MHz,CDCl3)δ:8.06(m,2H),7.55(t,J＝8.0,8.0Hz,1H),7.44(t,J＝8.0,8.0Hz,2H),5.46(s,1H),5.22(m,1H),5.03(m,1H),2.48-2.37(m,3H),2.33-2.20(m,1H),2.20-2.00(m,3H),1.94-1.84(m,1H),1.81-1.60(m,9H),1.51-1.16(m,5H),1.13(s,3H),0.84(s,3H).
实施例7：化合物2的合成
Figure PCTCN2016074662-appb-000014
5000ml三口圆底烧瓶中加入化合物1(220g，544mmol)和二氯甲烷(2200ml，10V)搅拌溶解，进行氮气置换。将反应体系降温至-5～5℃之间，约15min滴加完丙烯酸甲酯(117g，1360mmol)，继续搅拌30min，控制反应体系温度在-5～5℃，随后滴加二氯乙基铝溶液(25％己烷溶液，829mL，1631mmol)，继续搅拌30min后，将反应体系升温至25～30℃搅拌反应48小时。经HPLC监测化合物1<3％(归一化法面积)，停止反应。
搅拌条件下，将反应液缓慢加入到冰水混合物(4400g，20V)中，分液，萃取，合并有机相。有机相先后用1mol/L盐酸(2200ml，10V)和10％氯化钠溶液(2200ml，10V)洗涤。有机相减压除去溶剂后，加入异丙醇(1320ml，6V)，继续减压蒸馏直至蒸出的液体密度与异丙醇密 度一致，补加异丙醇(1320ml，6V)，然后滴加水(275ml，1.25V)，大量固体析出，在20～30℃下搅拌2小时，然后降温至0～5℃下继续搅拌2h，停止搅拌。过滤，滤饼用少量低温的异丙醇/水(4/1)洗涤，抽干，50℃下鼓风干燥直至水分<1％，得到化合物2(238g，收率89％)。
1H-NMR(400M,DMSO-d6)δ:7.93-7.95(d,2H),7.63-7.67(t,1H),7.49-7.53(t,3H),5.43(s,1H),5.34(s,1H),4.92(s,1H),3.58(s,3H),2.21-2.26(m,2H),2.10-2.14(m,4H),1.95-2.03(m,2H),1.81-1.87(m,2H),1.71-1.72(m,1H),1.54-1.70(m,5H),1.47-1.53(q,1H),1.33-1.35(d,2H),1.16-1.19(q,1H),1.10(s,3H),1.02-1.03(d,1H),1.01-1.02(d,3H),0.65(s,3H).
m.p.＝109-109.7℃.
Figure PCTCN2016074662-appb-000015
(c＝1,氯仿).
HPLC(UV,aera):98.4％.
实施例8：化合物3的合成
Figure PCTCN2016074662-appb-000016
1.0L的洁净高压釜中加入化合物2(1000g，2.04mol)，四氢呋喃(5000mL，5V)，和10％Pd/C(50％w.t.，120g，12％w.t.)后，将装置密封好，先后进行氮气置换和氢气置换，保持氢气压力为1.2MPa下反应24小时。经HPLC监测化合物2<2％(面积归一化法)，停止反应。进行氮气置换后，取出反应浆液，过滤，滤液减压除去溶剂，再加入乙腈(2000mL，2V)后，继续减压蒸馏除去溶剂，随后加入乙腈(12L，12V)加热溶清，不进行纯化直接进行下一步反应。
实施例9：化合物4的合成
Figure PCTCN2016074662-appb-000017
控制实施例8中所得化合物3和乙腈的反应液温度在45～50℃，向其中加入碘化亚铜(309g，1624mmol)后，加入TBHP(70％)(783g，6089mmol)，继续搅拌24小时，HPLC监测化合物3(1.2％)<2％(面积归一化法)，停止反应。将反应体系温度降至15～25℃，随后加入乙酸乙酯(5.0L，5V)，滴加饱和亚硫酸钠溶液(5.0L，5V)，搅拌，过滤，滤液加入饱和氯化钠溶液(3.0L，3V)搅拌，分液，合并有机相，减压去除部分溶剂，保持体系的体积在13L左右。
控制上述去除溶剂的有机相体系温度在20～30℃，分批加入氯铬酸吡啶盐(481g，2233mmol)，HPLC监测化合物4a<2％(面积归一化法)，停止反应。加入乙酸乙酯(5.0L，5V)，过滤除去不溶物，滤液加入饱和亚硫酸钠溶液(5.0L，5V)和饱和氯化钠溶液(3.0L，3V)，搅拌分液，合并有机相。有机相用氯化钠溶液(3.0L,3V)洗涤一遍，有机相减压除去溶剂。加入二氯甲烷(3000ml，3V)溶解，经过硅胶柱(100-200目，10.0Kg，10w.t.)，二氯甲烷作为洗脱液，收集产品，减压除去部分二氯甲烷溶剂，加入正庚烷(15.0L,15v)，继续减压除去二氯甲烷，体系有大量固体析出，过滤得到化合物4(713g,收率71％)
1H-NMR(400M,DMSO-d6)δ:7.93-7.95(d,2H),7.62-7.64(t,1H),7.48-7.52(t,3H),5.64(s,1H),4.93(s,1H),3.58(s,3H),2.41-2.49(m,1H),2.34-2.36(m,1H),2.22-2.26(m,1H),2.10-2.13(m,2H),1.86-1.88(m,2H),1.64-1.75(m,6H),1.32-1.55(m,7H),1.20(s,3H),1.24-1.26(m,2H),0.91-0.93(d,3H),0.86(s,3H).
m.p.＝124.6-126.4℃.
Figure PCTCN2016074662-appb-000018
(c＝1,氯仿).
HPLC(UV,aera):96.9％.
实施例10：化合物5的合成
Figure PCTCN2016074662-appb-000019
10L洁净干燥的高压釜中加入化合物4(600g，1184mmol)，四氢呋喃(6.0L，10V)的溶液，和10％Pd/C(干，150g，25％w.t.)，先后进行氮气置换和氢气置换，保持体系压力在1.2Mpa，将反应体系加热至55～65℃，搅拌24小时，HPLC监测化合物5占67％，烯醇式化合物(5a)和羟基化合物(5b)占31％，未知杂质2％，停止反应。
过滤回收Pd/C，滤液减压除去溶剂后用乙酸乙酯(6.0L,10V)溶解，控制体系温度在20～30℃，分批加入氯铬酸吡啶盐(76.4g，355mmol)，继续搅拌12小时，HPLC显示烯醇式化合物和羟基化合物低于1％，经过硅藻土床过滤，滤液水洗，合并有机相，有机相减压除去溶剂，用四氢呋喃(6.0L，10V)溶解，得到溶液。
将溶液加入到10L洁净干燥的高压釜中，加入之前回收的Pd/C，保持体系氢气压力1.5MPa，温度55-65℃下，反应24小时，HPLC监测化合物4<1％，化合物5占比85％。过滤回收Pd/C，滤液减压除去溶剂后用乙酸乙酯(6.0L,10V)溶解，控制体系温度在20～30℃，分批加入氯铬酸吡啶盐(158g，734mmol)，继续搅拌12小时，HPLC显示烯醇式化合物和羟基 化合物低于1％，经过硅藻土床过滤，滤液水洗，合并有机相，有机相减压除去溶剂，用四氢呋喃(6.0L，10V)溶解，得到溶液。
将溶液加入到10L洁净干燥的高压釜中，加入之前回收的Pd/C，保持体系氢气压力1.5MPa，温度55-65℃下，反应24小时，HPLC监测化合物4<1％，化合物5占比92％。
反应体系用0.22微米有机滤膜过滤除去Pd/C，加入活性炭(60g，10％w.t)，加热回流30min，用0.22微米有机滤膜过滤除去活性炭，滤液减压除去溶剂，加入二氯甲烷(1800ml，3V)和甲醇(4800ml，8V)。减压除去二氯甲烷，过程有白色固体析出，降温析晶，保持体系温度在-5～0℃下搅拌2小时，停止搅拌，过滤，滤饼用冷甲醇(600mL，1V)洗涤，抽干，50℃鼓风干燥直至衡重为止，得到化合物5(510g,收率85％)。
1H-NMR(400M,DMSO-d6)δ:7.95-7.96(d,2H),7.62-7.66(m,1H),7.49-7.52(t,2H),4.84-4.89(m,1H),3.57(s,3H),2.44-2.54(m,1H),2.30-2.37(m,1H),2.17-2.25(m,1H),1.58-1.92(m,13H),1.22-1.49(m,8H),1.05-1.17(m,2H),1.02(s,3H),0.97(s,3H),0.75-0.77(m,3H).
m.p.＝123.2-125.2℃.
Figure PCTCN2016074662-appb-000020
(c＝1,氯仿).
HPLC(UV,aera):97.2％.
实施例11：化合物6的合成
Figure PCTCN2016074662-appb-000021
氮气保护下，3000ml三口圆底烧瓶中加入化合物5(170g，334mmol)，四氢呋喃(1020ml,6V)，搅拌溶解。控制体系温度在-5～5℃，滴加1mol/L三叔丁氧基氢化铝锂四氢呋喃溶液(501mL，501mmol)，滴加完成后，在-5～5℃下继续搅拌24小时。HPLC监测化合物5(aera)<1％，停止反应。将体系冷却，保持体系温度不高于10℃，滴加2mol/L盐酸(600ml)，分液，合并有机相，饱和氯化钠(170ml，1V)和2mol/L盐酸(170ml，1V)一起搅拌洗涤，分液获得有机相，饱和氯化钠(340ml，2V)洗，分液获得有机相，有机相减压除去部分溶剂，剩约300ml溶剂体积时，加入正庚烷(1700ml，10V)搅拌，分液，获得有机相，继续减压蒸馏除去四氢呋喃后(通过蒸出的液体密度与正庚烷一致来判断)，同时保证体系体积在1700ml左右溶液，在10～25℃下搅拌2小时，过滤，滤饼用少量正庚烷洗涤，抽干，得化合物6(145g，收率85％)。
1H-NMR(400M,DMSO-d6)δ:7.96-7.98(d,2H),7.63-7.67(t,1H),7.50-7.54(t,2H),4.88(m,1H),4.27-4.28(m,1H),4.27-4.28(d,1H),3.80-3.81(d,1H),3.60(s,3H),2.28-2.35(m,1H),2.16-2.24(m,1H),1.85-1.97(m,2H),1.68-1.82(m,6H),1.55-1.66(m,4H),1.48-1.51(m,2H),1.32-1.48(m,4H),1. 14-1.28(m,3H),0.96-1.14(m,3H),0.93(s,3H),0.91(s,3H),0.61(s,3H).
m.p.＝107.7-112.3℃.
Figure PCTCN2016074662-appb-000022
(c＝1,氯仿).
HPLC(UV,aera):98.81％.
实施例12：粗去氧胆酸的合成
Figure PCTCN2016074662-appb-000023
2000ml三口圆底烧瓶中加入化合物6(100g，196mmol)，四氢呋喃(600ml，6V)和甲醇(600ml，6V)，搅拌溶解，保持体系温度低于25℃下，滴加4mol/L氢氧化钠溶液(196ml，784mmol)，在20-30℃温度下搅拌24小时。HPLC监测反应完成，补加水(800ml，8V)，将体系温度降到10～15℃后，滴加1mol/L盐酸调节pH至9～10，然后减压除去有机溶剂，冷却至10～25℃，二氯甲烷(500ml*2)洗涤两遍，用1mol/L盐酸调节pH至1～2，搅拌2小时，过滤，滤液用水(500ml，5V)洗涤，抽干，鼓风干燥得到固体101g。15～25℃下，将产品溶于甲基叔丁基醚(1000ml,10V)，搅拌12小时以上，过滤，滤饼用甲基叔丁基醚(400ml,4V)洗涤后，经过鼓风干燥得到去氧胆酸粗品(73.1g，95％)。
实施例13：去氧胆酸的纯化
2000ml三口圆底烧瓶中加入去氧胆酸粗品(100g，196mmol)和10％甲醇的二氯甲烷溶液(1500ml，15V)，加热搅拌溶解，过滤除去不溶物，继续加热蒸馏，同时滴加二氯甲烷(2000ml)，保证滴加速度与蒸馏出液体速度一致，通过气相测定体系的甲醇含量在2.5％～3％，降温至5～10℃，搅拌2小时后过滤，滤饼用二氯甲烷(200ml，2V)洗涤，鼓风干燥，经过HPLC(ELSD)确定最大单杂低于0.1％。将所得产品(为二氯甲烷合物)加入到水中(1000ml)，再加入氢氧化钠溶液调节pH至9-10，搅拌溶解，然后滴加1mol/L盐酸调节pH至1～2，在10～25℃下搅拌2小时后，过滤，滤饼用水(500ml)洗涤，然后滤饼用纯水(2000ml,20V)在60-80℃下浆化4-8h，然后过滤，抽干，经过干燥得到去氧胆酸纯品(92g，收率92％)。
1H-NMR(400M,DMSO-d6)δ:11.99(s,1H),4.38-4.58(m,1H),4.21-4.30(m,1H),3.71-3.79(m,1H),3.30-3.51(m,2H),2.12-2.31(m,1H),2.05-2.12(m,1H),1.71-1.91(m,4H),1.42-1.71(m,5H),1.28-1.38(m,9H),1.15-1.25(m,3H),1.11(s,3H),0.95-1.08(m,2H),0.91(d,3H),0.86(s,3H).
m.p.＝173.2-174.1℃.
Figure PCTCN2016074662-appb-000024
(c＝1,氯仿)；
Figure PCTCN2016074662-appb-000025
(c＝1,乙醇).
HPLC(ELSD)纯度：99.9％.

Claims (8)

  1. 一种制备去氧胆酸或其酯或其药学可接受盐的方法：
    Figure PCTCN2016074662-appb-100001
    所述方法包括，
    c)在氢化条件下，使式1.3化合物与H2反应形成式1.4化合物
    Figure PCTCN2016074662-appb-100002
    d)式1.4化合物经羰基还原和脱保护获得式1.5化合物
    Figure PCTCN2016074662-appb-100003
    e)式1.5化合物与苯甲酰氯反应生成式1.6化合物
    Figure PCTCN2016074662-appb-100004
    f)在烯烃形成条件下，使式1.6化合物与二碳烯化剂反应形成式1化合物
    Figure PCTCN2016074662-appb-100005
    g)在路易斯酸存在下使式1化合物与丙烯酸甲酯反应形成式2化合物
    Figure PCTCN2016074662-appb-100006
    h)在氢化条件下使式2化合物与H2反应形成式3化合物
    Figure PCTCN2016074662-appb-100007
    i)使式3化合物与氧化剂反应形成式4化合物
    Figure PCTCN2016074662-appb-100008
    j)在氢化条件下使式4化合物与H2反应形成式5化合物
    Figure PCTCN2016074662-appb-100009
    k)使式5化合物与还原剂反应形成式6化合物
    Figure PCTCN2016074662-appb-100010
    l)使式6化合物暴露于去保护条件下形成其酯，并且任选地暴露于适宜水解条件下形成去氧胆酸或其药学上可接受的盐。
  2. 如权利要求1中所述的方法，其中所述c)项中的氢化条件是pd/C作为催化剂、N-甲基吡咯烷酮作为溶剂。
  3. 如权利要求1中所述的方法，其中所述d)项中的羰基还原和脱保护条件是将化合物1.5溶于四氢呋喃中，-5至5℃下滴加LiAl(OtBu)3H，室温搅拌，随后滴加对甲苯磺酸。
  4. 如权利要求1中所述的方法，其中所述f)项中二碳烯化剂是Ph3PCH2CH3Br，KOtBu；g)项中的路易斯酸是EtAlCl2；h)项中的氢化条件包含pd/C或PtO2催化剂；i)项中的氧化条件包含过氧化叔丁醇和氯铬酸吡啶盐；j)项中的氢化条件包含pd/C或PtO2催化剂；k)项中的还原剂是LiAl(OtBu)3H。
  5. 如权利要求1中所述的方法，其中所述l)项中的去保护和水解条件包含使化合物6与碱金金属氢氧化物、碱金金属醇盐、碱土金属氢氧化物、碱土金属醇盐、或其混合物反应。
  6. 如权利要求5所述的方法，其中所述碱金金属氢氧化物是NaOH。
  7. 一种制备式1.4化合物的方法，所述方法为：以N-甲基吡咯烷酮为溶剂、10％pd/C为催化剂，将式1.3化合物与H2反应生成式1.4化合物
    Figure PCTCN2016074662-appb-100011
  8. 一种选自由以下组成的群组的中间体化合物：
    (Z)-3α-苯甲酰氧基-5β-孕甾-9(11)，17(20)-二烯(1)；
    (E)-3α-苯甲酰氧基-5β-胆-9(11)，16-二烯-24-酸甲酯(2)；
    3α-苯甲酰氧基-5β-胆-9(11)-烯-24-酸甲酯(3)；
    3α-苯甲酰氧基-5β-胆-9(11)-烯-12-酮-24-酸甲酯(4)；
    3α-苯甲酰氧基-5β-胆烷-12-酮-24-酸甲酯(5)；
    3α-苯甲酰氧基-5β-胆-9(11)-烯-12-羟基-24-酸甲酯(5a)；
    3α-苯甲酰氧基-5β-胆烷-12β-羟基-24-酸甲酯(5b)；
    3α-苯甲酰氧基-5β-胆烷-12α-羟基-24-酸甲酯(6)；和
    5β-雄甾-9(11)-烯-17-(1,3-二氧戊烷基)-3-酮(1.4)。
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