WO2023168974A1 - 胆酸衍生物及其制备方法和作为tgr5别构激动剂的应用 - Google Patents

胆酸衍生物及其制备方法和作为tgr5别构激动剂的应用 Download PDF

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WO2023168974A1
WO2023168974A1 PCT/CN2022/131241 CN2022131241W WO2023168974A1 WO 2023168974 A1 WO2023168974 A1 WO 2023168974A1 CN 2022131241 W CN2022131241 W CN 2022131241W WO 2023168974 A1 WO2023168974 A1 WO 2023168974A1
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cholic acid
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陈新
孙晶晶
钱明成
赵帅
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常州大学
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  • the invention belongs to the field of medicinal chemistry, and particularly relates to cholic acid derivatives, preparation methods thereof and applications as TGR5 allosteric agonists.
  • G-protein-coupled bile acid receptor 1 is an important member of the A family GPCR. It can be removed by endogenous bile acids such as cholic acid (CA), taurocholic acid (TCA), glycocholic acid (GCA), deoxycholic acid (DCA), taurodeoxycholic acid (TDCA), angolanine Activated by oxycholic acid (CDCA), ursodeoxycholic acid (UDCA) and the semi-synthetic derivative INT-777.
  • TGR5 is widely expressed in human tissues, including spleen, pancreas, liver, skin, brain, and gastrointestinal tract.
  • Various diseases such as type II diabetes, cholestatic liver disease, fatty liver disease, and dyslipidemia are caused by abnormal regulation of bile acid signaling.
  • the present invention uses CA as the lead compound, performs different modifications on its 7-position, 12-position and 24-position through a series of reactions to obtain new cholic acid derivatives, and tests the TGR5 functional activity of these compounds.
  • TGR5 cholic acid derivatives (Formula 1, Formula 2, Formula 3 or Formula 4):
  • R 1 is: hydrogen, methyl, trifluoromethyl, ethyl, n-propyl, isopropyl, cyclopropyl, benzyl and other aryl and alkyl groups;
  • All R1 groups include ⁇ and ⁇ configurations
  • R2 is: and amino group or OCH 3 ,OC 2 H 5 ,OCH(CH 3 ) 2 , and other alkoxy groups;
  • R 3 is: O or NOH
  • R 4 is: methyl, trifluoromethyl, ethyl, n-propyl, isopropyl, cyclopropyl, phenyl and other aryl and alkyl groups.
  • the alkylating reagent is methyl iodide, ethyl bromide or propyl bromide, and the molar ratio of compound 6: sodium hydride: alkylating reagent is 1:3:8
  • the solvent is methylene chloride
  • the coupling agent is HATU or EDC
  • the base is triethylamine
  • the catalyst is a DMAP amine compound, specifically tetrahydropyrrole, dimethylamine, diethylamine, morpholine, piperazine, piperazine methylamine, ethylamine, n-propylamine, isopropylamine, glycine ethyl ester, glycine, tetrahydropyro-substituted glycine, cyclopropylamine, cyclopentylmethylamine, cyclopentylamine or cyclopentylmethylamine
  • the alcohol is methanol, ethanol, Isopropyl alcohol, cyclopropanol, cyclopropanemethanol, cyclopentanol, cyclopentanemethanol, phenol, benzyl alcohol, 1-naphthol or 2-naphthol; compound 9a
  • Dissolve compound A1 or A2 or A3 or A4 or A6 in methanol solvent, and add acetic acid trihydrate according to the molar ratio of compound A1 or A2 or A3 or A4 or A6: sodium acetate trihydrate: oximation reagent 1:7:4 Sodium, oximation reagent hydroxylamine hydrochloride, heated to reflux for 12 hours, and after post-treatment, the target compound C1 or C2 or C3 or C4 or C5 was obtained.
  • Cholic acid the endogenous ligand of G protein-coupled bile acid
  • different modifications were carried out on positions 7, 12 and 24 to obtain new cholic acid derivatives, and the accumulation of cAMP through GloSensor Experiment to test the functional activity of target compounds on TGR5.
  • Glosensor - a bioluminescence-based cAMP biosensor (Promega) - was used to test new compounds for screening for cytotoxic activity. The results show that the synthesized cholic acid derivative has good agonistic activity on TGR5 and can allosterically modulate the functional activity of the endogenous ligand of TGR5.
  • Figure 1 CDCA dose-response curve mediated by cholic acid derivatives A1, B1, and C1.
  • Step 4 Dissolve compound 3 (5g, 9.9mmol) in methanol (50mL), add excess 4M sodium hydroxide aqueous solution, and stir at room temperature for 14h. After the reaction is completed, add hydrochloric acid aqueous solution to adjust the pH value to acidic, and concentrate under reduced pressure. The solid was washed with water and dichloromethane and dried to obtain 43.5 g of a white solid compound with a yield of 87%.
  • Step 10 Dissolve compound 9a (100 mg, 0.24 mmol) in DCM (5 mL), add HATU (119 mg, 0.31 mmol) in an ice bath, slowly add triethylamine (100 ⁇ L, 0.72 mmol) dropwise, and stir in an ice bath for 15 After minutes, tetrahydropyrrole (24 ⁇ L, 0.29 mmol) was added and stirred at room temperature for 2 h. After the reaction, extract with dichloromethane (10 mL ⁇ 3), wash the organic phase with saturated brine, and concentrate the solvent to obtain a crude product.
  • Step 1 Dissolve compound CA (10g, 24.6mmol) in DMF (100mL), add HATU (12.15g, 32mmol) in an ice bath, slowly add triethylamine (10.2mL, 73.8mmol) dropwise, and stir in an ice bath. After 15 minutes, tetrahydropyrrole (2.5 mL, 29.5 mmol) was added, and the mixture was stirred at room temperature for 2 h. After the reaction was completed, the mixture was concentrated under reduced pressure, washed with dichloromethane, and dried to obtain 108.2 g of a white solid compound with a yield of 70%.
  • Step 4 Dissolve compound 12 (7g, 12.9mmol) in methanol (80mL), add excess 4M sodium hydroxide aqueous solution, and stir at room temperature for 14h. After the reaction is completed, add hydrochloric acid aqueous solution to adjust the pH value to acidic, and concentrate under reduced pressure. The solid was washed with water and dichloromethane, and dried to obtain 135.2 g of a white solid compound with a yield of 88%.
  • Example 55 Other conditions were the same as in Example 55, except that A1 was replaced by A4.
  • the product was white solid compound C5 with a yield of 85%.
  • cAMP accumulation experiments were used to test the functional activity of target compounds on TGR5 and to elucidate whether new compounds are TGR5PAMs.
  • the accumulation level of cAMP is mainly tested using GloSensor, a bioluminescence-based cAMP biosensor (Promega). Briefly, HEK 293T cells were seeded into a 6-well plate at 3 ⁇ 10 5 cells per well. The next day, hTGR5 and pGloSensor-22F cAMP plasmids were simultaneously transfected into HEK 293T cells using FuGene transfection reagent (Promega).
  • the transfected cells were washed with CO 2 independent medium and then incubated with equilibrium solution containing 2% v/v GloSensor cAMP reagent stock solution (dissolved in 10% FBS CO 2 independent medium). Incubate at 37°C for 1 hour and then incubate at room temperature for 1 hour, and detect the bioluminescence signal until a steady-state baseline signal is obtained. Then, different concentration gradients of TGR5 agonist, positive control CDCA, or new compounds (final concentration 1 nM-50 ⁇ M) were added to the cells. Use a microplate reader to read changes in bioluminescence.
  • a cAMP accumulation assay was used to test whether new compounds can allosterically modulate the functional activity of the TGR5 endogenous ligand CDCA to determine whether they are TGR5 positive allosteric modulators (PAMs). Briefly, first test the dose-response curve of CDCA (1nM-100 ⁇ M). When its bioluminescence signal reaches the highest, add a new compound (1nM-100 ⁇ M) with a multiple concentration relationship to test whether the change in bioluminescence occurs at this time. Concentration-dependent limited upward trend. The specific experimental steps are the same as the accumulation test of Glosensor cAMP above.
  • Table 1 EC 50 values of class A and class C target compounds activating TGR5
  • Table 2 EC 50 values of class B target compounds activating TGR5
  • the target compound of the present invention has good agonistic activity on TGR5.
  • those with pharmacological activity below 600nM include A1, B1, C1, C2, C4 and C5.

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Abstract

一种胆酸衍生物及其制备方法和作为TGR5别构激动剂的应用。以CA 为先导化合物，经过一系列反应对其7位，12 位和24 位进行修饰得到新的胆酸衍生物。药理结果显示合成的大部分胆酸衍生物对TGR5具有很好的激动活性以及正向别构调节CDCA的功能活性。

Description

胆酸衍生物及其制备方法和作为TGR5别构激动剂的应用 技术领域
本发明属于药物化学领域，特别涉及胆酸衍生物及其制备方法和作为TGR5别构激动剂的应用。
背景技术
G-蛋白偶联胆汁酸受体1属于A家族GPCR的重要一员。它可以被内源性的胆汁酸例如胆酸(CA)、牛磺胆酸(TCA)、甘氨胆酸(GCA)、脱氧胆酸(DCA)、牛磺脱氧胆酸(TDCA)、鹅去氧胆酸(CDCA)、熊去氧胆酸(UDCA)和半合成衍生物INT-777等激活。TGR5在人体组织中广泛表达，包括脾脏、胰腺、肝脏、皮肤、大脑、和胃肠道等。II型糖尿病、胆汁淤积性肝病、脂肪肝以及血脂异常等多种疾病都是由胆汁酸信号传导调节异常引起。
2020年，Yang等人(Nature.2020,587,499-504.)在Nature期刊上首次报道分子中含有12-OH的TGR5内源性胆汁酸(CA、TCA、GCA、DCA、TDCA、INT-777)具有潜在的别构效应。然而，当羟基位于7位时，例如CDCA和UDCA，则失去了别构效应。此外，TGR5和胆汁酸的共晶结构显示，胆汁酸的12-OH与TGR5结合位点处的关键性氨基酸残基Thr131形成氢键，这对受体的别构效应起至关重要的作用。
发明内容
本发明以CA为先导化合物，经过一系列反应对其7位，12位和24位进行不同的修饰得到新的胆酸衍生物，并对这些化合物进行TGR5功能活性的测试。
TGR5胆酸衍生物(式1、式2、式3或式4)：
Figure PCTCN2022131241-appb-000001
Figure PCTCN2022131241-appb-000002
其中，R 1为：氢，甲基，三氟甲基，乙基，正丙基，异丙基，环丙基，苄基及其它芳基，烷基；
注：所有R1基团都包括α,β两种构型；
R 2为：
Figure PCTCN2022131241-appb-000003
Figure PCTCN2022131241-appb-000004
Figure PCTCN2022131241-appb-000005
及氨基基团或OCH 3,OC 2H 5,OCH(CH 3) 2,
Figure PCTCN2022131241-appb-000006
及其它烷氧基基团；
R 3为：O或NOH；
R 4为：甲基，三氟甲基，乙基，正丙基，异丙基，环丙基，苯基及其它芳基，烷基。
TGR5胆酸衍生物的路线1的具体合成方法：
(1)将胆酸溶于甲醇溶剂中，按照胆酸：催化剂＝1:0.1的摩尔比加入催化剂对甲苯磺酸一水合物(PTSA·H 2O)，常温搅拌12h，后处理得到中间体化合物1。
(2)将化合物1溶于二氯甲烷溶剂中，按照化合物1：催化剂：敷酸剂：酰化试剂＝1:0.1：3：3的摩尔比加入催化剂对二甲氨基吡啶(DMAP)，敷酸剂TEA，酰化试剂乙酸酐，常温搅拌2h，后处理得到中间体化合物2。
(3)将化合物2溶于丙酮溶剂中，冰浴条件下按照化合物2：氧化剂＝1：2的摩尔比滴加氧化剂琼斯试剂，冰浴搅拌5分钟，后处理得到中间体化合物3。
(4)将化合物3溶于甲醇溶剂中，按照化合物3：氢氧化钠＝1：2的摩尔比加入氢氧化 钠的水溶液，常温搅拌14h，后处理得到中间体化合物4。
(5)将化合物4溶于甲醇溶剂中，按照化合物4：催化剂＝1:0.1的摩尔比加入催化剂PTSA·H 2O，常温搅拌12h，后处理得到中间体化合物5。
(6)将化合物5溶于二氯甲烷溶剂中，按照化合物5：敷酸剂：保护基＝1：12：2.5的摩尔比加入敷酸剂咪唑，保护基TBDMSCl，常温搅拌30分钟，后处理得到中间体化合物6。
(7)将化合物6溶于无水四氢呋喃溶剂中，冰浴条件下加入氢化钠，常温搅拌30分钟后，加入烷基化试剂，70℃加热搅拌24h，后处理得到中间体7a或7b或7c。
其中，烷基化试剂是碘甲烷、溴乙烷或溴丙烷，化合物6：氢化钠：烷基化试剂的摩尔比为1：3：8
(8)将化合物7a或7b或7c溶于四氢呋喃溶剂中，按照化合物7a或7b或7c：TBAF＝1：2的摩尔比加入TBAF，常温搅拌10h，后处理得到中间体8a或8b或8c。
(9)将化合物8a或8b或8c溶于甲醇溶剂中，按照化合物8a或8b或8c：碱＝1：2的摩尔比加入氢氧化钠的水溶液，常温搅拌14h，后处理得到中间体9a或9b或9c。
(10)将化合物9a或9b或9c溶于溶剂中，加入偶联剂，冰浴搅拌的条件下搅拌15分钟，缓慢加入碱或催化剂和胺类化合物或相应的醇常温搅拌反应2h，经后处理得到目标化合物A1-18,A23-26。
其中，溶剂为二氯甲烷，偶联剂为HATU或EDC，碱为三乙胺，催化剂为DMAP胺类化合物，具体为四氢吡咯、二甲胺、二乙胺、吗啉、哌嗪、哌啶、甲胺、乙胺、正丙胺、异丙胺、甘氨酸乙酯、甘氨酸、四氢吡罗取代甘氨酸、环丙胺、环戊甲胺、环戊胺或环戊甲胺，醇为甲醇、乙醇、异丙醇、环丙醇、环丙甲醇、环戊醇、环戊甲醇、苯酚、苯甲醇、1-萘酚或2-萘酚；化合物9a或9b或9c：偶联剂：胺类化合物：碱的摩尔比为1:1.1:1.2:3；化合物9a：偶联剂：催化剂：醇的摩尔比为1：1.2：0.1：1.5。
(11)将化合物A1-18,A23-26分别溶于甲醇溶剂中，按照化合物A1-18、A23-26：催化剂：硼氢化钠＝1：1：10的摩尔比加入催化剂氯化钯，还原剂硼氢化钠，冰浴搅拌10分钟，经处理得到目标化合物B1-18,B23,B25-27。
或
将化合物A1或A2或A3或A4或A6溶于甲醇溶剂中，按照化合物A1或A2或A3或A4或A6：三水合乙酸钠：肟化试剂＝1：7：4的摩尔比加入三水合乙酸钠，肟化试剂盐酸羟胺，加热回流12h，经后处理得到目标化合物C1或C2或C3或C4或C5。
Figure PCTCN2022131241-appb-000007
或
Figure PCTCN2022131241-appb-000008
TGR5胆酸衍生物的路线2的具体合成方法：
(1)将胆酸溶于溶剂DMF中，按照胆酸：偶联剂：胺类化合物：碱＝1:1.1:1.2:3的摩尔比加入偶联剂HATU，冰浴搅拌的条件下搅拌15分钟，缓慢加入碱三乙胺和胺类化合物四氢吡咯常温搅拌反应2h，经后处理得到中间体化合物10。
(2)将化合物10溶于二氯甲烷溶剂中，按照化合物10：催化剂：敷酸剂：乙酰化试剂＝1:0.1：3：3的摩尔比加入催化剂对二甲氨基吡啶(DMAP)，敷酸剂TEA，乙酰化试剂乙酸酐，常温搅拌2h，后处理得到中间体化合物11。
(3)将化合物11溶于丙酮溶剂中，冰浴条件下按照化合物11：氧化剂＝1：2的摩尔比滴加氧化剂琼斯试剂，冰浴搅拌5分钟，后处理得到中间体化合物12。
(4)将化合物12溶于甲醇溶剂中，按照化合物12：氢氧化钠＝1：2的摩尔比加入氢氧化钠的水溶液，常温搅拌14h，后处理得到中间体化合物13。
(5)将化合物13溶于二氯甲烷溶剂中，按照化合物13：敷酸剂：保护基＝1：12：2.5的摩尔比加入敷酸剂咪唑，保护基TBDMSCl，常温搅拌30分钟，后处理得到中间体化合物14。
(6)将化合物14溶于二氯甲烷溶剂中，加入催化剂DMAP，敷酸剂TEA，酰化试剂， 常温搅拌2h，后处理得到中间体15a或15b或15c或15d。其中，酰化试剂是乙酸酐、丙酸酐、异丁酸酐或苯甲酸酐，化合物14：催化剂：敷酸剂：酰化试剂摩尔比为1:0.1：3：3。
(7)将化合物15a或15b或15c或15d溶于四氢呋喃溶剂中，按照化合物16a或16b或16c或16d：TBAF＝1：2的摩尔比加入TBAF，常温搅拌10h，后处理得到中间体A19或A20或A21或A22。
(8)将化合物A19或A20或A21或A22溶于甲醇溶剂中，按照化合物A19或A20或A21或A22：催化剂：硼氢化钠＝1：1：10的摩尔比加入催化剂氯化钯，还原剂硼氢化钠，冰浴搅拌10分钟，经处理得到目标化合物B19或B20或B21或B22。
本发明的有益效果为:
选取G蛋白偶联胆汁酸内源性配体胆酸为先导化合物，经过一系列反应对其7位，12位和24位进行不同的修饰得到新的胆酸衍生物，并通过GloSensor cAMP的累积实验来测试目标化合物对TGR5的功能活性。Glosensor-一种基于生物发光的cAMP生物传感器(Promega)-用来测试对新化合物进行细胞毒活性筛选。结果显示合成的胆酸衍生物对TGR5具有很好激动活性并可以别构调节TGR5内源性配体的功能活性。
附图说明
图1胆酸衍生物A1,B1,C1介导的CDCA剂量-响应曲线。
具体实施方式
现在结合实例对本发明做进一步的说明。
实施例1
(3R,5S,7R,8R,9S,10S,13R,14S,17R)-3-羟基-7-甲氧基-10,13-二甲基-17-((R)-5-氧代-5-(吡咯烷-1-基)戊烷-2-基)十六氢-12H-环戊烷[a]菲-12-酮(A1)的制备
步骤一：将胆酸(10g,24.4mmol)溶于甲醇(200mL)中，接着加入PTSA·H 2O(266mg,2.4mmol)，常温搅拌12h。反应结束后，加入30mL饱和NaHCO 3溶液，浓缩后用二氯甲烷(150mL×3)，用饱和食盐水洗涤有机相，浓缩溶剂得到粗产物。柱层析(V二氯甲烷:甲醇＝V30:1)，浓缩得到白色固体化合物110.2g，产率99％。
步骤二：将化合物1(5g,11.8mmol)，三乙胺(4.9mL,35.6mmol)，乙酸酐(3.4mL,35.6mmol)，DMAP(144mg,1.2mmol)，干燥二氯甲烷(100mL)的混合物搅拌2h，TCL检测。反应结束后，浓缩溶剂，用二氯甲烷(80mL×3)萃取，用水(20mL)洗涤有机相，浓缩溶剂得到粗产物。柱层析(V石油醚:V乙酸乙酯＝3:1)，浓缩得到白色固体化合物25.5g，产率92％。
步骤三：将化合物2(5.5g,10.9mmol)溶于丙酮(100mL)中，冰浴条件下缓慢滴加过量的琼斯试剂，冰浴搅拌5分钟，TCL检测。反应结束后，加入10mL异丙醇，搅拌至溶液变绿色，减压浓缩。用乙酸乙酯(80mL×3)萃取，饱和食盐水洗涤有机相，减压浓缩。柱层析(V石油醚:V乙酸乙酯＝3:1)，浓缩得到白色固体化合物35.4g，产率98％。
步骤四：将化合物3(5g,9.9mmol)溶于甲醇(50mL)中，加入过量的4M氢氧化钠水溶液，常温搅拌14h。反应结束后，加入盐酸水溶液调PH值至酸性，减压浓缩。用水和二氯甲烷洗涤固体，烘干得到白色固体化合物43.5g,产率87％。
步骤五：将化合物4(3g,7.4mmol)溶于甲醇(60mL)中，接着加入PTSA·H 2O(140mg,0.7mmol)，常温搅拌12h。反应结束后，加入10mL饱和NaHCO 3溶液，浓缩后用二氯甲烷(50mL×3)萃取，用饱和食盐水洗涤有机相，浓缩溶剂得到粗产物。柱层析(V二氯甲烷:V甲醇＝50:1)，浓缩得到白色固体化合物52.9g，产率93％。
步骤六：将化合物5(3g,7.1mmol)溶于二氯甲烷(50mL)，加入咪唑(5.8g,84.8mmol)，吡啶(1mL)，TBDMSCl(2.7g,17.7mmol)，常温搅拌30分钟，TCL检测反应。用二氯甲烷(50mL×3)萃取，用饱和食盐水洗涤有机相，浓缩溶剂得到粗产物。柱层析(V石油醚:V乙酸乙酯＝10:1)，浓缩得到白色固体化合物63.5g，产率92％。
步骤七：将化合物6(4g,7.5mmol)溶于无水四氢呋喃(50mL)，冰浴条件下加入NaH(894mg,22.35mmol)，搅拌30分钟后缓慢滴加MeI(3.7mL,59.6mmol)，N 2保护下70℃加热搅拌24h。用甲醇淬灭反应，减压浓缩，用二氯甲烷(50mL×3)萃取，用饱和食盐水洗涤有机相，浓缩溶剂得到粗产物。柱层析(V石油醚:V乙酸乙酯＝20:1)，浓缩得到油状液体化合物7a2.5g，产率60％。
步骤八：将化合物7a(2.5g,4.6mmol)溶于1M TBAF in THF(15mL)，常温搅拌10h。反应结束后，用乙酸乙酯(20mL×3)萃取，用饱和食盐水洗涤有机相，浓缩溶剂得到粗产物。柱层析(V石油醚:V乙酸乙酯＝3:1)，浓缩得到白色固体化合物8a1.5g，产率75％。
步骤九：将化合物8a(2g,4.6mmol)溶于甲醇(20mL)中，加入过量的4M氢氧化钠水溶液，常温搅拌4h。反应结束后，加入盐酸水溶液调PH值至酸性，减压浓缩，用二氯甲烷(30mL×3)萃取，用饱和食盐水洗涤有机相，浓缩溶剂得到粗产物。柱层析(V二氯甲烷:V甲醇＝25:1),浓缩得到白色固体化合物9a1.7g,产率88％。
步骤十：将化合物9a(100mg,0.24mmol)溶于DCM(5mL)中，冰浴条件下加入HATU(119mg,0.31mmol)，缓慢滴加三乙胺(100μL,0.72mmol)，冰浴搅拌15分钟之后加入四氢吡咯(24μL,0.29mmol)，常温搅拌2h。反应结束后，用二氯甲烷(10mL×3)萃取，用饱和食盐水洗涤 有机相，浓缩溶剂得到粗产物。柱层析(V二氯甲烷:V甲醇＝50:1),浓缩得到白色固体化合物A1100mg,产率89％。 1H NMR(400MHz,CDCl 3):δ3.39(t,J＝6.9Hz,4H),3.25(s,1H),3.20-3.17(m,4H),2.44-2.38(m,1H),2.34-2.22(m,2H),2.19-2.11(m,1H),2.07-1.98(m,3H),1.94-1.88(m,3H),1.86-1.77(m,5H),1.69-1.59(m,5H),1.44-1.39(m,1H),1.35-1.25(m,7H),0.97(s,3H),0.96(s,3H),0.82(d,J＝6.4Hz,3H).
实施例2
(R)-4-((3R,5S,7R,8R,9S,10S,13R,14S,17R)-3-羟基-7-甲氧基-10,13-二甲基-12-氧代十六氢-1H-环戊烷[a]菲-17-基)-N,N-二甲基戊酰胺(A2)的制备。
其他条件同实施例1，将四氢吡咯替换成二甲胺，产物为白色固体化合物A2，产率79％。 1H NMR(400MHz,CDCl 3):δ3.44-3.37(m,1H),3.27-3.26(m,1H),3.20(s,3H),2.99(s,3H),2.91(s,3H),2.45-2.33(m,2H),2.31-2.17(m,2H),2.09-1.99(m,4H),1.96-1.90(m,1H),1.86-1.78(m,4H),1.68-1.60(m,5H),1.45-1.41(m,1H),1.38-1.26(m,5H),0.98(s,3H),0.97(s,3H),0.84(d,J＝6.5Hz,3H).
实施例3
(R)-4-((3R,5S,7R,8R,9S,10S,13R,14S,17R)-3-3-羟基-7-甲氧基-10,13-二甲基-12-氧代十六氢-1H-环戊烷[a]菲-17-基)-N-甲基戊酰胺(A3)的制备
其他条件同实施例1，将四氢吡咯替换成甲胺，产物为白色固体化合物A3，产率为80％。 1H NMR(400MHz,CDCl 3):δ5.78(s,1H),3.45-3.38(m,1H),3.27-3.25(m,1H),3.20(s,3H),2.77(d,J＝4.8Hz,3H),2.42(t,J＝12.5Hz,1H),2.31-2.20(m,2H),2.11-1.99(m,4H),1.94-1.89(m,1H),1.87-1.78(m,4H),1.68-1.60(m,5H),1.45-1.40(m,1H),1.37-1.25(m,6H),0.98(s,3H),0.97(s,3H),0.82(d,J＝6.5Hz,3H).
实施例4
(R)-N-乙基-4-((3R,5S,7R,8R,9S,10S,13R,14S,17R)-3-3-羟基-7-甲氧基-10,13-二甲基-12-氧代十六氢-1H-环戊烷[a]菲-17-基)-N-戊酰胺(A4)的制备
其他条件同实施例1，将四氢吡咯替换成乙胺，产物为白色固体化合物A4，产率为91％。 1H NMR(400MHz,CDCl 3):δ5.65(t,J＝5.6Hz,1H),3.44-3.38(m,1H),3.28-3.23(m,3H),3.20(s,3H),2.42(t,J＝12.5Hz,1H),2.31-2.19(m,2H),2.09-1.97(m,5H),1.95-1.89(m,1H), 1.86-1.78(m,4H),1.68-1.60(m,5H),1.45-1.40(m,1H),1.38-1.26(m,5H),1.10(t,J＝7.3Hz,3H),0.98(s,3H),0.97(s,3H),0.83(d,J＝6.5Hz,3H).
实施例5
(R)-N-丙基-4-((3R,5S,7R,8R,9S,10S,13R,14S,17R)-3-3-羟基-7-甲氧基-10,13-二甲基-12-氧代十六氢-1H-环戊烷[a]菲-17-基)-N-戊酰胺(A5)的制备
其他条件同实施例1，将四氢吡咯替换成正丙胺，产物为白色固体化合物A5，产率为85％。 1H NMR(400MHz,CDCl 3):δ5.68(t,J＝5.9Hz,1H),3.44-3.37(m,1H),3.27-3.25(m,1H),3.20(s,3H),3.18-3.15(m,2H),2.42(t,J＝12.5Hz,1H),2.31-2.20(m,2H),2.10-1.99(m,5H),1.95-1.89(m,1H),1.86-1.78(m,4H),1.68-1.60(m,5H),1.51-1.42(m,3H),1.37-1.24(m,5H),0.97(s,3H),0.97(s,3H),0.89(t,J＝7.4Hz,3H),0.83(d,J＝6.5Hz,3H).
实施例6
(R)-4-((3R,5S,7R,8R,9S,10S,13R,14S,17R)-3-羟基-7-甲氧基-10,13-二甲基-12-氧代十六氢-1H-环戊[a]菲-17-基)戊酸甲酯(A6)的制备
将化合物9a(200mg,0.48mmol)溶于DCM中，冰浴条件下加入DMAP(6mg,0.05mmol)，甲醇(24μL,0.58mmol)，EDC(111mg,0.58mmol)冰浴搅拌1h之后移至常温搅拌2h。反应结束后，用二氯甲烷(10mL×3)萃取，用饱和食盐水洗涤有机相，浓缩溶剂得到粗产物。柱层析(V二氯甲烷:V甲醇＝50:1),浓缩得到白色固体化合物A6190mg,产率89％。 1H NMR(400MHz,CDCl 3):δ3.64(s,3H),3.45-3.38(m,1H),3.26(s,1H),3.20(s,3H),2.45-2.33(m,2H),2.31-2.19(m,2H),2.10-2.00(m,3H),1.97-1.92(m,1H),1.86-1.79(m,4H),1.69-1.60(m,5H),1.54(s,1H),1.46-1.23(m,6H),0.97(s,6H),0.83(d,J＝6.7Hz,3H).
实施例7
(R)-4-((3R,5S,7R,8R,9S,10S,13R,14S,17R)-3-羟基-7-甲氧基-10,13-二甲基-12-氧代十六氢-1H-环戊[a]菲-17-基)戊酸甲酯(A7)的制备
其他条件同实施例6，将甲醇换成乙醇，产物为白色固体化合物A7，产率为85％。 1H NMR(400MHz,CDCl3):δ4.08(q,J＝7.0Hz,2H),3.44-3.37(m,1H),3.26-3.25(M,1H),3.20(s,3H),2.44-2.17(m,4H),2.09-1.99(m,3H),1.96-1.90(M,1H),1.86-1.77(m,4H),1.68-1.60(m,5H),1.46-1.40(m,1H),1.38-1.20(m,9H),0.97(s,6H),0.82(d,J＝6.5Hz,3H).
实施例8
(R)-4-((3R,5S,7R,8R,9S,10S,13R,14S,17R)-3-羟基-7-甲氧基-10,13-二甲基-12-氧代十六氢-1H-环戊[a]菲-17-基)戊酸异丙酯(A8)的制备
其他条件同实施例6，将甲醇换成异丙醇，产物为白色固体化合物A8，产率为80％。 1H NMR(400MHz,CDCl 3):δ4.99(p,J＝6.3Hz,1H),3.46-3.40(m,1H),3.28-3.28(m,1H),3.22(s,3H),2.44(t,J＝12.5Hz,1H),2.39-2.17(m,3H),2.11-1.95(m,4H),1.88-1.81(m,3H),1.68-1.63(m,5H),1.52-1.44(m,3H),1.39-1.26(m,5H),1.22(s,3H),1.21(s,3H),0.99(s,6H),0.85(d,J＝6.5Hz,3H).
实施例9
(R)-4-((3R,5S,7R,8R,9S,10S,13R,14S,17R)-3-羟基-7-甲氧基-10,13-二甲基-12-氧代十六氢-1H-环戊[a]菲-17-基)戊酸环丙酯(A9)的制备
其他条件同实施例6，将甲醇换成环丙醇，产物为白色固体化合物A9，产率为82％。 1H NMR(400MHz,CDCl 3):δ4.10-4.05(m,1H),3.45-3.37(m,1H),3.28-3.25(m,1H),3.21(s,3H),2.42(t,J＝12.5Hz,1H),2.37-2.16(m,3H),2.09-1.92(m,4H),1.90-1.75(m,4H),1.69-1.59(m,6H),1.47-1.40(m,1H),1.39-1.23(m,5H),0.98(s,6H),0.82(d,J＝6.5Hz,3H),0.71-0.63(m,4H).
实施例10
(R)-4-((3R,5S,7R,8R,9S,10S,13R,14S,17R)-3-羟基-7-甲氧基-10,13-二甲基-12-氧代十六氢-1H-环戊[a]菲-17-基)戊酸环丙甲酯(A10)的制备
其他条件同实施例6，将甲醇换成环丙甲醇，产物为白色固体化合物A10，产率为89％。 1H NMR(400MHz,CDCl 3):δ3.87(d,J＝8.7Hz,2H),3.45-3.37(m,1H),3.27-3.26(m,1H),3.21(s,3H),2.46-2.35(m,2H),2.32-2.22(m,2H),2.10-1.94(m,4H),1.89-1.79(m,4H),1.69-1.57(m,6H),1.47-1.24(m,6H),1.14-1.07(m,1H),0.99(s,6H),0.85(d,J＝6.5Hz,3H),0.56-0.52(m,2H),0.27-0.23(m,2H).
实施例11
(R)-4-((3R,5S,7R,8R,9S,10S,13R,14S,17R)-3-羟基-7-甲氧基-10,13-二甲基-12-氧代十六氢-1H-环戊[a]菲-17-基)戊酸环戊酯(A11)的制备
其他条件同实施例6，将甲醇换成环戊醇，产物为白色固体白色固体化合物A11，产率为89％。 1H NMR(400MHz,CDCl 3):δ5.14-5.10(m,1H),3.44-3.37(m,1H),3.27-3.26(m,1H),3.20(s,3H),2.42(t,J＝12.5Hz,1H),2.35-2.24(m,2H),2.22-2.15(m,1H),2.10-1.98(m,3H), 1.97-1.93(m,1H),1.88-1.75(m,6H),1.71-1.60(m,9H),1.57-1.41(m,3H),1.38-1.20(m,6H),0.97(s,6H),0.83(d,J＝6.5Hz,3H).
实施例12
(R)-4-((3R,5S,7R,8R,9S,10S,13R,14S,17R)-3-羟基-7-甲氧基-10,13-二甲基-12-氧代十六氢-1H-环戊[a]菲-17-基)戊酸环戊甲酯(A12)的制备
其他条件同实施例6，将甲醇换成环戊甲醇，产物为白色固体白色固体化合物A12，产率为86％。 1H NMR(400MHz,CDCl 3):δ3.92(d,J＝7.2Hz,2H),3.45-3.37(m,1H),3.273.26(m,1H),3.20(s,3H),2.45-2.12(m,5H),2.11-2.00(m,3H),1.97-1.90(m,1H),1.89-1.75(m,4H),1.74-1.51(m,12H),1.47-1.41(m,1H),1.35-1.21(m,7H),0.98(s,6H),0.84(d,J＝6.5Hz,3H).
实施例13
(R)-4-((3R,5S,7R,8R,9S,10S,13R,14S,17R)-3-羟基-7-甲氧基-10,13-二甲基-12-氧代十六氢-1H-环戊[a]菲-17-基)戊酸苯酯(A13)的制备
其他条件同实施例6，将甲醇换成苯酚，产物为白色固体化合物A13，产率为91％。 1H NMR(400MHz,CDCl 3):δ7.38-7.34(m,2H),7.23-7.18(m,1H),7.08-7.04(m,2H),3.46-3.38(m,1H),3.28-3.27(m,1H),3.22(s,3H),2.68-2.60(m,1H),2.55-2.41(m,2H),2.34-2.27(m,1H),2.13-2.04(m,3H),2.02-1.93(m,2H),1.90-1.80(m,3H),1.69-1.61(m,6H),1.55-1.44(m,2H),1.40-1.26(m,4H),1.01(s,3H),0.99(s,3H),0.92(d,J＝6.7Hz,3H).
实施例14
(R)-4-((3R,5S,7R,8R,9S,10S,13R,14S,17R)-3-羟基-7-甲氧基-10,13-二甲基-12-氧代十六氢-1H-环戊[a]菲-17-基)戊酸苄酯(A14)的制备
其他条件同实施例6，将甲醇换成苄醇，产物为白色固体化合物A14，产率为93％。 1H NMR(400MHz,CDCl 3):δ7.38-7.29(m,5H),5.14-5.06(m,2H),3.46-3.38(m,1H),3.28-3.27(m,1H),3.22(s,3H),2.45-2.40(m,2H),2.34-2.25(m,2H),2.10-2.00(m,3H),1.96-1.89(m,1H),1.87-1.80(m,3H),1.68-1.63(m,5H),1.48-1.34(m,3H),1.32-1.24(m,5H),0.99(s,3H),0.96(s,3H),0.84(d,J＝6.7Hz,3H).
实施例15
萘-1-基(R)-4-((3R,5S,7R,8R,9S,10S,13R,14S,17R)-3-羟基-7-甲氧基-10,13-二甲基-12-氧代十六氢-1H-环戊[a]菲-17-基)戊酸酯(A15)的制备
其他条件同实施例6，将甲醇换成1-萘酚，产物为白色固体化合物A15，产率为88％。 1H NMR(400MHz,CDCl 3):δ7.88-7.84(m,2H),7.73(d,J＝8.3Hz,1H),7.53-7.44(m,3H),7.23(d,J＝7.0Hz,1H),3.46-3.38(m,1H),3.28-3.28(m,1H),3.22(s,3H),2.87-2.79(m,1H),2.74-2.66(m,1H),2.46(t,J＝12.5Hz,1H),2.36-2.28(m,1H),2.19-2.00(m,5H),1.91-1.80(m,3H),1.73-1.61(m,6H),1.49-1.27(m,6H),1.04(s,3H),1.04-0.99(m,6H).
实施例16
萘-2-基(R)-4-((3R,5S,7R,8R,9S,10S,13R,14S,17R)-3-羟基-7-甲氧基-10,13-二甲基-12-氧代十六氢-1H-环戊[a]菲-17-基)戊酸酯(A16)的制备
其他条件同实施例6，将甲醇换成2-萘酚，产物为白色固体化合物A16，产率为92％。 1H NMR(300MHz,CDCl 3):δ7.86-7.78(m,3H),7.55-7.54(m,1H),7.51-7.42(m,2H),7.24-7.20(m,1H),3.48-3.37(m,1H),3.30-3.27(m,1H),3.22(s,3H),2.76-2.66(m,1H),2.63-2.52(m,1H),2.50-2.42(m,1H),2.36-2.27(m,1H),2.18-1.96(m,5H),1.92-1.79(m,3H),1.71-1.59(m,6H),1.49-1.25(m,6H),1.03(s,3H),1.00(s,3H),0.95(d,J＝6.6Hz,3H).
实施例17
(3R,5S,7R,8R,9S,10S,13R,14S,17R)-3-羟基-7-乙氧基-10,13-二甲基-17-((R)-5-氧代-5-(吡咯烷-1-基)戊烷-2-基)十六氢-12H-环戊烷[a]菲-12-酮(A17)的制备
其他条件同实施例1，将步骤七中的碘甲烷替换成溴乙烷，产物为白色固体化合物A17，产率70％。 1H NMR(400MHz,CDCl 3):δ3.63-3.55(m,1H),3.46-3.40(m,5H),3.37-3.36(m,1H),3.17-3.09(m,1H),2.44(t,J＝12.4Hz,1H),2.36-2.29(m,2H),2.24-2.03(m,4H),1.99-1.80(m,8H),1.78-1.74(m,1H),1.69-1.63(m,5H),1.46-1.24(m,7H),1.10(t,J＝7.0Hz,3H),1.00(s,3H),0.98(s,3H),0.86(d,J＝6.5Hz,3H).
实施例18
(3R,5S,7R,8R,9S,10S,13R,14S,17R)-3-羟基-7-丙氧基-10,13-二甲基-17-((R)-5-氧代-5-(吡咯烷-1-基)戊烷-2-基)十六氢-12H-环戊烷[a]菲-12-酮(A18)的制备
其他条件同实施例1，将步骤七中的碘甲烷替换成溴丙烷，产物为白色固体化合物A18，产率63％。 1H NMR(400MHz,CDCl 3):δ3.55-3.49(m,1H),3.44-3.38(m,5H),3.35-3.33(m,1H),2.99-2.93(m,1H),2.43(t,J＝12.5Hz,1H),2.35-2.28(m,2H),2.21-2.13(m,1H),2.10-2.01(m, 3H),1.97-1.73(m,10H),1.68-1.61(m,5H),1.52-1.22(m,8H),0.99(s,3H),0.97(s,3H),0.87-0.83(m,6H).
实施例19
(3R,5S,7R,8R,9S,10S,13R,14S,17R)-3-羟基-10,13-二甲基-12-氧代-17-((R)-5-氧代-5-(吡咯烷-1-基)戊烷-2-基)十六氢-1H-环戊烷[a]菲-7-基乙酸酯(A19)的制备
步骤一：将化合物CA(10g,24.6mmol)溶于DMF(100mL)中，冰浴条件下加入HATU(12.15g,32mmol)，缓慢滴加三乙胺(10.2mL,73.8mmol)，冰浴搅拌15分钟之后加入四氢吡咯(2.5mL,29.5mmol)，常温搅拌2h。反应结束后，减压浓缩，用二氯甲烷洗涤固体，烘干得到白色固体化合物108.2g,产率70％。
步骤二：将化合物10(11g,23.1mmol)，三乙胺(9.6mL,69.4mmol),乙酸酐(5.5mL,57.8mmol)，DMAP(282mg,2.3mmol)，干燥二氯甲烷(200mL)的混合物搅拌2h，TCL检测。反应结束后，浓缩溶剂，用二氯甲烷(100mL×3)萃取，用水(30mL)洗涤有机相，浓缩溶剂得到粗产物。柱层析(V二氯甲烷:V乙酸乙酯＝3:1)，浓缩得到白色固体化合物1111.6g，产率94％。
步骤三：将化合物11(8g,14.7mmol)溶于丙酮(100mL)中，冰浴条件下缓慢滴加过量的琼斯试剂，冰浴搅拌5分钟，TCL检测。反应结束后，加入10mL异丙醇，搅拌至溶液变绿色，减压浓缩。用乙酸乙酯(80mL×3)萃取，饱和食盐水洗涤有机相，减压浓缩。柱层析(V石油醚:V乙酸乙酯＝3:1)，浓缩得到白色固体化合物127.8g，产率98％。
步骤四：将化合物12(7g,12.9mmol)溶于甲醇(80mL)中，加入过量的4M氢氧化钠水溶液，常温搅拌14h。反应结束后，加入盐酸水溶液调PH值至酸性，减压浓缩。用水和二氯甲烷洗涤固体，烘干得到白色固体化合物135.2g,产率88％。
步骤五：将化合物13(3.5g,7.4mmol)溶于二氯甲烷(50mL)，加入咪唑(6g,88.6mmol)，吡啶(1mL)，TBDMSCl(2.8g,18.44mmol)，常温搅拌30分钟，TCL检测反应。用二氯甲烷(50mL×3)萃取，用饱和食盐水洗涤有机相，浓缩溶剂得到粗产物。柱层析(V石油醚:V乙酸乙酯＝10:1)，浓缩得到白色固体化合物144g，产率92％。
步骤六：将化合物14(300mg,0.5mmol)，三乙胺(212μL,1.5mmol),乙酸酐(121μL,1.3mmol)，DMAP(6mg,0.05mmol)，干燥二氯甲烷(10mL)的混合物搅拌2h,TCL检测。反应结束后，浓缩溶剂，用二氯甲烷(20mL×3)萃取，用水(5mL)洗涤有机相，浓缩溶剂得到粗产物。柱层析(V二氯甲烷:V乙酸乙酯＝2:1)，浓缩得到白色固体化合物15a294mg，产率92％。
步骤七：将化合物15a(250mg,0.4mmol)溶于1M TBAF in THF(5mL)，常温搅拌10h。反应结束后，用乙酸乙酯(10mL×3)萃取，用饱和食盐水洗涤有机相，浓缩溶剂得到粗产物。柱层析(V石油醚:V乙酸乙酯＝3:1)，浓缩得到白色固体白色固体化合物A19160mg，产率80％。 1H NMR(400MHz,CDCl 3):δ4.94-4.92(m,1H),3.48-3.36(m,5H),2.47(t,J＝12.5Hz,1H),2.32-2.25(m,2H),2.19-1.88(m,13H),1.86-1.76(m,4H),1.69-1.45(m,7H),1.38-1.27(m,4H),1.02(s,3H),0.99(s,3H),0.83(d,J＝6.4Hz,3H).
实施例20
(3R,5S,7R,8R,9S,10S,13R,14S,17R)-3-羟基-10,13-二甲基-12-氧代-17-((R)-5-氧代-5-(吡咯烷-1-基)戊烷-2-基)十六氢-1H-环戊烷[a]菲-7-基丙酸酯(A20)的制备
其他条件同实施例19，将乙酸酐替换为丙酸酐，产物为白色固体白色固体化合物A20，产率86％。 1H NMR(300MHz,CDCl 3):δ4.96-4.93(m,1H),3.48-3.33(m,5H),2.47(t,J＝12.4Hz,1H),2.33-1.78(m,18H),1.70-1.25(m,12H),1.08(t,J＝7.6Hz,3H),1.00(s,3H),0.99(s,3H),0.83(d,J＝6.4Hz,3H).
实施例21
(3R,5S,7R,8R,9S,10S,13R,14S,17R)-3-羟基-10,13-二甲基-12-氧代-17-((R)-5-氧代-5-(吡咯烷-1-基)戊烷-2-基)十六氢-1H-环戊烷[a]菲-7-基异丁酸酯(A21)的制备
其他条件同实施例19，将乙酸酐替换为异丁酸酐，产物为白色固体化合物A21，产率90％。 1H NMR(400MHz,CDCl 3):δ4.95-4.93(m,1H),3.49-3.33(m,5H),2.51-2.44(s,2H),2.34-2.25(m,2H),2.19-2.09(m,2H),2.03-1.78(m,11H),1.70-1.27(m,12H),1.11(d,J＝2.6Hz,3H),1.09(d,J＝2.5Hz,3H),1.00(s,3H),0.99(s,3H),,0.84(d,J＝6.4Hz,3H).
实施例22
(3R,5S,7R,8R,9S,10S,13R,14S,17R)-3-羟基-10,13-二甲基-12-氧代-17-((R)-5-氧代-5-(吡咯烷-1-基)戊烷-2-基)十六氢-1H-环戊烷[a]菲-7-基苯甲酸酯(A22)的制备
其他条件同实施例19，将乙酸酐替换为苯甲酸酐，产物为白色固体化合物A22，产率82％。 1H NMR(300MHz,CDCl 3):δ7.98-7.94(m,2H),7.57-7.52(m,1H),7.47-7.41(m,2H),5.23-5.20(m,1H),3.43-3.34(m,5H),2.58-2.40(m,2H),2.32-2.06(m,5H),2.02-1.99(m,2H),1.92-1.69(m,11H),1.54-1.43(m,3H),1.39-1.23(m,5H),1.05(s,3H),1.03(s,3H),0.84(d,J＝5.9Hz,3H).
实施例23
((R)-4-((3R,5S,7R,8R,9S,10S,13R,14S,17R)-3-羟基-7-甲氧基-10,13-二甲基-12-氧代十六氢-1H-环戊基[a]菲-17-基)戊酰基)甘氨酸乙酯(A23)的制备
其他条件同实施例1，将四氢吡咯替换成甘氨酸乙酯，产物为白色固体化合物A23，产率为87％。 1H NMR(400MHz,CDCl 3):δ6.15(t,J＝5.5Hz,1H),4.18(q,J＝7.1Hz,2H),3.99(d,J＝5.3Hz,2H),3.45-3.37(m,1H),3.27-3.25(m,1H),3.20(s,3H),2.43(t,J＝12.6Hz,1H),2.36-2.23(m,2H),2.19-1.99(m,5H),1.96-1.90(m,1H),1.87-1.79(m,3H),1.68-1.60(m,4H),1.45-1.24(s,11H),0.98(s,3H),0.97(s,3H),0.83(d,J＝6.7Hz,3H).
实施例24
(R)-N-环丙基-4-((3R,5S,7R,8R,9S,10S,13R,14S,17R)-3-羟基-7-甲氧基-10,13-二甲基-12-氧代十六氢-1H-环戊烷[a]菲-17-基)戊酰胺(A24)的制备
其他条件同实施例1，将四氢吡咯替换成环丙胺，产物为白色固体化合物A24，产率为80％。 1H NMR(400MHz,CDCl 3):δ5.84(s,1H),3.44-3.37(m,1H),3.27-3.25(m,1H),3.20(s,3H),2.70-2.63(m,1H),2.42(t,J＝12.6Hz,1H),2.31-2.15(m,2H),2.07-1.78(m,11H),1.68-1.61(m,4H),1.45-1.42(m,1H),1.37-1.24(m,5H),0.97(s,6H),0.81(d,J＝6.5Hz,3H),0.75-0.70(m,2H),0.48-0.44(m,2H).
实施例25
(R)-N-环戊基-4-((3R,5S,7R,8R,9S,10S,13R,14S,17R)-3-羟基-7-甲氧基-10,13-二甲基-12-氧代十六氢-1H-环戊烷[a]菲-17-基)戊酰胺(A25)的制备
其他条件同实施例1，将四氢吡咯替换成环戊胺，产物为白色固体化合物A25，产率为85％。 1H NMR(400MHz,CDCl 3):δ5.54(d,J＝7.5Hz,1H),4.21-4.12(m,1H),3.45-3.37(m,1H),3.27-3.25(m,1H),3.20(s,3H),2.42(t,J＝12.5Hz,1H),2.31-2.17(m,2H),2.07-1.78(m,12H),1.68-1.54(m,9H),1.45-1.42(m,1H),1.37-1.25(m,7H),0.97(s,6H),0.83(d,J＝6.5Hz,3H).
实施例26
(R)-N-环戊甲基-4-((3R,5S,7R,8R,9S,10S,13R,14S,17R)-3-羟基-7-甲氧基-10,13-二甲基-12-氧代十六氢-1H-环戊烷[a]菲-17-基)戊酰胺(A26)的制备
其他条件同实施例1，将四氢吡咯替换成环戊甲胺，产物为白色固体白色固体化合物A26，产率为81％。 1H NMR(400MHz,CDCl 3):δ5.61(t,J＝6.0Hz,1H),3.45-3.37(m,1H),3.27-3.25 (m,1H),3.20(s,3H),3.17-3.14(m,2H),2.42(t,J＝12.5Hz,1H),2.31-2.20(m,2H),2.11-1.93(m,6H),1.87-1.78(m,5H),1.72-1.52(m,10H),1.45-1.42(m,1H),1.37-1.14(m,8H),0.98(s,6H),0.84(d,J＝6.5Hz,3H).
实施例27
(R)-4-((3R,5S,7R,8R,9S,10S,13R,14S,17R)-3,12-二羟基-7-甲氧基-10,13-二甲基十六氢-1H-环戊[a]菲-17-基)-1-(吡咯烷-1-基)戊烷-1-酮(B1)的制备
将化合物A1(200mg,0.42mmol)溶于甲醇(10mL)中，加入PdCl 2(74mg,0.42mmol)，冰浴条件下加入NaBH 4(160mg,4.23mmol)，冰浴条件下搅拌10分钟。反应结束后，抽滤除去黑色固体，减压浓缩。柱层析(V二氯甲烷:V甲醇＝V25:1),浓缩得到白色固体化合物B1110mg,产率55％。 1H NMR(400MHz,MeOH-d 4):δ3.94(s,1H),3.79(s,1H),3.51(t,J＝6.8Hz,2H),3.40(t,J＝7.0Hz,2H),3.26(s,3H),3.22(s,1H),2.43-2.36(m,1H),2.28-2.22(m,3H),2.16-2.08(m,1H),2.02-1.95(m,2H),1.92-1.87(m,5H),1.82-1.69(m,3H),1.69-1.57(m,8H),1.46-1.36(m,5H),1.22-1.11(m,2H),1.04(d,J＝6.5Hz,3H),0.92(s,3H),0.71(s,3H).
实施例28
(R)-4-((3R,5S,7R,8R,9S,10S,13R,14S,17R)-3,12-二羟基-7-甲氧基-10,13-二甲基十六氢-1H-环戊烷[a]菲-17-基)-N，N-二甲基戊酰胺(B2)的制备
其他条件同实施例27，将A1替换成A2，产物为白色固体化合物B2，产率为70％。 1H NMR(400MHz,CDCl 3):δ3.92(t,J＝3.3Hz,1H),3.45-3.38(m,1H),3.26(s,3H),3.21-3.20(m,1H),3.00(s,3H),2.93(s,3H),2.41-2.33(m,1H),2.25-2.11(s,6H),1.97-1.85(m,2H),1.81-1.73(m,3H),1.66-1.28(s,12H),2.10-1.03(m,1H),0.99(d,J＝6.4Hz,3H),0.88(s,3H),0.66(s,3H).
实施例29
(R)-4-((3R,5S,7R,8R,9S,10S,13R,14S,17R)-3,12-二羟基-7-甲氧基-10,13-二甲基十六氢-1H-环戊烷[a]菲-17-基)-N-甲基戊酰胺(B3)的制备
其他条件同实施例27，将A1替换成A3，产物为白色固体化合物B3，产率为65％。 1H NMR(400MHz,MeOH-d 4):δ3.93(t,J＝3.1Hz,1H),3.42-3.33(m,1H),3.26(s,3H),3.23-3.21(m,1H),2.70(s,3H),2.28-2.19(m,3H),2.15-2.05(m,2H),1.92-1.75(m,5H),1.70-1.54(m,7H),1.46-1.26(m,6H),1.17-1.07(m,1H),1.02(d,J＝6.4Hz,3H),0.92(s,3H),0.70(s,3H).
实施例30
(R)-4-((3R,5S,7R,8R,9S,10S,13R,14S,17R)-3,12-二羟基-7-甲氧基-10,13-二甲基十六氢-1H-环戊烷[a]菲-17-基)-N-乙基戊酰胺(B4)的制备
其他条件同实施例27，将A1替换成A4，产物为白色固体化合物B4，产率为73％。 1H NMR(300MHz,CDCl 3):δ5.61(s,1H),3.92(t,J＝3.1Hz,1H),3.49-3.37(m,1H),3.32-3.21(m,6H),2.22-2.09(m,6H),1.99-1.74(m,6H),1.68-1.51(m,6H),1.48-1.28(m,6H),1.12(t,J＝7.2Hz,3H),0.98(d,J＝6.3Hz,3H),0.88(s,3H),0.66(s,3H).
实施例31
(R)-4-((3R,5S,7R,8R,9S,10S,13R,14S,17R)-3,12-二羟基-7-甲氧基-10,13-二甲基十六氢-1H-环戊烷[a]菲-17-基)-N-丙基戊酰胺(B5)的制备
其他条件同实施例27，将A1替换成A5，产物为白色固体化合物B5，产率为80％。 1H NMR(300MHz,CDCl 3):δ5.64(s,1H),3.91(t,J＝3.1Hz,1H),3.49-3.38(m,1H),3.26(s,3H),3.23-3.16(m,3H),2.26-2.09(m,7H),1.96-1.73(m,6H),1.65-1.49(m,7H),1.47-1.28(m,6H),0.98(d,J＝6.4Hz,3H),0.93-0.88(m,6H),0.65(s,3H).
实施例32
(R)-4-((3R,5S,7R,8R,9S,10S,13R,14S,17R)-3-羟基-7-甲氧基-10,13-二甲基十六氢-1H-环戊烷[a]菲-17-基)戊酸甲酯(B6)的制备
其他条件同实施例27，将A1替换成A6，产物为白色固体化合物B6，产率为76％。 1H NMR(400MHz,CDCl 3):δ3.91(t,J＝3.3Hz,1H),3.65(s,3H),3.46-3.38(m,1H),3.26(s,3H),3.21-3.21(m,1H),2.40-2.33(m,1H),2.27-2.05(m,6H),1.97-1.85(m,2H),1.81-1.75(m,3H),1.67-1.50(m,6H),1.40-1.27(m,5H),1.11-1.03(m,1H),0.97(d,J＝6.3Hz,3H),0.88(s,3H),0.66(s,3H).
实施例33
(R)-4-((3R,5S,7R,8R,9S,10S,13R,14S,17R)-3-羟基-7-甲氧基-10,13-二甲基十六氢-1H-环戊烷[a]菲-17-基)戊酸乙酯(B7)的制备
其他条件同实施例36，将A1替换成A7，产物为白色固体化合物B7，产率为83％。 1H NMR(400MHz,CDCl 3):δ4.11(q,J＝7.2Hz,2H),3.92(t,J＝3.1Hz,1H),3.46-3.39(m,1H),3.26(s,3H),3.22-3.21(m,1H),2.39-2.31(m,1H),2.26-2.09(m,3H),2.00-1.84(m,6H),1.80-1.72(m, 3H),1.67-1.50(m,7H),1.41-1.33(m,4H),1.26-1.23(m,3H),0.97(d,J＝6.3Hz,3H),0.88(s,3H),0.66(s,3H).
实施例34
(R)-4-((3R,5S,7R,8R,9S,10S,13R,14S,17R)-3-羟基-7-甲氧基-10,13-二甲基十六氢-1H-环戊烷[a]菲-17-基)戊酸异丙酯(B8)的制备
其他条件同实施例27，将A1替换成A8，产物为白色固体化合物B8，产率为69％。 1H NMR(400MHz,CDCl 3):δ5.00-4.94(m,1H),3.89(t,J＝3.2Hz,1H),3.45-3.39(m,1H),3.25(s,3H),3.23-3.16(m,1H),2.34-2.27(m,1H),2.21-2.10(m,3H),1.93-1.84(m,2H),1.79-1.72(m,5H),1.65-1.49(m,7H),1.40-1.30(m,5H),1.21(s,3H),1.19(s,3H),1.09-1.01(m,1H),0.96(d,J＝6.3Hz,3H),0.87(s,3H),0.64(s,3H).
实施例35
(R)-4-((3R,5S,7R,8R,9S,10S,13R,14S,17R)-3-羟基-7-甲氧基-10,13-二甲基十六氢-1H-环戊烷[a]菲-17-基)戊酸环丙酯(B9)的制备
其他条件同实施例27，将A1替换成A9，产物为白色固体化合物B9，产率为67％。 1H NMR(400MHz,CDCl 3):δ4.11-4.07(m,1H),3.91(t,J＝3.1Hz,1H),3.46-3.38(m,1H),3.26(s,3H),3.23-3.21(m,1H),2.36-2.29(m,1H),2.23-2.05(m,6H),1.97-1.85(m,2H),1.80-1.74(m,3H),1.67-1.48(m,7H),1.40-1.27(m,4H),1.11-1.03(m,1H),0.96(d,J＝6.3Hz,3H),0.88(s,3H),0.73-0.63(m,7H).
实施例36
(R)-4-((3R,5S,7R,8R,9S,10S,13R,14S,17R)-3-羟基-7-甲氧基-10,13-二甲基十六氢-1H-环戊烷[a]菲-17-基)戊酸环丙酯(B10)的制备
其他条件同实施例27，将A1替换成A10，产物为白色固体化合物B10，产率为77％。 1H NMR(300MHz,CDCl 3):δ3.92(t,J＝2.9Hz,1H),3.89(d,J＝7.2Hz,2H),3.49-3.37(m,1H),3.26(s,3H),3.23-2,20(m,1H),2.44-2.33(m,1H),2.30-2.08(m,4H),1.99-1.89(m,4H),1.84-1.75(m,4H),1.68-1.62(m,2H),1.59-1.54(m,2H),1.51-1.50(m,1H),1.42-1.30(m,5H),1.15-1.04(m,2H),0.98(d,J＝6.3Hz,3H),0.88(s,3H),0.66(s,3H),0.58-0.52(m,2H),0.29-0.23(m,2H).
实施例37
(R)-4-((3R,5S,7R,8R,9S,10S,13R,14S,17R)-3-羟基-7-甲氧基-10,13-二甲基十六氢-1H-环戊烷[a]菲-17-基)戊酸环戊酯(B11)的制备
其他条件同实施例27，将A1替换成A11，产物为白色固体化合物B11，产率为71％。 1H NMR(400MHz,CDCl 3):δ5.16-5.12(m,1H),3.92(t,J＝3.2Hz,1H),3.46-3.38(m,1H),3.26(s,3H),3.23-3.20(m,1H),2.35-2.27(m,1H),2.23-2.04(m,5H),1.90-1.55(m,20H),1.40-1.28(m,5H),1.09-1.03(m,1H),0.97(d,J＝6.3Hz,3H),0.88(s,3H),0.65(s,3H).
实施例38
(R)-4-((3R,5S,7R,8R,9S,10S,13R,14S,17R)-3-羟基-7-甲氧基-10,13-二甲基十六氢-1H-环戊烷[a]菲-17-基)戊酸环丙甲酯(B12)的制备
其他条件同实施例27，将A1替换成A12，产物为白色固体化合物B12，产率为60％。 1H NMR(300MHz,CDCl 3):δ3.96-3.91(m,3H),3.48-3.38(m,1H),3.26(s,3H),3.22-3.19(m,1H),2.42-2.08(m,5H),1.96-1.53(m,20H),1.41-1.20(m,7H),1.13-1.05(m,1H),0.98(d,J＝6.3Hz,3H),0.89(s,3H),0.66(s,3H).
实施例39
(R)-4-((3R,5S,7R,8R,9S,10S,13R,14S,17R)-3-羟基-7-甲氧基-10,13-二甲基十六氢-1H-环戊烷[a]菲-17-基)戊酸苯酯(B13)的制备
其他条件同实施例27，将A1替换成A13，产物为白色固体化合物B13,产率85％。 1H NMR(300MHz,CDCl 3):δ7.40-7.34(m,2H),7.24-7.19(m,1H),7.09-7.05(m,2H),3.95(t,J＝3.1Hz,1H),3.49-3.39(m,1H),3.23-3.21(m,3H),3.22(d,J＝6.5Hz,1H),2.68-2.44(m,2H),2.25-2.09(m,2H),2.00-1.92(m,6H),1.84-1.74(m,3H),1.68-1.48(m,8H),1.42-1.30(m,3H),1.05(d,J＝6.3Hz,3H),0.90(s,3H),0.69(s,3H).
实施例40
(R)-4-((3R,5S,7R,8R,9S,10S,13R,14S,17R)-3-羟基-7-甲氧基-10,13-二甲基十六氢-1H-环戊烷[a]菲-17-基)戊酸苄酯(B14)的制备
其他条件同实施例27，将A1替换成A14，产物为白色固体化合物B14，产率为98％。 1H NMR(300MHz,CDCl 3):δ7.39-7.29(m,5H),5.15-5.06(m,2H),3.90(t,J＝3.2Hz,1H),3.49-3.37(m,1H),3.26(s,3H),3.23-3.19(m,1H),2.47-2.24(m,2H),2.17-2.09(m,4H),1.98-1.54(m,13H),1.42-1.32(m,4H),1.10-1.02(m,1H),0.97(d,J＝6.2Hz,3H),0.88(s,3H),0.63(s,3H).
实施例41
萘-1-基(R)-4-((3R,5S,7R,8R,9S,10S,13R,14S,17R)-3-羟基-7-甲氧基-10,13-二甲基十六氢-1H-环戊烷[a]菲-17-基)戊酸酯(B15)的制备
其他条件同实施例27，将A1替换成A15，产物为白色固体化合物B15，产率为88％。 1H NMR(300MHz,CDCl 3):δ7.89-7.84(m,2H),7.74(d,J＝8.2Hz,1H),7.54-7.44(m,3H),7.25-7.22(m,1H),3.97(t,J＝3.0Hz,1H),3.50-3.41(m,1H),3.27(s,3H),3.23-3.22(m,1H),2.86-2.76(m,1H),2.73-2.62(m,1H),2.26-2.11(m,2H),2.06-1.92(m,6H),1.86-1.77(m,3H),1.69-1.53(m,8H),1.43-1.34(m,3H),1.12(d,J＝6.3Hz,3H),0.90(s,3H),0.71(s,3H).
实施例42
萘-2-基(R)-4-((3R,5S,7R,8R,9S,10S,13R,14S,17R)-3-羟基-7-甲氧基-10,13-二甲基十六氢-1H-环戊烷[a]菲-17-基)戊酸酯(B16)的制备
其他条件同实施例27，将A1替换成A16，产物为白色固体化合物B16，产率为95％。 1H NMR(400MHz,CDCl 3):δ7.86-7.78(m,3H),7.55-7.54(m,1H),7.50-7.43(m,2H),7.23-7.20(m,1H),3.94(t,J＝3.1Hz,1H),3.48-3.41(m,1H),3.28(s,3H),3.25-3.22(m,1H),2.72-2.65(m,1H),2.60-2.52(m,1H),2.22-2.13(m,2H),2.00-1.51(m,16H),1.43-1.32(m,4H),1.08(d,J＝6.1Hz,3H),0.90(s,3H),0.70(s,3H). 13C NMR(100MHz,CDCl 3):δ173.1,148.5,133.9,131.5,129.5,127.9,127.7,126.6,125.7,121.3,118.6,77.9,73.2,71.9,55.9,47.1,46.5,42.0,41.7,39.6,38.7,35.4,35.2,34.8,31.5,31.0,30.6,28.5,28.0,27.6,27.5,23.5,22.6,17.5,12.6.HRMS(ESI):m/z calcd C 38H 48O 5[M+K] +571.3394,found:571.3397.
实施例43
((R)-4-((3R,5S,7R,8R,9S,10S,13R,14S,17R)-7-乙氧基-3,12-二羟基-10,13-二甲基十六氢-1H-环戊烷[a]菲-17-基)-1-(吡咯烷-1-基)戊烷-1酮(B17)的制备
其他条件同实施例27，将A1替换成A17，产物为白色固体化合物B17，产率为78％。 1H NMR(400MHz,CDCl 3):δ3.90(s,1H),3.67-3.61(m,1H),3.44-3.38(m,4H),3.35-3.28(m,2H),3.25-3.17(m,1H),2.32-2.25(m,1H),2.20-2.03(m,3H),1.95-1.47(m,17H),1.42-1.27(m,5H),1.19(t,J＝7.0Hz,3H),0.07-0.93(m,5H),0.86(s,3H),0.63(s,3H).
实施例44
(3R,5S,7R,8R,9S,10S,13R,14S,17R)-3,12-二羟基-10,13-二甲基-17-((R)-5-氧代-5-(吡咯烷-1-基)戊烷-2-基)十六氢-1H-环戊烷[a]菲-7-基乙酸酯(B18)的制备
其他条件同实施例27，将A1替换成A18，产物为白色固体化合物B18，产率为69％。 1H NMR(400MHz,CDCl 3):δ3.90(t,J＝3.2Hz,1H),3.58-3.52(m,1H),3.44-3.37(m,4H),3.36-3.29(m,2H),3.07-3.01(m,1H),2.33-2.25(m,1H),2.19-2.05(m,3H),1.95-1.89(m,3H),1.85-1.70(m, 6H),1.67-1.46(m,9H),1.45-1.22(m,7H),1.08-1.01(m,1H),0.97(d,J＝6.3Hz,3H),0.90(t,J＝7.4Hz,3H),0.86(s,3H),0.64(s,3H).
实施例45
(3R,5S,7R,8R,9S,10S,13R,14S,17R)-3,12-二羟基-10,13-二甲基-17-((R)-5-氧代-5-(吡咯烷-1-基)戊烷-2-基)十六氢-1H-环戊烷[a]菲-7-基乙酸酯(B19)的制备
其他条件同实施例27，将A1替换成A19，产物为白色固体化合物B19，产率为70％。 1H NMR(400MHz,CDCl 3):δ4.85-4.83(m,1H),3.96(t,J＝3.0Hz,1H),3.48-3.45(m,5H),2.32-2.09(m,5H),2.03(s,3H),1.98-1.71(m,11H),1.68-1.64(m,1H),1.61-1.51(m,4H),1.43-1.26(m,6H),1.09-1.00(m,1H),0.96(d,J＝6.4Hz,3H),0.87(s,3H),0.65(s,3H).
实施例46
(3R,5S,7R,8R,9S,10S,13R,14S,17R)-3,12-二羟基-10,13-二甲基-17-((R)-5-氧代-5-(吡咯烷-1-基)戊烷-2-基)十六氢-1H-环戊烷[a]菲-7-基丙酸酯(B20)的制备
其他条件同实施例27，将A1替换成A20，产物为白色固体化合物B20，产率为73％。 1H NMR(300MHz,CDCl 3):δ4.88-4.85(m,1H),3.96(t,J＝3.1Hz,1H),3.49-3.34(m,5H),2.36-3.23(m,3H),2.21-2.08(m,4H),1.96-1.88(m,4H),1.86-1.72(m,6H),1.69-1.51(m,7H),1.46-1.26(m,6H),1.12(t,J＝7.6Hz,3H),0.96(d,J＝6.3Hz,3H),0.88(s,3H),0.65(s,3H).
实施例47
(3R,5S,7R,8R,9S,10S,13R,14S,17R)-3,12-二羟基-10,13-二甲基-17-((R)-5-氧代-5-(吡咯烷-1-基)戊烷-2-基)十六氢-1H-环戊烷[a]菲-7-基异丁酸酯(B21)的制备
其他条件同实施例27，将A1替换成A21，产物为白色固体化合物B21，产率为66％。 1H NMR(400MHz,CDCl 3):δ4.87-4.84(m,1H),3.97(t,J＝3.1Hz,1H),3.50-3.34(m,5H),2.59-2.49(m,1H),2.33-2.10(m,3H),2.03-1.75(m,12H),1.71-1.49(s,7H),1.44-1.27(m,6H),1.15(t,J＝7.2Hz,6H),0.97(d,J＝6.4Hz,3H),0.88(s,3H),0.66(s,3H).
实施例48
(3R,5S,7R,8R,9S,10S,13R,14S,17R)-3,12-二羟基-10,13-二甲基-17-((R)-5-氧代-5-(吡咯烷-1-基)戊烷-2-基)十六氢-1H-环戊烷[a]菲-7-基苯甲酸酯(B22)的制备
其他条件同实施例27，将A1替换成A22，产物为白色固体化合物B22，产率为50％。 1H NMR(400MHz,CDCl 3):δ8.06(d,J＝7.2Hz,2H),7.53-7.49(m,1H),7.44-7.40(m,2H),5.15-5.13(m,1H),4.00(t,J＝3.1Hz,1H),3.48-3.32(m,5H),2.44-2.37(m,1H),2.28-2.20(m,1H),2.14-1.97 (m,7H),1.92-1.85(m,2H),1.81-1.63(m,10H),1.61-1.57(m,1H),1.52-1.37(s,5H),1.11-1.05(m,1H),0.96(d,J＝6.5Hz,3H),0.93(s,3H),0.69(s,3H).
实施例49
乙基((R)-4-((3R,5S,7R,8R,9S,10S,13R,14S,17R)-3,12-二羟基-7-甲氧基-10,13-二甲基十六氢-1H-环戊基[a]菲-17-基)戊酰基)甘氨酸酯(B23)的制备
其他条件同实施例27，将A1替换成A23，产物为白色固体化合物B23，产率77％。 1H NMR(400MHz,CDCl 3):δ6.21(t,J＝5.1Hz,1H),4.20(q,J＝7.2Hz,2H),4.01(d,J＝5.3Hz,2H),3.91(t,J＝3.1Hz,1H),3.45-3.37(m,1H),3.26(s,3H),3.23-3.20(m,1H),2.34-2.28(m,4H),2.21-2.08(m,3H),1.97-1.74(m,5H),1.67-1.36(m,10H),1.27(t,J＝7.2Hz,4H),1.10-1.03(m,1H),0.98(d,J＝6.3Hz,3H),0.88(s,3H),0.65(s,3H).
实施例50
((R)-4-((3R,5S,7R,8R,9S,10S,13R,14S,17R)-3,12-二羟基-7-甲氧基-10,13-二甲基十六氢-1H-环戊基[a]菲-17-基)戊酰基)甘氨酸(B24)的制备
将化合物B23(100mg,0.20mmol)溶于甲醇(5mL)中，加入过量的4M氢氧化钠水溶液，常温搅拌4h。反应结束后，加入盐酸水溶液调PH值至酸性，减压浓缩，用二氯甲烷(10mL×3)萃取，用饱和食盐水洗涤有机相，浓缩溶剂得到粗产物。柱层析(V二氯甲烷:V甲醇＝30:1),浓缩得到白色固体化合物B2480mg,产率82％。 1H NMR(400MHz,MeOH-d 4):δ3.94(t,J＝2.9Hz,1H),3.77(s,2H),3.41-3.36(m,1H),3.26(s,3H),3.23-3.21(m,1H),2.37-2.08(m,5H),1.97-1.78(m,5H),1.71-1.54(m,7H),1.46-1.31(m,6H),1.17-1.10(m,1H),1.03(d,J＝6.3Hz,3H),0.92(s,3H),0.71(s,3H).
实施例51
(R)-4-((3R,5S,7R,8R,9S,10S,13R,14S,17R)-3,12-二羟基-7-甲氧基-10,13-二甲基十六氢-1H-环戊烷[a]菲-17-基)-N-环丙基基戊酰胺(B25)的制备
其他条件同实施例27，将A1替换成A24，产物为白色固体化合物B25，产率为77％。 1H NMR(400MHz,CDCl 3):δ5.95(s,1H),3.90(s,1H),3.42-3.37(m,1H),3.26(s,3H),3.23-3.22(m,1H),2.70-2.66(m,1H),2.21-2.03(m,4H),1.96-1.74(m,6H),1.68-1.49(m,7H),1.41-1.28(m,6H),1.10-1.01(m,1H),0.95(d,J＝6.3Hz,3H),0.88(s,3H),0.76-0.71(m,2H),0.65(s,3H),0.48-0.45(m,2H).
实施例52
(R)-4-((3R,5S,7R,8R,9S,10S,13R,14S,17R)-3,12-二羟基-7-甲氧基-10,13-二甲基十六氢-1H-环戊烷[a]菲-17-基)-N-环戊基戊酰胺(B26)的制备
其他条件同实施例27，将A1替换成A25，产物为白色固体化合物B26，产率为81％。 1H NMR(400MHz,CDCl 3):δ5.61(d,J＝7.8Hz,1H),4.23-4.14(m,1H),3.92(t,J＝3.2Hz,1H),3.43-3.38(m,1H),3.26(s,3H),3.23-3.22(m,1H),2.23-2.07(m,7H),1.97-1.90(m,3H),1.84-1.74(m,4H),1.68-1.51(m,10H),1.42-1.29(m,7H),1.10-1.04(m,1H),0.97(d,J＝6.4Hz,3H),0.88(s,3H),0.66(s,3H).
实施例53
(R)-4-((3R,5S,7R,8R,9S,10S,13R,14S,17R)-3,12-二羟基-7-甲氧基-10,13-二甲基十六氢-1H-环戊烷[a]菲-17-基)-N-环戊甲基戊酰胺(B27)的制备
其他条件同实施例27，将A1替换成A26，产物为白色固体化合物B27，产率为73％。 1H NMR(400MHz,CDCl 3):δ5.64(s,1H),3.91(t,J＝3.1Hz,1H),3.45-3.38(m,1H),3.26(s,3H),3.23-3.21(m,1H),3.17(t,J＝6.5Hz,2H),2.25-2.05(m,7H),2.03-1.97(m,1H),1.95-1.86(m,2H),1.81-1.51(m,15H),1.42-1.28(m,5H),1.22-1.14(m,2H),1.11-1.03(m,1H),0.98(d,J＝6.4Hz,3H),0.88(s,3H),0.65(s,3H).
实施例54
((R)-4-((3R,5S,7R,8R,9S,10S,13R,14S,17R)-3,12-二羟基-7-甲氧基-10,13-二甲基十六氢-1H-环戊基[a]菲-17-基)-N-(2-氧代-2-(吡咯烷-1-基)乙基)戊酰胺(B28)的制备
将化合物B24(50mg,0.1mmol)溶于DMF(5mL)中，冰浴条件下加入HATU(52mg,0.14mmol)，缓慢滴加三乙胺(44μL,0.31mmol)，冰浴搅拌15分钟之后加入四氢吡咯(10μL,0.13mmol)，常温搅拌2h。反应结束后，用二氯甲烷(10mL×3)萃取，用饱和食盐水洗涤有机相，浓缩溶剂得到粗产物。柱层析(V二氯甲烷:V甲醇＝50:1),浓缩得到白色固体化合物B2847mg,产率83％。 1H NMR(400MHz,CDCl 3):δ6.62(t,J＝4.0Hz,1H),3.97(d,J＝4.3Hz,2H),3.92(t,J＝3.0Hz,1H),3.49(t,J＝6.9Hz,2H),3.45-3.36(m,3H),3.25(s,3H),3.20-3.19(m,1H),2.36-2.28(m,1H),2.20-2.06(s,6H),2.02-1.93(m,3H),1.91-1.86(m,3H),1.82-1.73(m,3H),1.67-1.46(m,7H),1.42-1.28(m,4H),1.10-1.02(m,1H),0.98(d,J＝6.3Hz,3H),0.88(s,3H),0.65(s,3H).
实施例55
(R)-4-((3R,5S,7R,8R,9S,10S,13R,14S,17R,E)-3-羟基-12-(羟基亚氨基)-7-甲氧基-10,13-二甲基十六氢-1H-环戊基[a]菲-17-基)-1-(吡咯烷-1-基)戊烷-1-酮(C1)的制备
将化合物A1(60mg,0.13mmol)、盐酸羟胺(36mg,0.52mmol)、三水合乙酸钠(124mg,0.91mmol)和甲醇(5mL)的混合物回流10h。加压浓缩除去溶剂，将白色粗品重新溶解在二氯甲烷中，用饱和食盐水洗涤三次，使用无水Na 2SO 4干燥有机层。柱层析(V二氯甲烷:V甲醇＝20:1)，浓缩得到白色固体化合物C150mg，产率81％。 1H NMR(400MHz,CDCl 3):δ3.45-3.38(m,5H),3.30-3.25(m,1H),3.20(s,4H),2.34-2.27(m,1H),2.21-1.89(m,9H),1.85-1.75(m,6H),1.71-1.55(m,5H),1.47-1.35(m,5H),1.20-1.14(m,1H),1.05-1.00(m,1H),0.97-0.92(m,6H),0.88(s,3H).
实施例56
(R)-4-((3R,5S,7R,8R,9S,10S,13R,14S,17R,E)-3-羟基-12-(羟基亚氨基)-7-甲氧基-10,13-二甲基十六氢-1H-环戊基[a]菲-17-基)-1-(吡咯烷-1-基)N，N-二甲基戊酰胺(C2)的制备
其他条件同实施例55，将A1替换成A2，产物为白色固体化合物C2，产率为90％。 1H NMR(400MHz,CDCl 3):δ3.47-3.39(m,1H),3.30-3.26(m,1H),3.25-3.23(m,1H),3.22(s,3H),3.01(s,3H),2.93(s,3H),2.42-2.34(m,1H),2.27-2.15(m,2H),2.13-2.03(m,2H),2.01-1.95(m,1H),1.85-1.61(m,10H),1.55-1.52(m,1H),1.48-1.35(m,5H),2.22-1.15(s,1H),1.07-1.02(m,1H),0.97(s,3H),0.95(d,J＝6.6Hz,3H),0.89(s,3H).HRMS(ESI):m/z calcd C 27H 46N 2O 4[M+Na] +485.3350,found:485.3351.
实施例57
甲基(R)-4-((3R,5S,7R,8R,9S,10S,13R,14S,17R,E)-3-羟基-12-(羟基亚氨基)-7-甲氧基-10,13-二甲基十六氢-1H-环戊基[a]菲-17-基)戊酸酯(C3)的制备
其他条件同实施例55，将A1替换成A6，产物为白色固体化合物C3，产率为95％。 1H NMR(400MHz,CDCl 3)δ3.65(s,3H),3.47-3.40(m,1H),3.32-3.27(m,1H),3.25-3.24(m,1H),3.23(s,3H),2.42-2.34(m,1H),2.29-2.21(m,1H),2.17-2.03(m,3H),2.01-1.95(m,1H),1.90-1.59(m,11H),1.45-1.36(m,5H),1.22-1.16(m,1H),1.07-1.02(m,1H),0.97(s,3H),0.93(d,J＝6.5Hz,3H),0.89(s,3H).
实施例58
(R)-4-((3R,5S,7R,8R,9S,10S,13R,14S,17R,E)-3-羟基-12-(羟基亚氨基)-7-甲氧基-10,13-二甲基十六氢-1H-环戊基[a]菲-17-基)-1-(吡咯烷-1-基)-N-甲基戊酰胺(C4)的制备
其他条件同实施例55，将A1替换成A3，产物为白色固体化合物C4，产率为80％。 1H NMR(400MHz,CDCl 3):δ6.00-5.96(m,1H),3.46-3.38(m,1H),3.29-3.25(m,1H),3.23-3.22(m,1H),3.21(s,3H),2.76(d,J＝4.8Hz,3H),2.27-2.01(m,7H),1.99-1.92(m,1H),1.85-1.75(m,4H),1.72-1.55(m,5H),1.46-1.33(m,5H),1.21-1.15(m,1H),1.05-1.01(m,1H),0.96(s,3H),0.91(d,J＝6.5Hz,3H),0.88(s,3H).
实施例59
(R)-4-((3R,5S,7R,8R,9S,10S,13R,14S,17R,E)-3-羟基-12-(羟基亚氨基)-7-甲氧基-10,13-二甲基十六氢-1H-环戊基[a]菲-17-基)-1-(吡咯烷-1-基)-N-乙基戊酰胺(C5)的制备
其他条件同实施例55，将A1替换成A4，产物为白色固体化合物C5，产率为85％。 1H NMR(400MHz,CDCl 3):δ5.92-5.88(m,1H),3.46-3.38(m,1H),3.29-3.20(s,6H),2.25-1.92(m,7H),1.85-1.51(m,10H),1.49-1.30(m,5H),1.23-1.14(s,2H),1.09(t,J＝7.3Hz,3H),1.05-1.00(M,1H),0.95(s,3H),0.91(d,J＝6.4Hz,3H),0.88(s,3H).
生物活性测试
cAMP的累积实验被用来测试目标化合物对TGR5的功能活性以及阐明新化合物是否是TGR5PAM。cAMP的累积水平主要利用GloSensor-一种基于生物发光的cAMP生物传感器(Promega)-来测试。简要来说，将HEK 293T细胞种入6孔板中，每孔种3×10 5个细胞。第二天，使用FuGene转染试剂(Promega)将hTGR5和pGloSensor-22F cAMP质粒同时转染到HEK 293T细胞中。48h后，用CO 2独立培养基洗涤转染后的细胞，再和含有2％v/v GloSensor cAMP试剂储备液(溶于10％FBS CO 2独立培养基)的平衡液一起孵育。在37℃条件下孵育1h后再室温孵育1h，检测生物发光信号直到获得稳态的基线信号。然后，向细胞中加入不同浓度梯度的TGR5激动剂、阳性对照CDCA或者新化合物(最终浓度1nM-50μM)。用酶标仪读取生物荧光的变化。
使用cAMP累积试验测试新化合物能否别构调节TGR5内源性配体CDCA的功能活性以确定它们是否是TGR5正向别构调节剂(PAM)。简要来说，首先测试CDCA(1nM-100μM)的剂量-响应曲线，当其生物发光信号到达最高时，加入浓度成倍数关系的新化合物(1nM-100μM)，测试此时生物荧光的变化是否呈现浓度依赖的有限上移趋势。具体实验步骤同上文Glosensor cAMP的累积试验。
Figure PCTCN2022131241-appb-000009
表1 A类和C类目标化合物激活TGR5的EC 50值
Figure PCTCN2022131241-appb-000010
Figure PCTCN2022131241-appb-000011
表2 B类目标化合物激活TGR5的EC 50值
Figure PCTCN2022131241-appb-000012
从表1和表2中结果可知，本发明中的目标化合物对TGR5具有较好的激动活性。新化合物中，除了A12,A14,A16,B14,B15,B16，其它化合物对TGR5的激动活性是先导化合物CA(EC 50＝38.7μM)的1-227倍。其中，药理活性在600nM以下的有A1,B1,C1,C2,C4和C5。
此外，测试了目标化合物A1,B1和C1对TGR5内源性配体CDCA的别构调节功能(图1)。结果表明，随着目标化合物A1,B1和C1浓度的逐渐增加，它们所介导的CDCA的量效曲线呈现有限的上移，表明A1,B1和C1均能够正向别构调节TGR5内源性配体CDCA的功能活性，即本发明中的三类目标化合物均是TGR5别构激动剂或正向别构调节剂。

Claims (10)

  1. 一种胆酸衍生物，其特征在于，所述胆酸衍生物的结构如式1、式2、式3或式4所示：
    Figure PCTCN2022131241-appb-100001
    其中，R 1为：氢，甲基，三氟甲基，乙基，正丙基，异丙基，环丙基，苄基及其它芳基，烷基；
    注：所有R 1基团都包括α,β两种构型；
    R 2为：
    Figure PCTCN2022131241-appb-100002
    Figure PCTCN2022131241-appb-100003
    Figure PCTCN2022131241-appb-100004
    及氨基基团或OCH 3，OC 2H 5，OCH(CH 3) 2，
    Figure PCTCN2022131241-appb-100005
    及其它烷氧基基团；
    R 3为：O或NOH；
    R 4为：甲基，三氟甲基，乙基，正丙基，异丙基，环丙基，苯基及其它芳基，烷基。
  2. 一种胆酸衍生物的制备方法，其特征在于，所述制备方法步骤如下：
    (1)将化合物Ⅰ溶于DCM中，加入偶联剂2-(7-偶氮苯并三氮唑)-N,N,N’,N’-四甲基脲 六氟磷酸酯(HATU)，滴加三乙胺，冰浴的条件下搅拌反应15min后，加入胺类化合物，得到化合物Ⅱ的结构式为
    Figure PCTCN2022131241-appb-100006
    或
    将化合物Ⅰ溶于DCM中，冰浴条件下加入4-二甲氨基吡啶(DMAP)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺(EDC)，醇类化合物，冰浴搅拌1h之后移至常温搅拌2h，得到化合物Ⅱ的结构式为
    Figure PCTCN2022131241-appb-100007
    (2)将化合物Ⅱ溶于甲醇中，冰浴条件下加入PdCl 2，NaBH 4搅拌10分钟，抽滤除去黑色固体，得到化合物的结构为
    Figure PCTCN2022131241-appb-100008
    或
    将化合物Ⅱ溶于甲醇中，加入盐酸羟胺，三水合乙酸钠加热回流10h，得到化合物的结构为
    Figure PCTCN2022131241-appb-100009
    其中R 1为氢，甲基，乙基，正丙基，异丙基，三氟甲基，环丙基，苄基；
    R 2为OCH 3,OC 2H 5,OCH(CH 3) 2,
    Figure PCTCN2022131241-appb-100010
    Figure PCTCN2022131241-appb-100011
    或
    (1)将化合物Ⅲ溶于四氢呋喃中，加入四丁基氟化铵常温搅拌12h，得到化合物Ⅳ的结 构为
    Figure PCTCN2022131241-appb-100012
    将化合物Ⅳ溶于甲醇中，冰浴条件下加入PdCl 2，NaBH 4搅拌10分钟，抽滤除去黑色固体，得到化合物的结构为
    Figure PCTCN2022131241-appb-100013
    其中，R 4为甲基，三氟甲基，乙基，正丙基，异丙基，环丙基，苯基。
  3. 如权利要求2所述的胆酸衍生物的制备方法，其特征在于，所述化合物Ⅰ的结构式为
    Figure PCTCN2022131241-appb-100014
  4. 如权利要求2所述的胆酸衍生物的制备方法，其特征在于，所述胺类化合物为：四氢吡咯、二甲胺、二乙胺、吗啉、哌嗪、哌啶、甲胺、乙胺、正丙胺、异丙胺、甘氨酸乙酯、甘氨酸、四氢吡罗取代甘氨酸、环丙胺、环戊甲胺、环戊胺或环戊甲胺；所述醇类化合物为：甲醇、乙醇、异丙醇、环丙醇、环丙甲醇、环戊醇、环戊甲醇、苯酚、苯甲醇、1-萘酚或2-萘酚。
  5. 如权利要求2所述的胆酸衍生物的制备方法，其特征在于，所述化合物Ⅰ：2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯：胺类化合物：三乙胺的摩尔比为1:1.1:1.2:3；化合物Ⅰ：1-(3-二甲基氨基丙基)-3-乙基碳二亚胺：4-二甲氨基吡啶：醇类化合物的摩尔比为1：1.2：0.1：1.5。
  6. 如权利要求2所述的胆酸衍生物的制备方法，其特征在于，所述化合物Ⅱ或化合物Ⅳ、二氯化钯和硼氢化钠的摩尔比为1：1：10。
  7. 如权利要求2所述的胆酸衍生物的制备方法，其特征在于，所述化合物Ⅱ：三水合乙酸钠：盐酸羟胺的摩尔比为1：7：4。
  8. 如权利要求2所述的胆酸衍生物的制备方法，其特征在于，所述化合物Ⅲ的结构式为
    Figure PCTCN2022131241-appb-100015
  9. 如权利要求2所述的胆酸衍生物的制备方法，其特征在于，所述化合物Ⅲ：四丁基氟化铵的摩尔比为1：2。
  10. 一种如权利要求1所述的胆酸衍生物的应用，其特征在于：所述衍生物作为G蛋白偶联胆汁酸受体1(TGR5)的别构激动剂，应用于开发治疗相关疾病的药。
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