CN115819492A - 一种c14位取代甾体及其制备方法 - Google Patents
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- 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
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- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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Abstract
本发明公开了一种C14位取代甾体及其制备方法。本发明方法以含有14，15位烯烃基团的甾体为起始原料，在金属催化剂、氢供体、自由基捕获剂以及保护气体的作用下，在25‑60℃下于有机溶剂中搅拌反应，即可得到C14位取代的新型甾体化合物。本发明方法具有反应条件温和，制备过程简单，底物兼容性强，区域选择性好等优点，具有较大的应用潜力，为针对开发新型甾体药物的研究奠定了良好的基础。
Description
技术领域
本发明属于有机合成领域，具体涉及一种C14位取代甾体及其制备方法。
背景技术
甾体化合物是一类以环戊烷多氢菲为母核的有机小分子，广泛存在于自然界中，并具有广泛的生理活性，包括抗癌、抗炎、免疫抑制、孕激素、抗雄激素、利尿和避孕活性等(Salvador,J.A.；Carvalho,J.F.；Neves,M.A.；Silvestre,S.M.；Leitao,A.J.；Silva,M.M.；Sa e Melo,M.L.Nat Prod Rep 2013,30,324.)。目前，临床上使用的甾体药物多达400余种，占全部临床使用药物总数的15％左右，年产量超过100万吨，年度全球市值超过1000亿美元(Fernandez-Cabezon,L.；Galan,B.；Garcia,J.L.Front Microbiol 2018,9,958)。对天然存在的甾体化合物进行结构修饰得到新型甾体，可以为寻找新的甾体药物提供坚实的基础。天然甾体中C14除H之外的取代基团一般仅限于羟基、环氧或甲基，如C14位羟基和环氧取代的强心甾类和蟾蜍毒素类家族化合物都很明显表现出较强的生理活性或具有药用价值([1]Gao,H.；Popescu,R.；Koppb,B.；Wang,Z.Nat.Prod.Rep.2011,28,953；[2]Zhong,Y.；Zhao,C.；Wu,W.；Fan,T.；Li,N.；Chen,M.；Duan,J.；Shi,Z.Eur.J.Med.Chem.2020,189,112038)。据文献报道，C14位氨基取代的非天然甾体Lnf-209也表现出较强抗毒蕈碱活性(Lullmann,H.；Mohr,K.J.Cardiovasc.Pharmacol.1992,20,807)。然而，目前对甾体C14位进行结构修饰具有相当大的难度，利用C14位烯烃对甾体进行结构改造是得到C14位官能团化甾体的有效手段。然而该烯烃未被活化，且空间位阻较大，除在C14位构建碳氧键之外，碳碳键或碳杂键的构建很少报道。Ponsold等人于1983年利用NBS或NIS和亲核试剂结合对C14，15位烯烃进行了双官能团化反应，得到溴或异氰酸酯取代的C14位衍生甾体，1986年利用重氮甲烷作为烷基源，在C14位引入亚甲基，得到C14，15环丙烷化甾体产物([1]Ponsold,K.；Wunderwald,M.J.prakt.Chem.1983,325,123；[2]Prousa,R.；Schoenecker,B.；Tresselt,D.；Ponsold,K.J.prakt.Chem.1986,328,55)；Baran课题组2013年报道了利用金属氢迁移的策略，以Selectfluor作为自由基保护剂，成功在C14位上引入了氟原子(Science 2013,339,59)。目前，仍缺少合成多样化C14取代甾体的方法，发展一种能构建甾体C14位碳碳键或碳杂键的方法具有重要意义。
发明内容
为了解决现有技术中存在的不足，本发明提供一种C14位取代甾体及其制备方法。该方法反应条件温和，制备过程简单，底物兼容性强，区域选择性好。
本发明提供的技术方案具体如下：
第一方面，本发明提供一种C14位取代甾体的制备方法，步骤如下：
在保护气体氛围下，以含有C14，15烯烃基团的甾体A作为起始原料，在金属催化剂B、氢供体C、自由基捕获剂D的作用下，25～60℃于有机溶剂E中搅拌反应至完全；反应结束后，反应混合物经过滤、浓缩、柱层析纯化即得到如式F的C14位取代的甾体化合物；
其中：
R1为烷基、酮羰基-COR4、羟基、氨基、氰基或硝基；
R2为氢或者羟基；
R3为-SeR5或-(CH2)2R6；
n为氢的个数，取1或者2。
进一步，所述R1中，烷基为C1～6的烷基；-COR4中，R4为C1～6的烷基。进一步，所述金属催化剂B选自Co(acac)2、Co-salen、CoCl2、Co(BF4)2、Fe(acac)3、Fe(acac)2、FeCl3、FeCl2、Fe2(ox)3 .6H2O、Mn(acac)2、Mn(dpm)3中的一种或几种。
进一步，氢供体C为Et3SiH、PhSiH3、Ph3SiH、NaBH4、PMHS中的一种或几种。
进一步，所述自由基捕获剂D选自TsSeR5，CH2＝CHR6其中一种或几种；
其中，R5为C6-12的芳基或含有N、O、S的C6-12的杂芳基；R6为酯基，氰基，醛基，硝基，-SO2R7等吸电子基团，其中，酯基为-COOR’，R’为C1～6的烷基，R7为C6-12的芳基或含有N、O、S的C6-12的杂芳基。
进一步，所述溶剂E选自甲醇、乙醇、异丙醇、叔丁醇、四氢呋喃、2-甲基四氢呋喃、乙醚、二甲基乙二醚、甲基叔丁基醚、1,4-二氧六烷、1,3-二氧六烷、二氯甲烷、1,2-二氯乙烷、氯仿、四氯化碳、C4-12的饱和烷烃、C3-12的氟代或者氯代烷烃、苯、甲苯、二甲苯、三甲苯、二甲亚砜、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、丙酮、N-甲基吡咯烷酮、乙腈、C3-12的饱和烷基腈中的任意一种或几种。
进一步，A、B、C和D的摩尔比为1:(0.1～1):(1.5～10):(1～2)。
进一步，所述合成方法中，反应时间为1～36小时，反应温度为25～60℃。加热过程可采用油浴(如硅油、石蜡油等)或者其它加热方式。
进一步，在反应完成后对反应产物进行后处理，包括萃取、浓缩和纯化。所述萃取过程可使用分液漏斗进行萃取。所述浓缩过程可采用减压蒸馏等方法，例如用旋转蒸发仪减压浓缩。所述纯化方法可采用柱层析分离纯化。
第二方面，本发明提供利用第一方面所述方法制备的C14位取代甾体。
本发明的方法可以制备C14位多样化取代的甾体化合物，和现有技术相比，本发明具有以下有益效果：
i)本发明所涉及的金属催化剂均为廉价金属，种类繁多，无需特殊处理便可使用，部分催化剂经简单制备即可得到；氢供体试剂均为常见商品化试剂，无需特殊处理即可使用；自由基捕获试剂大都为商品化试剂，稳定易保存，价格低廉，部分仅需一步反应即可得到。
ii)本发明采用的金属氢迁移反应，具有非常高的区域选择性，单一地得到C14位取代甾体产物。
iii)本发明方法具有较好的官能团兼容性，可以兼容羰基，α,β-不饱和双键等基团。
iv)本发明方法可以制备C14位多样化官能团取代的新型甾体，为开发新的甾体药物提供了坚实的合成基础，具有较大的应用潜力。
具体实施方式
下面通过实例对本发明给予进一步说明，值得注意的是，本发明不仅限于下述的实施例。
实施例1：化合物F1和F2的制备
在氩气氛围下，向干燥并装有磁力搅拌子的反应管依次加入化合物A1(20.0mg,0.06mmol)、乙酰丙酮钴(16.4mg,0.06mmol)以及对甲苯磺酰基苯基硒醚(49.6mg,0.15mmol)和超干二氧六环溶剂(400μL)。搅拌2min后，向其中加入三乙基硅烷(102μL，0.64mmol)和叔丁基过氧化氢(12μL，0.06mmol)，保持在室温下搅拌过夜。反应结束后用短硅胶柱过滤掉固体，并用乙酸乙酯冲洗硅胶柱，收集的溶液在减压蒸馏下浓缩，除去溶剂。最后利用柱层析将粗产物进行分离纯化，得到白色固体F1(9.7mg,33％,回收收率41％)和F2(8.2mg,27％,回收收率34％)。F1:1H NMR(400MHz,CDCl3)δ7.67–7.58(m,2H),7.41–7.30(m,1H),7.32–7.25(m,2H),5.80(s,1H),3.98(t,J＝9.0Hz,1H),2.53–2.34(m,4H),2.18(s,3H),2.17–2.01(m,4H),1.96–1.58(m,8H),1.55–1.48(m,1H),1.34–1.28(m,1H),1.26(s,3H),0.90(s,3H)；13C NMR(151MHz,CDCl3)δ209.9,199.5,170.4,138.5,129.08,128.9,128.9,124.2,79.5,61.4,49.9,47.9,41.7,39.0,35.8,34.1,32.7,32.6,31.5,31.4,31.1,22.6,20.0,17.7,17.4。F2：1H NMR(400MHz,CDCl3)δ7.87–7.48(m,2H),7.35–7.28(m,1H),5.70(s,1H),2.71–2.61(m,1H),2.48–2.32(m,1H),2.30(s,2H),2.28–2.13(m,1H),2.10–1.94(m,2H),1.88–1.75(m,2H),1.67(td,J＝13.8,5.8Hz,1H),1.55–1.46(m,0H),1.44(s,2H),1.34(ddd,J＝21.4,12.1,3.2Hz,1H),1.19(td,J＝12.6,4.2Hz,1H),1.03(s,2H)；13CNMR(151MHz,CDCl3)δ209.5,199.4,170.5,138.3,129.3,128.9,128.7,123.9,74.1,63.7,51.3,49.6,42.4,42.0,39.2,35.8,34.0,33.2,32.4,32.0,31.3,24.3,22.7,20.9,17.5。
实施例2：化合物F3的制备
在氩气氛围下，向干燥并装有磁力搅拌子的反应管中依次加入化合物A1(10mg,0.03mmol)，乙酰丙酮铁(11.3mg,0.03mmol)以及超干二氯乙烷(240μL)和乙二醇(50μL)。搅拌2min后，在室温下依次加入丙烯酸甲酯(2.9μL,0.03mmol)和苯基硅烷(7.1μL,0.048mmol)。随后将反应升温至60℃，并持续搅拌2h，随后降温至室温，加入亚硫酸钠洗涤，并用二氯甲烷萃取。所得有机相经无水硫酸钠干燥后过滤，减压蒸馏下除去溶剂，最后再利用柱层析将粗产品纯化，得到白色固体化合物F3(1.5mg,收率12％)。1H NMR(400MHz,CDCl3)δ5.72(s,1H),3.68(s,3H),2.76(t,J＝8.6Hz,1H),2.48–2.25(m,6H),2.22–2.18(m,1H),2.16(s,3H),2.13–2.01(m,2H),1.95–1.82(m,2H),1.80–1.60(m,5H),1.54–1.46(m,1H),1.41–1.18(m,5H),1.16(s,3H),1.08(s,3H)；13C NMR(151MHz,CDCl3)δ211.7,199.6,174.4,170.6,123.9,77.4,77.2,76.9,62.8,51.9,49.8,48.6,48.0,42.7,39.0,37.6,36.0,34.0,33.5,33.3,31.1,30.4,29.8,29.0,24.2,21.8,19.3,17.8。
实施例3：化合物F4和F5的制备
在氩气氛围下，向干燥并装有磁力搅拌子的反应管中依次加入化合物A2(30.0mg,0.1mmol)、乙酰丙酮钴(24.6mg,0.1mmol)以及甲苯磺酰基苯基硒醚(74mg,0.24mmol)和超干二氧六环溶剂(1mL)。搅拌2min后，向其中加入三乙基硅烷(150μL,0.96mmol)和叔丁基过氧化氢(18μL,0.1mmol,5.5M in decane)，保持在室温下搅拌过夜。反应结束后用短硅胶柱过滤掉固体，并用乙酸乙酯冲洗硅胶柱，收集的溶液在减压蒸馏下浓缩，除去溶剂。最后利用柱层析将粗产物进行分离纯化，得到白色固体F4(24mg，收率53％，回收收率75％)和F5(6.2mg，收率14％，回收收率19％brsm)。F4:1H NMR(600MHz,CDCl3)δ7.68–7.62(m,2H),7.39–7.33(m,1H),7.28(t,J＝7.6Hz,2H),3.97(t,J＝9.0Hz,1H),2.96(t,J＝14.3Hz,1H),2.44(td,J＝14.7,5.5Hz,1H),2.33(td,J＝11.9,5.4Hz,1H),2.29–2.19(m,3H),2.18(s,3H),2.12(ddd,J＝15.0,4.6,2.3Hz,1H),2.05(m,2H),1.97(tt,J＝13.8,4.7Hz,1H),1.93–1.84(m,3H),1.62–1.57(m,1H),1.55–1.34(m,6H),1.20(dtd,J＝14.1,9.2,7.1Hz,1H),1.08(s,3H),0.88(s,3H)；13C NMR(151MHz,CDCl3)δ213.1,210.0,138.5,129.3,128.9,128.9,81.7,61.6,50.3,44.8,42.8,41.5,37.5,37.3,35.5,35.1,33.2,31.6,31.3,26.3,24.5,22.6,22.6,20.3,17.7。F5:1H NMR(400MHz,CDCl3)δ7.82–7.73(m,2H),7.37–7.27(m,3H),2.71–2.55(m,2H),2.51–2.33(m,3H),2.31(s,3H),2.21–2.07(m,2H),2.05–1.95(m,3H),1.90–1.64(m,7H),1.48–1.42(m,1H),1.40(s,3H),1.35–1.19(m,4H),0.90(s,3H)；13CNMR(151MHz,CDCl3)δ212.9,209.5,138.2,129.5,128.8,128.5,74.7,64.1,51.8,43.9,42.9,42.4,42.3,37.2,37.0,36.8,35.9,32.0,31.9,26.9,24.8,24.2,22.6,22.4,21.1。
实施例4：化合物F6和F7的制备
在氩气氛围下，向干燥并装有磁力搅拌子的反应管中依次加入化合物A2(50mg，0.16mmol)、乙酰丙酮铁(56mg，0.16mmol)以及超干二氯乙烷(1.2mL)和乙二醇(300μL)。搅拌2min后，在室温下依次加入丙烯酸甲酯(14.5μL，0.16mmol)和苯基硅烷(36μL，0.24mmol)。随后将反应升温至60℃，并持续搅拌2h，随后降温至室温，加入亚硫酸钠洗涤，并用二氯甲烷萃取。所得有机相经无水硫酸钠干燥后过滤，减压蒸馏下除去溶剂，最后再利用柱层析将粗产品纯化，得到白色固体化合物F6(2.5mg，收率4％)和F7(4.0mg，收率6％)。F6:1H NMR(600MHz,CDCl3)δ3.69(s,3H),3.13(dd,J＝10.3,7.8Hz,1H),2.62(t,J＝14.3Hz,1H),2.47(ddd,J＝16.6,12.5,4.4Hz,1H),2.42–2.30(m,2H),2.26–2.15(m,2H),2.14(s,3H),2.13–1.97(m,3H),1.96–1.76(m,4H),1.75–1.58(m,3H),1.54–1.27(m,7H),1.26(s,3H),1.24–1.09(m,2H),0.99(s,3H)；13C NMR(151MHz,CDCl3)δ213.0,210.4,174.5,62.0,51.9,51.4,47.7,43.8,42.3,37.7,37.2,36.9,35.4,34.2,33.0,32.3,31.8,31.2,31.0,26.9,22.7,22.2,22.1,21.9,21.0。F7:1H NMR(600MHz,CDCl3)δ3.68(s,3H),2.76(dd,J＝9.4,7.7Hz,1H),2.62(dd,J＝15.4,13.1Hz,1H),2.41–2.25(m,3H),2.22–2.16(m,1H),2.16(s,3H),2.13–1.95(m,5H),1.89–1.73(m,4H),1.70–1.57(m,3H),1.57–1.50(m,2H),1.50–1.37(m,3H),1.32–1.17(m,3H),1.05(s,3H),0.99(s,3H)；13C NMR(151MHz,CDCl3)δ213.1,211.7,174.6,63.1,51.8,49.9,48.9,43.7,43.1,42.2,37.6,37.3,36.9,35.5,34.7,33.4,33.2,31.0,30.4,26.9,24.2,22.8,22.5,22.0,19.4。
以上所述，仅为本发明较佳的具体实施方式，但本发明保护的范围并不局限于此，任何熟悉本技术领域的技术人员在本发明揭露的技术范围内所做的任何修改，等同替换和改进等，均应包含在发明的保护范围之内。
Claims (10)
1.一种C14位取代甾体的制备方法，其特征在于，步骤如下：
在保护气体氛围下，以含有C14，15烯烃基团的甾体A作为起始原料，在金属催化剂B、氢供体C、自由基捕获剂D的作用下，25～60℃于有机溶剂E中搅拌反应至完全；反应结束后，反应混合物经过滤、浓缩、柱层析纯化即得到如式F的C14位取代的甾体化合物；
其中：
R1为烷基、酮羰基-COR4、羟基、氨基、氰基或硝基；
R2为氢或者羟基；
R3为-SeR5或-(CH2)2R6；
n为氢的个数，取1或者2。
2.根据权利要求1所述的方法，其特征在于：所述R1中，烷基为C1～6的烷基；-COR4中，R4为C1～6的烷基。
3.根据权利要求1所述的方法，其特征在于：所述R3中，R5为C6-12的芳基或含有N、O、S的C6-12的杂芳基；-(CH2)2R6中，R6为酯基、氰基、醛基、硝基或-SO2R7，其中，酯基为-COOR’，R’为C1～6的烷基，R7为C6-12的芳基或含有N、O、S的C6-12的杂芳基。
4.根据权利要求1所述的方法，其特征在于：其特征在于：所述金属催化剂B选自Co(acac)2、Co-salen、CoCl2、Co(BF4)2、Fe(acac)3、Fe(acac)2、FeCl3、FeCl2、Fe2(ox)3 .6H2O、Mn(acac)2、Mn(dpm)3中的一种或几种。
5.根据权利要求1所述的方法，其特征在于：氢供体C为Et3SiH、PhSiH3、Ph3SiH、NaBH4、PMHS中的一种或几种。
6.根据权利要求1所述的方法，其特征在于：所述自由基捕获剂D选自TsSeR5或CH2＝CHR6其中一种或几种；
其中，R5为C6-12的芳基或含有N、O、S的C6-12的杂芳基；R6为酯基，氰基，醛基，硝基或-SO2R7，其中R7为C6-12的芳基或含有N、O、S的C6-12的杂芳基。
7.根据权利要求6所述的方法，其特征在于：R6中，酯基为-COOR’，R’为C1～6的烷基。
8.根据权利要求1所述的方法，其特征在于：所述溶剂E选自甲醇、乙醇、异丙醇、叔丁醇、四氢呋喃、2-甲基四氢呋喃、乙醚、二甲基乙二醚、甲基叔丁基醚、1,4-二氧六烷、1,3-二氧六烷、二氯甲烷、1,2-二氯乙烷、氯仿、四氯化碳、C4-12的饱和烷烃、C3-12的氟代或者氯代烷烃、苯、甲苯、二甲苯、三甲苯、二甲亚砜、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、丙酮、N-甲基吡咯烷酮、乙腈、C3-12的饱和烷基腈中的任意一种或几种。
9.根据权利要求1所述的方法，其特征在于：A、B、C和D的摩尔比为1:(0.1～1):(1.5～10):(1～2)。
10.一种C14位取代甾体及其制备方法，其特征在于：采用权利要求1-9任一项所述的方法制备。
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