CN106279327B - 17z‑(1‑羟基‑2‑氧代‑1‑亚乙基)雄甾烯酮衍生物的合成方法 - Google Patents

17z‑(1‑羟基‑2‑氧代‑1‑亚乙基)雄甾烯酮衍生物的合成方法 Download PDF

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CN106279327B
CN106279327B CN201610654023.3A CN201610654023A CN106279327B CN 106279327 B CN106279327 B CN 106279327B CN 201610654023 A CN201610654023 A CN 201610654023A CN 106279327 B CN106279327 B CN 106279327B
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王立中
王存德
卞小琴
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Taizhou Polytechnic College
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Abstract

本发明涉及一种17Z ‑(1‑羟基‑2‑氧代‑1‑亚乙基)雄甾烯酮衍生物的合成方法，包括如下步骤：通过使用催化剂邻碘苯甲酸和氧化剂过硫酸氢钾混合产生混合物糖皮质激素，加入溶剂DMSO，经混合搅拌反应，淬灭反应，再经萃取、洗涤、干燥、蒸去溶剂、柱层析，得到目标化合物17Z ‑(1‑羟基‑2‑氧代‑1‑亚乙基)雄甾烯酮衍生物。

Description

17Z-(1-羟基-2-氧代-1-亚乙基)雄甾烯酮衍生物的合成方法
技术领域
本发明属于化学合成领域，具体涉及17Z-(1-羟基-2-氧代-1-亚乙基)雄甾烯酮的合成方法。
背景技术
自然界中许多甾体化合物由于自身所具有的较强的生物活性，已广泛被作为药物应用到临床治疗上。许多甾体化合物经过适当的结构设计和修饰之后，就能够使之成为具有优于母体甾体化合物的生理功能的新型药物，比如药性提高，毒副作用降低等。通过多年的实验研究，发现甾体母核17位取代基的改变比其他位置上取代基的变化，在药物活性上有着更重要的作用(Chowdhury P,Borah JM,Goswami1P,Das AM.A convenient synthesisof the side chain of loteprednol etabonate-An ocular soft corticosteroid from20-oxopregnanes using metal-mediated halogenation as a key reaction.Steroids2011；76:497–501；Stulov SV,Zavialova MG,Mehtiev AR,Novikov RA,Tkachev YV,Timofeev VP,Misharin AY.[17(20)Z]-and[17(20)E]-pregna-5,17(20)-dien-21-oylamides.Facile synthesis and primary evaluation for proliferation of cancercells.Bioorg Med Chem Lett 2010；20:5495–8.)。所以对甾体D-环17位进行结构改造及生物活性研究有着更重要的应用价值。例如2011年4月28日美国FDA批准Centocor OrthoBiotech公司生产的Zytiga(乙酸阿比特龙酯，abiraterone acetate)与强的松(prednisone)联用治疗晚期(转移性)前列腺癌。2012年，我们课题组也发明了以雄甾表雄酮为原料，经过三步合成出了雄甾-17(20)-烯-21-酮，并对合成出的雄甾衍生物做了初步的抗肿瘤筛选，所合成的目标化合物具有较强的抗癌活性(Cunde Wang,Yan Li,Qian Sun,Jinliang Liu,Xingbin Wang,Chenggang Jiang.Method for synthesis of androst-17(20)-en-21-one with 3β-hydroxy-5α-androstan-17-one and medical application asantitumor agents.Faming Zhuanli Shenqing 2012,CN 102432658A 20120502.专利号：ZL 2011 1 0309027.5)。
17Z-(1-羟基-2-氧代-1-亚乙基)雄甾烯酮衍生物不仅作为重要的皮质醇代谢物被广泛研究(Monder,C.；Bradlow,H.L.Recent Prog.Horm.Res.1980,36,345.)，也是合成雄甾烯酮-21-酸衍生物的主要中间体，同时对这类化合物17位侧链羰基衍生可获得具有潜在生理活性的新型甾体药物。
先前报道的化学合成这类甾体化合物(Beyler,R.E.；Hoffman,F.J.Am.Chem.Soc.1957,79,9297.Herzog,H.L.；Gentles,M.J.；Marshall,H.；Hershberg,E.B.J.Am.Chem.Soc.1961,83,4073.),往往使用苛刻的反应条件，目标化合物的收率比较低，而且产物立体选择性不高，E和Z的同分异构体难以分离，不能够满足研究和应用。同样使用醋酸锌和冰醋酸体系也不能够提高目标化合物的收率(Lewbart,M.L.；Monder,C.；Boyko,W.J.；Singer,C.J.；Iohan,F.J.Org.Chem.1989,54,1332–1338.)。而使用对甲基苯磺酸促进上述反应，能够明显改善目标化合物的收率，但仍然给出E和Z的同分异构体混合物，也存在分离的困难(M.L.D.Gioia,A.Leggio,A.L.Pera,A.Liguori,A.Napoli,C.Siciliano,G.Sindona,Tetrahedron Lett.2001,42,7413–7415)。
发明内容
针对以上缺陷，本发明提供了一种使用催化剂邻碘苯甲酸和氧化剂过硫酸氢钾协同作用于糖皮质激素，高选择性合成出17Z-(1-羟基-2-氧代-1-亚乙基)雄甾烯酮衍生物的合成方法。
为达到以上目的，本发明采用了以下技术方案：一种17Z-(1-羟基-2-氧代-1-亚乙基)雄甾烯酮衍生物的合成方法，包括如下步骤：
通过使用催化剂邻碘苯甲酸和氧化剂过硫酸氢钾混合产生混合物糖皮质激素，加入溶剂DMSO，经混合搅拌反应，淬灭反应，再经萃取、洗涤、干燥、蒸去溶剂，得到目标化合物17Z-(1-羟基-2-氧代-1-亚乙基)雄甾烯酮衍生物。
a:X＝H,Y＝H；b:X,Y＝O；c:X＝OH,Y＝H
本发明所述步骤的反应温度为75℃，反应时间为12h，产率为89％-92％。
采用了以上技术方案后，本发明具有高度选择性，能够给出单一立体选择性产物，目标化合物收率高，能够满足科学研究和实际应用的需要。
下面结合实施例对本发明作进一步描述。
具体实施方式
本发明一种17Z-(1-羟基-2-氧代-1-亚乙基)雄甾烯酮衍生物的合成方法，包括如下步骤：
通过使用催化剂邻碘苯甲酸和氧化剂过硫酸氢钾混合产生混合物糖皮质激素，加入溶剂DMSO，经混合搅拌反应，淬灭反应，再经萃取、洗涤、干燥、蒸去溶剂，得到目标化合物17Z-(1-羟基-2-氧代-1-亚乙基)雄甾烯酮衍生物。
a:X＝H,Y＝H；b:X,Y＝O；c:X＝OH,Y＝H
本发明所述步骤的反应温度为75℃，反应时间为12h，产率为89％-92％。
测试仪器
红外光谱分析：Bruker tensor 27红外光谱仪，KBr压片法，检测范围为4000～400cm-1；熔点测量：WRR熔点仪，数据未经校正。1H-NMR及13C-NMR分析：Bruker Advance 600；反应进程用TLC跟踪检测。
17Z-(1-羟基-2-氧代-1-亚乙基)雄甾烯酮衍生物的合成
实施例1 17Z-(1-羟基-2-氧代-1-亚乙基)雄甾烯酮(2a)
取化合物1a 1.038g(3mmol)、邻碘苯甲酸0.93g(3.75mmol)、过硫酸氢钾2.30g(3.75mmol)，加入DMSO3.5mL，氮气保护下，75℃搅拌反应12h。反应混合物用3mL水淬灭，用氯仿萃取两次，每次20mL，合并有机相，依次用10％NaOH、水、饱和盐水洗涤，Na2SO4干燥。蒸去溶剂，残留物柱层析(硅胶，EtOAc/DCM:1/12)，得到白色固体产物17Z-(1-羟基-2-氧代-1-亚乙基)雄甾烯酮(2a)878mg，产率89％:mp150-152℃(EtOAc/hexanes):149-152℃)；1H-NMR(CDCl3,ppm):δ9.586(s,1H),5.746(s,1H),5.587(s,1H),1.218(s,3H),1.023(s,3H)；1H-NMR(CDCl3+D2O,ppm):δ9.583(s,1H),5.748(s,1H),1.219(s,3H),1.023(s,3H)；13C-NMR(CDCl3,ppm):δ199.52,186.09,170.87,147.02,141.83,123.92,54.02,53.64,46.13,38.58,35.59,34.99,34.76,33.88,32.68,31.87,25.15,24.80,20.90,17.26,15.44；IR(KBr)ν3435,2944,1723,1638,1584,1338,1233cm-1；MS(EI):329(M+1,65％)；Anal.Calcd.for C21H28O3:C,76.79；H,8.59；Found C,76.82；H,8.52.HRMS(ESI-TOF):calcdfor(C21H28O3+H)+329.2117,found 329.2109。
实施例2 17Z-(1-羟基-2-氧代-1-亚乙基)-4-雄甾-3,11-烯二酮(2b)
取化合物1a1.083g(3mmol)、邻碘苯甲酸0.93g(3.75mmol)、过硫酸氢钾2.30g(3.75mmol)，加入DMSO3.5mL，氮气保护下，75℃搅拌反应12h。反应混合物用3mL水淬灭，用氯仿萃取两次，每次20mL，合并有机相，依次用10％NaOH、水、饱和盐水洗涤，Na2SO4干燥。蒸去溶剂，残留物柱层析(硅胶，EtOAc/DCM:1/12)，得到白色固体产物17Z-(1-羟基-2-氧代-1-亚乙基)-4-雄甾-3,11-烯二酮(2b)0.946mg，产率92％:mp190-192℃(EtOAc/Hexanes):188-192℃)；1H-NMR(CDCl3,ppm):δ9.595(d,J＝0.9Hz,1H),5.740(s,1H),5.630(d,J＝0.9Hz,1H),3.250(d,J＝13.2Hz,1H),1.432(s,3H),0.978(s,3H)；1H-NMR(CDCl3+D2O,ppm):δ9.592(s,1H),5.746(s,1H),3.248(d,J＝13.2Hz,1H),1.432(s,3H),0.979(s,3H)；13CNMR(CD3Cl,ppm):δ208.65,199.51,185.71,168.29,142.76,142.16,124.51,63.11,53.96,53.11,48.53,38.16,35.40,34.62,33.57,32.09,31.98,25.24,24.48,17.07,16.73.IR(KBr)ν3432,2940,2829,1706,1665,1638,1580,1332,1230cm-1；MS(EI):343(M+1,64％)；Anal.Calcd.for C21H26O4:C,73.66；H,7.65；Found C,73.80；H,7.66.HRMS(ESI-TOF):calcdfor(C21H26O4+H)+343.1909,found 343.1897。
实施例3 17Z-(1-羟基-2-氧代-1-亚乙基)-11-羟基-4-雄甾-3-烯酮(2c)
取化合物1a 1.089g(3mmol)、邻碘苯甲酸0.93g(3.75mmol)、过硫酸氢钾2.30g(3.75mmol)，加入DMSO3.5mL，氮气保护下，75℃搅拌反应12h。反应混合物用3mL水淬灭，用氯仿萃取两次，每次20mL，合并有机相，依次用10％NaOH、水、饱和盐水洗涤，Na2SO4干燥。蒸去溶剂，残留物柱层析(硅胶，EtOAc/DCM:1/12)，得到白色固体产物17Z-(1-羟基-2-氧代-1-亚乙基)-11-羟基-4-雄甾-3-烯酮(2c)952mg，产率92％:mp 168-170℃(EtOAc/hexanes):166–170℃)；1H-NMR(CDCl3,ppm):δ9.567(s,1H),5.697(s,1H),5.661(s,1H),4.443(m,1H),1.477(s,3H),1.265(s,3H)；1H-NMR(CDCl3+D2O,ppm):δ9.567(s,1H),5.697(s,1H),4.443(m,H),1.477(s,3H),1.265(s,3H)；13C-NMR(CDCl3,ppm):δ199.52,186.09,170.87,147.02,141.83,123.92,54.02,53.64,46.13,38.58,35.59,34.99,34.76,33.88,32.68,31.87,25.15,24.80,20.90,17.26,15.44..IR(KBr)ν3435,2944,1663,1638,1584,1338,1233 cm-1；MS(EI):345(M+1,55％)；Anal.Calcd.for C21H28O4:C,73.23；H,8.19；Found C,73.18；H,8.22.HRMS(ESI-TOF):calcd for(C21H28O4+H)+345.2066,found345.2059。

Claims (1)

1.一种17Z -(1-羟基-2-氧代-1-亚乙基)雄甾烯酮衍生物的合成方法，其特征在于包括如下步骤：
将催化剂邻碘苯甲酸和氧化剂过硫酸氢钾以及化合物1a-c混合，加入溶剂DMSO，经混合搅拌反应，淬灭反应，再经萃取、洗涤、干燥、蒸去溶剂、柱层析，得到目标化合物17Z -(1-羟基-2-氧代-1-亚乙基)雄甾烯酮衍生物；所述步骤的反应温度为75℃，反应时间为12h，产率为89%-92%；
a: X = H, Y = H; b: X,Y = O; c: X = OH, Y = H。
CN201610654023.3A 2016-08-10 2016-08-10 17z‑(1‑羟基‑2‑氧代‑1‑亚乙基)雄甾烯酮衍生物的合成方法 Expired - Fee Related CN106279327B (zh)

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