CN102532236B - 甾体类5α-还原酶抑制剂、其制备方法及其医药用途 - Google Patents
甾体类5α-还原酶抑制剂、其制备方法及其医药用途 Download PDFInfo
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Abstract
本发明涉及药物化学领域,具体涉及通式一至通式三的甾体类5α-还原酶抑制剂、它们的制备方法以及它们的医药用途,这些化合物可以用于治疗主要由二氢睾酮引起的多种人类内分泌疾病,如良性前列腺增生、前列腺癌、脱发、粉刺、女性多毛症等。通式一:通式二:通式三:
Description
技术领域
本发明涉及药物化学和有机化学领域一系列甾体类5α-还原酶抑制剂。这些化合物可以用于治疗主要由二氢睾酮(Dihydrotestosterone,DHT)引起的多种人类内分泌疾病,如良性前列腺增生(Benign prostate hyperplasia,BPH)、前列腺癌、脱发、粉刺、女性多毛症。
背景技术
5α-还原酶是一个由254个氨基酸组成的多肽,是依赖NADPH辅助因子的膜结合酶,在雄激素敏感组织中都有分布。现已发现5α-还原酶有两种亚型,即αI、αII两种同功酶,它们分别由不同基因编码。αI型常见于肝脏、肾脏、脑、肺、皮肤等组织中;αII型则多分布在前列腺、精囊、附睾中。最新研究表明,在人前列腺组织中αI型和αII型酶都有表达,这两者在将睾酮转化为活性更强的二氢睾酮(DHT)中起到了关键作用。
二氢睾酮(DHT)的形成同很多人类内分泌疾病有关,如良性前列腺增生(BPH)、前列腺癌、脱发、粉刺、女性多毛症。BPH在老年男性中的发病率很高,50岁以上发病率近30%,80岁以上高达80%。人们期望通过对5α-还原酶抑制剂的研究,实现治疗BPH及其它与5α-还原酶相关疾病的新突破。
经典的甾体类5α-还原酶抑制剂共分3-烯酸类、氮杂类甾体和孕酮类三类。非那甾胺(Finasteride,商品名:Proscar,保列治)是首个上市的5α-还原酶抑制剂,属于4-氮杂类甾体化合物,于1988年经FDA批准用于治疗BPH。目前,已有多种5α-还原酶抑制剂进入临床研究或已上市。爱普列特(Epristeride)是一种3-烯酸类5α-还原酶抑制剂,其在美国、英国、意大利、日本、西班牙等国均进入三期临床研究。国内由中国药科大学、上海有机所、扬州制药厂合作攻关,按一类新药的研究要求通过新药审评,已于1998年投产上市。
本发明在基于甾体类5α-还原酶抑制剂的经典结构、作用机理和大量实验的基础上,对三类典型性的甾体类5α-还原酶抑制剂进行结构改造和优化,设计出一批结构新颖的甾体类5α-还原酶抑制剂,并通过药理实验,证明了其中一些化合物具有良好的5α-还原酶抑制活性。
发明内容
本发明公开了一系列通式一至通式三的甾体类5α-还原酶抑制剂化合物及其药学上可接受的盐。经药理实验证明该类化合物具有良好的5α-还原酶抑制活性。
本发明的化合物结构式如下:
通式一:
本通式结构基于对孕酮类5α-还原酶抑制剂的改造。
其中R1、R2各自独立表示H、C1~C6的直链烷基或支链烷基、环烷基、苯基、取代苯基、多取代苯、苯代烷基、取代苯代烷基;
或R1、R2连接成五至六原子的闭合环;
R3表示O、NOH;
Y表示CH2、C=CH2、C=CHOH。
当R3为NOH、Y为CH2时,为3-肟基-雄甾-4-烯-17β-酰胺类5α-还原酶抑制剂(I);
当R3为O、Y为C=CH2时,为2-亚甲基-雄甾-4-烯-17β-酰胺类5α-还原酶抑制剂(II);
当R3为O、Y为C=CHOH时,为2-羟亚甲基-雄甾-4-烯-17β-酰胺类5α-还原酶抑制剂(III)。
通式二:
本通式结构基于对氮杂类5α-还原酶抑制剂的改造,为4-氧杂-雄甾-3-酮-17β-酰胺类5α-还原酶抑制剂(IV)。
其中R1、R2各自独立表示H、C1~C6的直链烷基或支链烷基、环烷基、苯基、取代苯基、多取代苯、苯代烷基、取代苯代烷基;
或R1、R2连接成五至六原子的闭合环。
通式三:
本通式结构基于对3-烯酸类5α-还原酶抑制剂的改造。
其中R3表示COOH、四氮唑。
当R3表示COOH时,为雄甾-3,5-二烯-3-羧酸-17β-酰胺类5α-还原酶抑制剂(V);
R1、R2各自独立表示H、苯基、取代苯基、多取代苯、苯代烷基、取代苯代烷基;
当R3表示四氮唑时,为雄甾-3,5-二烯-3-四氮唑-17β-酰胺类5α-还原酶抑制剂(VI);R1、R2各自独立表示H、C1~C6的直链烷基或支链烷基。
本发明进一步涉及通式一至通式三的化合物与药学上可接受的载体组成的药用组合物。
药理实验显示,本系列发明化合物有不同程度的5α-还原酶抑制作用,部分化合物抑制活性与爱普列特相当,甚至更强。
本发明通式一至通式三所包含的I~VI类化合物可以用下列方法制备:
I:3-肟基-雄甾-4-烯-17β-酰胺类的合成
II~III:2-羟亚甲基-雄甾-4-烯-17β-酰胺类及2-亚甲基-雄甾-4-烯-17β-酰胺类的合成
IV:4-氧杂-雄甾-3-酮-17β-酰胺类的合成
V~VI:雄甾-3,5-二烯-3-羧酸-17β-酰胺类及雄甾-3,5-二烯-3-四氮唑-17β-酰胺类的合成
本发明的部分化合物的结构如下:
I:3-肟基-雄甾-4-烯-17β-酰胺类
II:2-羟亚甲基-雄甾-4-烯-17β-酰胺类
III:2-亚甲基-雄甾-4-烯-17β-酰胺类
IV:4-氧杂-雄甾-3-酮-17β-酰胺类
V~VI:雄甾-3,5-二烯-3-羧酸-17β-酰胺类及雄甾-3,5-二烯-3-四氮唑-17β-酰胺类
药理实验及实施例中化合物的代号等同于以上代号所对应的化合物结构。
下面是本发明部分化合物的部分药理学试验及结果:
1.实验材料
睾酮T(上海久邦化学有限公司产品,批号:0602801)用无水乙醇(AR)溶解稀释至20μmol/L;
还原性辅酶NADPH(南京大治生物有限公司产品,批号:621706)用Tris缓冲液配至6mmol/L;
酶反应缓冲液(buffer):Tris-HCl(10mmol/L)EDTA(1.5mmol/L)MgCl2(5mmol/L)β-巯基乙醇(15mmol/L)[酶反应缓冲液配制方法:Tris 1211.4mg,EDTA-Na2 18mg,MgCl2·6H2O 1024mg,β-巯基乙醇40mg,NaCl 2.92g,蔗糖45g,加三蒸水至1000ml(用盐酸调pH至7.0)]。
对照药爱普列特由本实验室合成。
受试样品由均以DMSO配制成1×10-2mol/L的母液,根据需要用磷酸缓冲液(PBS)稀释至所需浓度。
2.实验仪器
组织分散器(T25,ultra-turrax,德国);752紫外分光光度计(Mode 752c,上海第三分析仪器厂);Sovell高速低温离心机(Mode ST21,美国索福公司);Beckman超速低温离心机;旋涡混合器(MVS-1,北京北德科学器材有限公司);数显恒温水浴锅(HH-4,常州国华电器有限公司);电子天平(BS210S,北京赛多利斯有限公司).
3.试验方法
3.1.甾体5α-还原酶的制备
取3只雌性SD大鼠(体重300g左右),禁食一夜后取肝脏,静脉灌流并浸入PBS液中,洗净后每份1g左右,在冰台上剪碎(3mm大小),加10倍体积的PBS液,冰浴中用ULTRA-TURRAX匀浆机以12,000g/min匀浆三次,每次5秒,间隔30秒。操作过程中应保持低温,所用试剂和用品也须低温。将匀浆液用高速离心机10,000g×30min离心,取上清液(小心),得线粒体后上清液。将线粒体后上清液用超速离心机100,000g×1h离心,倒掉上清,将沉淀重悬于PBS(含30%甘油,1∶3v/v),得微粒体悬浊液。置于-80℃冰箱保存备用,如此可保存一个月。
3.2.酶活性的测定
5α-还原酶催化睾酮转变为二氢睾酮过程中需要辅酶NADPH的参与。还原型NADPH在340nm处有特征吸收,随着反应的进行NADPH将转变为氧化型NADP+,其340nm波长处的特征吸收消失。根据反应过程中NADPH在340nm波长处的特征吸收变化,可筛选5α-还原酶的抑制剂。
空白对照的测定:反应管中加入Buffer 1.660ml,睾酮100μl,PBS 200μl,NADPH 20μl,最后加入20μl酶,混合后测定A340nm值,37℃孵育,反应6min后测定A340nm值。扣除NADPH空白对照下降本底值,测出空白下降值(ΔA0)。在实验开始和结束时各重复三次。
抑制剂的测定:反应管中加入Buffer 1.660ml,睾酮100μl,抑制剂(终浓度为10-6mol/L,如果抑制率>50%,则向下稀释)200μl,NADPH 20μl,最后加入20μl酶,混合后测定A340nm值,37℃孵育,反应10min后测定A340nm值。扣除NADPH空白对照下降本底值,测出抑制剂下降值(ΔAn)。以爱普列特为阳性药,计算酶的抑制率。
计算公式:I(%)=(ΔA0-ΔAn)/ΔA0×100%
结果判断,如果在10-6mol/L浓度下受试样品的抑制率>50%,可认为受试样品具有较强的5α-还原酶抑制活性,可进行下一步的筛选,则受试样品浓度稀释10倍,再次进行抑制活性的测定,依此类推。
3.3.数据统计
结果显示,各受试化合物均有不同程度的5α-还原酶抑制活性。
Table.1 The inhibition Rate of Compounds to Rat Liver Microsomal 5α-Reductase
3.4.构效关系分析
活性测试显示I类化合物中,I 15具有较强的5α-还原酶抑制活性,I 21抑制活性最差,表明17β-酰胺的结构对活性非常重要。从I 12、I 13、I 14、I 15数据知,Z式构象的活性要略好于E式构象的化合物。另外可以看出,17β-酰胺的不同对活性影响很大。
第二个系列9个化合物均显示出一定的抑制活性,II3、II5、II6、II8表现出同爱普列特相近的抑制活性。测试结果说明在2位引入羟亚甲基后对活性具有相当的改善。酰胺的氨基为叔胺和仲胺时,活性相近。
第三个系列对7个化合物进行了活性测试,均显示出一定的抑制活性,III1表现出同爱普列特相近的抑制活性。
第四个系列对21个化合物进行了活性测试,均显示出一定的抑制活性,IV6、IV7、IV9、IV12、IV16表现出较强的抑制活性。说明六元疏水的酰胺侧链对于活性提高有帮助。
第五个系列对11个化合物进行了活性测试,均显示出一定的抑制活性,V1、V7、V8、V9、V10表现出比爱普列特更强的抑制活性。测试结果说明苯甲酰胺的邻位有吸电子基取代对活性提高有很大帮助。VI1的活性非常一般。推测可能因为四氮唑的位阻过大影响了同5α-还原酶的结合,造成了活性下降。进一步的研究还在进行中。
3.5结论
药理实验显示,本发明化合物可明显抑制5α-还原酶的体外活性,部分化合物抑制活性优于阳性对照爱普列特。本化合物可用于治疗BPH、前列腺癌等疾病。
本发明进一步涉及通式一至通式三的化合物与药学上可接受的载体组成的药用组合物。
本发明化合物可以单独或与一种或一种以上的药学上可以接受的载体组合制成制剂以供给药。可以用口服剂型给药,如普通片剂和胶囊、缓释片剂和胶囊、控释片剂和胶囊、滴丸、可分散粉末、颗粒剂等;也可制备成注射制剂。这些药用制剂中可以含有与载体组合的例如0.05%至90%重量的活性成分,更常见约15%至60%之间重量的活性成分。本发明化合物剂量可以是0.001~100mg/kg/天,也可根据疾病程度的不同或剂型的不同偏离此剂量范围。
具体实施方式(所述实施例只是用来说明本发明,而不是用来限定本发明)
部分化合物的制备实例如下:
熔点用XT4型显微熔点测定仪;核磁共振氢谱仪为Bruker AV 500型(TMS为内标);质谱仪为岛津GCMS-QP2010型质谱仪或Mariner质谱仪;红外光谱仪为Nicolet Impact 410型(KBr压片);元素分析仪为Elementar Vario EL III。
实施例1
17β-羧酸-雄甾-4-烯-3-酮(162)的制备
将雄甾-4-烯-3-酮-17β-羧酸甲酯(161,3.3g,10mmol)溶于40mL乙醇中,加入40%KOH(1.5mL)溶液,回流3h,冷却,蒸除大部分乙醇,将其倾入300mL碎冰水中,过滤得白色固体162(2.6g,82%)。m.p.239~243℃(文献m.p.245~248℃[1]);ESI-MS m/z:317.2[M+H] +
实施例2
17β-(N-叔丁基氨基甲酰)-雄甾-4-烯-3-酮(163-1)的制备
将162(6.0g,18.99mmol)溶于120mL甲苯中,冰浴下加入无水吡啶(2.1mL)和草酰氯(2.4mL),冰浴下搅拌1h,再在室温下搅拌1h,加入叔丁胺(10.0mL),反应2h,浓缩除去大部分溶剂,加入40mL CH2Cl2、10%H2SO4、H2O各洗3次,无水Na2SO4干燥,浓干得淡黄色固体163-1(6.4g,91%)。1H NMR(d6-DMSO,300MHz)δ:6.81(s,1H,N-H),5.62(s,1H,4-H),1.24(s,9H,t-Bu),1.14(s,3H,19-CH3),0.61(s,3H,18-CH3);IR(KBr)v:3441,1674,1622,1500,1450cm-1.
实施例3
17β-(N-叔丁基氨基甲酰)-雄甾-4-烯-3-酮肟(I 1,I 2)的制备
163-1(0.46g,1.2mmol)溶于12mL甲醇中,搅拌使溶,加入无水吡啶(3.3mL),盐酸羟胺(0.15g,2.2mmol),加热回流1h,冷却浓缩除去大部分溶剂,将其倾入到100mL碎冰水中,剧烈搅拌,过滤得白色固体,柱层析,用石油醚/乙酸乙酯=3∶1展开,得白色固体I 1(0.19g,50%),白色固体I 2(0.038g,10%)。Data for I 1:m.p.166~169℃;1H NMR(d6-DMSO,300MHz)δ:10.42(s,1H,N-OH),6.79(brs,1H,NH),5.69(d,1H,J=0.78Hz,4-H),1.24(s,9H,t-Bu),1.00(s,3H,19-CH3),0.59(s,3H,18-CH3);IR(KBr)v:3423,1641,1452cm-1;ESI-MS m/z:387.3[M+H]+;Anal.calcd for C24H38N2O2·1/4H2O:C 73.75,H 9.80,N 7.17;Found C 73.86,H 9.56,N 7.10.Data for I 2:m.p.191~194℃;1H NMR(d6-DMSO,300MHz)δ:10.16(s,1H,N-OH),6.79(brs,1H,NH),6.33(s,1H,4-H),1.24(s,9H,t-Bu),1.05(s,3H,19-CH3),0.60(s,3H,18-CH3);ESI-MS m/z:387.2[M+H]+;Anal.calcd for C24H38N2O2·1/4H2O:C 73.75,H 9.80,N 7.17;Found:C 73.88,H 9.54,N 7.09.
实施例4
17β-(N,N-二乙基氨基甲酰)-雄甾-4-烯-3-酮肟的制备(I 3,I 4)
具体操作同实施例3,投入163-2 0.74g,柱层析,用石油醚/乙酸乙酯=3∶1展开,得淡黄色固体I 3(0.46g,60%),淡黄色固体I 4(0.16g,15%)。Data for I 3:m.p.136~140℃;1HNMR(d6-DMSO,300MHz)δ:10.43(s,1H,N-OH),5.70(s,1H,4-H),3.57~3.54(m,2H,N-CH2),2.96~2.89(m,2H,N-CH2),1.05(t,3H,J=6.90Hz,N-CH2-CH3),0.99(t,3H,J=7.10Hz,N-CH2-CH3),0.97(s,3H,19-CH3),0.66(s,3H,18-CH3);IR(KBr)v:3314,1620,1448,970cm-1;ESI-MS m/z:387.2[M+H]+;Anal.calcd for C24H38N2O2:C 74.61,H 9.84,N 7.25;Found:C 74.24,H 9.68,N 7.16.Data for I 4:m.p.192~195℃;1H NMR(d6-DMSO,300MHz)δ:10.19(s,1H,N-OH),6.33(s,1H,4-H),3.60~3.52(m,2H,N-CH2),3.16~2.92(m,2H,N-CH2),1.01(s,3H,19-CH3),0.65(s,3H,18-CH3);Anal.calcd for C24H38N2O2:C 74.61,H 9.84,N 7.25;Found:C 74.24,H 9.68,N 7.16.
实施例5
17β-[N-(2-甲氧基苯基)氨基甲酰]-雄甾-4-烯-3-酮肟(I 5,I 6)的制备
具体操作同实施例3,投入163-30.84g,柱层析,用石油醚/乙酸乙酯=4∶1展开,得淡黄色固体I 5,(0.44g,50%),淡黄色固体I 6,(0.13g,15%)。Data for I 5:m.p.120~122℃; 1H NMR(d6-DMSO,300MHz)δ:10.43(s,1H,N-OH),8.37(s,1H,N-H),7.92(d,1H,J=7.47Hz,Ar-H),7.06~7.00,6.91~6.86(m,3H,Ar-H),5.70(s,1H,4-H),3.82(s,3H,OCH3),1.00(s,3H,19-CH3),0.63(s,3H,18-CH3);IR(KBr)v:3265,1618,1452,943cm-1;ESI-MS m/z:437.3[M+H]+;Anal.calcd for C27H36N2O3·1/4H2O:C 73.55,H 8.29,N 6.36;Found:C 73.35,H 8.18,N 6.18.Data for I 6:m.p.150~152℃;1H NMR(d6-DMSO,300MHz)δ:10.18(s,1H,N-OH),8.37(s,1H,N-H),7.92(d,1H,J=7.56Hz,Ar-H),7.08~7.00(m,2H,Ar-H),6.91~6.86(m,1H,Ar-H),6.34(s,1H,4-H),3.82(s,3H,OCH3),1.05(s,3H,19-CH3),0.66(s,3H,18-CH3);Anal.calcd for C27H36N2O3·1/4H2O:C 73.55,H 8.29,N 6.36;Found:C 73.33,H 8.16,N 6.17.
实施例6
17β-(1-吗啉基甲酰)-雄甾-4-烯-3-酮(163-4)的制备
具体操作同实施例2,得灰白色固体,收率70%。m.p.148~151℃;ESI-MS m/z:386.2[M+H] +
实施例7
17β-(1-吗啉基甲酰)-雄甾-4-烯-3-酮肟(I 7,I 8)的制备
具体操作同实施例3,投入163-4(0.76g),柱层析,用石油醚/乙酸乙酯=3∶1展开,得淡黄色固体I 7(0.44g,55%),淡黄色固体I 8(0.10g,13%)。Data for I 7:m.p.132~136℃;1H NMR(d6-DMSO,300MHz)δ:10.43(s,1H,N-OH),5.96(s,1H,4-H),3.52~3.32(m,8H,吗啉环),1.00(s,3H,19-CH3),0.64(s,3H,18-CH3);IR(KBr)v:3423,3245,1608,1434cm-1;ESI-MS m/z:401.2[M+H]+;Anal.calcd for C24H36N2O3·1H2O:C 68.89,H 9.09,N 6.70;Found:C 68.86,H 8.77,N 6.50.Data for I 8:m.p.210~212℃;1H NMR(d6-DMSO,300MHz)δ:10.44(s,1H,N-OH),6.33(s,1H,4-H),3.53~3.30(m,8H,吗啉环),1.00(s,3H,19-CH3),0.64(s,3H,18-CH3);IR(KBr)v:3448,1631,1433cm-1;ESI-MS m/z:401.2[M+H]+;Anal.calcd for C24H36N2O3·1H2O:C 68.89,H 9.09,N 6.70;Found:C 69.04,H 8.76,N 6.49.
实施例8
17β-(N-环丙基氨基甲酰)-雄甾-4-烯-3-酮(163-5)的制备
具体操作同实施例2,得白色固体,收率72%。m.p.161~164℃;ESI-MS m/z:356.3[M+H]+.
实施例9
17β-(N-环丙基氨基甲酰)-雄甾-4-烯-3-酮肟(I 9)的制备
具体操作同实施例3,投入163-5(0.71g),柱层析,用石油醚/乙酸乙酯=4∶1展开,得白色固体I 9,(0.38g,52%)。m.p.210~212℃;1H NMR(d6-DMSO,300MHz)δ:7.54(d,1H,J=2.34Hz,N-H),5.69(d,1H,J=0.72Hz,4-H),2.88~2.85(m,1H,N-CH),1.00(s,3H,19-CH3),0.59(s,3H,18-CH3);IR(KBr)v:3354,1655,1517,1454cm-1;ESI-MS m/z:371.2[M+H]+;Anal.calcd for C23H34N2O2·1/4H2O:C 73.70,H 9.21,N 7.48;Found:C 73.61,H 9.00,N 7.28.
实施例10
17β-(N-异丁基氨基甲酰)-雄甾-4-烯-3-酮(163-6)的制备
具体操作同实施例2,得白色固体,收率73%。m.p.60~62℃;ESI-MS m/z:372.3[M+H]+.
实施例11
17β-(N-异丁基氨基甲酰)-雄甾-4-烯-3-酮肟(I 10)的制备
具体操作同实施例3,投入163-6(0.74g),柱层析,用石油醚/乙酸乙酯=3∶1展开,得淡黄色固体I 10(0.31g,40%)。m.p.225~228℃;1H NMR(d6-DMSO,300MHz)δ:10.42(s,1H,N-OH),7.18(t,1H,J=7.72Hz,N-H),5.70(s,1H,4-H),3.91~3.84(m,2H,N-CH2),1.05(d,3H,J=2.81Hz,CH-CH3),1.02(d,3H,J=2.74Hz,CH-CH3),1.00(s,3H,19-CH3),0.60(s,3H,18-CH3);IR(KBr)v:3230,1641,1522,960cm-1;ESI-MS m/z:371.2[M+H]+;Anal.calcd for C23H36N2O2:C 74.19,H 9.68,N 7.53;Found:C 73.81,H 9.56,N 7.38.
实施例12
17β-[N-(3,5-二三氟甲基苯基)氨基甲酰]-雄甾-4-烯-3-酮肟(I 11)的制备
具体操作同实施例3,投入163-7(0.53g),柱层析,用石油醚/乙酸乙酯=3∶1展开,得 淡黄色固体I 11(0.38g,70%)。m.p.144~147℃;1H NMR(CDCl3,300MHz)δ:8.04(s,2H,Ar-H),7.59(brs,1H,N-H),6.50,5.81(s,共1H,4-H),1.12,1.08(s,共3H,19-CH3),0.81(s,3H,18-CH3);IR(KBr)v:3350,1678,1540,1383cm-1;ESI-MS m/z:543.3[M+H]+;Anal.calcd for C28H32F6N2O2:C 61.99,H 5.90,N 5.16Found:C 61.47,H 5.99,N 4.93.
实施例13
17β-[N-(2,3-二甲基苯基)氨基甲酰]-雄甾-4-烯-3-酮(163-8)的制备
具体操作参照化合物163-1的合成,黄色固体,收率60%。
Data for 163-8:1H NMR(CDCl3,300MHz)δ:7.23~7.03(m,2H,Ar-H),7.07~7.00(m,1H,Ar-H),5.74(s,1H,4-H),2.30(s,3H,3’-CH3),2.15(s,3H,2’-CH3),1.20(s,3H,19-CH3),0.85(s,3H,18-CH3).
实施例14
17β-[N-(2,3-二甲基苯基)氨基甲酰]-雄甾-4-烯-3-酮肟(I 12,I 13)的制备
具体操作同实施例3,投入163-8(0.83g),柱层析,用石油醚/乙酸乙酯=3∶1展开,得淡黄色固体I 12(0.45g,52%),淡黄色固体I 13(0.09g,11%)。Data for I 12:m.p.134~137℃; 1H NMR(d6-DMSO,300MHz)δ:8.97(s,1H,N-H),7.11~6.98(m,3H,Ar-H),5.71(s,1H,4-H),2.20(s,3H,3’-CH3),2.19(s,3H,2’-CH3),1.02(s,3H,19-CH3),0.71(s,3H,18-CH3);ESI-MS m/z:435.3[M+H]+;Anal.calcd for C28H38N2O2·1/4H2O:C 76.60,H 8.78,N 6.39;Found:C 76.19,H 8.55,N 6.44.Data for I 13:m.p.146~149℃;1H NMR(d6-DMSO,300MHz)δ:8.97(s,1H,N-H),7.31~7.28(m,1H,Ar-H),7.13~6.98(m,2H,Ar-H),6.34(s,1H,4-H),2.24(s,3H,3’-CH3),2.07(s,3H,2’-CH3),1.07(s,3H,19-CH3),0.71(s,3H,18-CH3);IR(KBr)v:3421,3288,1668,1516cm-1;Anal.calcd for C28H38N2O2·1/4H2O:C 76.60,H 8.78,N 6.39;Found:C 76.10,H 8.52,N 6.44.
实施例15
17β-(N-环己基氨基甲酰)-雄甾-4-烯-3-酮肟(I 14,I 15)的制备
具体操作同实施例3,投入163-9(0.20g),柱层析,用石油醚/乙酸乙酯=3∶1展开,得白色固体I 14(0.1g,48%),I 15(0.05g,24%)。Data for I 14:m.p.130~133℃;1H NMR(d6-DMSO,300MHz)δ:10.42(s,1H,N-OH),7.15(d,1H,J=7.95Hz,N-H),5.70(s,1H,4-H),3.56~3.29(m,1H,N-CH),1.00(s,3H,19-CH3),0.59(s,3H,18-CH3);IR(KBr)v:3437,1637,1384cm-1;ESI-MS m/z:495.3[M+H]+;Anal.calcd for C26H40N2O2·1H2O:C 72.59,H 9.77,N 6.51;Found:C 72.69,H 9.69,N 6.58.Data for I 15:1H NMR(d6-DMSO,300MHz)δ:10.16(s,1H,N-OH),7.15(d,1H,J=8.22Hz,N-H),6.33(s,1H,4-H),3.56~3.54(m,1H,N-CH),1.08(s,3H,19-CH3),0.59(s,3H,18-CH3);ESI-MS m/z:495.3[M+H]+;Anal.calcd for C26H40N2O2·1H2O:C 72.59,H 9.77,N 6.51;Found:C 72.69,H 9.69,N 6.58.
实施例16
17β-[N-(3,4-二甲氧)苯乙基氨基甲酰]-雄甾-4-烯-3-酮(163-10)的制备
具体操作同实施例2,得淡黄色固体,收率65%。m.p.68~70℃;ESI-MS m/z:480.3[M+H]+.
实施例17
17β-[N-(3,4-二甲氧基)苯乙基氨基甲酰]-雄甾-4-烯-3-酮肟(I 16)的制备
具体操作同实施例3,投入163-10(0.49g),柱层析,用石油醚/乙酸乙酯=3∶1展开,得淡黄色固体I 16(0.23g,47%)。m.p.97~100℃;1H NMR(d6-DMSO 300MHz)δ:6.90~6.72(m,3H,Ar-H),5.92(s,1H,4-H),5.28~5.24(m,1H,N-H),3.86(s,6H,OCH3),3.66~3.55(m,1H,N-CH2),3.51~3.46(m,1H,N-CH2),2.64(t,2H,J=6.99Hz,CH2-Ar),1.07(s,3H,19-CH3),0.68(s,3H,18-CH3);IR(KBr)v:3390,1655,1514cm-1;ESI-MS m/z:495.3[M+H]+;Anal.calcd for C30H42NO4·1H2O :C 70.31,H 8.50,N 5.47;Found:C 70.18,H 8.38,N 4.83.
实施例18
17β-(1-吡咯基甲酰)-雄甾-4-烯-3-酮(163-11)的制备
具体操作同实施例2,得淡黄色固体163-11,收率65%。m.p.183~186℃;ESI-MS m/z:370.2[M+H]+.
实施例19
17β-(1-吡咯基甲酰)-雄甾-4-烯-3-酮肟(I 17)的制备
具体操作同实施例3,投入163-11(0.18g),柱层析,用石油醚/乙酸乙酯=3∶1展开,得淡黄色固体I 17(0.13g,66%)。m.p.197~200℃;1H NMR(d6-DMSO,300MHz)δ:6.90,5.89(s,共1H,4-H),3.59~3.43(m,4H,CH2-N-CH2),1.08(s,3H,19-CH3),0.82(s,3H,18-CH3);IR(KBr)v:3253,3019,1618,1450,970cm-1;ESI-MS m/z:385.4[M+H]+;Anal.calcd for C24H36N2O2:C 75.00,H 9.38,N 7.29;Found:C 74.61,H 9.18,N 7.32.
实施例20
17β-[N-(4-甲基苯基)氨基甲酰]-雄甾-4烯-3-酮(163-12)的制备
具体操作同实施例2,得淡黄色固体,收率70%。1H NMR(CDCl3,300MHz)δ:7.41(d,2H,J=8.31Hz,2’,6’-H),7.14(d,2H,J=8.18Hz,3’,5’-H),6.94(br,1H,N-H),5.77(s,1H,4-H),2.34(s,3H,4’-CH3),1.21(s,3H,19-CH3),0.84(s,3H,18-CH3);IR(KBr)v:3432,1663,1516,1448,815cm-1.
实施例21
17β-[N-(4-甲基苯基)氨基甲酰]-雄甾-4-烯-3-酮肟(I 18)的制备
具体操作同实施例3,投入163-12(0.20g),柱层析,用石油醚/乙酸乙酯=3∶1展开,得淡黄色固体I 18(0.15g,70%)。m.p.134~140℃;1H NMR(CDCl3,300MHz)δ:7.38(d,2H,J=8.36Hz,2’,6’-H),7.11(d,2H,J=8.45Hz,3’,5’-H),6.89(s,1H,N-H),6.51,5.88(s,共1H,4-H),2.30(s,3H,4’-CH3),1.08(s,3H,19-CH3),0.79(s,3H,18-CH3);IR(KBr)v:3417,1664,1517,816cm-1;ESI-MS m/z:421.3[M+H]+;Anal.calcd for C27H36N2O2·1/2H2O:C 75.52,H 8.62,N 6.54;Found:C 75.51,H 8.45,N 6.03.
实施例22
17β-(N-甲基-N-苯基-氨基甲酰)-雄甾-4-烯-3-酮(163-13)制备
具体操作同实施例2,得淡黄色固体163-13,收率70%。1H NMR(CDCl3,300MHz)δ:7.42~7.38(m,2H,Ar-H),7.33~7.28(m,1H,Ar-H),7.14~7.11(m,2H,Ar-H),5.68(s,1H,4-H),3.26(s,3H,N-CH3),1.15(s,3H,19-CH3),0.69(s,3H,18-CH3).
实施例23
17β-(N-甲基-N-苯基-氨基甲酰)-雄甾-4烯-3-酮肟(I 19)的制备
具体操作同实施例3,投入163-13(0.20g),柱层析,用石油醚/乙酸乙酯=4∶1展开,得淡黄色固体I 19(0.15g,72%)。m.p.130~134℃;1H NMR(CDCl3,300MHz)δ:7.39~7.13(m,3H,Ar-H),7.13~7.10(m,2H,Ar-H),6.43,5.77(s,共1H,4-H),3.26(s,3H,N-CH3),1.08,1.03(s,共3H,19-CH3),0.85(s,3H,18-CH3);IR(KBr)v:3418,1651,1494,701cm-1;ESI-MS m/z:421.2[M+H]+;Anal.calcd for C27H36N2O2·1/2H2O:C 75.52,H 8.62,N 6.54;Found:C 75.33,H 8.60,N 6.33.
实施例24
17β-[N-(4-甲氧基苯基)氨基甲酰]-雄甾-4-烯-3-酮肟(I 20)的制备
具体操作同实施例3,投入163-14(0.21g),柱层析,用石油醚/乙酸乙酯=3∶1展开,得淡黄色固体I 20(0.10g,47%)。m.p.225~229℃;1H NMR(d6-DMSO,300MHz)δ:9.34(s,1H,N-H),7.49~7.45(m,2H,Ar-H),6.85(dd,2H,J=6.97and 2.07Hz,Ar-H),5.71(s,1H,4-H),3.71(s,3H,OCH3),1.01(s,3H,19-CH3),0.68(s,3H,18-CH3);IR(KBr)v:3418,1651,1494,701cm-1;ESI-MS m/z:437.3[M+H]+;Anal.calcd for C27H36N2O3·1/4H2O:C 73.55,H 8.29,N 6.36;Found:C 73.64,H 8.20,N 6.33.
实施例25
17β-羧酸-雄甾-4-烯-3-酮肟(I 21)的制备
具体操作同实施例3,投入162(0.16g),柱层析,用石油醚/乙酸乙酯=3∶1展开,得淡黄色固体I 20(0.12g,70%)。m.p.>240℃;1H NMR(d6-DMSO,300MHz)δ:11.82(s,1H, COOH),6.33,5.78(s,共1H,4-H),1.05,1.00(s,共3H,19-CH3),0.66(s,3H,18-CH3);IR(KBr)v:3397,3236,1700,1684cm-1;ESI-MS m/z:332.2[M+H]+;Anal.calcd for C20H29N O3·1/4H2O:C 71.53,H 8.79,N 4.17;Found:C 71.92,H 8.75,N 4.15.
实施例26
17β-(N-叔丁基氨基甲酰)-雄甾-4-烯-3-酮肟醋酯(I 22)的制备
I 1和I 2的混合物(0.39g,1.0mmol)加入无水吡啶(1mL),醋酐(1.5mL),室温反应1h,将其倾入到30mL碎冰水中,剧烈搅拌,过滤得白色固体,丙酮重结晶得白色固体I 22(0.3g,70%)。m.p.72~75℃;1H NMR(CDCl3,300MHz)δ:6.40,6.00(s,共1H,4-H),5.08(s,1H,N-H),2.20(s,3H,NOCOCH3),1.38(s,9H,t-Bu),1.15,1.11(s,共3H,19-CH3),0.75(s,3H,18-CH3);IR(KBr)v:3385,1762,1672,1217cm-1 ESI-MS m/z:429.3[M+H]+;Anal.calcd for C26H40N2O3·1H2O:C 69.96,H 9.42,N 6.28;Found:C 70.43,H 8.92,N 6.55.
实施例27
17β-[N-(4-甲氧基苯基)氨基甲酰]-雄甾-4-烯-3-酮肟醋酯(I 23)的制备
具体操作同实施例27,投入I 20(0.22g),柱层析,用石油醚/乙酸乙酯=4∶1展开,得淡黄色固体I 23(0.18g,75%)。1H NMR(CDCl3,300MHz)δ:7.40(m,2H,Ar-H),6.85(d,2H,J=8.64,Ar-H),6.86~6.43(m,2H,Ar-H),6.39,5.99(s,共1H,4-H),3.79(s,3H,OCH3),2.18(s,3H,NOCOCH3)1.13,1.08(s,共3H,19-CH3),0.80(s,3H,18-CH3);IR(KBr)v:3356,1759,1660,1240cm-1;ESI-MS m/z:479.2[M+H]+;Anal.calcd for C29H38N2O4·1/2H2O:C 71.46,H 8.01,N 5.75;Found:C 71.09,H 7.77,N 5.45.
实施例28
17β-(N,N-二乙基氨基甲酰)-雄甾-4-烯-3-酮肟醋酯(I 24)的制备
具体操作同实施例27,投入I 3,I 4(0.19g),柱层析,用石油醚/乙酸乙酯=4∶1展开,得白色固体I 24(0.16g,77%)。m.p.45~48℃;1H NMR(CDCl3,300MHz)δ:6.40,6.00(s,共1H,4-H),3.73~3.70(m,2H,N-CH2),3.09~3.07(m,2H,N-CH2),2.19(s,3H,COCH3),1.15(t,6H,J=6.90Hz,N-CH2-CH3),1.11(s,3H,19-CH3),0.82(s,3H,18-CH3);IR(KBr)v:3446,1763,633,1213cm-1;ESI-MS m/z:429.3[M+H]+;Anal.calcd for C26H40N2O3·1/2H2O:C 71.40,H 9.38,N 6.41;Found:C 71.62,H 8.92,N 6.23.
实施例29
17β-(N-苯甲氨基甲酰)-雄甾-4-烯-3-酮肟醋酯(I 25)的制备
具体操作同实施例27,投入17β-(N-苯甲氨基甲酰)-雄甾-4-烯-3-酮肟(0.21g),柱层析,用石油醚/乙酸乙酯=5∶1展开,得白色固体I 25(0.17g,76%)。m.p.73~76℃;1HNMR(CDCl3, 300MHz)δ:7.39~7.29(m,5H,Ar-H),6.39,6.00(s,共1H,4-H),5.56(s,1H,N-H),4.53(dd,J=14.63and 5.42Hz,1H,N-CH2),4.43(dd,J=14.56and 5.45Hz,1H,N-CH2),2.20(s,3H,COCH3),1.15,1.10(s,共3H,19-CH3),0.78(s,3H,18-CH3);IR(KBr)v:3415,1761,1655,1204cm-1;ESI-MS m/z:463.4[M+H]+;Anal.calcd for C29H38N2O3·1/2H2O:C 73.88,H 8.28,N 5.94;Found:C 73.86,H 8.03,N 5.86.
实施例30
17β-[N-(4-甲基苯基)氨基甲酰]-雄甾-4-烯-3-酮肟醋酯(I 26)的制备
具体操作同实施例27,投入I 18(0.21g),柱层析,用石油醚/乙酸乙酯=3∶1展开,得白色固体I 26(0.17g,74%)。m.p.194~197℃;1H NMR(CDCl3,300MHz)δ:9.34(s,1H,N-H),7.45(d,2H,J=8.43Hz,Ar-H),7.06(d,2H,J=8.37Hz,Ar-H),2.26(s,3H,COCH3),2.11(s,3H,Ar-CH3),1.05(s,3H,19-CH3),0.68(s,3H,18-CH3);ESI-MS m/z:463.2[M+H]+;Anal.calcd for C29H38N2O2·1/2H2O:C 73.88,H 8.28,N 5.94;Found:C 73.99,H 7.99,N 5.67.
实施例31
17β-[N-(2,3-二甲基苯基)氨基甲酰]-雄甾-4-烯-3-酮肟醋酯(I 27)的制备
具体操作同实施例27,投入I 12,I 13(0.22g)肟基物,柱层析,用石油醚/乙酸乙酯=4∶1展开,得淡黄色固体I 27(0.18g,77%)。m.p.194~197℃;1H NMR(CDCl3,300MHz)δ:8.94(s,1H,N-H),7.11~7.10(m,3H,Ar-H),6.33,5.86(s,1H,4-H),2.24(s,3H,COCH3),2.11(s,3H,3’-CH3),2.07(s,3H,2’-CH3),1.07(s,3H,19-CH3),0.72(s,3H,18-CH3);ESI-MS m/z:477.3[M+H]+.
实施例32
17β-(1-吡咯基甲酰)-雄甾-4-烯-3-酮肟醋酯(I 28,I 29)的制备
具体操作同实施例27,投入I 17(0.38g),柱层析,用石油醚/乙酸乙酯=4∶1展开,得白色固体I 28(0.21g,50%),淡黄色固体I 29(0.16g,37%)。Data for I 28:m.p.172~176℃;1H NMR(d6-DMSO,300MHz)δ:6.32(s,1H,4-H),3.50~3.35(m,4H,CH2-N-CH2),2.11(s,3H,COCH3),1.09(s,3H,19-CH3),0.69(s,3H,18-CH3);IR(KBr)v:3442,1763,1630cm-1;ESI-MS m/z:385.4[M+H]+;Anal.calcd for C24H38N2O3·1/4H2O:C 72.47,H 8.94,N 6.50;Found C 72.36,H 8.71,N 6.43.Data for I 29:m.p.187~190℃;1H NMR(d6-DMSO,300MHz)δ:5.84(s,1H,4-H),3.47~3.32(m,2H,-N-CH2),3.27~3.24(m,2H,-N-CH2),2.11(s,3H,COCH3),1.04(s,3H,19-CH3),0.69(s,3H,18-CH3);ESI-MS m/z:385.4[M+H]+.
实施例33
2-羟亚甲基-17β-甲氧基甲酰基-雄甾-4-烯-3-酮(164)的制备
将雄甾-4-烯-3-酮-17β-羧酸甲酯(161,2.12g,6.4mmol),溶于15mL THF,加入粉末状NaOCH3(2.0g),室温反应30min后,滴加新蒸甲酸乙酯(15mL),1h内滴完,升温到55℃,反应过夜。加入20mL饱和食盐水,乙酸乙酯萃取,无水Na2SO4干燥过夜,浓干,甲醇重结晶,得淡黄色固体164(1.71g,75%)。1H NMR(CDCl3,300MHz)δ:7.39(s,1H,2-CHOH),5.78(s,1H,4-H),3.68(s,3H,OCH3),1.04(s,3H,19-CH3),0.71(s,3H,18-CH3);ESI-MS m/z:357.1[M-H]-;Anal.calcd for C22H32O4·1H2O:C 70.21,H 8.51;Found:C 70.58,H 8.17.
实施例34
2-亚甲基-17β-甲氧基甲酰基-雄甾-4-烯(165)的制备
将164(0.36g,1mmol)溶于8mL丙酮中,加入甲醛溶液(0.33mL),20℃下反应1h,加入Na2CO3(0.33g),剧烈搅拌6h,浓缩至干,加入30mL饱和食盐水,用10%H2SO4调pH=7~6,乙酸乙酯萃取,依次用饱和NaHCO3溶液,饱和NaCl溶液洗涤,无水Na2SO4干燥,浓干得白色固体165(0.25g,72%)。m.p.140~143℃;1H NMR(CDCl3,300MHz)δ:5.93(t,1H,J=2.07Hz,4-H),5.83(s,1H,2=CH2),5.22(s,1H,2=CH2),3.67(s,3H,OCH3),1.23(s,3H,19-CH3),0.70(s,3H,18-CH3);IR(KBr)v:3379,1732,1676,1541,1234cm-1;ESI-MS m/z:357.1[M-H]-;Anal.calcd for C22H30O3·1/4H2O:C 76.19,H 8.80;Found:C 76.54,H 8.65.
实施例35
2-甲基-1,4-雄二烯-17-羧酸甲酯(168)及2-甲基-雄甾-1,4-二烯-17-羧酸(169)的制备
将164(0.3g,0.88mmol)溶于10mL丙酮,加入浓HCl(0.54mL),回流24h,加入饱和食盐水10mL,用饱和Na2CO3调pH=6,乙酸乙酯萃取,10%H2SO4洗涤3次,饱和食盐水洗3次,无水Na2SO4干燥,浓干柱层析,用石油醚/乙酸乙酯=4∶1展开,得白色固体168(20mg,7%),白色固体169(50mg,17%)。Data for 168:m.p.145~148℃;1H NMR(CDCl3,300MHz)δ:6.82(d,1H,J=1.20Hz,1-H),6.06(d,1H,J=1.89Hz,4-H),3.68(s,3H,OCH3),1.87(d,3H,J=1.26Hz,2-CH3),1.19(s,3H,19-CH3),0.73(s,3H,18-CH3);ESI-MS m/z:343.2[M+H]+;Anal.calcd for C22H30O3·1/2H2O:C 75.21,H 8.83;Found:C 75.50,H 8.82.Data for 169:m.p.185~189℃;1H NMR(CDCl3,300MHz)δ:6.84(d,1H,J=1.11Hz,1-H),6.10(d,1H,J=1.89Hz,4-H),1.90(d,3H,J=1.14Hz,2-CH3),1.20(s,3H,19-CH3),0.81(s,3H,18-CH3);ESI-MS m/z:327.1[M-H]-.
实施例36
2-羟亚甲基-17β-(N-叔丁基氨基甲酰)-雄甾-4-烯-3-酮(II1)的制备
具体操作同实施例33,投入163-1(0.37g),得白色固体II1(0.28g,70%)。m.p.82~85℃; 1H NMR(CDCl3,300MHz)δ:7.39(s,1H,2-CHOH),5.78(s,1H,4-H),5.07(s,1H,NH),1.36(s, 9H,t-Bu),1.04(s,3H,19-CH3),0.73(s,3H,18-CH3);IR(KBr)v:3423,1641,1452cm-1;ESI-MS m/z:400.2[M+H]+;Anal.calcd for C25H37N O3·1H2O:C 71.94,H 9.35,N 3.36;Found:C 72.29,H 9.06,N 3.74.
实施例37
17β-(N,N-二丙基氨基甲酰)-雄甾-4-烯-3-酮(163-7)的制备
具体操作同实施例2,得灰色固体,收率77%。m.p.104~107℃;ESI-MS m/z:400.4[M+H]+.
实施例38
2-羟亚甲基-17β-(N,N-二丙基氨基甲酰)-雄甾-4-烯-3-酮(II2)的制备
具体操作同实施例33,投入163-7(0.37g),得白色固体II-2(0.28g,70%)。m.p.91~93℃; 1H NMR(CDCl3,300MHz)δ:7.37(s,1H,2-CHOH),5.78(s,1H,4-H),3.76~3.74(m,2H,N-CH2),3.56~3.54(m,2H,N-CH2),1.04(s,3H,19-CH3),0.79(s,3H,18-CH3);IR(KBr)v:3403,1672,1203,889cm-1;ESI-MS m/z:426.3[M-H]-.Anal.calcd for C27H41NO3·1H2O:C 72.80,H 9.66,N 3.14;Found:C 72.54,H 9.29,N 3.36.
实施例39
2-羟亚甲基-17β-(1-哌啶基氨基甲酰)-雄甾-4-烯-3-酮(II3)的制备
具体操作同实施例33,投入163-15(0.38g),得白色固体II 3(0.30g,72%)。m.p.125~129℃;1H NMR(CDCl3,300MHz)δ:7.39(s,1H,2-CHOH),5.79(s,1H,4-H),3.54~3.48(m,4H,CH2-N-CH2),1.05(s,3H,19-CH3),0.79(s,3H,18-CH3);IR(KBr)v:3432,1637,1432,887cm-1;ESI-MS m/z:332.2[M+H]+;Anal.calcd for C26H37NO3·1/4H2O:C 75.09,H 9.03,N 3.37;Found:C 75.10,H 8.86,N 3.21.
实施例40
17β-(N-环己基氨基甲酰)-雄甾-4-烯-3-酮(163-9)的制备
具体操作同实施例2,得灰色固体,收率71%。1H NMR(CDCl3,300MHz)δ:5.73(s,1H,4-H),5.10(d,1H,J=6.12Hz,NH),3.81~3.80(m,1H,N-CH),1.19(s,3H,19-CH3),0.73(s,3H,18-CH3).
实施例41
2-羟亚甲基-17β-(N-环己基氨基甲酰)-雄甾-4-烯-3-酮(II4)的制备
具体操作同实施例33,投入163-9(0.40g),得白色固体II4(0.31g,74%)。m.p.106~109℃;1H NMR(CDCl3,300MHz)δ:7.38(s,1H,2-CHOH),5.78(s,1H,4-H),5.11(d,1H,J=8.10Hz,NH),3.82~3.80(m,1H,N-CH),1.04(s,3H,19-CH3),0.72(s,3H,18-CH3);IR(KBr)v:3423,1637,1457,1195cm-1;ESI-MS m/z:424.2[M-H]-;Anal.calcd for C27H39NO3·1H2O:C 73.14,H 9.26,N 3.16;Found:C 72.94,H 8.87,N 2.59.
实施例42
2-羟亚甲基-17β-(N,N-二乙基氨基甲酰)-雄甾-4-烯-3-酮(II5)的制备
具体操作同实施例33,投入163-2(0.37g),得白色固体II5(0.28g,71%)。m.p.138~140℃; 1H NMR(CDCl3,300MHz)δ:7.39(s,1H,2-CHOH),5.78(s,1H,4-H),3.69~3.68(m,2H,N-CH2),1.12(t,6H,J=7.07Hz,CH3-CH2-N-CH2-CH3),1.04(s,3H,19-CH3),0.82(s,3H,18-CH3);IR(KBr)v:3374,1668,1618,1452,1203cm-1;ESI-MS m/z:398.3[M-H]-;Anal.calcd for C25H37NO3·1H2O:C 71.94,H 9.35,N 3.36;Found:C 71.77,H 9.22,N 3.26.
实施例43
2-羟亚甲基-17β-[N-(3,4-二甲氧基)苯乙基氨基甲酰]-雄甾-4-烯-3-酮(II6)的制备
具体操作同实施例33,投入163-10(0.48g),得黄色固体II6(0.34g,68%)。m.p.83~85℃; 1H NMR(CDCl3,300MHz)δ:7.39(s,1H,2-CHOH),6.83~6.73(m,3H,Ar-H),5.78(s,1H,4-H),5.27(s,1H,NH),3.87(s,6H,-OCH3),3.59~3.47(m,2H,N-CH2),2.78(t,2H,J=6.85Hz,CH2-Ar),1.01(s,3H,19-CH3),0.69(s,3H,18-CH3);IR(KBr)v:3398,1637,1513,1261,1027cm-1;ESI-MS m/z:508.4[M+H]+;Anal.calcd for C31H41NO5·3/4H2O:C 71.47,H 8.16,N 2.68;Found:C 71.39,H 7.68,N 2.65.
实施例44
2-羟亚甲基-17β-(N-异丁基氨基甲酰)-雄甾-4-烯-3-酮(II7)的制备
具体操作同实施例33,投入163-6(0.37g),得黄色固体II 7(0.28g,69%)。m.p.102~105℃; 1H NMR(CDCl3,300MHz)δ:7.38(s,1H,2-CHOH),5.78~5.73(m,1H,4-H),3.23~3.16(m,2H,N-CH2),1.04(s,3H,19-CH3),0.92(d,6H,J=6.70Hz,CH3-CH-CH3),0.74(s,3H,18-CH3);IR(KBr)v:3423,1654,1135,620cm-1;ESI-MS m/z:400.4[M+H]+;Anal.calcd for C25H37NO3·3/4H2O:C 72.73,H 9.33,N 3.39;Found:C 72.93,H 8.92,N 3.55.
实施例45
2-羟亚甲基-17β-(N-环丙基氨基甲酰)-雄甾-4-烯-3-酮(II 8)的制备
具体操作同实施例33,投入163-5(0.36g),得黄色固体II8(0.27g,70%)。m.p.107~110℃; 1H NMR(CDCl3,300MHz)δ:7.39(s,1H,2-CHOH),5.78(s,1H,4-H),5.37(s,1H,NH),2.71~2.70(m,1H,N-CH),1.04(s,3H,19-CH3),0.72(s,3H,18-CH3);IR(KBr)v:3438,1643,1529cm-1;ESI-MS m/z:384.3[M+H]+;Anal.calcd for C24H33NO3·1H2O:C 71.82,H 8.72,N 3.49;Found:C 72.24,H 8.25,N 3.70.
实施例46
17β-(N-苯甲基氨基甲酰)-雄甾-4-烯-3-酮(163-16)的制备
具体操作同实施例2,白色固体,收率63%。1H NMR(CDCl3,300MHz)δ:7.38~7.25(m,5H,Ar-H),5.73(s,1H,4-H),5.55~5.53(m,1H,NH),4.55~4.50(m,2H,CH2-Ar),1.19(s,3H,19-CH3),0.77(s,3H,18-CH3).
实施例47
2-羟亚甲基-17β-(N-苯甲基氨基甲酰)-雄甾-4-烯-3-酮(II9)的制备
具体操作同实施例33,投入163-16(0.41g),得黄色固体II 9(0.30g,69%)。m.p.176~179℃;1H NMR(CDCl3,300MHz)δ:7.60(s,1H,2-CHOH),7.37~7.26(m,5H,Ar-H),5.78(s,1H,4-H),5.55(brs,1H,NH),4.55~4.39(m,2H,CH2-Ar),1.04(s,3H,19-CH3),0.76(s,3H,18-CH3);IR(KBr)v:3330,1645,1535,1198cm-1;ESI-MS m/z:434.2[M+H]+;Anal.calcd for C28H35NO3·1/2H2O:C 76.01,H 8.14,N 3.17;Found:C 75.56,H 7.91,N 3.61.
实施例48
2-羟亚甲基-17β-[N-(3,5-二三氟甲基苯基)氨基甲酰]-雄甾-4-烯-3-酮(II 10)的制备
具体操作同实施例33,投入163-17(0.53g),得黄色固体II 10(0.39g,71%)。m.p.115~119℃;1H NMR(CDCl3,300MHz)δ:8.03(s,2H,2’,6’-H),7.59(s,1H,4’-H),7.46(s,1H,NH),7.17(s,1H,2-CHOH),5.80(s,1H,4-H),1.06(s,3H,19-CH3),0.83(s,3H,18-CH3);IR(KBr)v:3346,1676,1641,1278,1132cm-1;ESI-MS m/z:556.2[M+H]+.
实施例49
2-亚甲基-17β-(N-叔丁基氨基甲酰)-雄甾-4-烯-3-酮(III 1)的制备
具体操作同实施例34,投入II 1(0.40g),得淡黄色固体III 1(0.25g,65%)。m.p.170~172℃; 1H NMR(CDCl3,300MHz)δ:5.95(t,1H,J=2.13Hz,2=CH2),5.84(s,1H,4-H),5.23(s,1H,2=CH2),5.07(brs,1H,N-H),1.36(s,9H,t-Bu),1.05(s,3H,19-CH3),0.74(s,3H,18-CH3);IR(KBr)v:3423,1611,1452,1195cm-1;ESI-MS m/z:422.1[M+Na]+;Anal.calcd for C25H37NO3·1/4H2O:C 77.41,H 9.68,N 3.61;Found:C 77.53,H 9.45,N 3.54.
实施例50
2-亚甲基-17β-(N,N-二丙基氨基甲酰)-雄甾-4-烯-3-酮(III 2)的制备
具体操作同实施例34,投入II2(0.43g),得淡黄色固体III 2(0.28g,69%)。m.p.59~68℃; 1H NMR(CDCl3,300MHz)δ:5.95(t,1H,J=2.07Hz,2=CH2),5.85(d,1H,J=1.02Hz,4-H),5.23(s,1H,2=CH2),3.37~3.32(m,2H,N-CH2),3.18~3.13(m,2H,N-CH2),1.11(s,3H,19-CH3),0.81(s,3H,18-CH3);ESI-MS m/z:426.3[M-H]-;Anal.calcd for C27H41NO3·1H2O:C 72.80,H 9.66,N 3.15;Found:C 72.42,H 9.04,N 3.41.
实施例51
2-亚甲基-17β-(1-哌啶基氨基甲酰)-雄甾-4-烯-3-酮(III 3)的制备
具体操作同实施例34,投入II3(0.41g),得淡黄色固体III 3(0.28g,70%)。m.p.166~169℃; 1H NMR(CDCl3,300MHz)δ:5.95(t,1H,J=2.07Hz,2=CH2),5.86(s,1H,4-H),5.23(s,1H,2=CH2),3.54(m,4H,CH2-N-CH2),1.12(s,3H,19-CH3),0.80(s,3H,18-CH3);IR(KBr)v:3438,1668,1625,1430cm-1;ESI-MS m/z:396.3[M+H]-;Anal.calcd for C26H37NO2·1/4H2O:C 78.10,H 9.39,N 3.34;Found:C 77.90,H 9.41,N 3.41.
实施例52
2-亚甲基-17β-[N-(3,5-二三氟甲基苯基)氨基甲酰]-雄甾-4-烯-3-酮(III 4)的制备
具体操作同实施例34,投入II 10(0.56g),得淡黄色固体III 4(0.35g,65%)。m.p.107~110℃;1H NMR(CDCl3,300MHz)δ:8.14(s,2H,2’,6’-H),7.77(s,1H,NH),7.59(s,1H,4’-H),5.95(s,1H,2=CH2),5.88(s,1H,4-H),5.27(s,1H,2=CH2),1.13(s,3H,19-CH3),0.82(s,3H,18-CH3);IR(KBr)v:3432,1664,1612,1279,887cm-1;ESI-MS m/z:538.2[M-H]-;Anal.calcd for C29H31F6NO2·1/2H2O:C 63.50,H 5.83,N 2.55;Found:C 63.50,H 5.86,N 2.43.
实施例53
2-亚甲基-17β-(N,N-二乙基氨基甲酰)-雄甾-4-烯-3-酮(III 5)的制备
具体操作同实施例34,投入II 5(0.40g),得淡黄色固体III 5(0.28g,72%)。m.p.117~120℃;1H NMR(CDCl3,300MHz)δ:5.94(t,1H,J=2.07Hz,2=CH2),5.84(s,1H,4-H),5.22(d,1H,J=1.89Hz,2=CH2),3.71~3.68(m,2H,N-CH2),3.09~3.07(m,2H,N-CH2),1.12(t,6H,J=7.07Hz,CH3-CH2-N-CH2-CH3),1.08(s,3H,19-CH3),0.81(s,3H,18-CH3);IR(KBr)v:3448,1670,1629,1448,939cm-1;ESI-MS m/z:384.3[M+H]+;Anal.calcd for C25H37NO2·1/2H2O:C 76.53,H 9.69,N 3.49;Found:C 76.25,H 9.07,N 3.35.
实施例54
2-亚甲基-17β-[N-(3,4-二甲氧基)苯乙基氨基甲酰]-雄甾-4-烯-3-酮(III 6)的制备
具体操作同实施例34,投入II6(0.51g),得黄色固体III 6(0.33g,68%)。m.p.69~72℃;1H NMR(CDCl3,300MHz)δ:6.82~6.80(m,1H,Ar-H),6.74~6.73(m,2H,Ar-H),5.94(t,1H,J=2.01Hz,2=CH2),5.83(s,1H,4-H),5.23(s,1H,2=CH2),3.59~3.57(m,1H,N-CH2),3.49~3.48(m,1H,N-CH2),2.78(t,2H,J=6.80Hz,CH2-Ar),1.09(s,3H,19-CH3),0.69(s,3H,18-CH3);IR(KBr)v:3408,1664,1515,1236cm-1;ESI-MS m/z:530.2[M+H]+;Anal.calcd for C31H41NO4·5/4H2O:C 73.73,H 8.62,N 2.78;Found:C 73.80,H 8.05,N 2.71.
实施例55
2-亚甲基-17β-(N-环丙基氨基甲酰)-雄甾-4-烯-3-酮(III 7)的制备
具体操作同实施例34,投入II8(0.38g),得淡黄色固体III 7(0.24g,65%)。m.p.116~119℃; 1H NMR(CDCl3,300MHz)δ:5.94(t,1H,J=2.18Hz,2=CH2),5.84(s,1H,4-H),5.39(brs,1H,NH),5.23(s,1H,2=CH2),2.71~2.67(m,1H,N-CH),1.10(s,3H,19-CH3),0.73(s,3H,18-CH3);IR(KBr)v:3429,1662,1527,1253cm-1;ESI-MS m/z:368.3[M+H]+;Anal.calcd for C24H33NO2·1/2H2O:C 76.59,H 9.04,N 3.72;Found:C 76.43,H 8.36,N 3.63.
实施例56
2-亚甲基-17β-(N-甲基-N-苯基-氨基甲酰)-雄甾-4-烯-3-酮(III 8)的合成
具体操作同实施例34,投入2-羟亚甲基-17β-(N-甲基N-苯基-氨基甲酰)-雄甾-4-烯-3-酮(0.43g),得淡黄色固体III 8(0.26g,62%)。m.p.176~179℃;1H NMR(CDCl3,300MHz)δ:7.42~7.37(m,2H,Ar-H),7.33~7.29(m,1H,Ar-H),7.12(d,2H,J=7.47Hz,Ar-H),5.92(s,1H,2=CH2),5.79(s,1H,4-H),5.19(s,1H,2=CH2),3.27(s,3H,N-CH3),1.07(s,3H,19-CH3),0.87(s,3H,18-CH3);IR(KBr)v:3440,1666,1649,1378,704cm-1;ESI-MS m/z:418.3[M+H]+;Anal.calcd for C28H35NO2:C 80.57,H 8.39N 3.36;Found:C 80.23,H 8.05,N 3.25.
实施例57
17β-羧酸甲酯-5-羰基-A-失碳-3,5-开裂-雄甾-3-酸(173)的制备
机械搅拌下,将161(3.3g)溶于65.0mL叔丁醇中,加入28%K2CO3水溶液10mL,升温至60℃,滴加60mL含NaIO4(10g)、KMnO4(0.20g)的水溶液,30min内加完,反应1~1.5h,冷却至室温,抽滤,滤饼用叔丁醇(8mL×3)洗涤,滤液在减压下蒸除叔丁醇,蒸至剩余40mL左右时,冷却,用6mol/L的盐酸溶液调pH=2,析出大量固体,用乙酸乙酯萃取(14mL×3),用10%NaHSO3(20mL×3),饱和食盐水洗涤(20mL×3),无水NaSO4干燥过夜。减压蒸干溶剂,得到白色固体,用丙酮重结晶(大约用130mL),活性炭脱色,过滤,冷至室温,放冰箱静置,析出白色晶体173(2.68g,76.6%)。m.p.156~161℃;ESI-MS m/z:351.1[M+H]+.
实施例58
4-氧杂-17β-羧酸甲酯-雄甾-3-酮(174)的制备
173(6.8g,19.4mmol)加入到30mL无水甲醇和40mL新蒸THF中,室温下加入NaBH4(1.4g,36.8mmol),反应5h,浓缩除去大部分溶剂,加入50mL饱和食盐水,用10%H2SO4调pH=3~4,搅拌30min,乙酸乙酯萃取,饱和食盐水洗涤3次,无水Na2SO4干燥,浓干后加入丙酮10mL,加热震荡,放入冰箱过夜,析出白色固体174(5.5g,84.7%)。1H NMR(CDCl3,300MHz)δ:4.16(m,0.15H,5β-H),3.95(dd,0.85H,J=11.95and 4.32Hz,5α-H),3.67(s, 3H,OCH3),1.00,0.94(s,3H,19-CH3),0.67(s,3H,18-CH3);Anal.calcd for C20H30O4:C 71.86,H 8.98;Found:C 71.94,H 8.72.
实施例59
17β-羧酸-5-羰基-A-失碳-3,5-开裂-雄甾-3-酸(176)的制备
具体操作同实施例57,投入162(0.63g),得白色固体176(0.44g,65%)。ESI-MS m/z:337.2[M+H]+.
实施例60
4-氧杂-17β-羧酸甲酯-雄甾-3-酮(175)的制备
将174(2.0g,5.99mmol)溶于50mL乙醇中,加入40%NaOH溶液2.2mL,回流1h,浓除大部分溶剂,倾入200mL碎冰水中,用10%H2SO4调pH=3~4,放置1h,过滤,得白色固体175(1.32g,69%)。1H NMR(CDCl3,300MHz)δ:4.16~4.15(m,0.15H,5β-H),3.96(dd,0.85H,J=11.96and 4.27Hz,5α-H),1.00,0.94(s,共3H,19-CH3),0.74(s,3H,18-CH3);IR(KBr)v:3429,1738,1724,1450,1160cm-1;ESI-MS m/z:319.2[M-H]-.
实施例61
17β-(N-环丙基氨基甲酰)-5-羰基-A-失碳-3,5-开裂-雄甾-3-酸(177-1)的制备
具体操作同实施例57,投入163-5(0.71g),得白色固体177-1(0.45g,60%)。
实施例62
4-氧杂-17β-(N-环丙基氨基甲酰)-雄甾-3-酮(IV 1)的制备
具体操作同实施例58,投入177-1(0.38g),柱层析,用石油醚/乙酸乙酯=4∶1展开,得白色固体IV 1(0.25g,70%)。1H NMR(CDCl3,300MHz)δ:5.38(br,1H,NH),4.16(t,0.3H,J=2.54Hz,5β-H),3.95(dd,0.7H,J=11.93and 4.25Hz,5αH),2.70(m,1H,N-CH),0.93(s,3H,19-CH3),0.69(s,3H,18-CH3);ESI-MS m/z:360.2[M+H]+
实施例63
4-氧杂-17β-(N-叔丁基氨基甲酰)-5α-雄甾-3-酮(IV 2)的合成
具体操作同实施例58,投入177-2(0.50g),柱层析,用石油醚/乙酸乙酯=4∶1展开,得白色固体IV 2(0.36g,75%)。m.p.:230-234℃;1H NMR(CDCl3,300MHz)δ:5.1(s,1H,NH),4.0(dd,1H,J=12.00and 4.20Hz,5α-H),1.4(s,9H,t-Bu),1.0(s,3H,19-CH3),0.6(s,3H,18-CH3)ppm;IR(KBr)v:3445,2967,1732,1390,1013cm-1;EI-MS m/z:375(M+);Anal.calcd for C23H37NO3:C 73.56,H 9.93,N 3.73;Found:C 73.87,H 9.86,N 3.48.
实施例64
4-氧杂-17β-(N,N-二乙基氨基甲酰)-5α-雄甾-3-酮(IV 3)的合成
具体操作同实施例58,投入177-3,柱层析,用石油醚/乙酸乙酯=4∶1展开,得白色固体IV 3(72%)。m.p.:140-145℃;1H NMR(CDCl3,300MHz)δ:4.0(dd,1H,J=11.7and 4.2Hz,5α-H),3.8~3.6(m,2H,N-CH2),3.2~3.0(m,2H,N-CH2),1.13(t,6H,J=6.6Hz,CH3-CH2-N-CH2-CH3),1.0(s,3H,19-CH3),0.8(s,3H,18-CH3)ppm;IR(KBr)v:2970,2848,1730,1487,1050cm-1;EI-MS m/z:375(M+);Anal.calcd for C23H37NO3:C 73.56,H 9.93,N 3.73;Found:C 73.81,H 9.35,N 3.72.
实施例65
4-氧杂-17β-(N,N-二丙基氨基甲酰)-5α-雄甾-3-酮(IV 4)的制备
具体操作同实施例58,投入177-4(0.42g),柱层析,用石油醚/乙酸乙酯=4∶1展开,得白色固体IV 4(0.19g,48%)。1H NMR(CDCl3,300MHz)δ:3.96(dd,1H,J=11.92and 4.15Hz,5α-H),3.81~3.72(m,1H,N-CH2),3.60~3.50(m,1H,N-CH2),3.03~2.93(m,1H,N-CH2),2.84~2.77(m,1H,N-CH2),0.94(s,3H,19-CH3),0.89(t,6H,J=7.34Hz,CH3-CH2-N-CH2-CH3),0.76(s,3H,18-CH3);ESI-MS m/z:404.3[M+H]+.
实施例66
4-氧杂-17β-(N,N-二丁基氨基甲酰)-5α-雄甾-3-酮(IV 5)的合成
具体操作同实施例58,投入177-5,柱层析,用石油醚/乙酸乙酯=4∶1展开,得白色固体IV 5 73%。m.p.:60-65℃;1H NMR(CDCl3,300MHz)δ:3.9(dd,1H,J=11.7and 3.9Hz,5α-H),3.82~3.7(m,2H,N-CH2),3.62~3.5(m,2H,N-CH2),1.0(s,3H,19-CH3),0.7(s,3H,18-CH3)ppm;IR(KBr)v:3481,2972,1742,1478,897cm-1;EI-MS m/z:431(M+);Anal.calcd for C27H45NO3:C 75.13,H 10.51,N 3.24;Found:C 75.52,H 10.65,N 2.987.
实施例67
4-氧杂-17β-(N-环己基氨基甲酰)-雄甾-3-酮(IV6,IV7)的制备
具体操作同实施例58,投入177-6(0.42g),柱层析,用石油醚/乙酸乙酯=5∶1展开,得淡黄色固体IV6(0.044g,11%),淡黄色固体IV7(0.17g,42%)。Data for IV6:m.p.175~178℃; 1H NMR(CDCl3,300MHz)δ:5.16(d,1H,J=7.77Hz,NH),4.16(t,1H,J=2.60Hz,5β-H),3.81(m,1H,N-CH),1.00(s,3H,19-CH3),0.70(s,3H,18-CH3);IR(KBr)v:3437,1724,1645cm-1;ESI-MS m/z:402.3[M+H]+;Anal.calcd for C25H39NO3·1/4H2O:C 73.98,H 9.74,N 3.45;Found:C 74.18,H 9.51,N 3.22.Data for IV7:1H NMR(CDCl3,300MHz)δ:5.12(d,1H,J=7.92Hz,NH),3.95(dd,1H,J=12.00 and 4.22Hz,5α-H),3.81(m,1H,N-CH),0.94(s,3H,19-CH3),0.69(s,3H,18-CH3);IR(KBr)v:3427,1735,1647,1529,1049cm-1;ESI-MS m/z:402.3[M+H]+.
实施例68
4-氧杂-17β-(N,N-二环己基氨基甲酰)-5α-雄甾-3-酮(IV8)的合成
具体操作同实施例58,投入177-8,柱层析,用石油醚/乙酸乙酯=4∶1展开,得白色固体IV8(73%)。m.p.:246-250℃;1H NMR(CDCl3,300MHz)δ:4.0(dd,1H,J=11.76and 3.75Hz,5α-H),3.7(s,1H,N-CH),2.9(s,1H,N-CH),1.0(s,3H,19-CH3),0.8(s,3H,18-CH3)ppm;IR(KBr)v:2969,2820,1734,1231,991cm-1;EI-MS m/z:483(M+);Anal.calcd for C31H49NO3:C 76.97,H 10.21,N 2.90;Found:C 76.62,H 10.40,N 2.63.
实施例69
4-氧杂-17β-(1-哌啶基甲酰)-5α-雄甾-3-酮(IV9)的合成
具体操作同实施例58,投入177-9,柱层析,用石油醚/乙酸乙酯=4∶1展开,得白色固体IV9(68%)。m.p.:140-148℃;1H NMR(CDCl3,300MHz)δ:4.0(dd,1H,J=11.79and 4.02Hz;5α-H),3.55(s,4H,CH2-N-CH2),1.0(s,3H,19-CH3),0.8(s,3H,18-CH3)ppm;IR(KBr)v:2980,2836,1739,1630,1133cm-1;EI-MS m/z:387(M+);Anal.calcd for C24H37NO3:C 74.38,H 9.62,N 3.61;Found:C 74.52,H 9.788,N 3.253.
实施例70
4-氧杂-17β-(1-吗啉基-甲酰)-5α-雄甾-3-酮(IV10)的制备
具体操作同实施例58,投入177-10(0.41g),柱层析,用石油醚/乙酸乙酯=4∶1展开,得白色固体IV10(0.21g,55%)。m.p.161~171℃;1H NMR(CDCl3,300MHz)δ:3.96(dd,1H,J=11.98and 3.97Hz,5α-H),3.65~3.46(m,8H,吗啉环),0.94(s,3H,19-CH3),0.75(s,3H,18-CH3);ESI-MS m/z:390.3[M+H]+;Anal.calcd for C23H35NO4·1/4H2O:C 70.14,H 9.02,N 3.56;Found:C 70.07,H 8.83,N 3.47.
实施例71
4-氧杂-17β-(N-苯基氨基甲酰)-5α-雄甾-3-酮(IV 11)的合成
具体操作同实施例58,投入177-11,柱层析,用石油醚/乙酸乙酯=4∶1展开,,得白色固体IV 11,收率46%。m.p.:208-215℃;1H NMR(CDCl3,300MHz)δ:7.5(d,2H,J=7.92Hz,2’,6’-H),7.3(t,2H,J=7.77Hz,3’,5’-H),7.1(m,1H,4’-H),7.1(s,1H,NH),4.0(dd,1H,J=11.61and 3.63Hz,5α-H),1.0(s,3H,19-CH3),0.8(s,3H,18-CH3)ppm;IR(KBr)v:3322,2969,1736,1440,755cm-1;EI-MS m/z:395(M+);Anal.calcd for C25H33NO3:C 75.91,H 8.41,N 3.54;Found:C 76.31,H 8.87,N 3.28.
实施例72
4-氧杂-17β-(N-甲基苯基氨基甲酰)-5α-雄甾-3-酮(IV 12)的合成
具体操作同实施例58,投入177-12,柱层析,用石油醚/乙酸乙酯=4∶1展开,,得白色固 体IV 12,收率56%。m.p.:90-96℃;1H NMR(CDCl3,300MHz)δ:7.43~7.3(m,3H,3’,4’,5’-H),7.1(d,2H,J=7.2Hz,2’,6’-H),4.1(s,1H,5α-H),3.3(s,3H,N-CH3),1.0(s,3H,19-CH3),0.8(s,3H,18-CH3)ppm;IR(KBr)v:2967,1740,1495,1261,705cm-1;EI-MS m/z:409(M+);Anal.calcd for C26H35NO3:C 76.25,H 8.61,N 3.42;Found:C 75.92,H 8.92,N 3.10.
实施例73
4-氧杂-17β-(N,N-二苯基氨基甲酰)-5α-雄甾-3-酮(IV 13)的合成
具体操作同实施例58,投入177-13,柱层析,用石油醚/乙酸乙酯=4∶1展开,得白色固体IV 13(41%)。m.p.:198-208℃;1H NMR(CDCl3,300MHz)δ:7.34~7.15(m,10H,Ar-H),3.9(dd,1H,J=12.0and 4.2Hz,5α-H),1.0(s,3H,19-CH3),0.8(s,3H,18-CH3)ppm;IR(KBr)v:3061,2939,1731,1397,704cm-1;EI-MS m/z:471(M+);Anal.calcd for C31H37NO3:C 78.95,H 7.91,N 2.97;Found:C 78.57,H 8.03,N 2.91.
实施例74
4-氧杂-17β-(N-苯基-N-苯甲基氨基甲酰)-5α-雄甾-3-酮(IV 14)的制备
具体操作同实施例58,投入177-14(0.50g),柱层析,用石油醚/乙酸乙酯=4∶1展开,得0.30g白色固体IV 14(61%)。m.p.108~111℃;1H NMR(CDCl3,300MHz)δ:7.29~7.24(m,5H,Ar-H),7.22~7.16(m,3H,Ar-H),6.92~6.00(m,2H,Ar-H),4.97(d,1H,J=14.22Hz,CH2-Ph),4.71(d,1H,J=14.16Hz,CH2-Ph),3.84(dd,1H,J=12.02and 4.35Hz,5α-H),0.90(s,3H,19-CH3),0.89(s,3H,18-CH3);IR(KBr)v:3442,1733,1641,1220,1050cm-1;ESI-MS m/z:484.2[M-H]-;Anal.calcd for C32H39NO3·1/4H2O:C 78.45,H 8.07,N 2.86;Found:C 78.46,H 8.00,N 3.00.
实施例75
4-氧杂-17β-(N,N-二苄基氨基甲酰)-5α-雄甾-3-酮(IV 15)的合成
具体操作同实施例58,投入177-15,柱层析,用石油醚/乙酸乙酯=4∶1展开,得白色固体IV 15(65%)。m.p.:74-78℃;1H NMR(CDCl3,300MHz)δ:7.4~7.0(m,10H,Ar-H),5.4(d,2H,J=14.7Hz,N-CH2-Ar),4.9(d,2H,J=10.1Hz,N-CH2-Ar),4.0(dd,1H,J=11.79and 4.02Hz,5α-H),0.9(s,3H,19-CH3),0.8(s,3H,18-CH3)ppm;IR(KBr)v:2941,2846,1736,1494,699cm-1;EI-MS m/z:499(M+);Anal.calcd for C33H41NO3:C 79.32,H 8.27,N 2.80;Found:C 78.93,H 8.324,N 2.429.
实施例76
4-氧杂-17β-[N-(对甲基苯基)氨基甲酰]-5α-雄甾-3-酮(IV 16)的合成
具体操作同实施例58,投入177-16,柱层析,用石油醚/乙酸乙酯=4∶1展开,得白色固 体IV 16(52%)。m.p.:226-230℃;1H NMR(CDCl3,300MHz)δ:7.4(d,2H,J=8.28Hz,2’,6’-H),7.1(d,2H,J=8.16Hz,3’,5’-H),6.9(s,1H,NH),4.0(dd,1H,J=11.79and 3.93Hz,5α-H),2.3(s,3H,Ar-CH3),1.0(s,3H,19-CH3),0.8(s,3H,18-CH3)ppm;IR(KBr)v:3377,2981,1716,1259,815cm-1;EI-MS m/z:409(M+);Anal.calcd for C26H35NO3:C 76.25,H 8.61,N 3.42;Found:C 76.61,H 8.92,N 3.23.
实施例77
4-氧杂-17β-[N-(2,3-二甲基苯基)氨基甲酰]-5α-雄甾-3-酮(IV 17)的制备
具体操作同实施例58,投入177-17(0.44g),柱层析,用石油醚/乙酸乙酯=4∶1展开,得淡黄色固体IV 17(0.23g,53%)。m.p.175~178℃;1H NMR(CDCl3,300MHz)δ:7.56(d,1H,J=7.86Hz,6’-H),7.09(d,1H,J=7.68Hz,Ar-H),6.98(d,1H,J=7.53Hz,Ar-H),3.97(dd,1H,J=11.91and 4.05Hz,5α-H),2.30(s,3H,3’-CH3),2.15(s,3H,2’-CH3),0.95(s,3H,19-CH3),0.81(s,3H,18-CH3);ESI-MS m/z:[M+H]+;Anal.calcd for C27H37NO3·1/2H2O:C 75.00,H 8.80,N 3.24;Found:C 75.17,H 8.49,N 3.03.
实施例78
4-氧杂-17β-[N-(4-甲氧基苯基)氨基甲酰]-雄甾-3-酮(IV 18,IV 19)的制备
具体操作同实施例58,投入177-18(0.44g),柱层析,用石油醚/乙酸乙酯=4∶1展开,得淡黄色固体IV 18(0.064g,15%),淡黄色固体IV 19(0.21g,50%)。Data for IV 18:m.p.114~117℃;1H NMR(CDCl3,300MHz)δ:7.41(d,2H,J=8.97Hz,2’,6’-H),6.98(brs,1H,N-H),6.84(d,2H,J=9.00Hz,3’,5’-H),4.17(m,1H,5β-H),3.79(s,3H,OCH3),1.01(s,3H,19-CH3),0.78(s,3H,18-CH3);IR(KBr)v:3417,1724,1680,1512,1242cm-1;ESI-MS m/z:448.2[M+K]+;Anal.calcd for C26H35NO3·1/4H2O:C 72.64,H 8.27,N 3.26;Found:C 72.52,H 8.00,N 3.08.Data for IV 19:1H NMR(CDCl3,300MHz)δ:7.39(d,2H,J=8.94Hz,2’,6’-H),6.84(d,2H,J=9.00Hz,3’,5’-H),3.97(dd,1H,J=11.91and 4.10Hz,5αH),3.79(s,3H,OCH3),0.94(s,3H,19-CH3),0.77(s,3H,18-CH3).
实施例79
4-氧杂-17β-[N-(2-甲氧基苯基)氨基甲酰]-雄甾-3-酮(IV 20,IV 21)的制备
具体操作同实施例58,投入177-20(0.44g),柱层析,用石油醚/乙酸乙酯=4∶1展开,得淡黄色固体IV 20(0.043g,10%),淡黄色固体IV 21(0.17g,40%)。Data for IV 20:m.p.193~195℃;1H NMR(CDCl3,300MHz)δ:8.39(dd,1H,J=7.78and 1.44Hz,6’-H),7.65(brs,1H,N-H),7.05~6.92(m,2H,3’,4’-H),6.87(dd,1H,J=7.89and 1.51Hz,5’-H),4.17(t,1H,J=2.79Hz,5β-H),3.89(s,3H,OCH3),1.00(s,3H,19-CH3),0.76(s,3H,18-CH3);IR(KBr)v:3431, 1736,1670,1521cm-1;ESI-MS m/z:426.3[M+H]+;Anal.calcd for C26H35NO4:C 73.41,H 8.23,N 3.29Found:C 73.23,H 8.07,N 3.24.Data for IV 21:m.p.200~202℃;1H NMR(CDCl3,300MHz)δ:8.38(dd,1H,J=7.83and 1.64Hz,6’-H),7.65(brs,1H,N-H),7.05~6.92(m,2H,3’,4’-H),6.86(dd,1H,J=7.90and 1.54Hz,5’-H),3.97(dd,1H,J=11.93and 4.18Hz,5αH),3.88(s,3H,OCH3),0.94(s,3H,19-CH3),0.75(s,3H,18-CH3);Anal.calcd for C26H35NO4:C 73.41,H 8.23,N 3.29;Found:C 73.18,H 8.07,N 3.17.
实施例80
4-氧杂-17β-[N-(4-氯苯基)氨基甲酰]-5α-雄甾-3-酮(IV 22,IV 23)的制备
具体操作同实施例58,投入177-22(0.45g),柱层析,用石油醚/乙酸乙酯=4∶1展开,得淡黄色固体IV 22(0.24g,55%),IV 23(0.12g,27%)。Data for IV 22:m.p.193~196℃;1H NMR(CDCl3,300MHz)δ:7.48~7.43(m,2H,2’,6’-H),7.28~7.25(m,2H,3’,5’-H),6.97(s,1H,N-H),3.96(dd,1H,J=11.94and 4.17Hz,5α-H),0.93(s,3H,19-CH3),0.76(s,3H,18-CH3);IR(KBr)v:3430,3356,1710,1686,1525cm-1;ESI-MS m/z:430.2[M+H]+;Anal.calcd for C25H32ClNO3:C 69.85,H 7.46,N 3.26;Found:C 69.41,H 7.63,N 2.91.Data for IV 23:m.p.140~143℃;1H NMR(CDCl3,300MHz)δ:7.50~7.49(m,2H,2’,6’-H),7.29~7.25(m,2H,3’,5’-H),4.18~4.15(m,1H,5β-H),1.00(s,3H,19-CH3),0.75(s,3H,18-CH3);IR(KBr)v:3427,3274,1735,1209cm-1;ESI-MS m/z:430.2[M+H]+.
实施例81
17β-[N-(对氟苯基)氨基甲酰]雄甾-4-烯-3-酮(178)的合成
将162(0.5g,1.58mmol)溶于二氯甲烷6mL中,降温至0℃,加入EDC·HCl(0.36g,1.9mmol),反应30min,将对氟苯胺(0.45mL,4.7mmol)及DMAP(0.23g,1.9mmol)混合溶于二氯甲烷4mL中,滴加入反应之中,滴毕,将反应温度升至室温,反应4h。加水10mL,分出有机层,水层用二氯甲烷萃取三次,合并有机相,用1N盐酸、饱和NaHCO3、饱和NaCl依次各洗涤三次,无水硫酸钠干燥,抽滤,减压旋除溶剂,得白色固体178(0.45g,收率70%)。EI-MS m/z:409(M+).
实施例82
4-氧杂-17β-[N-(对氟苯基)氨基甲酰]-5α-雄甾-3-酮(IV 24)的合成
具体操作同实施例58,投入177-24,柱层析,用石油醚/乙酸乙酯=4∶1展开,得白色固体IV 24(46%)。m.p.:250-254℃;1H NMR(CDCl3,300MHz)δ:7.5(m,2H,2’,6’-H),7.0(t,2H,J=8.7and 8.4Hz,3’,5’-H),7.0(s,1H,NH),4.0(dd,1H,J=14.4and 7.2Hz,5α-H),1.0(s,3H,19-CH3),0.8(s,3H,18-CH3)ppm;IR(KBr)v:3350,2940,1729,1510,975cm-1;EI-MS m/z:413 (M+);Anal.calcd for C25H32FNO3:C 72.61,H 7.80,N 3.39;Found:C 72.55,H 7.92,N 3.26.
实施例83
4-氧杂-17β-{N-[2,5-二(三氟甲基)苯基]氨基甲酰}-5α-雄甾-3-酮(IV 25)的合成
具体操作同实施例58,投入177-25,柱层析,用石油醚/乙酸乙酯=4∶1展开,得白色固体IV 25(40%)。m.p.:212-216℃;1H NMR(CDCl3,300MHz)δ:8.8(s,1H,NH),7.75(d,1H,J=8.10Hz,3’-H),7.5(t,2H,J=9.00and 8.40Hz,4’,6’-H),4.0(dd,1H,J=12.00and 3.95Hz,5α-H),0.9(s,3H,19-CH3),0.8(s,3H,18-CH3)ppm;IR(KBr)v:3455,2937,1741,1468,1132cm-1;EI-MS m/z:531(M+);Anal.calcd for C27H31F6NO3:C 61.01,H 5.88,N 2.64;Found:C 60.80,H 6.27,N 2.49.
实施例84
4-氧杂-17β-[N-(3,5-二三氟甲基苯基)氨基甲酰]-5α-雄甾-3-酮(IV 26)的制备
具体操作同实施例58,投入177-26(0.55g),柱层析,用石油醚/乙酸乙酯=5∶1展开,得白色固体IV 26(0.32g,60%)。m.p.121~124℃;1H NMR(CDCl3,300MHz)δ:8.04(s,2H,2’,6’-H),7.61(s,1H,4’-H),7.24(brs,1H,NH),4.00(dd,1H,J=12.00and 4.20Hz,5α-H),0.97(s,3H,19-CH3),0.81(s,3H,18-CH3);ESI-MS m/z:530.2[M-H]-;Anal.calcd for C27H31F6NO3·1H2O:C 59.01,H 6.01,N 2.55;Found:C 59.03,H 5.85,N 2.40.
实施例85
3-溴-17β-羧酸甲酯-雄甾-3,5二烯(179)的制备
将162(10g,0.032mol)溶于52mL冰醋酸中,室温搅拌溶解,滴加PBr3(4.6mL,0.048mol),反应30min,析出固体。抽滤,冰醋酸洗涤滤饼,红外灯干燥,得白色固体179(7.8g,65%)。m.p.:228-230℃;1H NMR(CDCl3,300MHz)δ:6.3(s,1H,C4-H),5.4(s,1H,C6-H),1.0(s,3H,19-CH3),0.77(s,3H,18-CH3)ppm;ESI-MS m/z:378[M-H]-.
实施例86
3-溴代N-[2,5-二(三氟甲基)苯基]雄甾-3,5-二烯-17β-甲酰胺(180-1)的合成
具体操作同实施例2,得黄色固体180-1(20%)。EI-MS m/z:590(M+).
实施例87
3-氰基-N-[2,5-二(三氟甲基)苯基]雄甾-3,5-二烯-17β-甲酰胺(181-1)的合成
将180-1(0.8g,1.35mmol)溶于15mL DMF中,加入氰化亚铜(0.24g,2.7mmol),升温至180℃反应12h。冷却,抽滤,收集滤液,倾倒入60mL水中,搅拌,静置,抽滤,红外灯干燥,得深黄色固体181-1(0.45g,62%)。ESI-MS m/z:559[M+Na]+.
实施例88
17β-{N-[2,5-二(三氟甲基)苯基]氨基甲酰}雄甾-3,5-二烯-3-羧酸(V 1)的合成
将181-1(0.45g,0.84mmol)溶于10mL乙醇中,加入20%NaOH溶液0.17mL,升温至回流反应6h。冷却,减压旋除溶剂乙醇,将产物溶于10mL水中,2N盐酸调节溶液pH值为2,析出固体,抽滤,红外灯干燥,得黄色固体,柱层析,用石油醚/乙酸乙酯=2∶1展开,得黄色固体V 1(0.2g,43%)。m.p.:280-284℃;1H NMR(DMSO,300MHz)δ:12.0(s,1H,COOH),9.4(s,1H,NH),8.0~7.7(m,3H,Ar-H),6.8(s,1H,C4-H),5.9(s,1H,C6-H),0.9(s,3H,19-CH3),0.8(s,3H,18-CH3)ppm;IR(KBr)v:3434,2930,1725,1384,1097cm-1;ESI-MS m/z:554[M-H]-;Anal.calcd for C29H31F6NO3:C 62.70,H 5.62,N 2.52;Found:C 62.84,H 5.384,N 2.318.
实施例89
17β-{N-[3,5-二(三氟甲基)苯基]氨基甲酰}雄甾-3,5-二烯-3-羧酸(V 2)的合成
具体操作同实施例88,得黄色固体V 2(23%)。m.p.:140-142℃;1H NMR(DMSO,300MHz)δ:10.2(s,1H,COOH),8.4(s,1H,NH),7.73~7.68(m,2H,Ar-H),7.3(s,1H,Ar-H),6.8(s,1H,C4-H),5.7(s,1H,C6-H),0.9(s,3H,19-CH3),0.7(s,3H,18-CH3)ppm;IR(KBr)v:3357,2941,1670,1436,1134cm-1;ESI-MS m/z:554[M-H]-;Anal.calcd for C29H31F6NO3:C 62.70,H 5.62,N 2.52;Found:C 62.95,H 5.298,N 2.309.
实施例90
17β-[N-(2-甲基-4-羧基苯基)氨基甲酰]雄甾-3,5-二烯-3-羧酸(V 3)的合成
具体操作同实施例88,得黄色固体V 3(35%)。m.p.:294-296℃;1H NMR(DMSO,300MHz)δ:9.0(s,1H,NH),7.8~7.6(m,3H,Ar-H),6.9(s,1H,C4-H),5.9(s,1H,C6-H),2.3(s,3H,Ar-H),0.9(s,3H,19-CH3),0.7(s,3H,18-CH3)ppm;IR(KBr)v:3439,2967,2200,1681,1292cm-1;ESI-MS m/z:476[M-H]-;Anal.calcd for C29H35NO5:C 72.93,H 7.39,N 2.93;Found:C 73.27,H 7.71,N 2.54.
实施例91
17β-[N-(4-甲氧基苯基)氨基甲酰]雄甾-3,5-二烯-3-羧酸(V 4)的合成
具体操作同实施例88,得黄色固体V4(24%)。m.p.:194-196℃;1H NMR(DMSO,300MHz)δ:9.4(s,1H,NH),7.5(d,2H,J=8.67Hz,2’,6’-H),6.9(d,2H,J=8.7Hz,3’,5’-H),6.7(s,1H,C4-H),5.7(s,1H,C6-H),3.7(s,3H,O-CH3),0.9(s,3H,19-CH3),0.7(s,3H,18-CH3)ppm;IR(KBr)v:3414,2940,1661,1511,1234cm-1;ESI-MS m/z:450[M+H]+;Anal.calcd for C28H35NO4:C 74.80,H 7.85,N 3.12;Found:C 74.55,H 8.117,N 2.755.
实施例92
17β-[N-(4-氯-3-三氟甲基苯基)氨基甲酰]雄甾-3,5-二烯-3-羧酸(V 5)的合成
具体操作同实施例88,得黄色固体V 5(13%)。m.p.:158-164℃;1H NMR(DMSO,300MHz)δ:10.0(s,1H,COOH),8.2(s,1H,NH),7.9(d,1H,J=8.7Hz,2’-H),7.7(d,1H,J=8.67Hz,5’-H),7.3(m,1H,6’-H),6.7(s,1H,C4-H),5.7(s,1H,C6-H),0.9(s,3H,19-CH3),0.7(s,3H,18-CH3)ppm;IR(KBr)v:3339,2940,1659,1413,1173cm-1;ESI-MS m/z:523[M+H]+;Anal.calcd for C28H31ClF3NO3:C 64.43,H 5.99,N 2.68;Found:C 64.55,H 5.776,N 2.556.
实施例93
17β-[N-(3-三氟甲基苯基)氨基甲酰]雄甾-3,5-二烯-3-羧酸(V 6)的合成
具体操作同实施例88,得黄色固体V 6(17%)。m.p.:140-142℃;1H NMR(DMSO,300MHz)δ:9.9(s,1H,NH),8.1(s,1H,2’-H),7.8(d,1H,J=8.01Hz,6’-H),7.5~7.3(m,2H,4’,5’-H),6.7(s,1H,C4-H),5.7(s,1H,C6-H),0.9(s,3H,19-CH3),0.7(s,3H,18-CH3)ppm;IR(KBr)v:3342,2937,1661,1333,698cm-1;ESI-MS m/z:488[M+H]+;Anal.calcd for C28H32F3NO3:C 68.98,H 6.62,N 2.87;Found:C 68.56,H 7.173,N 2.952.
实施例94
17β-(N-苯基氨基甲酰)雄甾-3,5-二烯-3-羧酸(V 7)的合成
具体操作同实施例88,得黄色固体V 7(24%)。m.p.:138-140℃;1H NMR(DMSO,300MHz)δ:9.5(s,1H,NH),7.6(d,2H,J=7.89Hz,2’,6’-H),7.3(t,2H,J=7.53Hz,3’,5’-H),7.0(t,1H,J=7.26Hz,4’-H),6.7(s,1H,C4-H),5.7(s,1H,C6-H),0.9(s,3H,19-CH3),0.7(s,3H,18-CH3)ppm;IR(KBr)v:3474,2936,1661,1439,753cm-1;ESI-MS m/z:420[M+H]+;Anal.calcd for C27H33NO3:C 77.29,H 7.93,N 3.34;Found:C 77.20,H 7.66,N 3.74.
实施例95
17β-[N-(2-氰基苯基)氨基甲酰]雄甾-3,5-二烯-3-羧酸(V 8)的合成
具体操作同实施例88,得黄色固体V 8(15%)。m.p.:175-180℃;1H NMR(DMSO,300MHz)δ:12.1(s,1H,COOH),11.9(s,1H,NH),8.1(d,1H,J=7.4Hz,6’-H),7.8(m,1H,5’-H),7.6(d,1H,J=7.52Hz,3’-H),7.4(m,1H,4’-H),6.9(s,1H,C4-H),5.9(s,1H,C6-H),0.85(s,3H,19-CH3),0.6(s,3H,18-CH3)ppm;IR(KBr)v:3457,2938,1672,1610,774cm-1;ESI-MS m/z:443[M-H]-;Anal.calcd for C28H32N2O3·1/4CH3OH:C 74.97,H 7.35,N 6.19;Found:C 75.06,H 7.831,N 5.986.
实施例96
17β-[N-(2,5-二甲基苯基)氨基甲酰]雄甾-3,5-二烯-3-羧酸(V 9)的合成
具体操作同实施例88,得黄色固体V 9(28%)。m.p.:200-205℃;1H NMR(DMSO,300 MHz)δ:12.1(s,1H,COOH),8.9(s,1H,NH),7.15(s,1H,6’-H),7.08(d,1H,J=7.68Hz,3’-H),6.94(s,1H,C4-H),6.9(d,1H,J=7.53Hz,4’-H),5.85(s,1H,C6-H),2.3(s,3H,Ar-CH3),2.2(s,3H,Ar-CH3),0.9(s,3H,19-CH3),0.8(s,3H,18-CH3)ppm;IR(KBr)v:2963,2360,1669,1284,804cm-1;ESI-MS m/z:446[M-H]-;Anal.calcd for C29H37NO3:C 77.82,H 8.33,N 3.13;Found:C 77.71,H 7.895,N 3.056.
实施例97
17β-[N-(2-甲氧基苯基)氨基甲酰]雄甾-3,5-二烯-3-羧酸(V10)的合成
具体操作参照化合物V1的合成,得黄色固体V10(26%)。m.p.:232-235℃;1H NMR(DMSO,300MHz)δ:12.1(s,1H,COOH),8.4(s,1H,NH),7.9(d,1H,J=8.07Hz,6’-H),7.1~6.9(m,3H,3’,4’,5’-H),6.9(s,1H,C4-H),5.9(s,1H,C6-H),3.8(s,3H,O-CH3),0.9(s,3H,19-CH3),0.7(s,3H,18-CH3)ppm;IR(KBr)v:3425,2946,1673,1483,741cm-1;ESI-MS m/z:448[M-H]-;Anal.calcd for C28H35NO4·1/2H2O:C 74.06,H 7.88,N 3.08;Found:C 73.68,H 8.135,N 2.738.
实施例98
3-溴-17β-(叔丁基氨基甲酰)-雄甾-3,5二烯(182)的制备
将163-1(1.5g,4.0mmol)溶于8mLHOAc中,滴加PBr3(0.39mL),10min内加完,反应30min,析出桔黄色固体182(1.47g,85%)。m.p.182~184℃(文献[3]m.p.184~186℃).
实施例99
3-腈基-17β-(叔丁基氨基甲酰)-雄甾-3,5二烯(183)的制备
将182(2.15g,4.96mmol)溶于55mLDMF中,加入CuCN(0.90g),加热到140℃,反应6h,冷却,倾入到500mL碎冰水中,过滤,干燥,加入10mL热丙酮,过滤,浓缩除去一半体积,放冰箱静置,析出淡黄色固体183(1.52g,81%)。m.p.193~195℃.(文献[4]m.p.195~197℃)。
实施例100
2-(5-1H-四氮唑)-17β-(N-叔丁基氨基甲酰)-雄甾-3,5二烯(VI 1)的制备
将183(0.7g,1.84mmol)溶于15mL DMF中,加入NH4Cl(0.19g),NaN3(0.38g),加热到150℃,反应48h,冷却,加入10%H2SO4溶液1mL,搅拌1h,将其倾入到200mL碎冰水中,过滤,得土黄色固体VI1(0.26g,29%)。1H NMR(CDCl3,300MHz)δ:7.06(s,1H,4-H),5.79(s,1H,6-H),5.23(s,1H,N-H),1.38(s,9H,tBu),0.99(s,3H,19-CH3),0.74(s,3H,18-CH3);IR(KBr)v:3442,1647,1606,1547,1385,1227cm-1;ESI-MS m/z:422.3[M-H]-。
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IT201700004904A1 (it) * | 2017-01-18 | 2018-07-18 | Ind Chimica Srl | PROCESSO PER LA PREPARAZIONE DI 9β,10α-PROGESTERONE (RETROPROGESTERONE) |
EP3875464A1 (en) * | 2020-03-06 | 2021-09-08 | F.I.S.- Fabbrica Italiana Sintetici S.p.A. | Process for the purification of etiocholenic acid |
Citations (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4191759A (en) * | 1978-04-13 | 1980-03-04 | Merck & Co., Inc. | N-substituted-17β-carbamoylandrost-4-en-3-one 5α reductase inhibitors |
CN1131424A (zh) * | 1993-09-17 | 1996-09-18 | 葛兰素惠尔康公司 | 雄烯酮衍生物 |
CN1134155A (zh) * | 1993-09-17 | 1996-10-23 | 葛兰素惠尔康公司 | 雄甾烯酮 |
CN1182091A (zh) * | 1996-11-29 | 1998-05-20 | 中国科学院上海有机化学研究所 | 一种含氟甾体5α-还原酶抑制剂、合成方法及其用途 |
US5777134A (en) * | 1995-10-26 | 1998-07-07 | Merck & Co., Inc. | 4-oxa and 4-thia steriods |
WO2003027132A2 (en) * | 2001-09-22 | 2003-04-03 | Hanmi Pharm. Co., Ltd. | METHOD OF PREPARING 17β-(N-TERT-BUTYLCARBAMOYL)-3-ONE STEROID DERIVATIVES |
WO2003029268A1 (en) * | 2001-10-03 | 2003-04-10 | Merck & Co., Inc. | Androstane 17-beta-carboxamides as androgen receptor modulators |
WO2005075497A1 (en) * | 2004-01-07 | 2005-08-18 | Ranbaxy Laboratories Limited | PROCESS FOR THE PREPARATION OF 17ß-SUBSTITUTED-3-OXO-4-AZA-5ALPHA-ANDROSTANE DERIVATIVES |
CN101863956A (zh) * | 2010-06-04 | 2010-10-20 | 上海应用技术学院 | 一种合成非那雄胺的方法 |
-
2012
- 2012-01-05 CN CN201210001077.1A patent/CN102532236B/zh not_active Expired - Fee Related
Patent Citations (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4191759A (en) * | 1978-04-13 | 1980-03-04 | Merck & Co., Inc. | N-substituted-17β-carbamoylandrost-4-en-3-one 5α reductase inhibitors |
CN1131424A (zh) * | 1993-09-17 | 1996-09-18 | 葛兰素惠尔康公司 | 雄烯酮衍生物 |
CN1134155A (zh) * | 1993-09-17 | 1996-10-23 | 葛兰素惠尔康公司 | 雄甾烯酮 |
US5777134A (en) * | 1995-10-26 | 1998-07-07 | Merck & Co., Inc. | 4-oxa and 4-thia steriods |
CN1182091A (zh) * | 1996-11-29 | 1998-05-20 | 中国科学院上海有机化学研究所 | 一种含氟甾体5α-还原酶抑制剂、合成方法及其用途 |
WO2003027132A2 (en) * | 2001-09-22 | 2003-04-03 | Hanmi Pharm. Co., Ltd. | METHOD OF PREPARING 17β-(N-TERT-BUTYLCARBAMOYL)-3-ONE STEROID DERIVATIVES |
WO2003029268A1 (en) * | 2001-10-03 | 2003-04-10 | Merck & Co., Inc. | Androstane 17-beta-carboxamides as androgen receptor modulators |
WO2005075497A1 (en) * | 2004-01-07 | 2005-08-18 | Ranbaxy Laboratories Limited | PROCESS FOR THE PREPARATION OF 17ß-SUBSTITUTED-3-OXO-4-AZA-5ALPHA-ANDROSTANE DERIVATIVES |
CN101863956A (zh) * | 2010-06-04 | 2010-10-20 | 上海应用技术学院 | 一种合成非那雄胺的方法 |
Non-Patent Citations (6)
Title |
---|
Dennis A. Holt 等.Inhibition of steroid 5α-reductase by 3-nitrosteroids:synthesis, mechanism of inhibition, and in vivo activity..《Bmorganrc & Medicinal Chemistry Letters》.1991,第1卷(第1期),第27-32页. |
Dennis A. Holt 等.Inhibition of steroid 5α-reductase by 3-nitrosteroids:synthesis, mechanism of inhibition, and in vivo activity..《Bmorganrc & * |
Medicinal Chemistry Letters》.1991,第1卷(第1期),第27-32页. * |
合成非那雄胺的新方法;姚志艺 等;《中国新药杂志》;20111130;第20卷(第22期);第2248-2250页 * |
姚志艺 等.合成非那雄胺的新方法.《中国新药杂志》.2011,第20卷(第22期),第2248-2250页. |
梁涌涛 等.新型抗前列腺增生药物度他雄胺的合成.《吉林大学学报(理学版)》.2007,第45卷(第6期),第1035-1038页. * |
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