CN105646637A - 一种阿比特龙衍生物及其制备方法和医药用途 - Google Patents
一种阿比特龙衍生物及其制备方法和医药用途 Download PDFInfo
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- CN105646637A CN105646637A CN201510848770.6A CN201510848770A CN105646637A CN 105646637 A CN105646637 A CN 105646637A CN 201510848770 A CN201510848770 A CN 201510848770A CN 105646637 A CN105646637 A CN 105646637A
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- dimethyl
- alkyl
- pyridyl
- cyclopenta
- base
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Abstract
本发明涉及一种通式(I)所示化合物及其立体异构体或药学上可接受的盐,以及在制备用于预防和治疗癌症药物中的用途,通式(I)化合物的结构如下所示,A的定义与说明书定义一致。
Description
技术领域
本发明涉及一种阿比特龙衍生物及其立体异构体或药学上可接受的盐,以及在制备用于预防和治疗癌症相关药物中的用途。
背景技术
前列腺癌是常见的恶性致死性癌症,近年我国的该病的发病率呈上升趋势,其市场需求将持续快速增长。
雄激素是前列腺癌发生的关键因素。雄激素生物合成首先通过17α-羟化酶活化将孕烯醇酮和孕酮转化为17α-羟基衍生物,再通过C17,20-裂解酶活形成脱氢表雄酮和雄烯二酮,两者均为睾酮的前体。在这个过程中,细胞色素P450是物合成途径中的关键酶。CYP17是一种细胞色素P450酶,它能催化两种独立调节类固醇17α-羟化酶和C17,20-裂解酶的酶活性,从而调节睾丸和身体其他部位的性类固醇前体的体内合成。
醋酸阿比特龙为阿比特龙前体药物,是一种CYP17酶抑制剂,于2011年在美国批准上市,适用于前列腺癌(CRPC)患者的治疗,推荐剂量为口服给予1000mg每天1次与泼尼松5mg口服给药每天2次联用。
目前有文献报道了阿比特龙的前体药物。
CN102477061公开了吡啶雄甾衍生物及其在制备预防和/或治疗前列腺癌药物中的用途,其中Rx选自多种酯类、碳酸酯类或胺类等前体药物基团,该文献涉及的通式结构如下:
CN102686600公开了甾体CYP17抑制剂/抗雄激素物质的新型药物前体,其中Y选自Z-L-C(=O)O-,Z是在正常生理条件下带有电荷的带电基团,其中带电基团是具有化学式(R3N+)-的季铵基团,该文献涉及的通式结构如下:
CN104017045公开了甾体CYP17抑制剂的新型药物前体,所述的前体药物可用于治疗泌尿生殖系统、雄激素相关的癌症,该文献涉及的结构如下:
WO2014111815公开了阿比特龙类似物及其在预防和/或治疗前列腺癌药物中的用途,其中R选自低链烷基、环烷基、胺基等,该文献涉及的结构如下:
本发明的目的在于提供一种新颖的具有高稳定性、良好溶解度、高生物利用度、低剂量、低毒副作用或具备长效潜力的阿比特龙前体药物,为癌症患者提供新的选择,所述癌症可选自泌尿生殖系统、雄激素相关的疾病,如前列腺癌。
发明内容
本发明涉及一种通式(I)所示化合物及其立体异构体或药学上可接受的盐,
其中:
A选自C(=O)R1、C(=O)XR2、(CRaRb)O(CRcRd)mC(=O)R3或-P(=O)(XR4)(XR5);
R1选自C10-20烷基、(CR1aR1b)nXC(=O)C1-6烷基、(CR1aR1b)nXC(=O)C1-6烷氧基、-(CR1aR1b)nC(=O)XC1-6烷基、CH(NH2)C1-6烷基-NH3 +、CH(NH2)C1-6烷基-NH2、C2-8烯基、C2-8炔基、(CR1cR1d)m-C3-10环烷基、(CR1cR1d)n-C3-10碳环或者(CR1cR1d)q-3至10元杂环,所述的烷基、烷氧基、烯基、炔基、杂环或碳环任选进一步被0至4个选自H、F、Cl、Br、I、OH、NH2、C1-4烷基、C1-4烷氧基、-NHC(=O)C1-4烷氧基、C(=O)C1-4烷氧基、-NHC(=O)(CR1eR1f)NH2、R1g、C5-6碳环或4至6元杂环的取代基所取代,所述的杂环含有1至4个选自N、O或S的杂原子;
Ra、Rb、Rc、Rd、R1c和R1d各自独立的选自H、OH、氨基或C1-4烷基,所述烷基任选进一步被0至4个选自H、F、Cl、Br、I、OH、C1-4烷基或C1-4烷氧基的取代基所取代;
R1a、R1b、R1e、R1f和R1g各自独立的选自H、OH、C1-4烷基或氨基酸的侧链基团,所述烷基任选进一步被0至4个选自H、F、Cl、Br、I、OH、C1-4烷基或C1-4烷氧基的取代基所取代,所述氨基酸选自赖氨酸、精氨酸、组氨酸、脯氨酸、2,3-二氨基丙酸、2,4-二氨基丙酸、丙氨酸、缬氨酸、亮氨酸、异亮氨酸、苯丙氨酸、色氨酸、蛋氨酸、甘氨酸、丝氨酸、苏氨酸、半胱氨酸、酪氨酸、天冬酰胺、谷氨酰胺、天冬氨酸、门冬氨酸或者谷氨酸;
R2选自C1-6烷基、-(CH2)nXC(=O)R2a、-(CH2)nXC(=O)OR2a、C(=O)R2b、(CH2)nXR2c、(CH2)nS(=O)pC1-6烷基、C3-10碳环或(CH2)m3至10元杂环,所述的烷基、杂环和碳环任选进一步被0至4个选自H、F、Cl、Br、I、(=O)、OH、NH2、C1-4烷基、C1-4烷氧基、C1-4烷基-羟基或(CH2)nOC(=O)C1-6烷基的取代基所取代,所述的杂环含有1至4个选自N、O或S的杂原子;
R2a、R2b和R2c各自独立的选自C1-6烷基、C1-6烷氧基、C3-10碳环或3至10元杂环,所述的烷基、烷氧基、杂环和碳环任选进一步被0至4个选自H、F、Cl、Br、I、OH、NH2、C1-4烷基、C1-4烷氧基、-NHC(=O)C1-4烷氧基、C3-10碳环或3至10元杂环的取代基所取代,所述的杂环含有1至4个选自N、O或S的杂原子;
R3选自R3a或OR3b;
R3a和R3b各自独立的选自C1-6烷基、-C3-10碳环、3至10元杂环、-C1-4烷基-C3-10碳环或-C1-4烷基-3至10元杂环,所述烷基、杂环或碳环任选被0至4个选自H、F、Cl、Br、I、OH、NH2、C1-4烷基、C1-4烷氧基或-NHC(=O)C1-4烷氧基的取代基所取代,所述的杂环含有1至4个选自N、O或S的杂原子;
R4和R5各自独立的选自H、-(CR4aR4b)OC(=O)R4c、-(CR4aR4b)OC(=O)OR4c、-(CR4aR4b)-C(=O)OR4d或-(CH2)m-C3-10碳环,所述的烷基和碳环任选进一步被0至4个选自H、F、Cl、Br、I、OH、NH2、C1-4烷基或者C1-4烷氧基的取代基所取代;
R4a和R4b各自独立的选自H或C1-4烷基;
R4c和R4d各自独立的选自C1-6烷基、C2-8烯基、C2-8炔基、C3-10碳环或3-10元杂环,所述的烷基、烯基、炔基和碳环任选进一步被0至4个选自H、F、Cl、Br、I、OH、NH2、C1-4烷基或者C1-4烷氧基的取代基所取代,所述的杂环含有1至4个选自N、O或S的杂原子;
X各自独立的选自O、S或NRx;
Rx各自独立的选自H或C1-4烷基;
n选自1、2、3或4;
m选自0、1、2、3或4;
q选自1、2、3或4;
p选自0、1或2;
条件是,当A选自C(=O)OR2时,R2不为烷基取代的烷基、未取代的烷基或硝基取代的苯基。
本发明优选方案,一种通式(I)所述化合物,其中:A选自C(=O)R1、C(=O)XR2、CH2O(CH2)mC(=O)R3或P(=O)(XR4)(XR5),优选C(=O)R1、C(=O)XR2、CH2OC(=O)R3、CH2OCH2C(=O)R3或P(=O)(XR4)(XR5),更优选C(=O)R1或者C(=O)XR2。
本发明优选方案,一种通式(I)所述化合物,其中:R1选自选自C10-20烷基、-(CR1aR1b)nXC(=O)C1-6烷基、(CR1aR1b)nXC(=O)C1-6烷氧基、-(CR1aR1b)nC(=O)XC1-6烷基、-CH(NH2)C1-6烷基-NH3 +、CH(NH2)C1-6烷基-NH2、C2-8烯基、C2-8炔基、3-10元杂环或者-(CR1cR1d)n-C3-10碳环,优选C10-20烷基、-(CR1aR1b)nXC(=O)C1-6烷基、-CH(NH2)C1-6烷基-NH3 +、CH(NH2)C1-6烷基-NH2、C2-6烯基、C2-6炔基、5至8元杂环或者-(CR1cR1d)n-C3-8碳环,进一步优选C12-16烷基、-(CR1aR1b)nXC(=O)C1-4烷基、CH(NH2)C1-6烷基-NH3 +、CH(NH2)C1-6烷基-NH2、C3-5烯基、C3-5炔基、5至6元杂环或-(CR1cR1d)n-C3-6碳环;所述的烷基、烷氧基、烯基、炔基、杂环或碳环任选进一步被0至4个选自H、F、Cl、Br、I、OH、NH2、C1-4烷基、C1-4烷氧基、-NHC(=O)C1-4烷氧基、C(=O)C1-4烷氧基、-NHC(=O)(CR1eR1f)NH2、R1g、C5-6碳环或4至6元杂环的取代基所取代,优选被0至4个选自H、NH2、甲基、乙基、丙基、异丙基、-NHC(=O)OC(CH3)3、-C(=O)OC(CH3)3、-NHC(=O)(CR1eR1f)NH2、R1g、苯基或氮杂五元环的取代基所取代,所述的杂环含有1至4个选自N、O或S的杂原子;
R1更优-C15H31或如下结构之一:
或取代或为取代的如下结构之一:
当被取代时,任选进一步被0至4个选自H、NH2、甲基、乙基、丙基、异丙基或-NHC(=O)OC(CH3)3、的取代基所取代;
R1c和R1d各自独立的选自H、OH或C1-4烷基,优选H、OH、甲基或羟甲基;所述烷基任选进一步被0至4个选自H、OH、C1-4烷基或C1-4烷氧基的取代基所取代;
R1a、R1b、R1e、R1f和R1g各自独立的选自H、OH、C1-4烷基或氨基酸的侧链基团,优选H、OH、甲基或氨基酸的侧链基团;所述烷基任选进一步被0至4个选自H、F、Cl、Br、I、OH、C1-4烷基或C1-4烷氧基的取代基所取代;
所述氨基酸选自赖氨酸、2,3-二氨基丙酸、2,4-二氨基丙酸、丙氨酸、缬氨酸、亮氨酸、异亮氨酸、苯丙氨酸、甘氨酸、丝氨酸、苏氨酸、酪氨酸、天冬酰胺、天冬氨酸、门冬氨酸或者谷氨酸,优选赖氨酸、2,3-二氨基丙酸、2,4-二氨基丙酸、丙氨酸、缬氨酸、亮氨酸、异亮氨酸、苯丙氨酸、甘氨酸或酪氨酸,进一步丙氨酸、缬氨酸、亮氨酸、苯丙氨酸或甘氨酸。
本发明优选方案,一种通式(I)所述化合物,其中:R2选自C1-6烷基、-(CH2)nXC(=O)R2a、-(CH2)nXC(=O)OR2a、-C(=O)R2b、-(CH2)nS(=O)pC1-6烷基、C3-10碳环或-(CH2)m3至10元杂环,优选C1-6烷基、-(CH2)nXC(=O)R2a、-(CH2)nXC(=O)OR2a、-C(=O)R2b、-(CH2)nS(=O)pC1-6烷基、C6-9碳环或-(CH2)m5至8元杂环,进一步优选C1-4烷基、(CH2)nOC(=O)R2a、-(CH2)nXC(=O)OR2a、C(=O)R2b、(CH2)nS(=O)2C1-4烷基、C6-9碳环或(CH2)m5至8元杂环,
所述的烷基、杂环和碳环任选进一步被0至4个选自H、F、Cl、Br、I、(=O)、OH、NH2、C1-4烷基、C1-4烷氧基、C1-4烷基-羟基或-OC(=O)C1-6烷基的取代基所取代,优选被0至4个选自H、F、Cl、Br、(=O)、OH、NH2、甲基、羟甲基或乙酰氧基的取代基所取代;所述的杂环含有1至4个选自N、O或S的杂原子;
R2更优选如下结构之一:
R2a选自C1-6烷基、C3-10碳环或3至10元杂环,优选C1-6烷基、C1-6烷氧基或5至6元杂环,进一步优选C1-4烷基、C5-6碳环或5至6元杂环;所述的烷基、杂环和碳环任选进一步被0至4个选自H、F、Cl、Br、I、OH、NH2、C1-4烷基、C1-4烷氧基、-NHC(=O)C1-4烷氧基/C3-10碳环或5至10元杂环的取代基所取代,优选被0至4个选自H、氨基、甲基、-NHC(=O)OC(CH3)3、苯基或5至10元杂环的取代基所取代;所述的杂环含有1至4个选自N、O或S的杂原子;
R2b选自C3-10碳环,优选C5-6碳环,进一步优选C6碳环,所述的碳环任选进一步被0至4个选自H、F、Cl、Br、I、OH、NH2、C1-4烷基或C1-4烷氧基的取代基所取代;
本发明优选方案,一种通式(I)所述化合物,其中:R3选自-C1-4烷基-C3-10碳环或C1-6烷基,优选-C1-4烷基-C5-6碳环或C1-4烷基,所述烷基或碳环任选被0至4个选自H、F、Cl、Br、I、OH、NH2、C1-4烷基、C1-4烷氧基或-NHC(=O)C1-4烷氧基的取代基所取代,优选被0至4个选自H、F、Cl、Br、I、OH、NH2、C1-4烷基、C1-4烷氧基或-NHC(=O)C1-4烷氧基的取代基所取代,进一步优选被H、NH2或-NHC(=O)OC(CH3)3的取代基所取代;
R3进一步优选
本发明优选方案,一种通式(I)所述化合物,其中:R4和R5各自独立的选自-(CR4aR4b)-C(=O)OC1-6烷基、-(CR4aR4b)OC(=O)OC1-6烷基或者-(CH2)m-C3-10碳环,优选-(CR4aR4b)-C(=O)OC1-6烷基、-(CR4aR4b)OC(=O)OC1-6烷基或者-(CH2)m-C5-6碳环,进一步优选-CH(CH3)C(=O)OC1-4烷基、-CH2OC(=O)OC1-4烷基或者-(CH2)m-C5-6碳环,进一步优选-CH(CH3)COOCH2CH3、-CH2OC(=O)OCH(CH3)2或者苯基,所述的烷基和碳环任选进一步被0至4个选自H、F、Cl、Br、I、OH、NH2、C1-4烷基或者C1-4烷氧基的取代基所取代。
本发明优选方案,一种通式(I)所述化合物,其中X各自独立的选自O、S或NH;
本发明优选方案,一种通式(I)所述化合物,其中:
A选自C(=O)R1、C(=O)XR2、CH2O(CH2)mC(=O)R3或P(=O)(XR4)(XR5);
R1选自C10-20烷基、-(CR1aR1b)nXC(=O)C1-6烷基、-CH(NH2)C1-6烷基-NH3 +、CH(NH2)C1-6烷基-NH2、C2-8烯基、C2-8炔基、3-10元杂环或者-(CR1cR1d)n-C3-10碳环,所述的烷基、烯基、炔基、杂环或碳环任选进一步被0至4个选自H、F、Cl、Br、I、OH、NH2、C1-4烷基、C1-4烷氧基、-NHC(=O)C1-4烷氧基、C(=O)C1-4烷氧基、-NHC(=O)(CR1eR1f)NH2、R1g、C5-6碳环或4至6元杂环的取代基所取代,所述的杂环含有1至4个选自N、O或S的杂原子;
R1c和R1d各自独立的选自H、OH或C1-4烷基;所述烷基任选进一步被0至4个选自H、OH、C1-4烷基或C1-4烷氧基的取代基所取代;
R1a、R1b、R1e、R1f和R1g各自独立的选自H、OH、C1-4烷基或氨基酸的侧链基团,所述烷基任选进一步被0至4个选自H、F、Cl、Br、I、OH、C1-4烷基或C1-4烷氧基的取代基所取代,所述氨基酸选自赖氨酸、2,3-二氨基丙酸、2,4-二氨基丙酸、丙氨酸、缬氨酸、亮氨酸、异亮氨酸、苯丙氨酸、甘氨酸、丝氨酸、苏氨酸、酪氨酸、天冬酰胺、天冬氨酸、门冬氨酸或者谷氨酸;
R2选自C1-6烷基、-(CH2)nXC(=O)R2a、-(CH2)nXC(=O)OR2a、-C(=O)R2b、-(CH2)nS(=O)pC1-6烷基、C3-10碳环或-(CH2)m3至10元杂环,所述的烷基、杂环和碳环任选进一步被0至4个选自H、F、Cl、Br、I、(=O)、OH、NH2、C1-4烷基、C1-4烷氧基、C1-4烷基-羟基或-OC(=O)C1-6烷基、的取代基所取代,所述的杂环含有1至4个选自N、O或S的杂原子;
R2a选自C1-6烷基、C3-10碳环或3至10元杂环,所述的烷基、烷氧基、杂环和碳环任选进一步被0至4个选自H、F、Cl、Br、I、OH、NH2、C1-4烷基、C1-4烷氧基、-NHC(=O)C1-4烷氧基、C3-10碳环或5至10元杂环的取代基所取代,所述的杂环含有1至4个选自N、O或S的杂原子;
R2b选自C3-10碳环,所述的碳环任选进一步被0至4个选自H、F、Cl、Br、I、OH、NH2、C1-4烷基或C1-4烷氧基的取代基所取代;
R3选自-C1-4烷基-C3-10碳环或C1-6烷基,所述烷基或碳环任选被0至4个选自H、F、Cl、Br、I、OH、NH2、C1-4烷基、C1-4烷氧基或-NHC(=O)C1-4烷氧基的取代基所取代;
R4和R5各自独立的选自-(CR4aR4b)-C(=O)OC1-6烷基、-(CR4aR4b)OC(=O)OC1-6烷基或者-(CH2)m-C3-10碳环,所述的烷基和碳环任选进一步被0至4个选自H、F、Cl、Br、I、OH、NH2、C1-4烷基或者C1-4烷氧基的取代基所取代。
本发明优选方案,一种通式(I)所述化合物,其中:
A选自C(=O)R1、C(=O)XR2、CH2O(CH2)mC(=O)R3或P(=O)(XR4)(XR5);
R1选自C10-20烷基、-(CR1aR1b)nXC(=O)C1-6烷基、-CH(NH2)C1-6烷基-NH3 +、CH(NH2)C1-6烷基-NH2、C2-6烯基、C2-6炔基、5至8元杂环或者-(CR1cR1d)n-C3-8碳环,所述的烷基、烷氧基、烯基、炔基、杂环或碳环任选进一步被0至4个选自H、F、Cl、Br、I、OH、NH2、C1-4烷基、C1-4烷氧基、-NHC(=O)C1-4烷氧基、C(=O)C1-4烷氧基、-NHC(=O)(CR1eR1f)NH2、R1g、C5-6碳环或4至6元杂环的取代基所取代,所述的杂环含有1至4个选自N、O或S的杂原子;
R1c和R1d各自独立的选自H、OH或C1-4烷基;所述烷基任选进一步被0至4个选自H或OH的取代基所取代;
R1a、R1b、R1e、R1f和R1g各自独立的选自H、OH、C1-4烷基或氨基酸的侧链基团,所述烷基任选进一步被0至4个选自H、F、Cl、Br、I、OH、C1-4烷基或C1-4烷氧基的取代基所取代,所述氨基酸选自赖氨酸、2,3-二氨基丙酸、2,4-二氨基丙酸、丙氨酸、缬氨酸、亮氨酸、异亮氨酸、苯丙氨酸、甘氨酸或酪氨酸;
R2选自C1-6烷基、-(CH2)nXC(=O)R2a、-(CH2)nXC(=O)OR2a、-C(=O)R2b、-(CH2)nS(=O)pC1-6烷基、C6-9碳环或-(CH2)m5至8元杂环,所述的烷基、杂环和碳环任选进一步被0至4个选自H、F、Cl、Br、I、(=O)、OH、NH2、C1-4烷基、C1-4烷氧基、-C1-4烷基-羟基或-OC(=O)C1-6烷基的取代基所取代,所述的杂环含有1至4个选自N、O或S的杂原子;
R2a选自C1-6烷基、C5-6碳环或5至6元杂环,所述的烷基、碳环和杂环任选进一步被0至4个选自H、氨基、甲基、-NHC(=O)OC(CH3)3、苯基或5至10元杂环的取代基所取代,所述的杂环含有1至4个选自N、O或S的杂原子;
R2b选自C5-6碳环,所述的碳环任选进一步被0至4个选自H、F、Cl、Br、I、OH、NH2、C1-4烷基或C1-4烷氧基的取代基所取代;
R3选自-C1-4烷基-C5-6碳环或C1-4烷基,所述烷基或碳环任选被0至4个选自H、F、Cl、Br、I、OH、NH2、C1-4烷基、C1-4烷氧基或-NHC(=O)C1-4烷氧基的取代基所取代;
R4和R5各自独立的选自-(CR4aR4b)-C(=O)OC1-6烷基、-(CR4aR4b)OC(=O)OC1-6烷基或者-(CH2)m-C5-6碳环,所述的烷基和碳环任选进一步被0至4个选自H、F、Cl、Br、I、OH、NH2、C1-4烷基或者C1-4烷氧基的取代基所取代。
本发明优选方案,一种通式(I)所述化合物,其中:
A选自C(=O)R1、C(=O)XR2、CH2O(CH2)mC(=O)R3或P(=O)(XR4)(XR5);
R1选自C12-16烷基、-(CR1aR1b)nXC(=O)C1-4烷基、CH(NH2)C1-6烷基-NH3 +、CH(NH2)C1-6烷基-NH2、C3-5烯基、C3-5炔基、5至6元杂环或-(CR1cR1d)n-C3-6碳环,所述的烷基、烯基、炔基、杂环、碳环任选进一步被0至4个选自H、NH2、甲基、乙基、丙基、异丙基、-NHC(=O)OC(CH3)3、-C(=O)OC(CH3)3、-NHC(=O)(CR1eR1f)NH2、R1g、苯基或氮杂五元环的取代基所取代;
R1c和R1d各自独立的选自H、OH、甲基或羟甲基;
R1a、R1b、R1e、R1f和R1g各自独立的选自H、OH、甲基或氨基酸的侧链基团,所述氨基酸选自丙氨酸、缬氨酸、亮氨酸、异亮氨酸、苯丙氨酸或甘氨酸;
R2选自C1-4烷基、(CH2)nOC(=O)R2a、-(CH2)OC(=O)OR2a、C(=O)R2b、(CH2)nS(=O)2C1-4烷基、C6-9碳环或(CH2)m5至8元杂环,所述的烷基、烷氧基、杂环和碳环任选进一步被0至4个选自H、F、Cl、Br、(=O)、OH、NH2、甲基、羟甲基或乙酰氧基的取代基所取代;
R2a选自C1-4烷基、C5-6碳环或5至6元杂环,所述的烷基、碳环和杂环任选进一步被0至4个选自H、氨基、甲基、-NHC(=O)OC(CH3)3、苯基或5至10元杂环的取代基所取代,所述的杂环含有1至4个选自N、O或S的杂原子;
R2b选自C6碳环;
R3选自-C1-4烷基-C5-6碳环或C1-4烷基,所述烷基任选被0至4个选自H、NH2或-NHC(=O)OC(CH3)3的取代基所取代;
R4和R5各自独立的-CH(CH3)C(=O)OC1-4烷基、-CH2OC(=O)OC1-4烷基或者-(CH2)m-C5-6碳环;
X各自独立的选自O、S或NH。
本发明优选方案,一种通式(I)所述化合物,其中:
A选自C(=O)R1、C(=O)XR2、CH2OC(=O)R3、CH2OCH2C(=O)R3或P(=O)(XR4)(XR5);
R1选自-C15H31或如下结构之一:
或取代或为取代的如下结构之一:
当被取代时,任选进一步被0至4个选自H、NH2、甲基、乙基、丙基、异丙基或-NHC(=O)OC(CH3)3、的取代基所取代;
R1a、R1e和R1g各自独立的选自H、甲基或氨基酸的侧链基团,所述氨基酸选自丙氨酸、缬氨酸、亮氨酸、苯丙氨酸或甘氨酸;
R2选自如下结构之一:
R3选自如下结构之一:
R4和R5各自独立的选自-CH(CH3)COOCH2CH3、-CH2OC(=O)OCH(CH3)2或者苯基;
X各自独立的选自O、S或NH。
本发明优选方案,一种通式(I)所示化合物及其立体异构体或药学上可接受的盐,其中:
A选自C(=O)R1或C(=O)XR2;
R1选自C10-20烷基、(CR1aR1b)nXC(=O)C1-6烷基、(CR1aR1b)nXC(=O)C1-6烷氧基、-(CR1aR1b)nC(=O)XC1-6烷基、CH(NH2)C1-6烷基-NH2、C2-8烯基、C2-8炔基、(CR1cR1d)m-C3-10环烷基、(CR1cR1d)n-C3-10碳环或者(CR1cR1d)q-3至10元杂环,所述的烷基、烷氧基、烯基、炔基、杂环或碳环任选进一步被0至4个选自H、F、Cl、Br、I、OH、NH2、C1-4烷基、C1-4烷氧基、-NHC(=O)C1-4烷氧基、C(=O)C1-4烷氧基、-NHC(=O)(CR1eR1f)NH2、R1g、C5-6碳环或4至6元杂环的取代基所取代,所述的杂环含有1至4个选自N、O或S的杂原子;
R1c和R1d各自独立的选自H、OH、氨基或C1-4烷基,所述烷基任选进一步被0至4个选自H、F、Cl、Br、I、OH、C1-4烷基或C1-4烷氧基的取代基所取代;
R1a、R1b、R1e、R1f和R1g各自独立的选自H、OH、C1-4烷基或氨基酸的侧链基团,所述烷基任选进一步被0至4个选自H、F、Cl、Br、I、OH、C1-4烷基或C1-4烷氧基的取代基所取代,所述氨基酸选自赖氨酸、精氨酸、组氨酸、脯氨酸、2,3-二氨基丙酸、2,4-二氨基丙酸、丙氨酸、缬氨酸、亮氨酸、异亮氨酸、苯丙氨酸、色氨酸、蛋氨酸、甘氨酸、丝氨酸、苏氨酸、半胱氨酸、酪氨酸、天冬酰胺、谷氨酰胺、天冬氨酸、门冬氨酸或者谷氨酸;
R2选自C1-6烷基、(CH2)nXC(=O)R2a、-(CH2)nXC(=O)OR2a、(CH2CH2O)nC(=O)R2a、C(=O)R2b、(CH2)nXR2c、(CH2)nS(=O)pC1-6烷基、C3-10碳环或(CH2)m3至10元杂环,所述的烷基、杂环和碳环任选进一步被0至4个选自H、F、Cl、Br、I、(=O)、OH、NH2、C1-4烷基、C1-4烷氧基、C1-4烷基-羟基或(CH2)nOC(=O)C1-6烷基的取代基所取代,所述的杂环含有1至4个选自N、O或S的杂原子;
R2a、R2b和R2c各自独立的选自C1-6烷基、C1-6烷氧基、C3-10碳环或3至10元杂环,所述的烷基、烷氧基、杂环和碳环任选进一步被0至4个选自H、F、Cl、Br、I、OH、NH2、C1-4烷基、C1-4烷氧基、-NHC(=O)C1-4烷氧基、C3-10碳环或3至10元杂环的取代基所取代,所述的杂环含有1至4个选自N、O或S的杂原子;
X各自独立的选自O、S或NRx;
Rx各自独立的选自H或C1-4烷基;
n选自1、2、3或4;
m选自0、1、2、3或4;
q选自1、2、3或4;
p选自0、1或2。
条件是,当A选自C(=O)OR2时,R2不为烷基取代的烷基、未取代的烷基或硝基取代的苯基。
本发明优选方案,一种通式(I)所示化合物及其立体异构体或药学上可接受的盐,其中:
A选自C(=O)R1或C(=O)XR2;
R1选自C12-16烷基、-(CR1aR1b)nXC(=O)C1-4烷基、-(CR1aR1b)nC(=O)XC1-4烷基、CH(NH2)C1-6烷基-NH2、C3-5烯基、C3-5炔基、(CR1cR1d)m-C3-6环烷基、-(CR1cR1d)q-5至6元杂环或-(CR1cR1d)n-C3-6碳环,所述的烷基、烯基、炔基、杂环、碳环任选进一步被0至4个选自H、NH2、甲基、乙基、丙基、异丙基、-NHC(=O)OC(CH3)3、-C(=O)OC(CH3)3、-NHC(=O)(CR1eR1f)NH2、R1g、苯基或氮杂五元环的取代基所取代;
R1c和R1d各自独立的选自H、OH、氨基、甲基或羟甲基;
R1a、R1b、R1e、R1f和R1g各自独立的选自H、OH、甲基或氨基酸的侧链基团,所述氨基酸选自丙氨酸、缬氨酸、亮氨酸、异亮氨酸、苯丙氨酸或甘氨酸;
R2选自C1-4烷基、(CH2)nOC(=O)R2a、(CH2)nOC(=O)OR2a、(CH2CH2O)nC(=O)R2a、C(=O)R2b、(CH2)nS(=O)2C1-4烷基、C6-9碳环或(CH2)m5至8元杂环,所述的烷基、杂环和碳环任选进一步被0至4个选自H、F、Cl、Br、(=O)、OH、NH2、甲基、甲氧基、乙氧基、异丙氧基、羟甲基或乙酰氧基的取代基所取代;
R2a选自C1-4烷基、C5-6碳环或5至6元杂环,所述的烷基、碳环和杂环任选进一步被0至4个选自H、氨基、甲基、乙基、异丙基、-NHC(=O)OC(CH3)3、苯基或5至10元杂环的取代基所取代,所述的杂环含有1至4个选自N、O或S的杂原子;
R2b选自C6碳环。
本发明优选方案,一种通式(I)所示化合物及其立体异构体或药学上可接受的盐,其中:
A选自C(=O)R1或C(=O)XR2,优选C(=O)XR2;
R1选自如下结构之一:
R1a、R1e和R1g各自独立的选自H、甲基或氨基酸的侧链基团,所述氨基酸选自丙氨酸、缬氨酸、亮氨酸、苯丙氨酸或甘氨酸;
R2选自如下结构之一:
X选自O、S或NH。
本发明优选方案,一种通式(I)所示化合物及其立体异构体或药学上可接受的盐,其中:其中该化合物选自如下结构之一:
本发明涉及通式(I)所述的化合物及其立体异构体或药学上可接受的盐,其中所述的盐优选盐酸盐。
本发明还提供一种药物组合物,所述药物组合物含有治疗有效剂量的本发明化合物及其立体异构体或药学上可接受的盐,以及药学上可接受的载体和赋形剂。
进一步,本发明还提供本发明所述的化合物及其立体异构体或药学上可接受的盐,以及本发明化合物的组合物在制备治疗与癌症相关疾病药物中的用途。
本发明优选方案,其中所述的癌症为前列腺癌。
除非有相反的陈述,在说明书和权利要求书中使用的术语具有下述含义。
本发明所述基团和化合物中所涉及的碳、氢、氧、硫、氮或卤素均包括它们的同位素,及本发明所述基团和化合物中所涉及的碳、氢、氧、硫、氮或卤素任选进一步被一个或多个它们对应的同位素所替代,其中碳的同位素包括12C、13C和14C,氢的同位素包括氕(H)、氘(D,又称为重氢)、氚(T,又称为超重氢),氧的同位素包括16O、17O和18O,硫的同位素包括32S、33S、34S和36S,氮的同位素包括14N和15N,氟的同位素19F,氯的同位素包括35Cl和37Cl,溴的同位素包括79Br和81Br。
“烷基”是指直链和支链的饱和脂肪族烃基团,主链包括1至20个碳原子,优选为1至12个碳原子,进一步优选为1至8个碳原子,更优选为1至6个碳原子,再进一步优选1至4个碳原子的直链与支链基团,最优选1至2个碳原子;烷基的实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、2-戊基、3-戊基、2-甲基-2-丁基、3-甲基-2-丁基、3-甲基-1-丁基、2-甲基-1-丁基、正己基、2-己基、3-己基、2-甲基-2-戊基、3-甲基-2-戊基、4-甲基-2-戊基、3-甲基-3-戊基、2-甲基-3-戊基、2,3-二甲基-2-丁基、3,3-二甲基-2-丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,2-二甲基戊基、2,3-二甲基戊基、2,4-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,2-二甲基己基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基和正癸基;烷基可以是取代的或未取代的,当被取代时,取代基可以在任何可使用的连接点上被取代,取代基优选为1至5个选自F、Cl、Br、I、烷基、环烷基、烷氧基、卤代烷基、硫醇、羟基、硝基、巯基、氨基、氰基、异氰基、芳基、杂芳基、杂环基、桥环基、螺环基、并环基、羟基烷基=O、羰基、醛、羧酸、羧酸酯芳基硫基、硫代羰基或硅烷基等。
“烷氧基”是指-O-烷基,其中烷基如本文上述定义。烷氧基可以是取代的或未取代的,烷氧基实施例包括但不限于甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、仲丁氧基、正戊氧基和正己氧基;当被取代时,取代基优选为1至5个选自F、Cl、Br、I、烷基、环烷基、烷氧基、卤代烷基、硫醇、羟基、硝基、巯基、氨基、氰基、异氰基、芳基、杂芳基、杂环基、桥环基、螺环基、并环基、羟基烷基、=O、羰基、醛、羧酸、羧酸酯芳基硫基、硫代羰基或硅烷基等。
“烷氧基烷基”指与烷氧基相连的烷基;烷氧基烷基可以是取代的或未取代的,其非限制性实施例包括,甲氧基甲基、甲氧基乙基、乙氧基甲基、乙氧基乙基、丙氧基甲基、丙氧基乙基、2-丙氧基甲基、丁氧基丙基、叔丁氧基乙基、戊氧基乙基、己氧基乙基、环丙氧基甲基、环丙氧基乙基、环丙氧基丙基和环己氧基甲基;当被取代时,取代基优选为1至5个选自F、Cl、Br、I、烷基、环烷基、烷氧基、卤代烷基、硫醇、羟基、硝基、巯基、氨基、氰基、异氰基、芳基、杂芳基、杂环基、桥环基、螺环基、并环基、羟基烷基、=O、羰基、醛、羧酸、羧酸酯芳基硫基、硫代羰基或硅烷基等。
“烯基”是指至少含一个碳-碳双键组成的如本文上述定义的烷基,优选含有2至20个碳原子,进一步优选2至12个碳原子,更优选在主链上有2至8个碳原子,烯基可以是取代的或未取代的;非限制性实施例包括乙烯基、烯丙基、1-丙烯基、2-丙烯基、1-丁烯基、2-丁烯基、3-丁烯基、1-戊烯基、2-戊烯基、3-戊烯基、4-戊烯基、1-甲基-1-丁烯基、2-甲基-1-丁烯基、2-甲基-3-丁烯基、1-己烯基、2-己烯基、3-己烯基、4-己烯基、5-己烯基、1-甲基-1-戊烯基、2-甲基-1-戊烯基、1-庚烯基、2-庚烯基、3-庚烯基、4-庚烯基、1-辛烯基、3-辛烯基、1-壬烯基、3-壬烯基、1-癸烯基、4-癸烯基、1,3-丁二烯、1,3-戊二烯、1,4-戊二烯、1,4-己二烯、3-十一烯基、4-十二烯基和4,8,12-十四碳三烯基;当被取代时,取代基为1至5个选自F、Cl、Br、I、烷基、环烷基、烷氧基、卤代烷基、硫醇、羟基、硝基、巯基、氨基、氰基、异氰基、芳基、杂芳基、杂环基、桥环基、螺环基、并环基、羟基烷基=O、羰基、醛、羧酸、羧酸酯芳基硫基、硫代羰基或硅烷基等。
“炔基”是指包含至少一个碳-碳三键组成的如本文上述定义的烷基,优选含有2至20个碳原子,进一步优选2至8个碳原子,更优选在主链上有2至4个碳原子的炔基;炔基可以是取代的或未取代的;非限制性实施例包括乙炔基、1-丙炔基、2-丙炔基、丁炔基、2-丁炔基、3-丁炔基、1-甲基-2-丙炔基、4-戊炔基、3-戊炔基、1-甲基-2-丁炔基、2-己炔基、3-己炔基、2-庚炔基、3-庚炔基、4-庚炔基、3-辛炔基、3-壬炔基、4-癸炔基、3-十一炔基和4-十二炔基;当被取代时,取代基优选为一个或多个以下基团,独立地选自F、Cl、Br、I、烷基、环烷基、烷氧基、卤代烷基、硫醇、羟基、硝基、巯基、氨基、氰基、异氰基、芳基、杂芳基、杂环基、桥环基、螺环基、并环基、羟基烷基、=O、羰基、醛、羧酸、羧酸酯芳基硫基、硫代羰基或硅烷基等。
“氨基”是指-NH2,可以是取代的或未取代的,当被取代时,取代基优选为1至3个以下基团,独立地选自烷基、环烷基、卤代烷基、硫醇、羟基、巯基、氨基、氰基、异氰基、芳基、杂芳基、杂环基、桥环基、螺环基、并环基、羟基烷基、=O、羰基、醛、羧酸、羧酸酯芳基硫基、硫代羰基或硅烷基等。
“杂环”或“杂环基”是指取代的或未取代的饱和或不饱和的至少含有1至5个选自N、O、S、S(=O)或S(=O)2原子或基团的非芳香环系统,非芳香环系统包含3至20个环原子,优选3至10个环原子,更优选3至8个环原子;杂环基环中选择性取代的N、S可被氧化成各种氧化态;非限制性实施例包括氧杂环丙烷基、氧杂环丁基、氧杂环戊基、氧杂环己基、氧杂环己基、氧杂环辛基、氮杂环丙烷基、氮杂环丁基、氮杂环戊基、氮杂环己基、氮杂环丙烯基、1,3二氧环戊基、1,4-二氧环戊基、1,3-二氧环戊基、1,3-二氧环己基、1,3-二硫环己基、氮杂环庚烯基、吗啉基、哌嗪基、吡啶基、呋喃基、噻吩基、吡咯基、吡喃基、N-烷基吡咯基、嘧啶基、吡嗪基、哒嗪基、咪唑基、哌啶基、硫代吗啉基、二氢吡喃、噻二唑基、噁唑基、噁二唑基、吡唑基、1,4-二氧杂环己二烯基、2H-1,2-噁嗪基或2,5-二氢噻吩基等;当被取代时,取代基为1至5个选自F、Cl、Br、I、烷基、环烷基、烷氧基、卤代烷基、硫醇、羟基、硝基、巯基、氨基、氰基、异氰基、芳基、杂芳基、杂环基、桥环基、螺环基、并环基、羟基烷基、=O、羰基、醛、羧酸、羧酸酯芳基硫基、硫代羰基或硅烷基等。
“碳环”是指饱和或者不饱和的芳香环或者非芳香环,芳香环或者非芳香可以是3至8元的单环,4至12元双环或者10至15元三环系统,碳环可以连接有桥环或者螺环,非限制性实施例包括环丙基、环丁基、环戊基、环己基、环己烯基、环庚基、环戊烯、环己二烯、环庚三烯、苯基、萘基、苯并环戊基、二环[3.2.1]辛烷基、二环[5.2.0]壬烷基、三环[5.3.1.1]十二烷基、金刚烷基或螺[3.3]庚烷基等。碳环可以被取代,当被取代时,取代基优选为1至5个,独立地选自F、Cl、Br、I、=O、烷基、烯基、炔基、烷氧基、烷巯基、烷基氨基、巯基、羟基、硝基、氰基、氨基、烷基酰基氨基、环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷基巯基、羟基烷基、羧酸、羧酸酯或杂环烷基巯基。
“芳基”是指取代的或未取代的6至14元环状芳香基团,包括单环芳香基和稠环芳香基;优选6至14元芳香环,进一步优选6至10元芳香环,其非限制性实例包括苯基、萘基、蒽基和菲基;所述芳基环可以稠合于杂芳基、杂环基或环烷基环上,其中与母体结构连接在一起的环为芳基环,非限制性实施例包含:
当被取代时,取代基为1至5个选自F、Cl、Br、I、烷基、环烷基、烷氧基、卤代烷基、硫醇、羟基、硝基、巯基、氨基、氰基、异氰基、芳基、杂芳基、杂环基、桥环基、螺环基、并环基、羟基烷基、=O、羰基、醛、羧酸、羧酸酯芳基硫基、硫代羰基或硅烷基等。
“杂芳基”是指取代或未取代的5至14元芳香环,且含有1至5个选自N、O或S(=O)n原子或基团,优选5至10元杂芳香环,进一步优选5至6元;杂芳基的非限制性实施例包括但不限于吡啶基、呋喃基、噻吩基、吡啶基、吡喃基、N-烷基吡咯基、嘧啶基、吡嗪基、哒嗪基、咪唑基、哌啶基、吗啉、硫代吗啉、1,3-二噻烷、苯并咪唑、哌叮基、苯并咪唑、苯并吡啶、吡咯并吡啶;所述杂芳基环可以稠合于芳基、杂环基或环烷基环上,其中与母体结构连接在一起的环为杂芳基环,非限制性实施例包含
当被取代时,取代基为1至5个选自F、Cl、Br、I、烷基、环烷基、烷氧基、卤代烷基、硫醇、羟基、硝基、巯基、氨基、氰基、异氰基、芳基、杂芳基、杂环基、桥环基、螺环基、并环基、羟基烷基、=O、羰基、醛、羧酸、羧酸酯芳基硫基、硫代羰基或硅烷基等。
“氨基酸的侧链基团”,氨基酸是指含有氨基和羧基的一类有机化合物的通称,其通式结构为所述的“氨基酸的侧链基团”是指此处的L基团,非限定实施例包括但不限于甘氨酸的侧链基团为H、丙氨酸的侧链基团为甲基、苯丙氨酸的侧链基团为苄基、缬氨酸的侧链基团为异丙基等。
“任选”或“任选地”是指随后所描述的事件或环境可以但不必须发生,该说明包括该事件或环境发生或不发生的场合,如:“任选被F取代的烷基”指烷基可以但不必须被F取代,说明包括烷基被F取代的情形和烷基不被F取代的情形。
“取代”是指基团中一个或多个氢原子被其它基团取代的情形,如果所述的基团被氢原子取代,形成的基团与被氢原子取代的基团相同。基团被取代的情形,例如氨基、C1-4烷基、C1-4烷氧基、C3-6碳环、3至6元杂环任选进一步被0至4个选自H、F、Cl、Br、I、羟基、氰基、氨基、C1-4烷基或C1-4烷氧基的取代基所取代,形成的基团包括但不限于甲基、氯甲基、三氯甲基、羟基甲基、-CH2OCH3、-CH2SH、-CH2CH2CN、-CH2NH2、-NHOH、-NHCH3、-OCH2Cl、-OCH2OCH2CH3、-OCH2CH2NH2、-OCH2CH2SH、-OCH2CH2OH、1-羟基环丙基、2-羟基环丙基、2-氨基环丙基、4-甲基呋喃基、2-羟基苯基、4-氨基苯基、苯基。
“取代或未取代的”是指基团可以被取代或不被取代的情形,若在本发明中没有指出基团可以被取代,则表示该基团为未取代的情形。
“作为选择”是指“作为选择”之后的方案与“作为选择”之前的方案为并列关系,而不是在前方案中的进一步选择情形。
“各自独立的选自”是指各取代基可以相同或不同,甚至在同一实施方案中用同一取代基符号表示的不同取代基也可以相同或不同,譬如所述“R1a、R1b、R1e、R1f和R1g各自独立的选自H、OH、C1-4烷基或氨基酸的侧链基团”,则表示即便是同一具体化合物上不同碳原子上的R1a(或者R1b、R1e、R1f)可以相同或不同,再具体譬如R1选自(CR1aR1b)nXC(=O)C1-6烷基时,当n大于1时,不同C上的R1a之间可以相同或不同,不同C上的R1b之间也可以相同或不同。
“药学上可接受的盐”或“其药学上可接受的盐”指的是保持游离酸或游离碱的生物有效性和特性,且所述的游离酸通过与无毒的无机碱或有机碱,或所述的游离酸通过与无毒的无机酸或有机酸反应获得的那些盐。
具体实施方式
以下通过具体实施例详细说明本发明的实施过程和产生的有益效果,旨在帮助阅读者更好地理解本发明的实质和特点,不作为对本案可实施范围的限定。
化合物的结构是通过核磁共振(NMR)或(和)质谱(MS)来确定的。NMR位移(δ)以10-6(ppm)的单位给出。NMR的测定是用(BrukerAvanceIII400和BrukerAvance300)核磁仪,测定溶剂为氘代二甲基亚砜(DMSO-d6),氘代氯仿(CDCl3),氘代甲醇(CD3OD),氘代乙腈(CD3CN),内标为四甲基硅烷(TMS)。
MS的测定用(Agilent6120B(ESI)和Agilent6120B(APCI))。
HPLC的测定使用安捷伦1260DAD高压液相色谱仪(ZorbaxSB-C18100×4.6mm)。
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板,薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm~0.20mm,薄层层析分离纯化产品采用的规格是0.4mm~0.5mm。
柱层析一般使用烟台黄海硅胶200~300目硅胶为载体。
本发明的己知的起始原料可以采用或按照本领域已知的方法来合成,或可购买于泰坦科技、安耐吉化学、上海德默、成都科龙化工、韶远化学科技、百灵威科技等公司。
BOC:叔丁氧基羰基;
DMAP:4-二甲氨基吡啶;
DCC:二环己基碳二亚胺;
EDCI:N,N-羰基二咪唑。
实施例1
[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]咪唑-1-甲酸酯(化合物1)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]imidazole-1-carboxylate
将(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-醇(1a)(20.0g,57.2mmol)溶于二氯甲烷(200mL)中,加入N'N-羰基二咪唑(18.5g,114.4mmol),50℃下反应2小时。向上述反应液中加入水(200mL×3)洗涤,无水硫酸钠干燥,减压浓缩得到白色固体状的[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]咪唑-1-甲酸酯(化合物1)(22.4g,产率88%)。
MSm/z(ESI):444.2[M+1]。
1HNMR(400MHz,CDCl3)δ8.63(d,1H),8.47(dd,1H),8.14(s,1H),7.65(d,1H),7.42(s,1H),7.23(dd,1H),7.07(s,1H),6.08–5.94(m,1H),5.49(d,1H),4.96–4.77(m,1H),2.53(m,2H),2.28(m,1H),2.08(m,4H),1.97(m,1H),1.83–1.49(m,7H),1.24(m,2H),1.13(s,3H),1.06(s,3H)。
实施例2
[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]3-甲基磺酰基丙基碳酸酯(化合物2)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]3-methylsulfonylpropylcarbonate
第一步:3-甲基磺酰基丙基-1-醇(2b)
3-methylsulfonylpropan-1-ol
将3-甲基巯基丙基-1-醇(2a)(40.0g,38.0mmol)溶于二氯甲烷(400mL)中,0℃下分小份加入间氯过氧苯甲酸(196.7g,114.0mmol),室温条件下反应12小时。将反应液过滤,滤液用水(200mL×2)洗涤,水层用二氯甲烷/异丙醇(v/v=1:1,200mL×2)萃取,无水硫酸钠干燥,减压浓缩得到无色液体3-甲基磺酰基丙基-1-醇(2b)(15.1g,产率38%)。
第二步:[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]3-甲基磺酰基丙基碳酸酯(化合物2)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]3-methylsulfonylpropylcarbonate
将3-甲基磺酰基丙基-1-醇(2b)(1.2g,8.5mmol)溶于四氢呋喃(25mL)中,0℃下分小份加氢化钠(wt=60%,338mg,8.5mmol),0℃下反应30分钟,滴加[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]咪唑-1-甲酸酯(化合物1)(2.5g,5.6mmol)的二氯甲烷(10mL)溶液,升至室温反应10分钟,加入水(50mL)淬灭反应,用二氯甲烷(100mL×2)萃取反应,无水硫酸钠干燥,减压浓缩,残留物用硅胶柱层析分离纯化(石油醚/乙酸乙酯(v/v)=1:2)得到白色固体的[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]3-甲基磺酰基丙基碳酸酯(化合物2)(1.4g,产率47%)。
MSm/z(ESI):498.2[M-CH3]。
1HNMR(400MHz,CDCl3)δ8.62(s,1H),8.46(d,1H),7.66(d,1H),7.23(dd,1H),6.00(s,1H),5.45(d,1H),4.63–4.42(m,1H),4.36–4.19(m,2H),2.88–2.72(m,2H),2.59(s,3H),2.46–2.35(m,2H),2.32–2.25(m,1H),2.25–2.15(m,2H),2.13–2.00(m,3H),1.93(m,2H),1.80–1.55(m,6H),1.49(m,1H),1.21–1.11(m,2H),1.08(s,3H),1.05(s,3H)。
实施例3
[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]2-吗啉乙基碳酸酯(化合物3)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]2-morpholinoethylcarbonate
将N-(2-羟乙基)吗啉(3a)(0.93g,6.7mmol)溶于四氢呋喃(20mL)中,0℃下分小份加氢化钠(wt=60%,270mg,6.7mmol),0℃下反应30分钟,滴加[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]咪唑-1-甲酸酯(化合物1)(2.0g,4.5mmol)的二氯甲烷(10mL)溶液,升至室温反应10分钟,加入水(50mL)淬灭反应,用二氯甲烷(100mL×2)萃取,无水硫酸钠干燥,减压浓缩,残留物用硅胶柱层析分离纯化(石油醚/乙酸乙酯(v/v)=1:2)得到白色固体的[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]2-吗啉乙基碳酸酯(化合物3)(0.9g,产率40%)。
MSm/z(ESI):507.3[M+H]。
1HNMR(400MHz,CDCl3)δ8.62(d,1H),8.46(dd,1H),7.65(m,1H),7.22(dd,1H),5.99(dd,1H),5.44(d,1H),4.49(m,1H),4.27(t,2H),3.81–3.64(m,4H),2.68(m,2H),2.55(s,4H),2.49–2.36(m,2H),2.27(m,1H),2.13–2.01(m,3H),1.91(m,2H),1.77–1.44(m,7H),1.17(m,2H),1.08(s,3H),1.05(s,3H)。
实施例4
[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基](3R)-四氢呋喃-3-基碳酸酯(化合物4)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl](3R)-tetrahydrofuran-3-ylcarbonate
将(R)-(-)-3-羟基四氢呋喃(4a)(0.59g,6.7mmol)溶于四氢呋喃(20mL)中,0℃下分小份加氢化钠(wt=60%,270mg,6.7mmol),0℃下反应30分钟,滴加[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]咪唑-1-甲酸酯(化合物1)(2.0g,4.5mmol)的二氯甲烷(10mL)溶液,升至室温反应10分钟,加入水(50mL)淬灭反应,用二氯甲烷(100mL×2)萃取,无水硫酸钠干燥,减压浓缩,残留物用硅胶柱层析分离纯化(石油醚/乙酸乙酯(v/v)=2:1),得到白色固体的[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基](3R)-四氢呋喃-3-基碳酸酯(化合物4)(1.1g,产率52%)。
MSm/z(ESI):464.1[M+H]。
1HNMR(400MHz,CDCl3)δ8.63(d,1H),8.47(m,1H),7.69(m,1H),7.28(s,1H),6.02(m,1H),5.44(d,1H),5.30–5.12(m,1H),4.49(m,1H),4.02–3.77(m,4H),2.49–2.35(m,2H),2.28(m,1H),2.21–2.02(m,5H),1.91(m,2H),1.81–1.42(m,7H),1.21–1.12(m,2H),1.08(s,3H),1.05(s,3H)。
实施例5
[(3aS,4R,6aR)-2,3,3a,4,5,6a-六氢呋喃并[2,3-b]呋喃-4-基][(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]碳酸酯(化合物5)
[(3aS,4R,6aR)-2,3,3a,4,5,6a-hexahydrofuro[2,3-b]furan-4-yl][(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]carbonate
将(3R,3aS,6aR)-六氢呋喃并[2,3-b]呋喃-3-醇(5a)(0.59g,6.7mmol)溶于四氢呋喃(20mL)中,0℃下分小份加氢化钠(wt=60%,270mg,6.7mmol),0℃下反应30分钟,滴加[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]咪唑-1-甲酸酯(化合物1)(2.0g,4.5mmol)的二氯甲烷(10mL)溶液,升至室温反应10分钟,加水(50mL)淬灭反应,用二氯甲烷(100mL×2)萃取,无水硫酸钠干燥,减压浓缩,残留物用硅胶柱层析分离纯化(石油醚/乙酸乙酯(v/v)=2:1),得到白色固体的[(3aS,4R,6aR)-2,3,3a,4,5,6a-六氢呋喃并[2,3-b]呋喃-4-基][(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]碳酸酯(化合物5)(1.5g,产率66%)。
MSm/z(ESI):506.1[M+H]。
1HNMR(400MHz,CDCl3)δ8.63(d,1H),8.48(dd,1H),7.75(d,1H),7.31(dd,1H),6.05(dd,1H),5.73(d,1H),5.45(d,1H),5.12(m,1H),4.59–4.43(m,1H),4.15–4.03(m,1H),3.96(m,,2H),3.81(m,1H),3.18–3.00(m,1H),2.42(m,2H),2.29(m,1H),2.16–2.06(m,4H),2.00–1.82(m,3H),1.79–1.47(m,7H),1.17(m,2H),1.08(s,3H),1.05(s,3H)。
实施例6
[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]2,2,2-三氟乙基碳酸酯(化合物6)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]2,2,2-trifluoroethylcarbonate
将2,2,2-三氟乙醇6a(670mg,6.7mmol)溶于四氢呋喃(20mL)中,60℃下加入碳酸钾(922mg,6.7mmol),将[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]2-咪唑甲酸酯(化合物1)(1.5g,3.4mmol)加至反应体系60℃反应6小时,加水(50mL)淬灭反应,二氯甲烷(100mL×2)萃取反应,无水硫酸钠干燥,减压浓缩干,用硅胶柱层析分离纯化(石油醚/乙酸乙酯(v/v)=3:1),得到白色固体的[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]2,2,2-三氟乙基碳酸酯(化合物6)(1.2g,产率75%)。
MSm/z(ESI):476.1[M+H]。
1HNMR(400MHz,CDCl3)δ8.62(d,1H),8.56–8.42(m,1H),7.68(d,1H),7.26–7.21(m,1H),6.14–5.84(m,1H),5.46(d,1H),4.65–4.37(m,3H),2.44(m,2H),2.28(m,1H),2.14–1.94(m,4H),1.93–1.84(m,1H),1.81–1.44(m,7H),1.17(m,2H),1.08(s,,3H),1.05(s,3H)。
实施例7
(2,3-二氢-1H-茚-5-基-)[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]碳酸酯(化合物7)
(2,3-dihydro-1H-inden-5-yl)[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]carbonate
室温条件下,将茚满-5-醇(7a)(45mg,0.23mmol)加入到乙腈(10mL)中,再加入碳酸钾(93mg,0.67mmol),搅拌20分钟后,加入[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]咪唑-1-甲酸酯(化合物1)(100mg,0.23mmol),室温搅拌反应4小时。向反应液中加入水(10mL),用二氯甲烷(10mL×3)萃取,合并有机相,有机相用无水硫酸钠干燥,减压浓缩,残留物用硅胶柱色谱分离(石油醚:乙酸乙酯(v/v)=6:1)得白色固体(2,3-二氢-1H-茚-5-基-)[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]碳酸酯(化合物7)(50mg,产率43%)。
1HNMR(400MHz,CDCl3)δ8.63(s,1H),8.47(s,1H),7.70(d,1H),7.26(dd,1H),7.18(s,1H),7.02(s,2H),6.91(m,1H),6.02(m,1H),5.46(d,1H),4.63–4.53(m,1H),2.89(m,4H),2.84–1.91(m,2H),2.08(m,1H),2.19–1.43(m,13H),1.35–1.24(m,2H),1.15-1.05(m,3H),0.91-0.83(m,3H)。
MSm/z(ESI):508.5[M-H]。
实施例8
[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]2-(叔丁氧羰基氨基)-3-丁炔酸酯(化合物8)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]2-(tert-butoxycarbonylamino)but-3-ynoate
第一步:2-叔丁氧羰基氨基-4-丁炔酸(8b)
2-(tert-butoxycarbonylamino)pent-4-ynoicacid
室温下,将二苯亚甲基甘氨酸乙酯(8a)(13.3g,0.05mol),炔丙基苯磺酸(12.2g,0.06mol),碳酸铯(53g,0.15mol),四丁基溴化铵(1.6g,5mmol)混悬于甲基叔丁基醚300mL中,升温至50℃反应过夜,冷却,倾出上清液,固体水溶解后,用甲基叔丁基醚(100mL×2)萃取,合并有机层,减压浓缩至剩余约1L,加入浓盐酸65mL和水250mL,室温搅拌2小时。静置分层,水层用甲基叔丁基醚(100mL×2)洗涤,加入氢氧化钠(8.0g,0.2mol),温度小于60℃反应5小时后,加入二碳酸二叔丁酯(13.1g,0.06mol),室温反应3小时。将反应液分液,水层用甲基叔丁基醚(MTBE)(1L×2)洗涤,弃去有机层,水层冷却,保温0-10℃滴入盐酸,调pH至3-4,乙酸乙酯(100mL×2)萃取,合并有机层,饱和氯化钠(300mL)洗涤,无水硫酸钠干燥,过滤,减压浓缩,得粗品化合物2-叔丁氧羰基氨基-4-丁炔酸(8b)(10.66g,100%)。
第二步:[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]2-(叔丁氧羰基)氨基-3-丁炔酸酯(化合物8)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]2-(tert-butoxycarbonylamino)but-3-ynoate
室温下,将2-叔丁氧羰基氨基-4-丁炔酸(8b)(1.5g,6.86mmol)溶于二氯甲烷20ml中,加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI)(2.0g,10.30mmol)和4-二甲氨基吡啶(DMAP)(140mg,1.14mmol),室温搅拌5分钟后,加入阿比特龙(2.0g,5.72mmol)后,室温反应过夜。浓缩,残余物用硅胶柱色谱分离(石油醚/乙酸乙酯(v/v)=4:1)得标题化合物[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]2-(叔丁氧羰基)氨基-3-丁炔酸酯(化合物8)(2.2g,72%)。
1HNMR(400MHz,CDCl3)δ8.62(d,1H),8.46(dd,1H),7.65(m,1H),7.22(m,1H),6.00(dd,1H),5.43(d,2H),4.71(m,1H),4.43(m,1H),2.74(s,1H),2.38(m,2H),2.27(m,1H),2.06(m,3H),1.90(m,2H),1.64(m,6H),1.48(m,11H),1.07(m,9H)。
实施例9
[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]2-氨基-3-丁炔酸酯(化合物9)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]2-amino-3-ynoate
将[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]2-(叔丁氧羰基)氨基-3-丁炔酸酯(化合物8)(1.8g,3.31mmol)溶于乙酸乙酯(20mL)中,加入4N的盐酸乙酸乙酯(10mL)溶液,室温反应1.5小时。向反应液中滴加浓氨水,调节pH>10,分出有机层,水层用乙酸乙酯(100mL)萃取,合并有机层,有机层用饱和氯化钠洗涤一次,无水硫酸钠干燥,过滤,减压浓缩,得白色粉末状固体的[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]2-氨基-3-丁炔酸酯(化合物9)(1.2g,82%)。
1HNMR(400MHz,DMSO)δ8.59(d,1H),8.43(dd,1H),7.76(m,1H),7.33(dd,1H),6.11(dd,1H),5.40(s,1H),4.51(m,1H),3.46(m,1H),2.85(m,1H),2.45(m,2H),2.31(m,2H),2.22(m,1H),2.05(m,4H),1.83(m,5H),1.61(m,4H),1.41(m,1H),1.08(m,8H)。
MSm/z(ESI):445.2.[M+H]。
实施例10
[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]3-苯基丙酸酯(化合物10)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]3-phenylpropanoate
室温下,将氢化肉桂酸(1.03g,6.86mmol)溶于二氯甲烷(20ml)中,加入N,N-羰基二咪唑(EDCI)(2.0g,10.30mmol)和4-二甲氨基吡啶(DMAP)(140mg,1.14mmol),室温搅拌5分钟,加入(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-醇(1a)(2.0g,5.72mmol),室温反应3小时。将反应液浓缩,残余物硅胶柱色谱分离(石油醚/乙酸乙酯(v/v)=4:1)得白色粉末状固体的[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]3-苯基丙酸酯(化合物10)(780mg,28%)。
1HNMR(400MHz,CDCl3)δ8.62(d,1H),8.46(d,1H),7.66(m,1H),7.25(m,6H),6.00(dd,1H),5.41(d,1H),4.62(m,1H),2.95(t,2H),2.61(t,2H),2.28(m,3H),2.06(m,3H),1.67(m,9H),1.12(m,8H)。
MSm/z(ESI):482.1.[M+H]。
实施例11
O4-[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]O1-甲基丁二酸酯(化合物11)
O4-[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]O1-methylbutanedioate
第一步:4-甲氧基-4-氧代丁酮酸(11b)
4-methoxy-4-oxo-butanoicacid
将丁二酸酐(11a)(10.0g,0.1mol)溶于甲醇20mL中,加热至回流反应3小时,浓缩得白色固体4-甲氧基-4-氧代丁酮酸(11b)(13.2g,100%)。
第二步:O4-[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]O1-甲基丁二酸酯(化合物11)
O4-[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]O1-methylbutanedioate
室温下,将4-甲氧基-4-氧代丁酮酸(11b)(1.7g,12.88mmol)溶于二氯甲烷20ml中,加入N,N-羰基二咪唑(EDCI)(3.3g,17.16mmol)和4-二甲氨基吡啶(DMAP)(314mg,2.57mmol),室温搅拌5分钟后,加入(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-醇(1a)(3.0g,8.58mmol),室温反应5小时。将反应液浓缩,残余物用硅胶柱色谱分离(石油醚/乙酸乙酯(v/v)=4:1)得白色粉末状固体O4-[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]O1-甲基丁二酸酯(化合物11)(2.1g,53%)。
1HNMR(400MHz,CDCl3)δ8.62(d,1H),8.46(dd,1H),7.67(d,1H),7.24(dd,1H),6.00(m,1H),5.42(d,1H),4.64(m,1H),3.70(s,3H),2.62(m,4H),2.30(m,3H),2.06(m,3H),1.86(m,2H),1.63(m,7H),1.12(m,8H)。
MSm/z(ESI):[M+H]+:464.1。
实施例12
[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基](2E,4E)-2,4-二烯己酸酯(化合物12)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl](2E,4E)-hexa-2,4-dienoate
室温下,将山梨酸(12a)(770mg,6.87mmol)溶于二氯甲烷(20mL)中,加入二环己基碳二亚胺(DCC)(2.12g,10.30mmol),4-二甲氨基吡啶(DMAP)(140mg,1.14mmol)和碘化钾(190mg,1.14mmol),室温搅拌5分钟后,加入(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-醇(1a)(2.0g,5.72mmol),室温反应5小时。将反应液过滤,滤液浓缩,残余物用硅胶柱色谱分离(石油醚/乙酸乙酯(v/v)=4:1)得淡黄色色粉末状固体[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基](2E,4E)-2,4-二烯己酸酯(化合物12)(1.1g,42%)。
1HNMR(400MHz,CDCl3)δ8.63(d,1H),8.46(dd,1H),7.67(m,1H),7.24(m,1H),6.16(m,2H),6.01(dd,1H),5.76(d,1H),5.43(d,1H),4.69(m,1H),2.38(dt,2H),2.28(ddd,1H),2.07(m,3H),1.89(m,5H),1.68(m,6H),1.50(m,1H),1.14(m,8H)。
实施例13
[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基](2S)-2-羟基-2-苯基乙酸酯(化合物13)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl](2S)-2-hydroxy-2-phenyl-acetate
第一步:(2S)-2-[叔丁基(二甲基)硅基]氧基-2-苯基乙酸(13b)
(2S)-2-[tert-butyl(dimethyl)silyl]oxy-2-phenyl-aceticacid
将叔丁基二甲基氯硅烷(11.0g,72.36mmol)溶于乙腈(30mL)中,加入L-扁桃酸(13a)(3.0g,19.72mmol),降温至0℃,缓慢加入1,8-二氮杂二环十一碳-7-烯(DBU)(10.4g,69.02mmol),升至室温反应过夜。反应液用正己烷(50mL)萃取,有机层浓缩,残余物溶于甲醇(30mL)、四氢呋喃(15mL)和水(10mL)的混合溶剂中,加入2N氢氧化钠水溶液(40mL),反应1.5小时,加1N盐酸调接pH<6,加乙酸乙酯(50mL)萃取,有机层用饱和食盐水(100mL)洗涤,无水硫酸钠干燥,浓缩,残余物用硅胶硅胶柱色谱分离(石油醚/乙酸乙酯(v/v)=4:1)得无色油状物(2S)-2-[叔丁基(二甲基)硅基]氧基-2-苯基-乙酸(13b)(3.1g,60%)。
第二步:[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基](2S)-2-[叔丁基(二甲基)硅基]氧基-2-苯基乙酸酯(13c)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl](2S)-2-[tert-butyl(dimethyl)silyl]oxy-2-phenylacetate
室温下,将4-甲氧基-4-氧-丁酮酸(13b)(2.8g,10.53mmol)溶于二氯甲烷20mL中,加入N’N-羰基二咪唑(EDCI)(2.2g,11.58mmol)和4-二甲氨基吡啶(DMAP)(128mg,1.05mmol),室温搅拌5分钟后,加入阿比特龙(1.84g,5.26mmol)后,室温反应5h。浓缩,残余物用硅胶柱色谱分离(石油醚/乙酸乙酯(v/v)=4:1)得白色粉末状固体[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊基[a]并菲-3-基](2S)-2-[叔丁基(二甲基)硅基]氧基-2-苯基乙酸酯(13c)(800mg,25%)。
第三步:[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基](2S)-2-羟基-2-苯基乙酸酯(化合物13)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl](2S)-2-hydroxy-2-phenyl-acetate
室温下,将[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基](2S)-2-[叔丁基(二甲基)硅基]氧基-2-苯基乙酸酯(13c)(800mg,1.34mmol)溶于四氢呋喃(10mL)中,加入四丁基氟化氨(TBAF)(1.05g,4.01mmol),室温搅拌30分钟,加入冰水(10mL)终止反应后,加乙酸乙酯(30mL×3)萃取,有机层用饱和食盐水清洗,无水硫酸钠干燥浓缩,残余物硅胶柱色谱分离(石油醚/乙酸乙酯(v/v)=4:1)得白色粉末状固体[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基](2S)-2-羟基-2-苯基乙酸酯(化合物13)(500mg,77%)。
1HNMR(400MHz,CDCl3)δ8.61(d,1H),8.45(d,1H),7.66(d,1H),7.36(m,5H),7.23(dd,1H),6.00(m,1H),5.39(dd,1H),5.14(s,1H),4.69(m,1H),3.57(m,1H),2.38(dd,1H),2.24(m,2H),2.06(m,3H),1.71(m,9H),1.11(m,8H)。
MSm/z(ESI):484.2[M+H]。
实施例14
[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]1,3-二氧六环-5-基碳酸酯(化合物14)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]1,3-dioxan-5-ylcarbonate
无水无氧,氮气保护下,将甘油缩甲醛(1.06g,10.14mmol)溶于四氢呋喃(20mL)中,冷却至0℃,加入氢化钠(wt=60%,406mg,10.14mmol),搅拌30分钟后,将(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]1H-咪唑-1-甲酸酯(化合物1)(3.0g,6.76mmol)的二氯甲烷(10ml)溶液缓慢的滴入反应液中,升温至室温反应30分钟,加入冰水10(mL)终止反应后,加乙酸乙酯(30mL×3)萃取,有机层用饱和食盐水清洗,无水硫酸钠干燥浓缩,残余物硅胶柱色谱分离(石油醚/乙酸乙酯(v/v)=4:1)得白色粉末状固体[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]1,3-二氧六环-5-基碳酸酯(化合物14)(1.4g,44%)。
1HNMR(400MHz,CDCl3)δ8.62(s,1H),8.46(d,1H),7.65(dt,1H),7.23(dd,1H),6.00(dd,1H),5.44(d,1H),5.05(s,1H),4.90(s,1H),4.50(m,1H),4.30(dd,1H),4.18(m,2H),3.99(m,1H),3.74(m,1H),2.43(m,2H),2.27(m,1H),2.07(m,3H),1.98(m,1H),1.89(m,1H),1.67(m,6H),1.49(m,1H),1.17(m,1H),1.09(m,7H)。
MSM/Z(ESI):480.2[M+H]。
实施例15
[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基][(3S,6S)-3-羟基-2,3,3a,5,6,6a-六氢呋喃[3,2-b]呋喃-6-基]碳酸酯(化合物15)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl][(3S,6S)-3-hydroxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl]carbonate
第一步:(3S,6S)-6-[叔丁基(二甲基)硅基]氧基-2,3,3a,5,6,6a-六氢呋喃并[3,2-b]呋喃-3-醇(15b)
(3S,6S)-6-[tert-butyl(dimethyl)silyl]oxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol
将异甘露糖醇(10.0g,68.43mmol)溶于N,N-二甲基甲酰胺(15mL)中,加入咪唑(7.0g,0.1mol),将叔丁基二甲基氯硅烷(15.5g,0.1mol)的N,N-二甲基甲酰胺溶液(15mL)缓慢的滴入反应液中,室温搅拌3小时,加水(100mL)终止反应,用乙酸乙酯(50ml×3)萃取,合并有机相,有机层用饱和食盐水洗涤,无水硫酸钠干燥浓缩,残余物用硅胶柱色谱分离(石油醚/乙酸乙酯(v/v)=5:1)得白色粉末状固体(3S,6S)-6-[叔丁基(二甲基)硅基]氧基-2,3,3a,5,6,6a-六氢呋喃[3,2-b]呋喃-3-醇(15b)(5.9g,34%)。
第二步:[(3S,6S)-6-[叔丁基(二甲基)硅基]氧基-2,3,3a,5,6,6a-六氢呋喃[3,2-b]呋喃-3-基][(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]碳酸酯(15c)
[(3S,6S)-6-[tert-butyl(dimethyl)silyl]oxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-yl][(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]carbonate
无水无氧,氮气保护下,将(3S,6S)-6-[叔丁基(二甲基)硅基]氧基-2,3,3a,5,6,6a-六氢呋喃[3,2-b]呋喃-3-醇(15b)(879mg,3.38mmol)溶于四氢呋喃(10mL)中,0℃,加入氢化钠(wt=60%,135mg,3.38mmol),搅拌30分钟后,将(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]1H-咪唑-1-碳酸酯(1.0g,2.25mmol)的二氯甲烷溶液(10mL)缓慢的滴入反应液中,升温至室温反应30分钟,加入冰水(10mL)终止反应后,加乙酸乙酯(30mL×3)萃取,有机层用饱和食盐水清洗,无水硫酸钠干燥浓缩,残余物用硅胶柱色谱分离(石油醚/乙酸乙酯(v/v)=4:1)得白色粉末状固体[(3S,6S)-6-[叔丁基(二甲基)硅基]氧基-2,3,3a,5,6,6a-六氢呋喃[3,2-b]呋喃-3-基][(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]碳酸酯(15c)(1.3g,91%)。
第三步:[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基][(3S,6S)-3-羟基-2,3,3a,5,6,6a-六氢呋喃[3,2-b]呋喃-6-基]碳酸酯(化合物15)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl][(3S,6S)-3-hydroxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl]carbonate
室温下,将6-[叔丁基(二甲基)硅基]氧基-2,3,3a,5,6,6a-六氢呋喃[3,2-b]呋喃-3-基][(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]碳酸酯(15c)(1.3g,2.05mmol)溶于四氢呋喃(15ml)中,加入四丁基氟化氨(TBAF)(1.94g,6.14mmol),室温搅拌30分钟,加入冰水(10mL)终止反应后,加乙酸乙酯(30ml×3)萃取,合并有机相,有机层用饱和食盐水清洗,无水硫酸钠干燥浓缩,残余物用硅胶柱色谱分离(石油醚/乙酸乙酯(v/v)=4:1)得白色粉末状固体[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基][(3S,6S)-3-羟基-2,3,3a,5,6,6a-六氢呋喃[3,2-b]呋喃-6-基]碳酸酯(化合物15)(530mg,77%)。
1HNMR(400MHz,CDCl3)δ8.63(d,1H),8.47(dd,1H),7.70(d,1H),7.27(m,1H),6.02(m,1H),5.45(m,1H),5.07(dd,1H),4.75(t,1H),4.50(m,2H),4.30(m,1H),4.09(dd,1H),4.02(dd,1H),3.93(dd,1H),3.59(dd,1H),2.48(m,3H),2.28(m,1H),2.07(m,3H),1.96(m,1H),1.89(m,1H),1.67(m,6H),1.50(m,1H),1.17(m,1H),1.09(m,7H)。
MSm/z(ESI):522.1.[M+H]。
实施例16
[[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]N-苯甲酰基氨基甲酸酯(化合物16)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]N-benzoylcarbamate
室温下,将苯甲酰异氰酸酯(16a)(1.1g,10.53mmol)溶于四氢呋喃(20mL)中,加入(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-醇(1a)(2.0g,5.72mmol),室温反应3小时。将反应液浓缩,残余物用硅胶柱色谱分离(石油醚/乙酸乙酯(v/v)=4:1)得白色粉末状固体[[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]N-苯甲酰基氨基甲酸酯(化合物16)(1.3g,46%)。
1HNMR(400MHz,CDCl3)δ8.62(d,1H),8.46(dd,1H),8.04(s,1H),7.82(m,2H),7.69(m,1H),7.59(t,1H),7.48(t,2H),7.26(m,1H),6.02(dd,1H),5.45(m,1H),4.71(m,1H),2.50(m,1H),2.41(dd,1H),2.29(m,1H),2.06(m,4H),1.91(m,1H),1.68(m,6H),1.51(m,1H),1.20(m,1H),1.10(m,7H)。
MSM/Z(ESI):497.3[M+H]。
实施例17
[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]4-乙酰氧基丁酸(化合物17)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]4-acetoxybutanoate
第一步:4-溴丁酸苄基酯(17b)
benzyl4-bromobutanoate
将4-溴丁酸(17a)(8.51g,51mmol,德默)溶于乙腈(70mL)中,氮气保护下,依次加入苯甲醇(6.8mL,66mmol)和对甲基苯磺酸(0.97g,5.1mmol),90℃反应过夜,体系加入饱和碳酸氢钠(50mL)和乙酸乙酯(200mL),分液,有机相用饱和食盐水(150mL)洗涤,有机相用无水硫酸钠干燥,过滤,将滤液减压浓缩,残留物用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(v/v)=100:1)得到无色油状的4-溴丁酸苄基酯(17b)(5.6g,产率43.0%)。
1HNMR(400MHz,CDCl3)δ7.40–7.29(m,5H),5.13(s,2H),3.46(t,2H),2.55(dd,2H),2.24–2.14(m,2H)。
第二步:4-乙酰氧基丁酸苄酯(17c)
benzyl4-acetoxybutanoate
将4-溴丁酸苄基酯(17b)(5.4g,21mmol)溶于乙腈(125mL)中,室温搅拌下缓慢加入乙酸钾(4.12g,42mmol),氮气保护,升温至90℃搅拌过夜,过滤,滤液浓缩,得到淡黄色油状的4-乙酰氧基丁酸苄酯(17c)(4.75g,产率96%)。
1HNMR(400MHz,DMSO)δ7.41–7.31(m,5H),5.11(s,2H),4.03(t,2H),2.45(t,2H),1.98(s,3H),1.92–1.81(m,2H)。
第三步:4-乙酰氧基丁酸(17d)
4-acetoxybutanoicacid
向反应瓶中依次加入4-乙酰氧基丁酸苄酯(17c)(4.7g,20mmol)、钯/炭(0.24g,钯含量wt=10%)和乙醇(50mL),在氢气氛下,室温反应4小时,过滤,将滤液减压浓缩,得到无色油状的4-乙酰氧基丁酸(17d)(2.8g,产率96.6%,)。
1HNMR(400MHz,CDCl3)δ4.13(t,2H),2.46(t,2H),2.05(s,3H),2.02–1.94(m,2H)。
第四步:[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]4-乙酰氧基丁酸(化合物17)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]4-acetoxybutanoate
向反应瓶中依次加入4-乙酰氧基丁酸(17d)(0.88g,6mmol)、(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-醇(1a)(1.4g,4mmol)、4-二甲氨基吡啶(DMAP)(0.15g,1.2mmol)、N,N-羰基二咪唑(EDCI)(1.15g,6mmol)和二氯甲烷(120mL),室温反应23小时,体系加入水(100mL),用二氯甲烷(100mL×3)萃取,合并有机相,有机相用无水硫酸镁干燥,过滤,将滤液减压浓缩,,残留物用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(v/v)=5:1)得到得到淡黄色油状的[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]4-乙酰氧基丁酸(化合物17)(0.7g,产率37%)。
MSm/z(ESI):478.2[M+1]。
1HNMR(400MHz,CDCl3)δ8.63(s,1H),8.47(d,1H),7.68(dt,1H),7.25(dd,1H),6.01(dd,1H),5.42(d,1H),4.64(m,1H),4.13–4.08(m,2H),2.41–2.35(m,3H),2.35–2.31(m,1H),2.28(m,1H),2.12–2.01(m,6H),2.01–1.92(m,2H),1.88(m,2H),1.83–1.45(m,7H),1.21–1.10(m,2H),1.08(s,3H),1.05(s,3H)。
实施例18
[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基](2S)-吡咯烷-2-甲酸酯(化合物18)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl](2S)-pyrrolidine-2-carboxylate
第一步:(2S)-1-叔丁氧基羰基吡咯烷-2-羧酸(18b)
(2S)-1-tert-butoxycarbonylpyrrolidine-2-carboxylicacid
将二碳酸二叔丁酯(30.8mL,144mmol)溶于四氢呋喃(150mL)中,冰浴下缓慢滴加至的L-脯氨酸(18a)(15.07g,131mmol)和饱和碳酸氢钠(200mL)体系中,室温搅拌16小时,用2N的盐酸调节pH<3,用乙酸乙酯(150mL×2)萃取,合并有机相,用无水硫酸钠干燥,过滤,减压浓缩,,得到白色固状的(2S)-1-叔丁氧基羰基吡咯烷-2-羧酸(18b)(25.18g,产率89%)。
1HNMR(400MHz,CDCl3)δ4.30(d,1H),3.45(t,2H),2.32(d,1H),2.15–1.74(m,3H),1.46(d,9H)。
第二步:O1-叔丁基O2-[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基](2S)-吡咯烷-1,2-二羧酸酯(18c)
O1-tert-butylO2-[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl](2S)-pyrro-lidine-1,2-dicarboxylate
向反应瓶中依次加入(2S)-1-叔丁氧基羰基吡咯烷-2-羧酸(18b)(2.59g,12mmol)、阿比特龙(1.68g,4.81mmol)、4-二甲氨基吡啶(DMAP)(0.18g,1.44mmol)、N,N-羰基二咪唑(EDCI)(2.3g,12mmol)和二氯甲烷(120mL),室温反应24小时,体系加入100mL水,用二氯甲烷(100mL×3)萃取,有机相用无水硫酸镁干燥,过滤,将滤液减压浓缩,残留物用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(v/v)=4:1)得到得到白色固状的O1-叔丁基O2-[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基](2S)-吡咯烷-1,2-二羧酸酯(18c)(1.6g,产率61%)。
MSm/z(ESI):547.3[M+1]。
1HNMR(400MHz,CDCl3)δ8.63(s,1H),8.47(d,1H),7.69(d,1H),7.29–7.23(m,1H),6.02(s,1H),5.42(s,1H),4.65(d,1H),4.33–4.16(m,1H),3.47(m,2H),2.42–2.12(m,4H),2.07(m,3H),2.00–1.80(m,5H),1.80–1.55(m,6H),1.49(m,1H),1.45(d,9H),1.24(d,2H),1.08(d,3H),1.05(s,3H)。
第三步:[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]-(2S)-吡咯烷-2-甲酸酯(化合物18)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl](2S)-pyrrolidine-2-carboxyl--ate
将O1-叔丁基O2-[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]-(2S)-吡咯烷-1,2-二羧酸酯(18c)(1.1g,2.0mmol)溶于二氯甲烷(20mL),冰浴,缓慢滴加三氟乙酸(4mL),加完恢复室温反应2小时。冰浴下,体系加入氨水调节pH>7,用二氯甲烷(100mL×2)萃取,有机相用无水硫酸镁干燥,过滤,将滤液减压浓缩,,残留物用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=20:1)得到得到白色固状的[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基](2S)-吡咯烷-2-甲酸酯(化合物18)(0.86g,产率88%)。
MSm/z(ESI):447.2[M+1]。
1HNMR(400MHz,CDCl3)δ8.62(d,1H),8.46(dd,1H),7.64(m,1H),7.21(m,1H),5.99(m,1H),5.42(d,1H),4.77-4.57(m,1H),3.80(m1H),3.13(m,1H),2.97(m,1H),2.36(d,2H),2.27(m,1H),2.23-2.12(m,1H),2.11-2.00(m,3H),1.93-1.54(m,11H),1.51(m,1H),1.18(m2H),1.08(s,3H),1.05(s,3H)。
实施例19
2-[[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]氧基羰基氧基]乙基(2S)-2-氨基-3-甲基-丁酸酯(化合物19)
2-[[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]oxycarbonyloxy]ethyl(2S)-2-amino-3-methyl-butanoate
第一步:2-羟基乙基(2S)-2-(叔丁氧基羰基氨基)-3-甲基-丁酸酯(19b)
2-hydroxyethyl(2S)-2-(tert-butoxycarbonylamino)-3-methyl-butanoate
向反应瓶中依次加入N-叔丁氧基羰基-L-缬氨酸(19a)(6.52g,30mmol)、乙二醇(5.0mL,90mmol)、4-二甲氨基吡啶(DMAP)(3.66g,30mmol)、二环己基碳二亚胺(DCC)(6.8g,33mmol)和二氯甲烷(100mL),室温反应5小时,体系抽滤,将滤液减压浓缩,加入100mL乙酸乙酯,用稀盐酸(100mL×2)洗涤,有机相用无水硫酸镁干燥,过滤,将滤液减压浓缩,残留物用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(v/v)=5:1)得到得到无色油状的2-羟基乙基(2S)-2-(叔丁氧基羰基氨基)-3-甲基-丁酸酯(19b)(4.4g,产率56%)。
1HNMR(400MHz,CDCl3)δ5.05(d,1H),4.38–4.22(m,2H),4.20–4.07(m,1H),3.83(t,2H),2.78(s,1H),2.14(td,1H),1.45(s,9H),0.99(d,3H),0.93(d,3H)。
第二步:2-[[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]氧基羰基氧基]乙基(2S)-2-(叔丁氧基羰基氨基)-3-甲基-丁酸酯(19c)
2-[[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]oxycarbonyloxy]ethyl(2S)-2-(tert-butoxycarbonylamino)-3-methyl-butanoate
向反应瓶中依次加入[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]咪唑-1-羧酸酯(化合物1)(2.5g,5.64mmol)、2-羟基乙基(2S)-2-(叔丁氧基羰基氨基)-3-甲基-丁酸酯(19b)(2.21g,8.45mmol)、碳酸钾(7.2g,8.45mmol)和四氢呋喃(60mL),75℃反应12小时。将反应液抽滤,滤液减压浓缩,残留物用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(v/v)=5:1)得到得到无色油状的2-[[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]氧基羰基氧基]乙基(2S)-2-(叔丁氧基羰基氨基)-3-甲基-丁酸酯(19c)(2.92g,产率81%)。
MSm/z(ESI):637.5[M+1]。
1HNMR(400MHz,CDCl3)δ8.63(d,1H),8.47(d,1H),7.69(dt,1H),7.25(m,1H),6.02(dd,1H),5.44(d,1H),5.02(d,1H),4.49(dt,1H),4.40(dt,1H),4.33(t,3H),4.26(dd,1H),2.42(m,2H),2.28(m,1H),2.15(m,1H),2.08(m,3H),1.92(m,2H),1.67(m,7H),1.45(s,9H),1.18(m,2H),1.08(s,3H),1.05(s,3H),0.97(m,3H),0.90(m,3H)。
第三步:2-[[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]氧基羰基氧基]乙基(2S)-2-氨基-3-甲基-丁酸酯(化合物19)
2-[[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]oxycarbonyloxy]ethyl(2S)-2-amino-3-methyl-butanoate
将2-[[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]氧基羰基氧基]乙基(2S)-2-(叔丁氧基羰基氨基)-3-甲基-丁酸甲酯(19c)(1.9g,2.98mmol)溶于二氯甲烷(50mL),冰浴,缓慢滴加三氟乙酸(5mL),加完恢复室温反应2小时。冰浴下,体系加入氨水调节pH>7,用二氯甲烷(100mL×2)萃取,有机相用无水硫酸镁干燥,过滤,将滤液减压浓缩,残留物用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(v/v)=4:1)得到得到浅黄色油状的2-[[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]氧基羰基氧基]乙基(2S)-2-氨基-3-甲基-丁酸酯(化合物19)(0.82g,产率51%)。
MSm/z(ESI):537.2[M+1]。
1HNMR(400MHz,CDCl3)δ8.62(d,1H),8.46(dd,1H),7.64(dt,1H),7.22(dd,1H),5.99(dd,1H),5.44(d,1H),4.50(m,1H),4.35(m,4H),3.34(d,1H),2.42(m,2H),2.27(m,1H),2.06(m,4H),1.92(m,3H),1.75(m,2H),1.62(m,4H),1.48(m,1H),1.20(m,3H),1.08(s,3H),1.05(s,3H),0.99(d,3H),0.91(d,3H)。
实施例20
[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基](3S)-吡咯-3-甲酸酯(化合物20)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl](3S)-pyrrolidine-3-carboxylate
第一步:O1-叔丁基O3-[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基](3S)-吡咯-1,3-二甲酸酯(20b)
O1-tert-butylO3-[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl](3S)-pyrrolidine-1,3-dicarboxylate
向反应瓶中依次加入(3S)-1-叔丁氧基羰基吡咯烷-3-羧酸(20a)(1.06g,3.57mmol)、(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-醇(1a)(1.68g,4.81mmol)、4-二甲氨基吡啶(DMAP)(0.18g,1.44mmol)、N’N-羰基二咪唑(EDCI)(2.3g,12mmol)和二氯甲烷(120mL),室温反应8小时,体系加入水(100mL),用二氯甲烷(100mL×3)萃取,合并有机相,有机相用无水硫酸镁干燥,过滤,将滤液减压浓缩,残留物用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(v/v)=4:1)得到得到白色固状的O1-叔丁基O3-[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基](3S)-吡咯-1,3-二甲酸酯(20b)(1.49g,产率78%)。
MSm/z(ESI):547.4[M+1]。
1HNMR(400MHz,CDCl3)δ8.62(s,1H),8.47(d,1H),7.69(dd,1H),7.25(m,1H),6.02(d,1H),5.42(d,1H),4.64(m,1H),3.50(m,4H),3.00(d,1H),2.34(m,2H),2.28(m,1H),2.07(m,5H),1.87(m,2H),1.67(m,6H),1.15(m,1H),1.47(d,9H),1.19(m,2H),1.09(s,3H),1.05(d,3H)。
第二步:[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基](3S)-吡咯-3-甲酸酯(化合物20)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl](3S)-pyrrolidine-3-carboxylate
将O1-叔丁基O3-[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基](3S)-吡咯-1,3-二甲酸酯(20b)(1.28g,2.34mmol)溶于二氯甲烷(40mL),冰浴,缓慢滴加三氟乙酸(4mL),加完恢复室温反应2小时。冰浴下,体系加入氨水调节pH>7,用二氯甲烷(100mL×2)萃取,合并有机相,有机相用无水硫酸镁干燥,过滤,将滤液减压浓缩,,残留物用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=20:1)得到得到白色固状的[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基](3S)-吡咯-3-甲酸酯(化合物20)(0.91g,产率87%)。
MSm/z(ESI):447.2[M+1]。
1HNMR(400MHz,CDCl3)δ8.62(d,1H),8.46(dd,1H),7.64(m,1H),7.21(m,1H),5.99(m,1H),5.42(d,1H),4.63(m,1H),3.13(m,3H),2.91(m,2H),2.43(m,1H),2.34(d,2H),2.27(m1H),2.04(m,5H),1.88(m,2H),1.63(m,7H),1.17(m,2H),1.09(s,3H),1.05(s,3H)。
实施例21
[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]氧基羰基氧基亚甲基2-甲基丙酸酯(化合物21)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]oxycarbonyloxymethyl2-methylpropanoate
第一步:[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]氯甲基碳酸酯(21b)
chloromethyl[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]carbonate
向反应瓶中依次加入(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-醇(1a)(4.06g,11.62mmol)、吡啶(1.55mL,19.3mmol)和二氯甲烷(120mL),冰浴下,滴加氯甲酸氯甲酯(21a)(2.1mL,23.25mmol),室温反应3小时,体系用稀盐酸调节pH为酸性,用二氯甲烷(100mL×2)萃取,合并有机相,有机相用无水硫酸镁干燥,过滤,将滤液减压浓缩,残留物用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(v/v)=5:1)得到得到白色固状的[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]氯甲基碳酸酯(21b)(2.44g,产率48%)。
1HNMR(400MHz,CDCl3)δ8.62(s,1H),8.47(d,1H),7.66(dt,1H),7.23(dd,1H),6.00(dd,1H),5.73(s,2H),5.46(d,1H),4.57(ddd,1H),2.46(ddd,2H),2.28(ddd,1H),2.13–1.95(m,4H),1.91(dt,1H),1.83–1.54(m,6H),1.49(td,1H),1.28–1.10(m,2H),1.08(d,3H),1.05(s,3H)。
第二步:[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]氧基羰基氧基亚甲基2-甲基丙酸酯(化合物21)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]oxycarbonyloxymethyl2-methyl-propanoate
向反应瓶中依次加入[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]氯甲基碳酸酯(21b)(1.33g,3.0mmol)、异丁酸(1.67mL,18mmol)、二异丙基乙胺(4mL)和N,N-二甲基甲酰胺(40mL),78℃反应1小时。将反应液用水(100mL×5)洗涤,无水硫酸镁干燥,过滤,将滤液减压浓缩,残留物用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(v/v)=15:1)得到得到白色固状的[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]氧基羰基氧基亚甲基2-甲基丙酸酯(化合物21)(0.6g,产率41%)。
MSm/z(ESI):494.1[M+1]。
1HNMR(400MHz,CDCl3)δ8.62(s,1H),8.46(d,1H),7.66(dt,1H),7.23(dd,1H),6.00(dd,1H),5.80–5.72(m,2H),5.45(d,1H),4.53(ddd,1H),2.61(dt,1H),2.50–2.36(m,2H),2.27(ddd,1H),2.08(ddd,2H),2.03–1.83(m,3H),1.83–1.40(m,8H),1.29–1.23(m,2H),1.20(s,3H),1.19(s,3H),1.08(s,3H),1.05(s,3H)。
实施例22
[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]2-(4-甲基哌嗪-1-基)乙基碳酸酯(化合物22)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]2-(4-methylpiperazin-1-yl)ethylcarbonate
将1-(2-羟乙基)-4-甲基哌嗪(22a)(1.28g,8.5mmol)溶于四氢呋喃(20mL)中,0℃下分小份加60%的氢化钠(330mg,8.5mmol),0℃下反应30分钟,滴加[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]咪唑-1-甲酸酯(化合物1)(2.5g,5.6mmol)的二氯甲烷(10mL)溶液,升至室温反应10分钟,加水(50mL)淬灭反应,用二氯甲烷(100mL×2)萃取,无水硫酸钠干燥,减压浓缩干,残留物用硅胶柱层析分离纯化(石油醚/乙酸乙酯(v/v)=1:2),得到白色固体的[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]2-(4-甲基哌嗪-1-基)乙基碳酸酯(化合物22)(1.0g,产率34%)。
MSm/z(ESI):520.2[M+H]。
1HNMR(400MHz,CDCl3)δ8.62(d,1H),8.46(dd,1H),7.70–7.56(m,1H),7.22(ddd,1H),5.99(dd,1H),5.44(d,1H),4.48(ddd,1H),4.24(t,2H),2.68(t,2H),2.64–2.38(m,10H),2.32(s,3H),2.31–2.22(m,1H),2.12–2.01(m,3H),2.01–1.85(m,2H),1.64(dddd,7H),1.20–1.06(m,5H),1.05(s,3H)。
实施例23
(2,2-二甲基-1,3-二氧杂环己烷-5-基)甲基[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]碳酸酯(化合物23)
(2,2-dimethyl-1,3-dioxan-5-yl)methyl[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]carbonate
将(2,2-二甲基-1,3-二氧杂环己烷-5-基)甲醇(23a)(745mg,5.1mmol)溶于四氢呋喃(20mL)中,60℃下加入碳酸钾(938mg,6.8mmol),将[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]咪唑-1-甲酸酯(化合物1)(1.5g,3.4mmol)加至反应体系60℃反应6小时,加水(50mL)淬灭反应,二氯甲烷(100mL×2)萃取反应,无水硫酸钠干燥,减压浓缩干,用硅胶柱层析分离纯化(石油醚/乙酸乙酯(v/v)=3:1),得到白色固体的(2,2-二甲基-1,3-二氧杂环己烷-5-基)甲基[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]碳酸酯(化合物23)(1.0g,产率56%)。
MSm/z(ESI):522.2[M+H]。
1HNMR(400MHz,CDCl3)δ8.63(d,1H),8.48(dd,1H),7.76(dd,1H),7.31(dd,1H),6.05(dd,1H),5.44(d,1H),4.49(ddd,1H),4.24(d,2H),4.02(dd,2H),3.76(dd,2H),2.52–2.33(m,2H),2.29(ddd,1H),2.14–1.86(m,6H),1.84–1.45(m,7H),1.44(s,3H),1.40(s,3H),1.31–1.06(m,5H),1.05(s,3H)。
实施例24
[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]氧基羰基氧基甲基2,2-二甲基丙酸酯(化合物24)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]oxycarbonyloxymethyl2,2-dimethylpropanoate
将三甲基乙酸(24a)(408mg,4mmol)溶于N,N-二甲基甲酰胺(15mL)中,加入碘化钠(1.79g,12mmol),二异丙基乙胺(3mL),将[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]氯甲基碳酸酯(21b)(880mg,2mmol)加至反应体系80℃反应4小时,加水(50mL)淬灭反应,二氯甲烷(100mL×2)萃取反应,水洗(100mL×2),无水硫酸钠干燥,减压浓缩干,用硅胶柱层析分离纯化(石油醚/乙酸乙酯(v/v)=3:1),得到白色固体的[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]氧基羰基氧基甲基2,2-二甲基丙酸酯(化合物24)(1.0g,产率98%)。
MSm/z(ESI):508.1[M+H]。
1HNMR(400MHz,CDCl3)δ8.62(s,1H),8.57–8.34(m,1H),7.68(t,1H),7.24(s,1H),6.01(dd,1H),5.75(d,2H),5.45(d,1H),4.63–4.44(m,1H),2.44(d,2H),2.35–2.16(m,1H),2.04(ddd,5H),1.83–1.40(m,7H),1.23(d,9H),1.15(dd,2H),1.08(s,3H),1.05(d,3H)
实施例25
[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]2-异丙氧基羰基氧基乙基碳酸酯(化合物25)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]2-isopropoxycarbonyloxyethylcarbonate
第一步:2-羟乙基异丙基碳酸酯(25b)
2-hydroxyethylisopropylcarbonate
将乙二醇(16.8mL,0.3mol)溶于二氯甲烷(120mL)中,加入吡啶(24mL,0.3mol)0℃下缓慢滴加氯甲酸异丙酯25a(12.3g,0.1mol),室温条件下反应2小时,用1mol/L的盐酸洗(100mL×3),无水硫酸钠干燥,减压浓缩干得到无色液体2-羟乙基异丙基碳酸酯25b(10.2g,产率69%)。
第二步:[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]2-异丙氧基羰基氧基乙基碳酸酯(化合物25)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]2-isopropoxycarbonyloxyethylcarbonate
将2-羟乙基异丙基碳酸酯(25b)(980mg,6.8mmol)溶于四氢呋喃(20mL)中,60℃下加入碳酸钾(924mg,6.8mmol),将[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]咪唑-1-甲酸酯(化合物1)(2g,4.5mmol)加至反应体系60℃反应6小时,加水(50mL)淬灭反应,二氯甲烷(100mL×2)萃取反应,无水硫酸钠干燥,减压浓缩干,用硅胶柱层析分离纯化(石油醚/乙酸乙酯(v/v)=3:1),得到白色固体的[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]2-异丙基氧基羰基氧基乙基碳酸酯(化合物25)(1.1g,产率47%)。
MSm/z(ESI):524.3[M+H]。
1HNMR(400MHz,CDCl3)δ8.63(s,1H),8.47(d,1H),7.68–7.65(m,1H),7.25-7.22(m,1H),6.02-6.00(m,1H),5.44(d,1H),4.92-4.89(m,1H),4.51–4.48(m,1H),4.34(s,4H),2.44-2.40(m,2H),2.30-2.24(m,1H),2.12–1.87(m,5H),1.79–1.49(m,7H),1.31(d,6H),1.20–1.09(m,2H),1.08(s,3H),1.05(s,3H)。
实施例26
2-[[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]氧基羰基氧基]乙基(2S)-2-氨基-3-苯基-丙酸酯(化合物26)
2-[[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]oxycarbonyloxy]ethyl(2S)-2-amino-3-phenyl-propanoate
第一步:2-((叔丁基二甲基硅基)氧基)乙醇(26b)
2-((tert-butyldimethylsilyl)oxy)ethanol
将乙二醇26a(10g,0.16mol)溶于四氢呋喃(200mL)中,0℃下分小份加60%的氢化钠(6.45g,0.16mol),0℃下反应30分钟,将叔丁基二甲基氯硅烷溶于四氢呋喃(125mL)滴加至反应体系,室温反应2小时,加水(50mL)淬灭反应,乙酸乙酯(200mL×2)萃取反应,无水硫酸钠干燥,减压浓缩干得到无色液体2-((叔丁基二甲基硅基)氧基)乙醇(26b)(20g,产率70%)。
第二步:2-[叔丁基(二甲基)硅基]氧基乙基[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]碳酸酯(26c)
2-[tert-butyl(dimethyl)silyl]oxyethyl[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]carbonate
将2-((叔丁基二甲基硅基)氧基)乙醇(26b)(5.7g,34mmol)溶于四氢呋喃(50mL)中,0℃下分小份加60%的氢化钠(1.35g,34mmol),0℃下反应30分钟将[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]咪唑-1-甲酸酯(化合物1)(10.0g,22.6mmol)溶于二氯甲烷(20mL)滴加至反应体系,升至室温反应10分钟,加水(50mL)淬灭反应,乙酸乙酯(200mL×2)萃取反应,无水硫酸钠干燥,减压浓缩干,用硅胶柱层析分离纯化(石油醚/乙酸乙酯(v/v)=3:1),得到白色固体的2-[叔丁基(二甲基)硅基]氧基乙基[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]碳酸酯(26c)(12g,产率96%)。
第三步:[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]2-羟乙基碳酸酯(26d)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]2-hydroxyethylcarbonate
将2-[叔丁基(二甲基)硅基]氧基乙基[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]碳酸酯(26c)(12g,22mmol)溶于二氯甲烷(120mL)中,加入四丁基氟化铵(17.1g,66mmol),室温反应3小时,加水(50mL)淬灭反应,乙酸乙酯(200mL×2)萃取反应,无水硫酸钠干燥,减压浓缩干,用硅胶柱层析分离纯化(石油醚/乙酸乙酯(v/v)=2:1),得到白色固体的(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]2-羟乙基碳酸酯(26d)(4.2g,产率43%)。
第四步:2-[[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]氧基羰基氧基]乙基(2S)-2-(叔丁氧基羰基氨基)-3-苯基丙酸酯(26e)
2-[[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]oxycarbonyloxy]ethyl
(2S)-2-(tert-butoxycarbonylamino)-3-phenyl-propanoate
将(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]2-羟乙基碳酸酯(26d)(1.7g,3.9mmol)溶于二氯甲烷(20mL)中,加入L-苯丙氨酸(1.5g,5.8mmol)、二环己基碳二亚胺(881mg,4.3mmol)和4-二甲氨基吡啶(474mg,3.9mmol),室温反应2小时,将反应液抽滤,减压浓缩干滤液,残留物用硅胶柱层析分离纯化(石油醚/乙酸乙酯(v/v)=2:1),得到白色固体的2-[[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]氧基羰基氧基]乙基(2S)-2-(叔丁氧基羰基氨基)-3-苯基丙酸酯(26e)(2.0g,产率77%)。
第五步:2-[[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]氧基羰基氧基]乙基(2S)-2-氨基-3-苯基-丙酸酯(化合物26)
2-[[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]oxycarbonyloxy]ethyl(2S)-2-amino-3-phenyl-propanoate
将2-[[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]氧基羰基氧基]乙基(2S)-2-(叔丁氧基羰基氨基)-3-苯基丙酸酯(26e)(1.3g,1.9mmol)溶于盐酸乙酸乙酯(4mol/L,20mL)中,室温搅拌30分钟,过滤得到白色固体,加入氨水(20mg)碱化,减压浓缩干,用硅胶柱层析分离纯化(石油醚/乙酸乙酯(v/v)=1:3),得到白色固体的2-[[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]氧基羰基氧基]乙基(2S)-2-氨基-3-苯基-丙酸酯(化合物26)(400mg,产率36%)。
MSm/z(ESI):585.3[M+H]。
1HNMR(400MHz,CDCl3)δ8.62(d,1H),8.46(dd,1H),7.65(dt,1H),7.36–7.28(m,2H),7.26–7.15(m,4H),6.00(dd,1H),5.44(d,1H),4.46(s,1H),4.42–4.20(m,4H),3.83(dd,1H),3.15(d,1H),2.94(dd,1H),2.49–2.20(m,6H),2.07(ddd,2H),2.00–1.83(m,2H),1.84–1.44(m,7H),1.22–1.08(m,2H),1.07(s,3H),1.05(s,3H)。
实施例27
2-[[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]氧基羰基氧基]乙基吡啶-3-甲酸酯(化合物27)
2-[[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]oxycarbonyloxy]ethylpyridine-3-carboxylate
将(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]2-羟乙基碳酸酯(26d)(437mg,1.0mmol)溶于二氯甲烷(10mL)中,加入烟酸(27a)(184mg,1.5mmol)、二环己基碳二亚胺(226mg,1.1mmol)和4-二甲氨基吡啶(122mg,1.0mmol)室温反应2小时后40℃反应2小时,抽滤固体,减压浓缩干滤液,用硅胶柱层析分离纯化(石油醚/乙酸乙酯(v/v)=1:1),得到白色固体的2-[[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]氧基羰基氧基]乙基吡啶-3-甲酸酯(化合物27)(430mg,产率79%)。
MSm/z(ESI):542.2。
1HNMR(400MHz,CDCl3)δ9.25(d,1H),8.79(dd,1H),8.62(s,1H),8.47(s,1H),8.31(dt,1H),7.66(d,1H),7.40(dd,1H),7.24(d,1H),6.00(s,1H),5.43(d,1H),4.59(dd,2H),4.57–4.36(m,3H),2.42(dd,2H),2.33–2.23(m,1H),2.11–2.05(m,3H),1.99–1.87(m,2H),1.65(qdd,7H),1.22–1.09(m,2H),1.07(s,3H),1.05(s,3H)。
实施例28
2-[[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]氧基羰基氧基]乙基2,2-二甲基丙酸酯(化合物28)
2-[[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]oxycarbonyloxy]ethyl2,2-dimethylpropanoate
将(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]2-羟乙基碳酸酯(26d)(600mg,1.4mmol)溶于二氯甲烷(10mL)中,加入三甲基乙酸(28a)(210mg,2.1mmol),1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(288mg,1.5mmol),4-二甲氨基吡啶(167mg,1.4mmol)室温反应6小时,水(50mL×2)洗,无水硫酸钠干燥,减压浓缩,用硅胶柱层析分离纯化(石油醚/乙酸乙酯(v/v)=3:1),得到白色固体的2-[[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]氧基羰基氧基]乙基2,2-二甲基丙酸酯(化合物28)(500mg,产率70%)。
MSm/z(ESI):522.2[M+H]。
1HNMR(400MHz,CDCl3)δ8.62(s,1H),8.47(d,1H),7.70(dd,1H),7.25(s,1H),6.02(s,1H),5.44(d,1H),4.51(dt,1H),4.41–4.31(m,2H),4.32–4.20(m,2H),2.51–2.37(m,2H),2.28(ddd,1H),2.15–2.00(m,3H),1.91(ddd,2H),1.81–1.46(m,7H),1.29–1.17(m,9H),1.17–1.08(m,2H),1.08(s,3H),1.05(s,3H)。
实施例29
[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]十六酸酯(化合物29)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]hexadecanoate
将(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-醇(1a)(2.0g,5.7mmol)溶于二氯甲烷(20mL)中,加入棕榈酸(29a)(2.2g,8.6mmol),1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(1.1mg,6.3mmol),4-二甲氨基吡啶(695mg,5.7mmol)室温反应6小时,水(50mL×2)洗,无水硫酸钠干燥,减压浓缩,用硅胶柱层析分离纯化(石油醚/乙酸乙酯(v/v)=3:1),得到白色固体的[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]十六酸酯(化合物29)(1.5g,产率43%)。
1HNMR(400MHz,CDCl3)δ8.63(d,1H),8.47(dd,1H),7.70(dd,1H),7.25(d,,1H),6.02(s,1H),5.42(d,1H),4.83–4.46(m,1H),2.44–2.18(m,5H),2.18–1.97(m,3H),1.92–1.80(m,2H),1.79–1.71(m,2H),1.69–1.47(m,7H),1.27(d,24H),1.15(ddd,2H),1.09(s,3H),1.05(s,3H),0.88(t,3H)。
实施例30
[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基][(3S)-四氢呋喃-3-基]碳酸酯(化合物30)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl][(3R)-tetrahydrofuran-3-yl]carbonate
室温条件下,将(3S)-四氢呋喃-3-醇(30a)(0.76g,6.8mmol)加入到四氢呋喃(10mL)中,无水无氧,氮气保护的条件下,加入氢化钠(0.16g,6.7mmol),冰浴条件下搅拌30分钟后,加入[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]咪唑-1-甲酸酯(化合物1)(2.0g,4.5mmol)的二氯甲烷(15mL)溶液,反应室温搅拌10分钟。向反应液中加入水(30mL),用二氯甲烷(10mL×3),合并有机相,有机相用无水硫酸钠干燥,减压浓缩干,残留物用硅胶柱色谱分离(石油醚:乙酸乙酯(v/v)=2:1)得标题化合物[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基][(3S)-四氢呋喃-3-基]碳酸酯(化合物30),白色固体(1.4g,产率67%)。
1HNMR(400MHz,CDCl3)δ8.62(d,1H),8.47(dd,1H),7.68(d,1H),7.25–7.17(m,1H),6.01(dd,1H),5.44(d,1H),5.21(ddt,1H),4.67–4.42(m,1H),4.08–3.73(m,5H),2.42(dd,2H),2.28(ddd,1H),2.23–2.01(m,5H),2.01–1.85(m,2H),1.83–1.43(m,7H),1.22–1.00(m,8H)。
MSm/z(ESI):464.1[M+H]。
实施例31
[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]1-甲基哌啶-4-甲酸酯盐酸盐(化合物31)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]1-methylpiperidine-4-carboxylatehydrochloride
第一步:[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]1-甲基哌啶-4-甲酸酯(化合物31b)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]1-methylpiperidine-4-carboxylate
将(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-醇(1a)(10.49g,30mmol)、1-甲基哌啶-4-甲酸(8.6g,60mmol)、4-二甲氨基吡啶(1.1g,9.0mmol)和二氯甲烷(300mL)加入反应瓶中,搅拌下分批加入N’N-羰基二咪唑(EDCI)(17.26g,90mmol),室温搅拌反应10小时。向反应液中加入水(300mL),搅拌5分钟,静置分层,有机层用无水硫酸钠干燥,过滤,减压浓缩干,残留物用硅胶柱层析分离(二氯甲烷:甲醇(v/v)=50:1)得白色固体状[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]1-甲基哌啶-4-甲酸酯(化合物31b),(7.8g,产率:55%)。
MSm/z(ESI):475.2[M+1]。
1HNMR(400MHz,CDCl3)δ8.62(d,1H),8.46(dd,1H),7.66(dt,1H),7.24(dd,1H),6.00(dd,1H),5.43(d,1H),4.66-4.59(m,1H),2.84-2.81(m,2H),2.34-2.22(m,7H),2.10-2.02(m,5H),1.93-1.45(m,13H),1.20-1.05(m,8H)。
第二步:[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]1-甲基哌啶-4-甲酸酯盐酸盐(化合物31)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]1-methylpiperidine-4-carboxylatehydrochloride
向反应瓶中加入[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]1-甲基哌啶-4-甲酸酯(化合物31b)(0.95g,2mmol),室温下滴加2N的盐酸乙酸乙酯溶液(8mL),室温反应1小时,过滤,将滤饼用乙酸乙酯(5mL×2)洗涤,得到白色固状的[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]1-甲基哌啶-4-甲酸酯盐酸盐(化合物31)(0.87g,产率80%)。
1HNMR(400MHz,D2O)δ8.73(s,1H),8.60(d,1H),8.53(d,1H),7.97(dd,1H),6.42(s,1H),5.36(t,1H),4.56–4.33(m,1H),3.58–3.34(m,2H),3.01(dd,2H),2.83(d,3H),2.65(tt,1H),2.39–1.94(m,9H),2.42–1.34(m,20H),1.89–1.69(m,4H),1.65–1.46(m,5H),1.40(dd,1H),1.03–0.98(m,6H),0.95(d,2H)。
MSm/z(ESI):475.4[M+1]。
实施例32
2-[[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]-氧基羰基氧基]乙基2-甲基丙酸酯(化合物32)
2-[[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]oxycarbonyloxy]ethyl2-methylpropanoate
向反应瓶中依次加入[(3S,8R,9S,10R,13S,14S)-10-13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]2-羟基乙氧基甲酸酯(32a)(0.9g,2mmol)、异丁酸(2g,22.70mmol)、4-二甲氨基吡啶(DMAP)(0.1g,0.8mmol)和二氯甲烷(20mL),搅拌下分批加入N,N-羰基二咪唑(EDCI)(1g,5.22mmol);加完室温搅拌反应2小时。TLC检测反应完全,加入水(100mL)和二氯甲烷(50mL),搅拌2分钟,静置分层;有机层饱和氯化钠溶液(100mL×1)洗,无水硫酸钠干燥,过滤,减压浓缩干,残留物用柱层析分离(石油醚/乙酸乙酯(v/v)=4/1)得标题化合物2-[[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]-氧基羰基氧基]乙基2-甲基丙酸酯(化合物32),白色固体(0.62g,产率:60%)。
MSm/z(ESI):508.2[M+1]。
1HNMR(400MHz,CDCl3)δ8.62(d,1H),8.47(dd,1H),7.68(dt,1H),7.26–7.18(m,1H),6.01(dd,1H),5.44(d,1H),4.89(dt,1H),4.57–4.42(m,1H),4.34(s,4H),2.42(dd,2H),2.28(ddd,1H),2.08(ddd,2H),2.02(d,1H),1.97(d,1H),1.89(dt,1H),1.83–1.55(m,6H),1.51(dd,1H),1.32(d,3H),1.30(d,3H),1.21–1.09(m,2H),1.08(s,3H),1.05(s,3H)。
实施例33
2-[[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]氧基羰氧基]乙基(2S)-2-(叔丁氧基羰基氨基)丙酸酯(化合物33)
2-[[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]oxycarbonyloxy]ethyl
第一步:2-羟基乙基(2S)-2-(叔丁氧基羰基氨基)丙酸酯(33b)
2-hydroxyethyl(2S)-2-(tert-butoxycarbonylamino)propanoate
向反应瓶中依次加入N-叔丁氧基羰基-L-丙氨酸(33a)(7.16g,37.85mmol)、乙二醇(7.0mL,128mmol)、4-二甲氨基吡啶(DMAP)(4.62g,37.85mmol)、二环己基碳二亚胺(DCC)(7.8g,41.46mmol)和二氯甲烷(100mL),室温反应8小时,体系抽滤,将滤液减压浓缩,加入100mL乙酸乙酯,用稀盐酸(100mL×2)洗涤,有机相用无水硫酸镁干燥,过滤,将滤液减压浓缩,得到白色固体2-羟基乙基(2S)-2-(叔丁氧基羰基氨基)丙酸酯(33b)(4.4g,产率56%)。
1HNMR(400MHz,CDCl3)δ5.03(s,1H),4.30(m,3H),3.82(td,2H),1.45(d,9H),1.41(dd,3H)。
第二步:2-[[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]氧基羰氧基]乙基(2S)-2-(叔丁氧基羰基氨基)丙酸酯(化合物33)
2-[[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]oxycarbonyloxy]ethyl
(2S)-2-(tert-butoxycarbonylamino)propanoate
向反应瓶中依次加入[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]咪唑-1-甲酸酯(化合物1)(2.5g,5.64mmol)、2-羟基乙基(2S)-2-(叔丁氧基羰基氨基)丙酸酯(33b)(1.97g,8.45mmol)、碳酸钾(1.7g,8.45mmol)、和四氢呋喃(60mL),75℃反应12小时,体系抽滤,将滤液减压浓缩,残留物用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(v/v)=4:1)得到得到白色固体2-[[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]氧基羰氧基]乙基(2S)-2-(叔丁氧基羰基氨基)丙酸酯(化合物33)(1.9g,产率55%)。
MSm/z(ESI):609.3[M+1]。
1HNMR(400MHz,CDCl3)δ8.62(s,1H),8.46(m,1H),7.68(dd,1H),7.24(dd,1H),6.01(d,1H),5.44(d,1H),5.03(s,1H),4.50(m,1H),4.37(m,4H),2.42(t,2H),2.27(ddd,1H),2.07(m,4H),1.97(d,1H),1.90(m,1H),1.64(m,7H),1.44(s,9H),1.40(m,3H),1.22(m,2H),1.09(d,3H),1.05(s,3H)。
实施例34
[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊并[一]菲-3-基]氧基羰基氧甲基(2R)-2-(叔丁氧基羰基)-2-苯基乙酸酯(化合物34)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]oxycarbonyloxymethyl(2R)-2-(tert-butoxycarbonylamino)-2-phenylacetate
向反应瓶中依次加入[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]氯甲基碳酸酯(21b)(1.33g,3.0mmol)、Boc-L-苯甘氨酸(1.51g,6.0mmol)、二异丙基乙胺(5mL)和N,N-二甲基甲酰胺(40mL),78℃反应1小时,加入二氯甲烷(800mL),体系用水(100mL×5)洗涤,有机相用无水硫酸镁干燥,过滤,将滤液减压浓缩,残留物用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(v/v)=5:1)得到得到白色固状的[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊并[一]菲-3-基]氧基羰基氧甲基(2R)-2-(叔丁氧基羰基)-2-苯基乙酸酯(化合物34)(1.51g,产率76.6%)。
MSm/z(ESI):657.3[M+1]。
1HNMR(400MHz,CDCl3)δ8.62(s,1H),8.47(d,1H),7.69(dt,1H),7.38–7.30(m,4H),7.28–7.23(m,2H),6.02(dd,1H),5.75(t,2H),5.42(dd,3H),4.45(tt,1H),2.44–2.22(m,3H),2.14–1.99(m,3H),1.88(d,2H),1.80–1.46(m,7H),1.43(s,9H),1.18–1.08(m,2H),1.07(s,3H),1.05(s,3H)。
实施例35
1-[[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]氧基羰基氧基]乙基乙酸酯(化合物35)
1-[[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]oxycarbonyloxy]ethylacetate
第一步:1-氯乙基[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]碳酸酯(35b)
1-[[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]1-chloroethylcarbonate
将(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-醇(1a)(3g,8.58mmol),吡啶((1.2g,15mmol)和二氯甲烷(50mL)加入反应瓶中,冰水冷却下,滴入1-氯乙基氯甲酸酯(1.8g,13mmol),滴完室温搅拌反应1小时。TLC检测反应完全,加入二氯甲烷(100mL),0.2N盐酸(10mLx2)洗涤,饱和碳酸氢钠(100mL×1)洗,饱和氯化钠溶液(100mL×1)洗;无水硫酸钠干燥,过滤,减压浓缩干得标题化合物1-氯乙基[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]碳酸酯(35b),白色固体(3.2g,产率82.05%)。
MSm/z(ESI):456.1[M+1]。
第二步:1-[[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]氧基羰基氧基]乙基乙酸酯
1-[[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]oxycarbonyloxy]ethylacetate
将1-氯乙基[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]碳酸酯(35b)(3.2g,7.02mmol)、碘化钾(6.7g,40mmol)和乙腈(50mL)加入反应瓶中,加热至50℃反应2小时;加入乙酸钾(4g,40.76mmol),加热至回流反应5小时。TLC检测原料基本反应完全,冷却,过滤,减压浓缩干,残留物用柱层析分离(石油醚/乙酸乙酯(v/v)=4/1)得标题化合物1-[[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]氧基羰基氧基]乙基乙酸酯(化合物35),黄白色固体(1.2g,产率:30.87%)。
MSm/z(ESI):480.1[M+1]。
1HNMR(400MHz,CDCl3)δ8.62(d,1H),8.50–8.42(m,1H),7.67(dt,1H),7.24(dd,1H),6.76(q,1H),6.01(dd,1H),5.44(t,1H),4.58–4.43(m,1H),2.45(ddd,2H),2.27(ddd,1H),2.13–1.93(m,8H),1.89(dt,1H),1.83–1.54(m,7H),1.54–1.42(m,4H),1.30–1.23(m,1H),1.20–1.13(m,1H),1.13–1.01(m,8H)。
实施例36
[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊二烯并[a]菲-3-基]氧基羰基氧基甲基(2R)-2-(叔丁氧基羰基氨基)丙酸酯(化合物36)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]oxycarbonyloxymethyl(2R)-2-(tert-butoxycar-bonylamino)propanoate
向反应瓶中依次加入[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]氯甲基碳酸酯(21b)(1.33g,3.0mmol)、N-叔丁氧基羰基-L-丙氨酸(0.62g,3.3mmol)、二异丙基乙胺(10mL)和N,N-二甲基甲酰胺(40mL),78℃反应1小时,加入二氯甲烷800mL,体系用水(100mL×5)洗涤,有机相用无水硫酸镁干燥,过滤,将滤液减压浓缩,残留物用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(v/v)=5:1)得到得到白色固状的[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊二烯并[a]菲-3-基]氧基羰基氧基甲基(2R)-2-(叔丁氧基羰基氨基)丙酸酯(化合物36)(1.09g,产率61%)。
MSm/z(ESI):595.3[M+1]。
1HNMR(400MHz,CDCl3)δ8.63(d,1H),8.47(dd,1H),7.70(dd,1H),7.31–7.24(m,1H),6.02(dd,1H),5.84(d,1H),5.76(d,1H),5.45(d,1H),5.00(s,1H),4.61–4.47(m,1H),4.37(s,1H),2.51–2.36(m,2H),2.28(ddd,1H),2.13–2.05(m,2H),2.02(d,1H),1.98(d,1H),1.90(dt,1H),1.83–1.55(m,6H),1.54–1.47(m,1H),1.45(s,9H),1.41(d,3H),1.18–1.07(m,2H),1.08(s,3H),1.05(s,3H)。
实施例37
[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊并[一]菲-3-基]氧基羰氧基甲基(2S)-2-(叔丁氧基羰基氨基)-3-苯基丙酸酯(化合物37)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]oxycarbonyloxymethyl(2S)-2-(tert-butoxycarbonylamino)-3-phenyl-propanoate
向反应瓶中依次加入[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]氯甲基碳酸酯(21b)(1.33g,3.0mmol)、N-叔丁氧基羰基-L-苯基丙氨酸(1.59g,6.0mmol)、二异丙基乙胺(10mL)和N,N-二甲基甲酰胺(40mL),78℃反应1小时,加入二氯甲烷800mL,体系用水(100mL×5)洗涤,有机相用无水硫酸镁干燥,过滤,将滤液减压浓缩,残留物用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(v/v)=5:1)得到得到白色固状的[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊并[一]菲-3-基]氧基羰氧基甲基(2S)-2-(叔丁氧基羰基氨基)-3-苯基丙酸酯(化合物37)(0.79g,产率35.6%)。
MSm/z(ESI):571.3[M+1]。
1HNMR(400MHz,CDCl3)δ8.64(s,1H),8.49(d,1H),7.84(d,1H),7.39(dd,1H),7.33–7.22(m,4H),7.14(d,2H),6.10(d,1H),5.79(dd,2H),5.45(d,1H),4.92(d,1H),4.64(m,1H),4.55(ddd,1H),3.22–2.99(m,2H),2.46(dd,2H),2.31(ddd,1H),2.17–1.95(m,4H),1.95–1.86(m,1H),1.81–1.55(m,5H),1.55–1.45(m,1H),1.41(s,9H),1.16(m,2H),1.09(s,3H),1.06(s,3H)。
实施例38
[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊二烯并[a]菲-3-基]氧基羰基氧基甲基吡啶-3-羧酸酯(化合物38)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]oxycarbonyloxymethylpyridine-3-carboxylate
向反应瓶中依次加入[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]氯甲基碳酸酯(21b)(2.2g,5.0mmol)、烟酸(1.23g,10.0mmol)、二异丙基乙胺(16mL)和N,N-二甲基甲酰胺(140mL),78℃反应1小时,加入二氯甲烷800mL,体系用水(100mL×5)洗涤,有机相用无水硫酸镁干燥,过滤,将滤液减压浓缩,残留物用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(v/v)=4:1)得到淡黄色固状的[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊二烯并[a]菲-3-基]氧基羰基氧基甲基吡啶-3-羧酸酯(化合物38)(1.0g,产率38.5%)。
MSm/z(ESI):529.2[M+1]。
1HNMR(400MHz,CDCl3)δ9.27(m,1H),8.82(dd,1H),8.62(d,1H),8.47(m,1H),8.34(dt,1H),7.70(d,1H),7.42(ddd,1H),7.27(d,1H),6.03(s,2H),5.45(d,1H),4.56(ddd,1H),2.45(m,2H),2.28(ddd,1H),2.11-2.02(m,4H),1.90(dt,1H),1.79-1.56(m,6H),1.48(m,1H),1.26(s,1H),1.15(m,2H).1.08(s,3H),1.05(s,3H)。
实施例39
[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊二烯并[a]菲-3-基]氧基羰基氧甲基乙酸酯(化合物39)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]oxycarbonyloxymethylacetate
向反应瓶中依次加入[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]氯甲基碳酸酯(21b)(2.2g,5.0mmol)、乙酸(0.6g,10.0mmol)、二异丙基乙胺(16mL)和N,N-二甲基甲酰胺(140mL),78℃反应1小时,加入二氯甲烷800mL,体系用水(100mL×5)洗涤,有机相用无水硫酸镁干燥,过滤,将滤液减压浓缩,残留物用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(v/v)=5:1)得到淡黄色固状的[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊二烯并[a]菲-3-基]氧基羰基氧甲基乙酸酯(化合物39)(1.1g,产率47%)。
MSm/z(ESI):466.1[M+1]。
1HNMR(400MHz,CDCl3)δ8.62(s,1H),8.46(d,1H),7.66(m,1H),7.23(dt,1H),6.00(m,1H),5.75(d,2H),5.45(d,1H),4.54(m,1H),2.44(m,2H),2.27(ddd,1H),2.12(d,3H),2.04(m,4H),1.89(m,1H),1.68(m,6H),1.48(m,1H),1.21–1.09(m,2H).1.08(s,3H),1.05(s,3H)。
实施例40
[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊二烯并[a]菲-3-基]哌啶-4-羧酸酯(化合物40)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]piperidine-4-carboxylate
第一步:O1-叔丁基O4-[(3S8R,9S,10R,13,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊二烯并[a]菲-3-基]氧基羰基氧基甲基哌啶-1,4-二羧酸酯(40b)
O1-tert-butylO4-[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]piperidine-1,4-dicarboxylate
向反应瓶中依次加入1-叔丁氧基羰基哌啶-4-羧酸(40a)(1.87g,8.2mmol)、阿比特龙(2.8g,8.0mmol)、4-二甲氨基吡啶(DMAP)(0.29g,2.4mmol)、N,N-羰基二咪唑(EDCI)(3.83g,20mmol)和二氯甲烷(150mL),室温反应7小时,体系加入100mL水,用二氯甲烷(100mL×3)萃取,有机相用无水硫酸镁干燥,过滤,将滤液减压浓缩,残留物用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(v/v)=5:1)得到得到白色固状的O1-叔丁基O4-[(3S8R,9S,10R,13,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊二烯并[a]菲-3-基]氧基羰基氧基甲基哌啶-1,4-二羧酸酯(40b)(3.13g,产率70%)。
MSm/z(ESI):561.4[M+1]。
1HNMR(400MHz,CDCl3)δ8.63(s,1H),8.46(d,1H),7.66(d,1H),7.23(dd,1H),6.00(dd,1H),5.42(d,1H),4.63(m,1H),3.99(m,2H),2.85(t,2H),2.34(m,4H),2.07(m,3H),1.87(m,4H),1.62(m,9H),1.46(s,9H),1.17(m,2H),1.08(s,3H),1.05(s,3H)。
第二步:[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊二烯并[a]菲-3-基]哌啶-4-羧酸酯(化合物40)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]piperidine-4-carboxylate
冰浴,反应瓶中依次加入O1-叔丁基O4-[(3S8R,9S,10R,13,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊二烯并[a]菲-3-基]氧基羰基氧基甲基哌啶-1,4-二羧酸酯(40b)(2.0g,3.57mmol),缓慢滴加3N浓度的盐酸乙酸乙酯溶液(15mL,45mmol),加完恢复室温反应1.5小时。体系抽滤,得到的白色盐酸盐用乙酸乙酯(10mL×2)洗,得到的白色固体用水溶解,体系加入氨水调节pH>7,用二氯甲烷(100mL×2)萃取,有机相用无水硫酸镁干燥,过滤,将滤液减压浓缩得到白色固状的[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊二烯并[a]菲-3-基]哌啶-4-羧酸酯(化合物40)(1.45g,产率88%)。
MSm/z(ESI):461.2[M+1]。
1HNMR(400MHz,CDCl3)δ8.62(d,1H),8.46(dd,1H),7.64(d,1H),7.21(dd,1H),5.99(dd,1H),5.42(d,1H),4.62(m,1H),3.11(d,2H),2.67(t,2H),2.34(m,5H),2.06(m,3H),1.87(m,4H),1.61(m,9H),1.15(m,2H),1.08(s,3H),1.05(s,3H)。
实施例41
[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]2-环丙基乙酸酯(化合物41)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]2-cyclopropylacetate
室温条件下,将(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-醇(1a)(1.5g,4.3mmol)溶于二氯甲烷(20mL)中,加入1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐(0.89g,4.6mmol)和4-二甲氨基吡啶(0.53g,4.3mmol),室温搅拌20分钟后,将1-环丙基乙酸(41a)(0.64g,6.4mmol)加入到上述反应液中,反应室温搅拌14小时。向反应液中加入水(10mL),用二氯甲烷(10mL×3)萃取,合并有机层,有机层用无水硫酸钠干燥,减压浓缩,残留物用硅胶柱色谱分离(石油醚/乙酸乙酯(v/v)=4:1)得白色固体[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]2-环丙基乙酸酯(化合物41)(1.3g,产率70%)。
HNMR(400MHz,CDCl3)δ8.62(d,1H),8.46(d,1H),7.65(dt,1H),7.29–7.18(m,1H),6.00(dd,1H),5.47–5.38(m,1H),4.65(dd,1H),2.41–2.16(m,5H),2.13–2.00(m,3H),1.87(dt,2H),1.81–1.44(m,7H),1.10–1.00(m,9H).,0.59–0.49(m,2H),0.16(q,2H)。
MSm/z(ESI):432.3[M+H]。
实施例42
[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊二烯并[a]菲-3-基]1-甲基吡咯烷-3-羧酸酯(化合物42)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]1-methylpyrrolidine-3-carboxylate
向反应瓶中依次加入1-甲基吡咯烷-3-甲酸盐酸盐(42a,2.25g,13.5mmol)、阿比特龙(3.15g,9mmol)、DMAP(0.6g,4.9mmol)、DCC(7.5g,36mmol)和二氯甲烷(300mL),室温反应8小时。向反应液中加入二氯甲烷(200mL),用水(100mL×3)洗涤,无水硫酸钠干燥,减压浓缩,残留物用硅胶柱色谱分离(二氯甲烷/甲醇(v/v)=50:1)得白色固体[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊二烯并[a]菲-3-基]1-甲基吡咯烷-3-羧酸酯(化合物42)(3.02g,产率76%)。
1HNMR(400MHz,CDCl3)δ8.62(d,1H),8.46(dd,1H),7.63(m,1H),7.21(m,1H),5.99(dd,1H),5.41(d,1H),4.63(m,1H),,3.10-2.97(m,1H),2.90(m,1H),2.72-2.61(m,2H),2.59-2.47(m,1H),2.39(s,3H),2.34(m,2H),2.27(m,1H),2.15-1.99(m,3H),1.98-1.83(m,3H),1.82-1.44(m,7H),1.42-1.28(m,1H),1.16(m,2H),1.09(s,3H),1.05(s,3H)。
MSm/z(ESI):461.2[M+H]。
实施例43
[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊二烯并[a]菲-3-基]环己烷羧酸酯(化合物43)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]cyclohexanecarboxylate
向反应瓶中依次加入环己基甲酸(43a)(0.77g,6.0mmol)、阿比特龙(1.4g,4.0mmol)、4-二甲氨基吡啶(DMAP)(0.25g,2.0mmol)、N,N-羰基二咪唑(EDCI)(3.07g,16mmol)和二氯甲烷(100mL),室温反应10小时,体系加入100mL水,用二氯甲烷(100mL×3)萃取,有机相用无水硫酸镁干燥,过滤,将滤液减压浓缩,残留物用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(v/v)=5:1)得到得到白色固状[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊二烯并[a]菲-3-基]环己烷羧酸酯(化合物43)(0.97g,产率52%)。
1HNMR(400MHz,CDCl3)δ8.63(s,1H),8.47(d,1H),7.67(d,1H),7.24(dd,1H),6.01(dd,1H),5.41(d,1H),4.68–4.53(m,1H),2.39–2.20(m,4H),2.12–1.99(m,3H),1.88(dd,4H),1.80–1.71(m,3H),1.60(qdd,6H),1.44(ddd,3H),1.35–1.24(m,3H),1.20–1.09(m,2H),1.08(s,3H),1.05(s,3H)。
MSm/z(ESI):462.2[M+H]。
实施例44
[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊二烯并[a]菲-3-基]四氢吡喃-4-羧酸酯(化合物44)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]tetrahydropyran-4-carboxylate
向反应瓶中依次加入四氢吡喃-4-甲酸(44a)(0.78g,6.0mmol)、阿比特龙(1.4g,4.0mmol)、4-二甲氨基吡啶(DMAP)(0.25g,2.0mmol)、N,N-羰基二咪唑(EDCI)(3.07g,16mmol)和二氯甲烷(100mL),室温反应6小时,体系加入100mL水,用二氯甲烷(100mL×3)萃取,有机相用无水硫酸镁干燥,过滤,将滤液减压浓缩,残留物用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(v/v)=3:1)得到得到白色固状[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊二烯并[a]菲-3-基]四氢吡喃-4-羧酸酯(化合物44)(0.89g,产率60%)。
1HNMR(400MHz,CDCl3)δ8.63(d,1H),8.53–8.40(m,1H),7.69(m,1H),7.26(m,1H),6.02(dd,1H),5.42(d,1H),4.73–4.54(m,1H),3.96(dt,2H),3.43(td,2H),2.56–2.44(m,1H),2.39–2.21(m,3H),2.13–2.00(m,3H),1.92–1.40(m,13H),1.20–1.10(m,2H),1.08(m,3H),1.05(s,3H)。
MSm/z(ESI):462.1[M+H]。
实施例45
[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊二烯并[a]菲-3-基](2S)-1-甲基吡咯烷-2-羧酸酯(化合物45)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl](2S)-1-methylpyrrolidine-2-carboxylate
第一步:N-甲基-L-脯氨酸(45b)
N-Methyl-l-Proline
向反应瓶中依次加入L-脯氨酸(45a)(2.0g,17.4mmol)、甲醛(1.4mL,19.1mmol)、P/C(0.5g)和甲醇(20mL),氢气氛下室温反应20小时,过滤,将滤液减压浓缩,残留物用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=1:1)得到得到白色固状的N-甲基-L-脯氨酸(45b)(0.8g,产率36%)。
1HNMR(400MHz,MeOD)δ3.81(dd,1H),3.73(ddd,1H),3.22–3.06(m,1H),2.94(s,3H),2.61–2.40(m,1H),2.22–2.07(m,2H),2.02–1.90(m,1H)。
第二步:[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊二烯并[a]菲-3-基](2S)-1-甲基吡咯烷-2-羧酸酯(化合物45)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl](2S)-1-methylpyrrolidine-2-carboxylate
向反应瓶中依次加入N-甲基-L-脯氨酸(45b)(0.68g,5.26mmol)、阿比特龙(1.22g,3.51mmol)、4-二甲氨基吡啶(DMAP)(0.13g,1.05mmol)、DCC(1.81g,8.78mmol)和二氯甲烷(100mL),室温反应72小时,体系加入100mL水,用二氯甲烷(100mL×3)萃取,有机相用无水硫酸镁干燥,过滤,将滤液减压浓缩,残留物用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(v/v)=3:1)得到得到白色固状[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊二烯并[a]菲-3-基](2S)-1-甲基吡咯烷-2-羧酸酯(化合物45)(0.54g,产率34%)。
1HNMR(400MHz,CDCl3)δ8.74(s,1H),8.56(d,1H),7.95(d,1H),7.49(m,1H),6.15(dd,1H),5.44(d,1H),4.73(m,1H),2.95(s,3H),2.58–2.00(m,11H),1.91-1.40(m,,10H),1.26–1.12(m,2H),1.09(s,3H),1.07(s,3H),0.92-0.88(m,1H)。
MSm/z(ESI):461.2[M+H]。
实施例46
[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H环戊二烯并[a]菲-3-基]1-(2,2,2-三氟乙酰基)哌啶-4-羧酸酯(化合物46)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]1-(2,2,2-trifluoroacetyl)piperidine-4-carboxylate
向反应瓶中依次加入[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊二烯并[a]菲-3-基]哌啶-4-羧酸酯(化合物40)(1.61g,3.5mmol)、三氟乙酸酐(2.2g,10.5mmol)和二氯甲烷(30mL),40℃反应5小时,减压浓缩,残留物用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=100:1)得到得到无色油状[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H环戊二烯并[a]菲-3-基]1-(2,2,2-三氟乙酰基)哌啶-4-羧酸酯(化合物46)(1.6g,产率82%)。
1HNMR(400MHz,CDCl3)δ8.92(s,1H),8.76(d,1H),8.37(d,1H),7.85(dd,1H),6.50–6.30(m,1H),5.43(d,1H),4.79–4.50(m,1H),4.39–4.16(m,1H),3.94(d,1H),3.39–3.24(m,1H),3.10(dd,1H),2.61(m,1H),2.44–2.27(m,3H),2.23–1.96(m,5H),1.94–1.43(m,11H),1.29-1.33(m,2H),1.11(d,3H),1.10(s,3H)。
MSm/z(ESI):557.2[M+H]。
实施例47
[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H环戊二烯并[a]菲-3-基]1-乙酰哌啶-4-羧酸酯(化合物47)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]1-acetylpiperidine-4-carboxylate
向反应瓶中依次加入[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊二烯并[a]菲-3-基]哌啶-4-羧酸酯(化合物40)(1.38g,3mmol)、吡啶(1.42g,18mmol)和二氯甲烷(50mL),室温下滴加乙酰氯(0.94g,12mmol),室温反应0.5小时,体系加入水(100mL),用二氯甲烷(100mL×3)萃取,有机相用无水硫酸镁干燥,过滤,将滤液减压浓缩,残留物用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(v/v)=1:1)得到得到白色固状[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H环戊二烯并[a]菲-3-基]1-乙酰哌啶-4-羧酸酯(化合物47)(1.2g,产率80%)。
1HNMR(400MHz,CDCl3)δ8.62(s,1H),8.46(d,1H),7.66(d,1H),7.32–7.10(m,1H),6.00(dd,1H),5.42(d,1H),4.64(m,1H),4.39(d,1H),3.85–3.68(m,1H),3.14(m,1H),2.90–2.72(m,1H),2.51(m,1H),2.39–2.22(m,3H),2.13–2.08(m,4H),2.08-1.99(m,2H),1.97–1.81(m,4H),1.81–1.44(m,9H),1.29-1.33(m,2H),1.09(s,3H),1.05(s,3H)。
MSm/z(ESI):503.4[M+H]。
实施例48
O4-[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊[a]菲-3-基]O1异丙哌啶-1,4-二羧酸酯(化合物48)
O4-[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]O1-isopropylpiperidine-1,4-dicarboxylate
向反应瓶中依次加入[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊二烯并[a]菲-3-基]哌啶-4-羧酸酯(化合物40)(0.45g,0.98mmol)、吡啶(0.233g,2.94mmol)和二氯甲烷(30mL),室温下滴加氯甲酸异丙酯(0.24g,1.95mmol),室温反应0.5小时,体系加入100mL水,用二氯甲烷(100mL×3)萃取,有机相用无水硫酸镁干燥,过滤,将滤液减压浓缩,残留物用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(v/v)=1:1)得到得到白色固状O4-[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊[a]菲-3-基]O1异丙哌啶-1,4-二羧酸酯(化合物48)(0.45g,产率88%)。
1HNMR(400MHz,CDCl3)δ8.62(d,1H),8.51–8.42(m,1H),7.68–7.58(m,1H),7.22(dd,1H),5.99(dd,1H),5.42(d,1H),4.91(m,1H),4.71–4.54(m,1H),4.04(d,2H),2.95–2.80(m,2H),2.43(m,1H),2.38–2.16(m,3H),2.14–1.99(m,3H),1.86(m,4H),1.81–1.42(m,10H),1.25(m,7H),1.08(s,3H),1.05(s,3H)。
实施例49
O4-[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊[a]菲-3-基]O1乙基哌啶-1,4-二羧酸酯(化合物49)
O4-[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]O1-ethylpiperidine-1,4-dicarboxylate
向反应瓶中依次加入[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊二烯并[a]菲-3-基]哌啶-4-羧酸酯(化合物40)(2.21g,4.8mmol)、吡啶(1.4g,14.4mmol)和二氯甲烷(50mL),室温下滴加氯甲酸乙酯(1.04g,9.6mmol),室温反应5小时,体系加入100mL水,用二氯甲烷(100mL×3)萃取,有机相用无水硫酸镁干燥,过滤,将滤液减压浓缩,残留物用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(v/v)=1:1)得到得到白色固状O4-[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊[a]菲-3-基]O1乙基哌啶-1,4-二羧酸酯(化合物49)(2.1g,产率82%)。
1HNMR(400MHz,CDCl3)δ8.62(s,1H),8.46(d,1H),7.65(d,1H),7.22(dd,1H),6.00(dd,1H),5.42(d,1H),4.63(m,1H),4.16-4.10(m,2H),4.07–3.96(m,2H),2.91(t,2H),2.43(m,1H),2.37–2.22(m,3H),2.12–2.00(m,3H),1.93–1.81(m,4H),1.80–1.38(m,9H),1.26(t,3H),1.22-1.10(m,2H),1.08(s,3H),1.05(s,3H)。
MSm/z(ESI):533.3[M+H]。
实施例50
[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H环戊二烯并[a]菲-3-基]1-(2-羟丙基)哌啶-4-羧酸酯(化合物50)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]1-(2-hydroxypropyl)piperidine-4-carboxylate
向密封瓶中依次加入[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊二烯并[a]菲-3-基]哌啶-4-羧酸酯(化合物40)(0.16g,0.35mmol)、环氧丙烷(0.02g,0.35mmol)和乙醇(4mL),90℃反应5小时,减压浓缩,残留物用硅胶柱色谱分离提纯(石油醚/二氯甲烷/甲醇(v/v/v)=20:20:1)得到得到黄色固状[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H环戊二烯并[a]菲-3-基]1-(2-羟丙基)哌啶-4-羧酸酯(化合物50)(0.11g,产率60%)。
1HNMR(400MHz,CDCl3)δ8.62(d,1H),8.46(dd,1H),7.64(m,1H),7.21(dd,1H),5.99(dd,1H),5.42(d,1H),4.72–4.56(m,1H),3.82(dd,1H),2.99(d,1H),2.77(d,1H),2.41–2.16(m,7H),2.13–1.96(m,4H),1.69(m,14H),1.23–1.15(m,1H),1.16–1.01(m,10H)。
MSm/z(ESI):216.1[M+2H/2]。
实施例51
[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊二烯并[a]菲-3-基]1-乙基哌啶-4-羧酸酯(化合物51)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]1-ethylpiperidine-4-carboxylate
第一步:N-乙基-4-哌啶甲酸乙酯(51b)
1-ethyl-piperidine-4-carboxylicacidethylester
向反应瓶中依次加入4-哌啶甲酸乙酯(51a)(4.72g,30mmol)、碘乙烷(5.15g,33mmol)和乙醇(100mL),80℃反应16小时,过滤,将滤液减压浓缩,体系加入100mL水,用二氯甲烷(100mL×3)萃取,有机相用无水硫酸镁干燥,过滤,将滤液减压浓缩,残留物用硅胶柱色谱分离提纯(石油醚/乙酸乙酯/甲醇(v/v/v)=5:5:1)得到黄色油状N-乙基-4-哌啶甲酸乙酯(51b)(3.8g,产率68%)。
第二步:N-乙基-4-哌啶甲酸(51c)
1-ethyl-piperidine-4-carboxylicacid
向反应瓶中依次加入N-乙基-4-哌啶甲酸乙酯(51b)(3.8g,20mmol)、浓盐酸(39mL,468mmol)和水(20mL),100℃反应8小时,减压浓缩,残留物用硅胶柱色谱分离提纯(石油醚/甲醇(v/v)=5:1)得到黄色固体N-乙基-4-哌啶甲酸(51c)(2.5g,产率70%)。
第三步:[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊二烯并[a]菲-3-基]1-乙基哌啶-4-羧酸酯(化合物51)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]1-ethylpiperidine-4-carboxylate
向反应瓶中依次加入N-乙基-4-哌啶甲酸(51c)(0.71g,4.5mmol)、阿比特龙(1.05g,3mmol)、4-二甲氨基吡啶(DMAP)(0.11g,0.9mmol)、N,N-羰基二咪唑(EDCI)(1.73g,9.0mmol)和二氯甲烷(60mL),室温反应5小时,体系加入100mL水,用二氯甲烷(100mL×3)萃取,有机相用无水硫酸镁干燥,过滤,将滤液减压浓缩,残留物用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(v/v)=5:1)得到得到白色固状的[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊二烯并[a]菲-3-基]1-乙基哌啶-4-羧酸酯(化合物51)(0.9g,产率61%)。
1HNMR(400MHz,CDCl3)δ8.62(d,1H),8.46(dd,1H),7.70–7.58(m,1H),7.21(ddd,1H),5.99(dd,1H),5.42(d,1H),4.76–4.50(m,1H),2.91(d,2H),2.50–2.37(m,2H),2.37–2.20(m,4H),2.171.43(m,18H),1.33-1.06(m,11H)。
MSm/z(ESI):489.3[M+1]。
实施例52
[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊二烯并[a]菲-3-基]1-(3-吡啶基)哌啶-4-羧酸酯(化合物52)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]1-(3-pyridyl)piperidine-4-carboxylate
第一步:1-吡啶基-3-哌啶-4-甲酸乙酯(52b)
1-pyridin-3-ylpiperidine-4-carboxylicacidethylester
向反应瓶中依次加入4-哌啶甲酸乙酯(51a)(20g,127mmol)、溴苯(21.1g,133.5mmol)、叔丁醇钠(18.4g,191mmol)、1,1'-联萘-2,2'-双二苯膦(BINAP)(0.83g,13.3mmol)、三(二亚苄基茚丙酮)二钯(0.62g,0.68mmol)和二氧六环(300mL),86℃反应6小时,减压浓缩,体系加入800mL二氯甲烷,饱和食盐水(600mL×1)洗涤,有机相用无水硫酸镁干燥,过滤,将滤液减压浓缩,残留物用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(v/v)=4:1)得到得到黄色油状的1-吡啶基-3-哌啶-4-甲酸乙酯(52b)(8.0g,产率26%)。
1HNMR(400MHz,CDCl3)δ8.31(d,1H),8.08(dd,1H),7.23–7.10(m,2H),4.16(q,2H),3.65(dt,2H),2.85(td,2H),2.46(ddd,1H),2.11–1.96(m,2H),1.94–1.78(m,2H),1.27(t,3H)。
第二步:1-吡啶基-3-哌啶-4-甲酸(52c)
1-pyridin-3-ylpiperidine-4-carboxylicacid
向反应瓶中依次加入1-吡啶基-3-哌啶-4-甲酸乙酯(52b)(4.36g,18.6mmol)、八水氢氧化钡(10.57g,33.5mmol)、乙醇(50ml)和水(40mL),60℃反应2.5小时,减压浓缩,加水30mL,分批加入碳酸铵(7.3g,74.4mmol),室温反应2小时。抽滤,将滤液减压浓缩得到黄色固体1-吡啶基-3-哌啶-4-甲酸(52c)(2.5g,产率66%)。
1HNMR(400MHz,DMSO)δ8.29(d,1H),7.96(dd,1H),7.31(ddd,1H),7.19(dd,1H),3.67(dt,2H),2.80(td,2H),2.37(tt,1H),2.03–1.80(m,2H),1.71–1.55(m,2H)。
第三步:[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊二烯并[a]菲-3-基]1-(3-吡啶基)哌啶-4-羧酸酯(化合物52)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]1-(3-pyridyl)piperidine-4-carboxylate
向反应瓶中依次加入1-吡啶基-3-哌啶-4-甲酸(52c)(2.06g,10mmol)、阿比特龙(3.5g,10mmol)、4-二甲氨基吡啶(DMAP)(0.37g,3.0mmol)、N,N-羰基二咪唑(EDCI)(5.75g,30mmol)和二氯甲烷(100mL),室温反应8小时,体系加入100mL水,用二氯甲烷(100mL×3)萃取,有机相用无水硫酸镁干燥,过滤,将滤液减压浓缩,残留物用硅胶柱色谱分离提纯(石油醚/二氯甲烷/甲醇(v/v/v)=30:30:1)得到得到白色固状的[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊二烯并[a]菲-3-基]1-(3-吡啶基)哌啶-4-羧酸酯(化合物52)(3.7g,产率69%)。
1HNMR(400MHz,CDCl3)δ8.62(d,1H),8.46(dd,1H),8.31(d,1H),8.08(dd,1H),7.64(dt,1H),7.24–7.07(m,3H),5.99(dd,1H),5.43(d,1H),4.66(tdd,1H),3.65(dt,2H),2.87(td,2H),2.45(ddd,1H),2.40–2.32(m,2H),2.27(ddd,1H),2.06(ddd,5H),1.94–1.81(m,4H),1.81–1.39(m,7H),1.22-1.10(m,2H),1.09(s,3H),1.05(s,3H)。
MSm/z(ESI):538.3[M+H]+。
实施例53
[(3S,10R,13S)-10,13二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊[a]菲-3-基]1-(2-二甲氨基乙基)哌啶-4-羧酸酯(化合物53)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]1-(2-dimethylaminoethyl)piperidine-4-carboxylate
第一步:1-(2-二甲基氨基-乙基)-哌啶-4-羧酸乙酯(53b)
1-(2-dimethylamino-ethyl)-piperidine-4-carboxylicacidethylester
向反应瓶中依次加入二甲氨基氯乙烷盐酸(51a)(2.88g,20mmol)、4-哌啶甲酸乙酯(51b)(1.57g,10mmol)、碳酸钠(2.12g,20mmol)和甲苯(30mL),120℃反应16小时,过滤,将滤液减压浓缩,残留物用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=25:1)得到得到黄色油状的1-(2-二甲基氨基-乙基)-哌啶-4-羧酸乙酯(53b)(0.83g,产率36%)。
1HNMR(400MHz,CDCl3)δ4.13(q,2H),2.89(dt,2H),2.51–2.36(m,4H),2.33–2.18(m,7H),2.04(td,2H),1.94–1.83(m,2H),1.83–1.70(m,2H),1.24(t,3H)。
第二步:1-(2-二甲基氨基-乙基)-哌啶-4-羧酸(53c)
1-(2-dimethylamino-ethyl)-piperidine-4-carboxylicacid
向反应瓶中依次加入1-(2-二甲基氨基-乙基)-哌啶-4-羧酸乙酯(53b)(3.3g,14.4mmol)、八水氢氧化钡(8.19g,26mmol)、乙醇(50ml)和水(40mL),60℃反应2.5小时,减压浓缩,加水30mL,分批加入碳酸铵(7.3g,74.4mmol),室温反应2小时。抽滤,将滤液减压浓缩得到黄色固体1-(2-二甲基氨基-乙基)-哌啶-4-羧酸(53c)(2.5g,产率87%)。
第三步:[(3S,10R,13S)-10,13二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊[a]菲-3-基]1-(2-二甲氨基乙基)哌啶-4-羧酸酯(化合物53)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]1-(2-dimethylaminoethyl)piperidine-4-carboxylate
向反应瓶中依次加入1-(2-二甲基氨基-乙基)-哌啶-4-羧酸(53c)(2.0g,10mmol)、阿比特龙(3.5g,10mmol)、4-二甲氨基吡啶(DMAP)(0.37g,3.0mmol)、N,N-羰基二咪唑(EDCI)(5.75g,30mmol)和二氯甲烷(100mL),室温反应8小时,体系加入100mL水,用二氯甲烷(100mL×3)萃取,有机相用无水硫酸镁干燥,过滤,将滤液减压浓缩,残留物用硅胶柱色谱分离提纯(石油醚/二氯甲烷/甲醇(v/v/v)=30:30:1)得到得到白色固状的[(3S,10R,13S)-10,13二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊[a]菲-3-基]1-(2-二甲氨基乙基)哌啶-4-羧酸酯(化合物53)(2.2g,产率41%)。
1HNMR(400MHz,CDCl3)δ8.62(d,1H),8.45(dd,1H),7.64(dt,1H),7.21(dd,1H),6.04–5.94(m,1H),5.41(d,1H),4.73–4.51(m,1H),2.55–2.40(m,4H),2.35–2.19(m,10H),2.11–1.99(m,7H),1.94–1.54(m,13H),1.28–1.09(m,2H),1.08(s,3H),1.04(s,3H)。
MSm/z(ESI):532.5[M+1]。
实施例54
[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H环戊二烯并[a]菲-3-基]1-(2-氟乙基)哌啶-4-羧酸乙酯盐酸盐(化合物54)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]1-(2-fluoroethyl)piperidine-4-carboxylatehydrochloride
第一步:[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H环戊二烯并[a]菲-3-基]1-(2-氟乙基)哌啶-4-羧酸乙酯(化合物54b)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]1-(2-fluoroethyl)piperidine-4-carboxylate
向反应瓶中依次加入[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊二烯并[a]菲-3-基]哌啶-4-羧酸酯(化合物40)(1.61g,3.5mmol)、1-溴-2-氟乙烷(2.22g,17.5mmol)碳酸钾(2.9g,21mmol)和丙酮(30mL),回流反应6小时,体系加入100mL水,用二氯甲烷(100mL×3)萃取,有机相用无水硫酸镁干燥,过滤,将滤液减压浓缩,残留物用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(v/v)=1:1)得到得到褐色固状[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H环戊二烯并[a]菲-3-基]1-(2-氟乙基)哌啶-4-羧酸乙酯(化合物50b)(0.38g,产率20%)。
1HNMR(400MHz,MeOD)δ8.87(s,1H),8.72(d,1H),8.65(d,1H),8.05(dd,1H),6.50(dd,1H),5.48(d,1H),4.94(d,1H),4.62(d,1H),3.72(d,2H),3.63–3.47(m,2H),3.16(t,2H),2.70(s,1H),2.42(ddd,3H),2.34–2.20(m,3H),2.20–2.06(m,3H),2.03–1.82(m,5H),1.82–1.51(m,6H),1.23(dt,2H),1.17(s,3H),1.16(s,3H)。
MSm/z(ESI):507.2[M+H]。
第二步:[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H环戊二烯并[a]菲-3-基]1-(2-氟乙基)哌啶-4-羧酸乙酯盐酸盐(化合物54)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]1-(2-fluoroethyl)piperidine-4-carboxylatehydrochloride
向反应瓶中依次加入[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H环戊二烯并[a]菲-3-基]1-(2-氟乙基)哌啶-4-羧酸乙酯(54b)(0.38g,0.75mmol)盐酸乙酸乙酯溶液(4N,10mL,40mmol),室温反应1小时,过滤,滤饼用乙酸乙酯(5mL×2)洗,得到白色固状[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H环戊二烯并[a]菲-3-基]1-(2-氟乙基)哌啶-4-羧酸乙酯盐酸盐(化合物54)(0.35g,产率86%)。
1HNMR(400MHz,MeOD)δ8.87(s,1H),8.72(d,1H),8.65(d,1H),8.05(dd,1H),6.50(dd,1H),5.48(d,1H),4.94(d,1H),4.62(d,1H),3.72(d,2H),3.63–3.47(m,2H),3.16(t,2H),2.70(s,1H),2.42(ddd,3H),2.34–2.20(m,3H),2.20–2.06(m,3H),2.03–1.82(m,5H),1.82–1.51(m,6H),1.23(dt,2H),1.17(s,3H),1.16(s,3H)。
MSm/z(ESI):507.2[M+H]。
实施例55
[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H环戊二烯并[a]菲-3-基]1-甲基磺酰哌啶-4-羧酸酯(化合物55)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]1-methylsulfonylpiperidine-4-carboxylate
向反应瓶中依次加入[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊二烯并[a]菲-3-基]哌啶-4-羧酸酯(化合物40)(1.38g,3mmol)、甲基磺酰氯(0.29g,3.6mmol)、吡啶(0.36g,4.5mmol)和二氯甲烷(50mL),室温反应6小时,体系加入100mL水,用二氯甲烷(100mL×3)萃取,有机相用无水硫酸镁干燥,过滤,将滤液减压浓缩,残留物用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(v/v)=1:1)得到得到白色固状[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H环戊二烯并[a]菲-3-基]1-甲基磺酰哌啶-4-羧酸酯(化合物55)(1.4g,产率87%)。
1HNMR(400MHz,DMSO)δ8.63(d,1H),8.48(d,1H),7.85(d,1H),7.41(dd,1H),6.17(s,1H),5.41(d,1H),4.52(dd,1H),3.48(dd,3H),3.43–3.10(m,3H),2.86(s,3H),2.84–2.76(m,2H),2.49–2.42(m,1H),2.36–2.18(m,3H),2.14–1.98(m,3H),1.98–1.35(m,12H),1.06(s,3H),1.04(s,3H)。
MSm/z(ESI):539.2[M+H]。
实施例56
[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H环戊二烯并[a]菲-3-基]1-环丙基磺酰基哌啶-4-羧酸酯(化合物56)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]1-cyclopropylsulfonylpiperidine-4-carboxylate
向反应瓶中依次加入[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊二烯并[a]菲-3-基]哌啶-4-羧酸酯(化合物40)(2.21g,4.8mmol)、环丙基磺酰氯(2.7g,19.2mmol)、吡啶(2.28g,28.8mmol)和二氯甲烷(60mL),室温反应10小时,体系加入100mL水,用二氯甲烷(100mL×3)萃取,有机相用无水硫酸镁干燥,过滤,将滤液减压浓缩,残留物用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(v/v)=1:1)得到得到白色固状[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H环戊二烯并[a]菲-3-基]1-环丙基磺酰基哌啶-4-羧酸酯(化合物56)(1.2g,产率44%)。
1HNMR(400MHz,CDCl3)δ8.62(s,1H),8.47(d,1H),7.68(d,1H),7.26–7.22(m,1H),6.01(dd,1H),5.43(d,1H),4.64(ddd,1H),3.71(dt,2H),3.05–2.90(m,2H),2.48–2.38(m,1H),2.38–2.20(m,4H),2.15–1.93(m,6H),1.93–1.41(m,12H),1.17(dd,2H),1.09(s,3H),1.05(s,3H),1.01–0.93(m,2H)。
MSm/z(ESI):539.2[M+H]。
实施例57
[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊二烯并[a]菲-3-基]1-(环丙基甲基)哌啶-4-羧酸酯盐酸盐(化合物57)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]1-(cyclopropylmethyl)piperidine-4-carboxylatehydrochloride
第一步:1-(环丙基甲基)哌啶-4-羧酸(57b)
1-(cyclopropylmethyl)piperidine-4-carboxylate
向反应瓶中依次加入4-哌啶甲酸(57a)(1.29g,10mmol)、环丙甲醛(4.2g,60mmol)、钯碳0.26g)和甲醇(30mL),氢气氛下室温反应42小时,过滤,将滤液减压浓缩,残留物用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=1:1)得到得到淡黄色油状1-(环丙基甲基)哌啶-4-羧酸(57b)(1.6g,产率87%)。
1HNMR(400MHz,MeOD)δ3.37–3.20(m,2H),2.90–2.78(m,2H),2.76(d,2H),2.20(dd,1H),1.90(dd,2H),1.75(d,2H),0.97–0.82(m,1H),0.61–0.47(m,2H),0.24–0.15(m,2H)。
第二步:[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊二烯并[a]菲-3-基]1-(环丙基甲基)哌啶-4-羧酸酯(化合物57c)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]1-(cyclopropylmethyl)piperidine-4-carboxylate
向反应瓶中依次加入1-(环丙基甲基)哌啶-4-羧酸(57b)(1.47g,8mmol)、阿比特龙(1.4g,4mmol)、4-二甲氨基吡啶(DMAP)(0.25g,2.0mmol)、N,N-羰基二咪唑(EDCI)(3.3g,16mmol)和二氯甲烷(100mL),室温反应5小时,体系加入100mL水,用二氯甲烷(100mL×3)萃取,有机相用无水硫酸镁干燥,过滤,将滤液减压浓缩,残留物用硅胶柱色谱分离提纯(石油醚/乙酸乙酯/甲醇(v/v/v)=50:50:1)得到白色固状的[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊二烯并[a]菲-3-基]1-(环丙基甲基)哌啶-4-羧酸酯(化合物57c)(0.56g,产率28%)。
1HNMR(400MHz,CDCl3)δ8.62(d,1H),8.46(dd,1H),7.69–7.58(m,1H),7.21(dd,1H),5.99(dd,1H),5.42(d,1H),4.70–4.56(m,1H),3.02(d,2H),2.43–2.17(m,6H),2.10-2.03(m,5H),1.99–1.42(m,13H),1.23–1.10(m,2H),1.08(s,3H),1.05(s,3H),0.92-0.86(m,1H),0.53-0.51(m,2H),0.11-0.10(m,2H)。
MSm/z(ESI):515.3[M+1]。
第三步:[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊二烯并[a]菲-3-基]1-(环丙基甲基)哌啶-4-羧酸酯盐酸盐(化合物57)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]1-(cyclopropylmethyl)piperidine-4-carboxylatehydrochloride
向反应瓶中加入[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊二烯并[a]菲-3-基]1-(环丙基甲基)哌啶-4-羧酸酯(化合物57c)(0.514g,8mmol),室温下滴加2N的盐酸乙酸乙酯溶液(8mL),室温反应1小时,过滤,将滤饼用乙酸乙酯(5mL×2)洗涤,得到白色固状的[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊二烯并[a]菲-3-基]1-(环丙基甲基)哌啶-4-羧酸酯盐酸盐(化合物57)(0.42g,产率71.6%)。
1HNMR(400MHz,MeOD)δ8.88(s,1H),8.71(dd,2H),8.07(dd,1H),6.52(s,1H),5.49(s,1H),4.73–4.47(m,1H),3.78–3.67(m,2H),3.07(t,4H),2.76–2.60(m,1H),2.42(ddd,3H),2.30–2.07(m,5H),2.02–1.51(m,11H),1.29–1.18(m,2H),1.17(s,3H),1.16(s,1H),1.15(s,3H),0.80(q,2H),0.47(q,2H)。
MSm/z(ESI):515.3[M+1]。
实施例58
[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H环戊二烯并[a]菲-3-基]2-氟乙基碳酸酯(化合物58)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]2-fluoroethylcarbonate
将2-氟乙醇(320mg,5.5mmol)溶于四氢呋喃(20mL)中,0℃下分小份加60%的氢化钠(220mg,5.5mmol),0℃下反应30分钟,滴加[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]咪唑-1-甲酸酯(化合物1)(2.2g,5.0mmol)的二氯甲烷(10mL)溶液,升至室温反应10分钟,加水(50mL)淬灭反应,用二氯甲烷(100mL×2)萃取,无水硫酸钠干燥,减压浓缩干,残留物用硅胶柱层析分离纯化(石油醚/乙酸乙酯(v/v)=4:1),得到白色固体的[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H环戊二烯并[a]菲-3-基]2-氟乙基碳酸酯(化合物58)(1.6g,产率73%)。
MSm/z(ESI):440.2[M+H]。
1HNMR(400MHz,CDCl3)δ8.62(s,1H),8.46(dd,1H),7.73–7.53(m,1H),7.25–7.14(m,1H),6.09–5.83(m,1H),5.52–5.35(m,1H),4.71–4.64(m,1H),4.62–4.54(m,1H),4.54–4.45(m,1H),4.43–4.37(m,1H),4.37–4.29(m,1H),2.51–2.34(m,2H),2.27(ddd,1H),2.14–1.85(m,5H),1.85–1.41(m,7H),1.28–1.09(m,2H),1.08(s,3H),1.05(s,3H)。
实施例59
[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H环戊二烯并[a]菲-3-基]2-甲氧基乙基碳酸酯(化合物59)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]2-methoxyethylcarbonate
将乙二醇单甲醚(1.93g,25.3mmol)溶于四氢呋喃(300mL)中,0℃下分小份加60%的氢化钠(1.01g,25.3mmol),0℃下反应30分钟,滴加[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]咪唑-1-甲酸酯(化合物1)(10.2g,23mmol)的二氯甲烷(50mL)溶液,升至室温反应10分钟,加水(50mL)淬灭反应,用二氯甲烷(100mL×2)萃取,有机相用无水硫酸钠干燥,减压浓缩干,残留物用硅胶柱层析分离纯化(石油醚/乙酸乙酯(v/v)=4:1),得到白色固体的[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H环戊二烯并[a]菲-3-基]2-甲氧基乙基碳酸酯(化合物59)(7.1g,产率67%)。
MSm/z(ESI):452.2[M+H]。
1HNMR(400MHz,CDCl3)δ8.62(d,1H),8.46(dd,1H),7.66(dt,1H),7.23(dd,1H),6.00(dd,1H),5.44(d,1H),4.49(ddd,1H),4.33–4.15(m,2H),3.64–3.59(m,2H),3.39(s,3H),2.51–2.33(m,2H),2.27(ddd,1H),2.14–1.84(m,5H),1.84–1.41(m,7H),1.28–1.09(m,2H),1.07(s,3H),1.05(s,3H)。
实施例60
[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H环戊二烯并[a]菲-3-基]3-甲氧基丙基碳酸酯(化合物60)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]3-methoxypropylcarbonate
将1,3-丙二醇单甲醚(0.5g,5.5mmol)溶于四氢呋喃(600mL)中,0℃下分小份加60%的氢化钠(0.22g,5.5mmol),0℃下反应30分钟,滴加[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]咪唑-1-甲酸酯(化合物1)(2.2g,5mmol)的二氯甲烷(30mL)溶液,升至室温反应10分钟,加水(50mL)淬灭反应,用二氯甲烷(100mL×2)萃取,有机相用无水硫酸钠干燥,减压浓缩干,残留物用硅胶柱层析分离纯化(石油醚/乙酸乙酯(v/v)=4:1),得到白色固体的[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H环戊二烯并[a]菲-3-基]3-甲氧基丙基碳酸酯(化合物60)(1.86g,产率72%)。
MSm/z(ESI):466.5[M+H]。
1HNMR(400MHz,CDCl3)δ8.62(d,1H),8.46(dd,1H),7.65(dt,1H),7.22(dd,1H),6.00(dd,1H),5.44(d,1H),4.48(dt,1H),4.22(t,2H),3.47(t,2H),3.34(s,3H),2.42(dd,2H),2.27(ddd,1H),2.15–1.84(m,7H),1.84–1.41(m,7H),1.35–1.09(m,2H),1.08(s,3H),1.05(s,3H)。
实施例61
[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊二烯并[a]菲-3-基]2-[2-(2-异丙乙氧基)乙氧基]乙基碳酸酯(化合物61)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]
2-[2-(2-isopropoxycarbonyloxyethoxy)ethoxy]ethylcarbonate
第一步:2-[2-[2-[叔丁基(二甲基)甲硅烷基]氧基乙氧基]乙氧基]乙醇(61b)
2-[2-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]ethoxy]ethanol
将三甘醇61a(4.5g,30mmol)溶于四氢呋喃(250mL)中,0℃下分小份加60%的氢化钠(1.2g,30mmol),0℃下反应30分钟,将叔丁基二甲基氯硅烷溶于四氢呋喃(100mL)滴加至反应体系,室温反应2小时,加水(100mL)淬灭反应,乙酸乙酯(200mL×2)萃取反应,有机相用无水硫酸钠干燥,减压浓缩干得到无色液体2-[2-[2-[叔丁基(二甲基)甲硅烷基]氧基乙氧基]乙氧基]乙醇(61b)(6g,产率76%)。
1HNMR(400MHz,CDCl3)δ3.70(t,2H),3.66(dd,2H),3.63–3.56(m,4H),3.56–3.52(m,2H),3.50(t,2H),0.84–0.81(m,9H),0.01–-0.01(m,6H)。
第二步:2-[2-[2-[叔丁基(二甲基)甲硅烷基]氧基乙氧基]乙氧基]乙基[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊[a]菲-3-基]碳酸酯(61c)
2-[2-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]ethoxy]ethyl[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]carbonate
将2-[2-[2-[叔丁基(二甲基)甲硅烷基]氧基乙氧基]乙氧基]乙醇(61b)(1.45g,5.5mmol)溶于四氢呋喃(50mL)中,0℃下分小份加60%的氢化钠(0.22g,5.5mmol),0℃下反应30分钟将[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]咪唑-1-甲酸酯(化合物1)(2.2g,5.0mmol)溶于二氯甲烷(30mL)滴加至反应体系,升至室温反应10分钟,加水(50mL)淬灭反应,乙酸乙酯(200mL×2)萃取反应,有机相用无水硫酸钠干燥,减压浓缩干,用硅胶柱层析分离纯化(石油醚/乙酸乙酯(v/v)=3:1),得到白色固体的2-[2-[2-[叔丁基(二甲基)甲硅烷基]氧基乙氧基]乙氧基]乙基[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊[a]菲-3-基]碳酸酯(61c)(2.6g,产率81%)。
1HNMR(400MHz,CDCl3)δ8.62(s,1H),8.46(d,1H),7.66(d,1H),7.23(dd,1H),6.00(dd,1H),5.44(d,1H),4.49(tt,1H),4.27(dd,2H),3.81–3.70(m,4H),3.69–3.64(m,3H),3.56(q,2H),2.50–2.33(m,2H),2.27(tt,1H),2.12–2.00(m,4H),2.00–1.93(m,1H),1.93–1.84(m,1H),1.81–1.40(m,7H),1.38–1.11(m,2H),1.07(s,3H),1.05(s,3H),0.92–0.83(m,9H),0.10–0.03(m,6H)。
第三步:[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H环戊二烯并[a]菲-3-基]2-[2-(2-羟基乙氧基)乙氧基]乙基碳酸酯(61d)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]2-[2-(2-hydroxyethoxy)ethoxy]ethylcarbonate
将2-[2-[2-[叔丁基(二甲基)甲硅烷基]氧基乙氧基]乙氧基]乙基[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊[a]菲-3-基]碳酸酯(61c)(3.3g,5.1mmol)溶于二氯甲烷(80mL)中,加入四丁基氟化铵(1.33g,5.1mmol),0℃反应1.5小时,加水(50mL)淬灭反应,乙酸乙酯(200mL×2)萃取反应,有机相用无水硫酸钠干燥,减压浓缩干,用硅胶柱层析分离纯化(石油醚/乙酸乙酯(v/v)=1:1),得到淡黄油状的[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H环戊二烯并[a]菲-3-基]2-[2-(2-羟基乙氧基)乙氧基]乙基碳酸酯(61d)(1.7g,产率63%)。
1HNMR(400MHz,CDCl3)δ8.63(s,1H),8.46(s,1H),7.67(d,1H),7.26(d,1H),6.01(d,1H),5.44(d,1H),4.61–4.41(m,1H),4.28(dd,2H),3.77–3.70(m,4H),3.70–3.64(m,4H),3.64–3.58(m,2H),2.50–2.34(m,2H),2.34–2.18(m,1H),2.16–1.83(m,5H),1.83–1.40(m,8H),1.38–1.22(m,2H),1.08(d,3H),1.05(s,3H)。
第四步:[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊二烯并[a]菲-3-基]2-[2-(2-异丙乙氧基)乙氧基]乙基碳酸酯(化合物61)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]2-[2-(2-isopropoxycarbonyloxyethoxy)ethoxy]ethylcarbonate
将[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H环戊二烯并[a]菲-3-基]2-[2-(2-羟基乙氧基)乙氧基]乙基碳酸酯(61d)(1.7g,3.2mmol)溶于二氯甲烷(50mL)中,加入吡啶(1.52g,19.2mmol),0℃反应0.5小时,向反应瓶中滴加氯甲酸异丙酯(1.98g,16.2mmol),加完保持0℃反应40分钟。加水(100mL)淬灭反应,二氯甲烷(100mL×2)萃取反应,有机相用无水硫酸钠干燥,减压浓缩干,用硅胶柱层析分离纯化(石油醚/乙酸乙酯(v/v)=4:1),得到淡黄油状的[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊二烯并[a]菲-3-基]2-[2-(2-异丙乙氧基)乙氧基]乙基碳酸酯(化合物61)(0.75g,产率38%)。
MSm/z(ESI):612.5[M+H]。
1HNMR(400MHz,CDCl3)δ8.62(s,1H),8.46(d,1H),7.66(dd,1H),7.23(dd,1H),6.00(dd,1H),5.44(d,1H),4.87(hept,1H),4.49(ddd,1H),4.27(ddd,4H),3.76–3.68(m,4H),3.66(s,4H),2.50–2.33(m,2H),2.27(ddd,1H),2.14–1.84(m,5H),1.84–1.38(m,7H),1.30(d,6H),1.15(ddd,2H),1.07(s,3H),1.05(s,3H)。
实施例62
[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H环戊二烯并[a]菲-3-基]2-乙氧基乙基碳酸酯(化合物62)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]2-ethoxyethylcarbonate
将乙二醇单乙醚(0.5g,5.5mmol)溶于四氢呋喃(50mL)中,0℃下分小份加60%的氢化钠(0.22g,5.5mmol),0℃下反应30分钟,滴加[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]咪唑-1-甲酸酯(化合物1)(2.2g,5.0mmol)的二氯甲烷(50mL)溶液,升至室温反应10分钟,加水(50mL)淬灭反应,用二氯甲烷(100mL×2)萃取,有机相用无水硫酸钠干燥,减压浓缩干,残留物用硅胶柱层析分离纯化(石油醚/乙酸乙酯(v/v)=4:1),得到白色固体的[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H环戊二烯并[a]菲-3-基]2-乙氧基乙基碳酸酯(化合物62)(1.78g,产率76%)。
MSm/z(ESI):466.2[M+H]。
1HNMR(400MHz,CDCl3)δ8.62(d,1H),8.46(dd,1H),7.66(dt,1H),7.23(dd,1H),6.00(dd,1H),5.44(d,1H),4.49(ddd,1H),4.32–4.24(m,2H),3.69–3.61(m,2H),3.54(q,2H),2.50–2.34(m,2H),2.27(ddd,1H),2.13–2.01(m,3H),2.01–1.84(m,2H),1.82–1.40(m,7H),1.22(dd,3H),1.19–1.09(m,2H),1.07(s,3H),1.05(s,3H)。
实施例63
[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H环戊二烯并[a]菲-3-基]2-异丙氧基碳酸酯(化合物63)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]2-isopropoxyethylcarbonate
将乙二醇单异丙醚(0.57g,5.5mmol)溶于四氢呋喃(50mL)中,0℃下分小份加60%的氢化钠(0.22g,5.5mmol),0℃下反应30分钟,滴加[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]咪唑-1-甲酸酯(化合物1)(2.2g,5.0mmol)的二氯甲烷(50mL)溶液,升至室温反应10分钟,加水(50mL)淬灭反应,用二氯甲烷(100mL×2)萃取,有机相用无水硫酸钠干燥,减压浓缩干,残留物用硅胶柱层析分离纯化(石油醚/乙酸乙酯(v/v)=4:1),得到白色固体的[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H环戊二烯并[a]菲-3-基]2-异丙氧基碳酸酯(化合物63)(1.87g,产率78%)。
MSm/z(ESI):480.2[M+H]。
1HNMR(400MHz,CDCl3)δ8.62(d,1H),8.46(dd,1H),7.66(dt,1H),7.23(dd,1H),6.00(dd,1H),5.44(d,1H),4.49(dq,1H),4.28–4.19(m,2H),3.68–3.57(m,3H),2.50–2.34(m,2H),2.31–2.21(m,1H),2.12–1.84(m,5H),1.84–1.38(m,7H),1.18(s,3H),1.16(s,3H),1.15–1.09(m,2H),1.07(s,3H),1.05(s,3H)。
实施例64
O4-[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊[a]菲-3-基]O1-2,2--二甲基丁二酸酯(化合物64)
O4-[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]O1-methyl2,2-dimethylbutanedioate
向反应瓶中依次加入2,2-二甲基琥珀酸1-甲酯(0.65g,7.2mmol)、(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-醇(1a)(2.1g,6mmol)、4-二甲氨基吡啶(DMAP)(0.27g,2.2mmol)、二环己基碳二亚胺(DCC)(4.5g,22.2mmol)和二氯甲烷(100mL),室温反应5小时,体系加入水(100mL),用二氯甲烷(100mL×3)萃取,合并有机相,有机相用无水硫酸镁干燥,过滤,将滤液减压浓缩,,残留物用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(v/v)=2:1)得到得到白色固体状的O4-[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊[a]菲-3-基]O1-2,2-二甲基丁二酸酯(化合物64)(2.82g,产率95%)。
MSm/z(ESI):492.3[M+H]。
1HNMR(400MHz,CDCl3)δ8.62(d,1H),8.46(d,1H),7.65(d,1H),7.22(dd,1H),5.99(d,1H),5.41(d,1H),4.61(dt,1H),3.70(s,3H),2.57(s,2H),2.39–2.22(m,3H),2.13–1.98(m,3H),1.92–1.82(m,2H),1.82–1.43(m,7H),1.27(s,6H),1.20–1.08(m,2H),1.07(s,3H),1.04(s,3H)。
实施例65
2,2-二氟乙基[(3S,8R,9S,10R,13S,14S)-10,13二甲基-17-(3-吡啶基)-2,3-,4,7,8,9,11,12,14,15-十氢-1H-环戊[a]菲-3-基]碳酸酯(化合物65)
2,2-difluoroethyl[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]carbonate
将2,2-二氟乙醇(287mg,3.85mmol)溶于四氢呋喃(40mL)中,0℃下加入60%氢化钠(154mg,3.85mmol),将[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]2-咪唑甲酸酯(化合物1)(1.55g,3.5mmol)加至反应体系,恢复室温反应0.5小时,加水(50mL)淬灭反应,二氯甲烷(100mL×2)萃取反应,有机相用无水硫酸钠干燥,减压浓缩干,用硅胶柱层析分离纯化(石油醚/乙酸乙酯(v/v)=8:1),得到白色固体的2,2-二氟乙基[(3S,8R,9S,10R,13S,14S)-10,13二甲基-17-(3-吡啶基)-2,3-,4,7,8,9,11,12,14,15-十氢-1H-环戊[a]菲-3-基]碳酸酯(化合物65)(1.4g,产率87.5%)。
MSm/z(ESI):458.1[M+H]。
1HNMR(400MHz,CDCl3)δ8.62(d,1H),8.46(d,1H),7.69–7.61(m,1H),7.23(dd,1H),5.98(dd,1H),5.45(d,1H),4.60–4.44(m,1H),4.31(td,2H),2.43(dd,2H),2.27(ddd,1H),2.14–2.01(m,3H),2.01–1.84(m,3H),1.84–1.54(m,6H),1.49(td,1H),1.35–1.09(m,2H),1.08(s,3H),1.05(s,3H)。
实施例66
[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H环戊二烯并[a]菲-3-基]3,3,3-三氟丙基碳酸酯(化合物66)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]3,3,3-trifluoropropylcarbonate
将3,3,3-三氟丙醇(502mg,4.4mmol)溶于四氢呋喃(40mL)中,0℃下加入60%氢化钠(176mg,4.4mmol),将[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]2-咪唑甲酸酯(化合物1)(1.77g,4.0mmol)加至反应体系,恢复室温反应0.5小时,加水(50mL)淬灭反应,二氯甲烷(100mL×2)萃取反应,有机相用无水硫酸钠干燥,减压浓缩干,用硅胶柱层析分离纯化(石油醚/乙酸乙酯(v/v)=10:1),得到淡黄色固体的[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H环戊二烯并[a]菲-3-基]3,3,3-三氟丙基碳酸酯(化合物66)(2.8g,产率71%)。
MSm/z(ESI):490.1[M+H]。
1HNMR(400MHz,CDCl3)δ8.62(s,1H),8.47(d,1H),7.68(d,1H),7.31–7.19(m,1H),6.01(dd,1H),5.45(d,1H),4.60–4.42(m,1H),4.35(t,2H),2.59–2.48(m,2H),2.48–2.34(m,2H),2.28(ddd,1H),2.14–2.01(m,2H),1.91(ddd,3H),1.83–1.55(m,6H),1.55–1.42(m,1H),1.38–1.09(m,2H),1.08(s,3H),1.05(s,3H)。
实施例67
[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H环戊二烯并[a]菲-3-基][(2S)-2-甲氧基丙基]碳酸酯(化合物67)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl][(2S)-2-methoxypropyl]carbonate
将(2S)-2-甲氧基-1-丙醇(397mg,4.4mmol)溶于四氢呋喃(40mL)中,0℃下加入60%氢化钠(176mg,4.4mmol),将[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]2-咪唑甲酸酯(化合物1)(1.77g,4.0mmol)加至反应体系,恢复室温反应0.5小时,加水(50mL)淬灭反应,二氯甲烷(100mL×2)萃取反应,有机相用无水硫酸钠干燥,减压浓缩干,用硅胶柱层析分离纯化(石油醚/乙酸乙酯(v/v)=10:1),得到白色固体的[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H环戊二烯并[a]菲-3-基][(2S)-2-甲氧基丙基]碳酸酯(化合物67)(1.1g,产率59%)。
MSm/z(ESI):466.2[M+H]。
1HNMR(400MHz,CDCl3)δ8.62(s,1H),8.46(d,1H),7.66(d,1H),7.23(dd,1H),6.00(dd,1H),5.44(d,1H),4.92(ddd,1H),4.48(ddd,1H),3.48(dd,1H),3.44–3.38(m,1H),3.37(s,3H),2.51–2.34(m,2H),2.27(ddd,1H),2.14–1.93(m,4H),1.88(dt,1H),1.82–1.41(m,7H),1.29(d,3H),1.21–1.09(m,2H),1.07(s,3H),1.05(s,3H)。
实施例68
[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H环戊二烯并[a]菲-3-基]异丙硫基甲酸酯(化合物68)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]isopropylsulfanylformate
将异丙基硫醇(457mg,6mmol)溶于四氢呋喃(50mL)中,0℃下加入60%氢化钠(280mg,7mmol),将[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]2-咪唑甲酸酯(化合物1)(2.2g,5mmol)加至反应体系,恢复室温反应0.5小时,加水(50mL)淬灭反应,二氯甲烷(100mL×2)萃取反应,有机相用无水硫酸钠干燥,减压浓缩干,用硅胶柱层析分离纯化(石油醚/乙酸乙酯(v/v)=30:1),得到白色固体的[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H环戊二烯并[a]菲-3-基]异丙硫基甲酸酯(化合物68)(1.65g,产率73%)。
1HNMR(400MHz,CDCl3)δ8.62(d,1H),8.56–8.41(m,1H),7.67(d,1H),7.26–7.21(m,1H),6.01(dd,1H),5.43(d,1H),4.83–4.52(m,1H),3.51(dt,1H),2.49–2.21(m,3H),2.17–1.41(m,12H),1.36(s,3H),1.34(s,3H),1.22–1.09(m,2H),1.08(s,3H),1.05(s,3H)。
MSm/z(ESI):452.2[M+H]。
实施例69
[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H环戊二烯并[a]菲-3-基]2-乙氧羰氧乙基碳酸酯(化合物69)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]2-ethoxycarbonyloxyethylcarbonate
将[(3S,8R,9S,10R,13S,14S)-10-13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]2-羟基乙氧基甲酸酯(32a)(1.31g,0.3mmol)溶于二氯甲烷(50mL)中,加入三乙胺(0.36mL,4.5mmol),0℃反应0.5小时,向反应瓶中滴加氯甲酸乙酯(0.37mL,3.9mmol),加完室温反应2小时。加水(100mL)淬灭反应,二氯甲烷(100mL×2)萃取反应,有机相用无水硫酸钠干燥,减压浓缩干,用硅胶柱层析分离纯化(石油醚/乙酸乙酯(v/v)=5:1),得到无色油状的[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H环戊二烯并[a]菲-3-基]2-乙氧羰氧乙基碳酸酯(化合物69)(0.8g,产率68%)。
MSm/z(ESI):510.2[M+H]。
1HNMR(400MHz,CDCl3)δ8.62(s,1H),8.46(d,1H),7.67(m,1H),7.32–7.18(m,1H),6.01(dd,1H),5.44(d,1H),4.50(m,1H),4.40–4.30(m,4H),4.21(m,2H),2.51–2.34(m,2H),2.27(m,1H),2.14–1.42(m,13H),1.36–1.29(m,2H),1.29–1.09(m,2H),1.08(s,3H),1.05(s,3H)。
实施例70
[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊二烯并[a]菲-3-基]3-异丙羰氧丙基碳酸酯(化合物70)
[(3S,10R,13S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]3-isopropoxycarbonyloxypropylcarbonate
第一步:3-[叔丁基(二甲基)甲硅烷基]氧基丙-1-醇(70b)
3-[tert-butyl(dimethyl)silyl]oxypropan-1-ol
将1,3-丙二醇70a(11.4g,150mmol)溶于四氢呋喃(250mL)中,0℃下分小份加60%的氢化钠(6.0g,1500mmol),0℃下反应30分钟,将叔丁基二甲基氯硅烷溶于四氢呋喃(100mL)滴加至反应体系,室温反应4小时,加饱和食盐水(300mL)淬灭反应,乙酸乙酯(300mL×2)萃取反应,有机相用无水硫酸钠干燥,减压浓缩干得到黄色油状3-[叔丁基(二甲基)甲硅烷基]氧基丙-1-醇(70b)(26.24g,产率92%)。
1HNMR(400MHz,CDCl3)δ3.88–3.73(m,1H),2.56(s,0H),1.81–1.73(m,0H),0.92–0.89(m,2H),0.09–0.06(m,2H)。
第二步:3-[叔丁基(二甲基)甲硅烷基]氧基丙基[(3S,8R,9S,10R,13S,14S)-10,13二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊二烯并[a]菲-3-基]碳酸酯(70c)
3-[tert-butyl(dimethyl)silyl]oxypropyl[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]carbonate
将3-[叔丁基(二甲基)甲硅烷基]氧基丙-1-醇(70b)(2.4g,12.6mmol)溶于四氢呋喃(50mL)中,0℃下分小份加60%的氢化钠(0.59g,14.7mmol),0℃下反应30分钟将[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]咪唑-1-甲酸酯(化合物1)(4.65g,10.5mmol)溶于二氯甲烷(30mL)滴加至反应体系,升至室温反应10分钟,加水(50mL)淬灭反应,乙酸乙酯(200mL×2)萃取反应,有机相用无水硫酸钠干燥,减压浓缩干,用硅胶柱层析分离纯化(石油醚/乙酸乙酯(v/v)=10:1),得到白色固体的3-[叔丁基(二甲基)甲硅烷基]氧基丙基[(3S,8R,9S,10R,13S,14S)-10,13二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊二烯并[a]菲-3-基]碳酸酯(70c)(3.7g,产率62%)
1HNMR(400MHz,CDCl3)δ8.63(d,1H),8.47(dd,1H),7.68(dt,1H),7.31–7.18(m,2H),6.01(dd,1H),5.44(d,1H),4.49(ddd,1H),4.23(t,2H),3.71(t,2H),2.50–2.34(m,2H),2.28(ddd,1H),2.13–2.00(m,3H),2.00–1.83(m,4H),1.83–1.54(m,6H),1.49(td,1H),1.08(s,3H),1.05(s,3H),0.90–0.87(m,9H),0.09–0.02(m,6H)。
第三步:[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H环戊二烯并[a]菲-3-基]3-羟丙基碳酸酯(70d)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]3-hydroxypropylcarbonate
将3-[叔丁基(二甲基)甲硅烷基]氧基丙基[(3S,8R,9S,10R,13S,14S)-10,13二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊二烯并[a]菲-3-基]碳酸酯(70c)(3.7g,6.5mmol)溶于四氢呋喃(100mL)中,加入四丁基氟化铵(1.33g,5.1mmol),0℃反应20分钟,加水(200mL)淬灭反应,乙酸乙酯(200mL×2)萃取反应,有机相用无水硫酸钠干燥,减压浓缩干,用硅胶柱层析分离纯化(石油醚/乙酸乙酯(v/v)=1:1),得到[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H环戊二烯并[a]菲-3-基]3-羟丙基碳酸酯(70d)(2.88g,产率98%)。
1HNMR(400MHz,CDCl3)δ8.62(s,1H),8.46(d,1H),7.81(d,1H),7.41–7.31(m,1H),6.07(s,1H),5.44(d,1H),4.57–4.43(m,1H),4.29(t,2H),3.74(t,2H),3.36(dd,1H),2.51–2.23(m,3H),2.17–1.37(m,16H),1.08(s,3H),1.05(s,3H)。
第四步:[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊二烯并[a]菲-3-基]3-异丙羰氧丙基碳酸酯(化合物70)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]3-isopropoxycarbonyloxypropylcarbonate
将[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H环戊二烯并[a]菲-3-基]3-羟丙基碳酸酯(70d)(1.44g,3.2mmol)溶于二氯甲烷(50mL)中,加入吡啶(0.38g,4.8mmol),0℃反应0.5小时,向反应瓶中滴加氯甲酸异丙酯(0.51g,4.15mmol),加完室温反应2小时。加水(100mL)淬灭反应,二氯甲烷(100mL×2)萃取反应,有机相用无水硫酸钠干燥,减压浓缩干,用硅胶柱层析分离纯化(石油醚/二氯甲烷/甲醇(v/v/v)=50:50:1),得到黄色固体[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊二烯并[a]菲-3-基]3-异丙羰氧丙基碳酸酯(化合物70)(0.53g,产率31%)。
MSm/z(ESI):538.3[M+H]。
1HNMR(400MHz,CDCl3)δ8.63(d,1H),8.47(dd,1H),7.77–7.63(m,1H),7.32–7.22(m,2H),6.02(dd,1H),5.44(d,1H),4.96–4.76(m,1H),4.49(m,1H),4.23(m,4H),2.50–2.34(m,2H),2.28(m,1H),2.14–2.00(m,5H),1.91(m,2H),1.84–1.41(m,8H),1.31(s,3H),1.29(s,3H),1.08(s,3H),1.05(s,3H)。
实施例71
[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]2-[(2-氨基乙酰基)氨基]乙酸酯(化合物71)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]2-[(2-aminoacetyl)amino]acetate
第一步:[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]2-((叔丁氧基羰基)氨基)乙酸酯(71b)
(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(pyridin-3-yl)-2,3,4,7,8,9,10,11,12,13,1415-dodecahydro-1H-cyclopenta[a]phenanthren-3-yl2-((tert-butoxycarbonyl)amino)acetate
将阿比特龙(71a)(3.49g,10mmol)、N-叔丁氧羰基甘氨酸(1.75g,10mmol)、DMAP(0.37g,3mmol)、EDCI(2.3g,12mmol)加入到二氯甲烷(50mL)中,50℃反应7小时,体系加入50mL水,用二氯甲烷(50mL×3)萃取,有机相用无水硫酸镁干燥,过滤,将滤液减压浓缩,残留物用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(v/v)=3:1)得到得白色固体化[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]2-((叔丁氧基羰基)氨基)乙酸酯(71b)(3.1g,产率61%。)。
第二步:[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]2-氨基乙酸酯(71c)
(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(pyridin-3-yl)-2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a]phenanthren-3-yl2-aminoacetate
将[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]2-((叔丁氧基羰基)氨基)乙酸酯(71b)(3.1g,6.12mmol)加入到3mol/L的盐酸/乙酸乙酯(50ml)中,反应2h。向反应体系中加入水(100ml),搅拌30分钟分液,水层用饱和碳酸氢钠碱化至PH>9,用二氯甲烷(50mL×2)萃取,合并有机相,无水硫酸镁干燥,过滤,将滤液减压浓缩得到得白色固体[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]2-氨基乙酸酯(71c)(2.4g,产率96%)。
第三步:[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]2-(2-((叔丁氧基羰基)氨基)乙酰基氨基)乙酸酯(71d)
(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(pyridin-3-yl)-2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a]phenanthren-3-yl2-(2-((tert-butoxycarbonyl)amino)acetamido)acetate
将[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]2-氨基乙酸酯(71c)(813mg,2mmol)、N-叔丁氧羰基甘氨酸(0.35g,2mmol)、TBTU(462mg,2.2mmol)、DIPEA(858mg,6mmol)加入到二氯甲烷(10mL)中,室温反应2小时,体系加入20mL水,用二氯甲烷(20mL×3)萃取,有机相用无水硫酸镁干燥,过滤,将滤液减压浓缩,残留物用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(v/v)=3:1)得到得白色固体[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]2-(2-((叔丁氧基羰基)氨基)乙酰基氨基)乙酸酯(71d)(1.03g,产率61%)。
第四步:[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]2-[(2-氨基乙酰基)氨基]乙酸酯(化合物71)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]2-[(2-aminoacetyl)amino]acetate
将[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]2-(2-((叔丁氧基羰基)氨基)乙酰基氨基)乙酸酯(71d)(1.03g,1.83mmol)加入到3mol/L的盐酸/乙酸乙酯(10ml)中,反应1h。向反应体系中加入水(10ml),搅拌30分钟分液,水层用饱和碳酸氢钠碱化至PH>9,用二氯甲烷(20mL×2)萃取,合并有机相,无水硫酸镁干燥,过滤,将滤液减压浓缩得到得白色固体[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]2-[(2-氨基乙酰基)氨基]乙酸酯(化合物71)(0.41g,产率48%。)。
Msm/z(ESI):464.3[M+1]。
1HNMR(400MHz,DMSO-d6):δ8.60(d,1H),8.45(dd,1H),8.20(m,1H),7.78(m,1H),7.36(m,1H),6.13(m,1H),5.41(d,1H),4.52(m,1H),3.86(d,2H),3.13(s,2H),2.33(d,2H),2.21(m,1H),2.06(m,3H),1.87-1.57(m,10H),1.45(m,1H),1.11-1.03(m,8H)。
实施例72
[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]2-[(2S)-2-氨基丙酰胺基]乙酸酯(化合物72)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]2-[[(2S)-2-aminopropanoyl]amino]acetate
第一步:[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]2-[(2S)-2-(叔丁氧基羰基)氨基丙酰胺基]乙酸酯(72b)
(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(pyridin-3-yl)-2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a]phenanthren-3-yl2-((S)-2-((tert-butoxycarbonyl)amino)propanamido)acetate
将[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]2-氨基乙酸酯(71c)(1g,2.46mmol)、N-叔丁氧羰基L-丙氨酸(0.465g,2.46mmol)、TBTU(870mg,2.71mmol)、DIPEA(950mg,7.38mmol)加入到二氯甲烷(10mL)中,室温反应2小时,体系加入20mL水,用二氯甲烷(20mL×3)萃取,有机相用无水硫酸镁干燥,过滤,将滤液减压浓缩,残留物用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(v/v)=3:1)得到得白色固体[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]2-[(2S)-2-(叔丁氧基羰基)氨基丙酰胺基]乙酸酯(72b)(0.96g,产率68%)。
第二步:[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]2-[(2S)-2-氨基丙酰胺基]乙酸酯(化合物72)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]2-[[(2S)-2-aminopropanoyl]amino]acetate
将[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]2-[(2S)-2-(叔丁氧基羰基)氨基丙酰胺基]乙酸酯(72b)(0.96g,1.66mmol)加入到3mol/L的HCl/EA(10ml)中,反应1h。向反应体系中加入水(10ml),搅拌30分钟分液,水层用饱和碳酸氢钠碱化至PH>9,用二氯甲烷(20mL×2)萃取,合并有机相,无水硫酸镁干燥,过滤,将滤液减压浓缩得到得白色固体[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]2-[(2S)-2-氨基丙酰胺基]乙酸酯(化合物72)(0.48g,产率61%。)。
Msm/z(ESI):478.3[M+1];
1HNMR(400MHz,DMSO-d6):δ8.60(d,1H),8.45(dd,1H),8.20(m,1H),7.81(dt,1H),7.35(ddd,1H),6.12(m,1H),5.41(d,1H),4.50(m,1H),3.83(d,2H),3.19(m,1H),2.32(d,2H),2.21(m,1H),2.06(m,3H),1.87-1.57(m,10H),1.41(m,1H),1.15(d,3H),1.11-1.03(m,8H)。
实施例73
[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基](2S)-2-[(2S)-2-氨基-3-苯基-丙酰胺基]丙酸脂(化合物73)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl](2S)-2-[[(2S)-2-amino-3-phenyl-propanoyl]amino]propanoate
第一步:[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]2-((叔丁氧基羰基)氨基)丙酸酯(73b)
(S)-(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(pyridin-3-yl)-2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a]phenanthren-3-yl2-((tert-butoxycarbonyl)amino)propanoate
将阿比特龙(1a)(3.49g,10mmol)、N-叔丁氧羰基L-丙氨酸(1.89g,10mmol)、DMAP(0.37g,3mmol)、EDCI(2.3g,12mmol)加入到二氯甲烷(50mL)中,50℃反应7小时,体系加入50mL水,用二氯甲烷(50mL×3)萃取,有机相用无水硫酸镁干燥,过滤,将滤液减压浓缩,残留物用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(v/v)=3:1)得到得白色固体[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]2-((叔丁氧基羰基)氨基)丙酸酯(73b)(3.2g,产率62%)。
第二步:[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]2-氨基丙酸酯(73c)
(S)-(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(pyridin-3-yl)-2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a]phenanthren-3-yl2-aminopropanoate
将[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]2-((叔丁氧基羰基)氨基)丙酸酯(73b)(3.2g,6.15mmol)加入到3mol/L的HCl/EA(30ml)中,反应2h。向反应体系中加入水(100ml),搅拌30分钟分液,水层用饱和碳酸氢钠碱化至PH>9,用二氯甲烷(50mL×2)萃取,合并有机相,无水硫酸镁干燥,过滤,将滤液减压浓缩得到得白色固体[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]2-氨基丙酸酯(73c)(2.6g,产率100%)。
第三步:[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基](2S)-2-[(2S)-2-(叔丁氧基羰基)氨基-3-苯基-丙酰胺基]丙酸脂(73d)
(S)-(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(pyridin-3-yl)-2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a]phenanthren-3-yl2-((S)-2-((tert-butoxycarbonyl)amino)-3-phenylpropanamido)propanoate
将[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]2-氨基丙酸酯(73c)(2.6g,6.18mmol)、N-叔丁氧羰基-L-苯丙氨酸(1.64g,6.18mmol)、TBTU(2.18g,6.8mmol)、DIPEA(2.4g,18.5mmol)加入到二氯甲烷(30mL)中,室温反应2小时,体系加入20mL水,用二氯甲烷(20mL×3)萃取,有机相用无水硫酸镁干燥,过滤,将滤液减压浓缩,残留物用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(v/v)=3:1)得到得白色固体[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基](2S)-2-[(2S)-2-(叔丁氧基羰基)氨基-3-苯基-丙酰胺基]丙酸脂(73d)(2.5g,产率61%。)。
第四步:[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基](2S)-2-[(2S)-2-氨基-3-苯基-丙酰胺基]丙酸脂(化合物73)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl](2S)-2-[[(2S)-2-amino-3-phenyl-propanoyl]amino]propanoate
将[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基](2S)-2-[(2S)-2-(叔丁氧基羰基)氨基-3-苯基-丙酰胺基]丙酸脂(73d)(2.5g,3.74mmol)加入到3mol/L的HCl/EA(30ml)中,反应1h。向反应体系中加入水(50ml),搅拌30分钟分液,水层用饱和碳酸氢钠碱化至PH>9,用二氯甲烷(50mL×2)萃取,合并有机相,无水硫酸镁干燥,过滤,将滤液减压浓缩得到得白色固体[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基](2S)-2-[(2S)-2-氨基-3-苯基-丙酰胺基]丙酸脂(化合物73)(1.9g,产率90%)。
Msm/z(ESI):568.3[M+1]。
1HNMR(400MHz,DMSO-d6):δ8.60(d,1H),8.45(dd,1H),8.23(d,1H),7.77(dt,1H),7.35(ddd,1H),7.30-7.18(m,5H),6.12(s,1H),5.41(d,1H),4.50(m,1H),4.25(m,1H),3.43(dd,1H),2.99(dd,1H),2.61(dd,1H),2.30(d,2H),2.21(m,1H),2.06(m,3H),1.87-1.57(m,10H),1.41(m,1H),1.29(d,3H),1.11-1.03(m,8H)。
实施例74
[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基](2S)-2-[(2S)-2-[2-氨基乙酰胺基]-3-苯基-丙酰胺基]丙酸脂(化合物74)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]
(2S)-2-[[(2S)-2-[(2-aminoacetyl)amino]-3-phenyl-propanoyl]amino]propanoate
第一步:[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基](2S)-2-[(2S)-2-[2-(叔丁氧基羰基)氨基乙酰胺基]-3-苯基-丙酰胺基]丙酸脂(74b)
(9S,12S)-(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(pyridin-3-yl)-2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a]phenanthren-3-yl9-benzyl-2,2,12-trimethyl-4,7,10-trioxo-3-oxa-5,8,11-triazatridecan-13-oate
将[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基](2S)-2-[(2S)-2-氨基-3-苯基-丙酰胺基]丙酸脂(化合物73)(1.6g,2.82mmol)、N-叔丁氧羰基L-丙氨酸(0.494g,2.82mmol)、TBTU(1g,3.1mmol)、DIPEA(1.1g,8.46mmol)加入到二氯甲烷(20mL)中,室温反应2小时,体系加入20mL水,用二氯甲烷(20mL×3)萃取,有机相用无水硫酸镁干燥,过滤,将滤液减压浓缩,残留物用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(v/v)=3:1)得到得白色固体[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基](2S)-2-[(2S)-2-[2-(叔丁氧基羰基)氨基乙酰胺基]-3-苯基-丙酰胺基]丙酸脂(74b)(1.7g,产率85%。)。
第二步:[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基](2S)-2-[(2S)-2-[2-氨基乙酰胺基]-3-苯基-丙酰胺基]丙酸脂(化合物74)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl](2S)-2-[[(2S)-2-[(2-aminoacetyl)amino]-3-phenyl-propanoyl]amino]propanoate
将[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基](2S)-2-[(2S)-2-[2-(叔丁氧基羰基)氨基乙酰胺基]-3-苯基-丙酰胺基]丙酸脂(74b)(1.7g,2.35mmol)加入到3mol/L的HCl/EA(30ml)中,反应1h。向反应体系中加入水(50ml),搅拌30分钟分液,水层用饱和碳酸氢钠碱化至PH>9,用二氯甲烷(50mL×2)萃取,合并有机相,无水硫酸镁干燥,过滤,将滤液减压浓缩得到得白色固体[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基](2S)-2-[(2S)-2-[2-(叔丁氧基羰基)氨基乙酰胺基]-3-苯基-丙酰胺基]丙酸脂(74b)(1.1g,产率75%)。
Msm/z(ESI):625.3[M+1]。
1HNMR(400MHz,DMSO-d6):δ8.60(d,1H),8.54(d,1H),8.45(dd,1H),7.98(br,1H),7.77(dt,1H),7.35(ddd,1H),7.28-7.16(m,5H),6.11(m,1H),5.41(d,1H),4.61(br,1H),4.50(m,1H),4.24(m,1H),3.05-3.01(m,3H),2.83(dd,1H),2.30(d,2H),2.21(m,1H),2.06(m,3H),1.87-1.57(m,10H),1.41(m,1H),1.32(d,3H),1.11-1.03(m,8H)。
实施例75
[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基](2S)-2,6-二氨基己酸酯(化合物75)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl](2S)-2,6-diaminohexanoate
第一步:[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基](2S)-2,6-二(叔丁氧基羰基)氨基己酸酯(75b)
(S)-(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(pyridin-3-yl)-2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a]phenanthren-3-yl2,6-bis((tert-butoxycarbonyl)amino)hexanoate
将阿比特龙1a(1.8g,5.16mmol)、N,N-二叔丁氧羰基-L-赖氨酸(1.79g,5.16mmol)、TBTU(1.82g,5.68mmol)、DIPEA(1.33g,10.32mmol)加入到二氯甲烷(20mL)中,室温反应2小时,体系加入20mL水,用二氯甲烷(20mL×3)萃取,有机相用无水硫酸镁干燥,过滤,将滤液减压浓缩,残留物用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(v/v)=3:1)得到得白色固体[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基](2S)-2,6-二(叔丁氧基羰基)氨基己酸酯(75b)(0.87g,产率25%)。
第二步:[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基](2S)-2,6-二氨基己酸酯(化合物75)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl](2S)-2,6-diaminohexanoate
将[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基](2S)-2,6-二(叔丁氧基羰基)氨基己酸酯(75b)(0.87g,2.23mmol)加入到3mol/L的HCl/EA(10ml)中,反应1h。向反应体系中加入水(10ml),搅拌30分钟分液,水层用饱和碳酸氢钠碱化至PH>9,用二氯甲烷(20mL×2)萃取,合并有机相,无水硫酸镁干燥,过滤,将滤液减压浓缩得到得白色固体[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基](2S)-2,6-二氨基己酸酯(化合物75)(0.5g,产率64%)。
Msm/z(ESI):478.3[M+1]。
1HNMR(400MHz,DMSO-d6):δ8.60(d,1H),8.45(dd,1H),7.78(dt,1H),7.36(ddd,1H),6.13(m,1H),5.41(d,1H),4.52(m,1H),3.25(dd,1H),3.13(s,2H),2.30-2.20(m,3H),2.06(m,3H),1.87-1.32(m,19H),1.11-1.03(m,8H)。
实施例76
[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基](1-甲基-4-哌啶基)碳酸酯(化合物16)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl](1-methyl-4-piperidyl)carbonate
向反应瓶中依次加入四氢呋喃(50mL)、氢化钠(0.2g,5mmol),冰浴,缓慢滴加N-甲基-4-哌啶醇(0.48g,4.2mmol),加完冰浴30分钟。将[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]咪唑-1-羧酸酯(化合物1)(1.55g,3.5mmol)溶于20mL四氢呋喃中,缓慢滴加至反应瓶,加完室温反应5小时.体系加入饱和氯化铵淬灭(100mL),用二氯甲烷(100mL×2)萃取,有机相用无水硫酸镁干燥,过滤,将滤液减压浓缩,,残留物用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=20:1)得到得到白色固状的[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H环戊二烯并[a]菲-3-基](1-甲基-4-哌啶基)碳酸酯(化合物76)(1.3g,76%)。
MSm/z(ESI):491.2[M+1]。
1HNMR(400MHz,CDCl3)δ8.62(d,1H),8.46(dd,1H),7.64(dt,1H),7.21(dd,1H),6.03–5.89(m,1H),5.44(d,1H),4.67(s,1H),4.49(tt,1H),2.72(s,2H),2.52–2.38(m,2H),2.32(s,3H),2.27(ddd,2H),2.04(ddd,6H),1.92–1.74(m,4H),1.74–1.40(m,7H),1.08(s,3H),1.05(s,3H)。
实施例77
2-[[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊二烯并[a]菲-3-基]氧基羰基]乙基(2S)-2-氨基-2-苯基-乙酸酯(化合物77)
2-[[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]oxycarbonyloxy]ethyl(2S)-2-amino-2-phenyl-acetate
第一步:2-[[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊二烯并[a]菲-3-基]氧基羰氧基]乙基(2S)-2-(叔丁氧基羰基)-2-苯基乙酸酯(77b)
2-[[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]oxycarbonyloxy]ethyl(2S)-2-(tert-butoxycarbonylamino)-2-phenyl-acetate
向反应瓶中依次加入[(3S,8R,9S,10R,13S,14S)-10-13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]2-羟基乙氧基甲酸酯(32a)(2.01g,8mmol)、(2S)-2-(叔丁氧基羰基)-2-苯基-乙酸(2.19g,5mmol)、4-二甲氨基吡啶(DMAP)(0.18g,1.5mmol)、二环己基碳二亚胺(DCC)(2.58g,12.5mmol)和二氯甲烷(100mL),室温反应5小时,体系加入水(100mL),用二氯甲烷(100mL×3)萃取,合并有机相,有机相用无水硫酸镁干燥,过滤,将滤液减压浓缩,残留物用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(v/v)=4:1)得到得到白色固体状的2-[[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊二烯并[a]菲-3-基]氧基羰氧基]乙基(2S)-2-(叔丁氧基羰基)-2-苯基乙酸酯(77b)(2.33g,产率70%)。
第二步:2-[[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊二烯并[a]菲-3-基]氧基羰基]乙基(2S)-2-氨基-2-苯基乙酸酯(化合物77)
2-[[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]oxycarbonyloxy]ethyl(2S)-2-amino-2-phenyl-acetate
向反应瓶中加入2-[[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊二烯并[a]菲-3-基]氧基羰氧基]乙基(2S)-2-(叔丁氧基羰基)-2-苯基乙酸酯(77a)(2.33g,3.5mmol)和乙酸乙酯盐酸溶液(3M)(20mL,60mmol),室温反应3小时,体系加入饱和碳酸氢钠溶液(100mL),用乙酸乙酯(100mL×3)萃取,合并有机相,有机相用无水硫酸镁干燥,过滤,将滤液减压浓缩,得到淡黄油状的2-[[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊二烯并[a]菲-3-基]氧基羰基]乙基(2S)-2-氨基-2-苯基-乙酸酯(化合物77)(1.9g,产率95%)。
1HNMR(400MHz,CDCl3)δ8.62(s,1H),8.46(d,1H),7.65(d,1H),7.42–7.27(m,5H),7.22(dd,1H),6.00(dd,1H),5.44(d,1H),4.68(s,1H),4.54–4.35(m,2H),4.35–4.20(m,3H),2.52(s,2H),2.47–2.33(m,2H),2.27(m,1H),2.14–2.00(m,4H),1.91(m,2H),1.82–1.54(m,6H),1.49(m,1H),1.08(s,4H),1.05(s,3H)。
MSm/z(ESI):571.3[M+1]。
实施例78
[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基](2S)-2-氨基-3-(1H-咪唑-4-基)丙酸酯(化合物78)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl](2S)-2-amino-3-(1H-imidazol-4-yl)propanoate
第一步:叔丁基4-[(2S)-2-(叔丁氧羰基氨基)-3-[[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]氧基]-3-氧代-丙基]咪唑基-1-甲酸酯(78b)
tert-butyl4-[(2S)-2-(tert-butoxycarbonylamino)-3-[[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]oxy]-3-oxo-propyl]imidazole-1-carboxylate
将(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-醇(1a)(3.0g,8.6mmol)溶于二氯甲烷(20mL)中,加入(S)-3-(1-(叔丁氧羰基)-1H-咪唑4-基)-2-((叔丁氧羰基)氨基)丙酸(78a)(6.1g,17.2mmol),1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(2.6mg,12.9mmol),4-二甲氨基吡啶(1.1mg,8.6mmol)室温反应6小时,水(50mL×2)洗,无水硫酸钠干燥,减压浓缩,用硅胶柱层析分离纯化(二氯甲烷/甲醇=20:1),得到白色固体的叔丁基-4-[(2S)-2-(叔丁氧羰基氨基)-3-[[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]氧基]-3-氧代-丙基]咪唑基-1-甲酸酯(78b)(2.0g,产率34%)。
第二步:[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基](2S)-2-氨基-3-(1H-咪唑-4-基)丙酸酯(化合物78)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl](2S)-2-amino-3-(1H-imidazol-4-yl)propanoate
将叔丁基4-[(2S)-2-(叔丁氧羰基氨基)-3-[[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]氧基]-3-氧代-丙基]咪唑基-1-甲酸酯(78b)(2.0g,2.9mmol)溶于盐酸乙酸乙酯(4mol/L,20mL)中,室温搅拌30分钟,过滤得到白色固体,加入氨水(20mL)碱化,减压浓缩干,用硅胶柱层析分离纯化(二氯甲烷/甲醇=10:1),得到白色固体的[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基](2S)-2-氨基-3-(1H-咪唑-4-基)丙酸酯(化合物78)(1.0g,产率58%)。
1HNMR(400MHz,MeOD)δ8.55(d,1H),8.40(dd,1.5Hz,1H),7.85(dt,1H),7.73(s,1H),7.40(ddd,1H),7.02(s,1H),6.11(dd,1H),5.46(d,1H),4.64(dt,1H),4.15-4.10(m,2H),3.13(ddd,J=22.5,15.1,6.6Hz,2H),2.40–2.27(m,3H),2.22–2.08(m,2H),1.98–1.82(m,3H),1.85–1.45(m,6H),1.24–1.01(m,8H)。
实施例79
2-[[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]氧基羰基氧基]乙基哌啶-4-甲酸酯(化合物79)
2-[[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]oxycarbonyloxy]ethylpiperidine-4-carboxylate
第一步:1-叔丁基-4-[2-[[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]氧基羰基氧基]乙基哌啶-1,4-二甲酸酯(79b)
1-tert-butyl-4-[2-[[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]oxycarbonyloxy]ethyl]piperidine-1,4-dicarboxylate
将(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]2-羟乙基碳酸酯(32a)(2.0g,4.6mmol)溶于二氯甲烷(30mL)中,加入1-(叔丁氧羰基)哌啶-4-羧酸(2.1g,9.2mmol)加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(1000mg,5.1mmol),4-二甲氨基吡啶(561mg,4.6mmol)室温反应2小时,抽滤固体,减压浓缩干滤液,用硅胶柱层析分离纯化(石油醚/乙酸乙酯=2:1),得到白色固体的1-叔丁基-4-[2-[[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]氧基羰基氧基]乙基哌啶-1,4-二甲酸酯(79b)(2.0g,产率67%)。
第二步:2-[[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]氧基羰基氧基]乙基哌啶-4-甲酸酯(化合物79)
2-[[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]oxycarbonyloxy]ethylpiperidine-4-carboxylate
将1-叔丁基-4-[2-[[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]氧基羰基氧基]乙基哌啶-1,4-二甲酸酯(79b)(2.0g,3.1mmol)溶于盐酸乙酸乙酯(4mol/L,20mL)中,室温搅拌30分钟,过滤得到白色固体,加入氨水(20mL)碱化,减压浓缩干,用硅胶柱层析分离纯化(二氯甲烷/甲醇=10:1),得到白色固体的2-[[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]氧基羰基氧基]乙基哌啶-4-甲酸酯(化合物79)(1.0g,产率60%)。
Msm/z(ESI):549.2[M+1]。
1HNMR(400MHz,CDCl3)δ8.61(d,J=1.7Hz,1H),8.46(dd,J=4.8,1.6Hz,1H),7.73–7.59(m,1H),7.25–7.12(m,1H),5.99(dd,J=3.1,1.7Hz,1H),5.44(d,J=5.1Hz,1H),4.49(dd,J=10.6,5.1Hz,1H),4.33(s,4H),3.22(dt,J=12.6,4.2Hz,2H),2.91–2.21(m,8H),2.14–2.02(m,5H),1.95–1.48(m,10H),1.17–0.98(m,8H)。
实施例80
2-[[(3S,8R,9S,10R,13S,14S)-10,13-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]氧基羰基氧基]乙基1-甲基哌啶-4-甲酸酯(化合物80)
2-[[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]oxycarbonyloxy]ethyl
1-methylpiperidine-4-carboxylate
将(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]2-羟乙基碳酸酯32a(1.0g,2.3mmol)溶于二氯甲烷(20mL)中,加入1-甲基-4-哌啶酸(184mg,1.5mmol),二环己基碳二亚胺(226mg,1.1mmol),4-二甲氨基吡啶(492mg,3.4mmol)室温反应2小时后40℃反应2小时,抽滤固体,减压浓缩干滤液,用硅胶柱层析分离纯化(二氯甲烷/甲醇=10:1),得到白色固体的2-[[(3S,8R,9S,10R,13S,14S)-10,13-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]氧基羰基氧基]乙基1-甲基哌啶-4-甲酸酯(化合物80)(400mg,产率27%)。
Msm/z(ESI):563.3[M+1]。
1HNMR(400MHz,CDCl3)δ8.62(d,1H),8.46(dd,1H),7.76–7.59(m,1H),7.22(m,1H),5.99(dd,1H),5.44(d,1H),4.50(m,1H),4.34(m,4H),3.04–2.91(m,2H),2.58–2.33(m,8H),2.27(m,2H),2.17–1.87(m,9H),1.85–1.44(m,6H),1.22–1.00(m,8H)。
实施例81
2-[[(3S,8R,9S,10R,13S,14S)-10,13-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]氧基羰基氧基]乙基(2S)-2-氨基-3-(1H-咪唑-4-基)丙酸脂(化合物81)
2-[[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]oxycarbonyloxy]ethyl
(2S)-2-amino-3-(1H-imidazol-4-yl)propanoate
第一步:叔丁基4-[(2S)-2-(叔丁氧羰基氨基)-3-[2-[[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]氧基羰基氧基]乙氧基]-3-氧代-丙基]咪唑基-1-甲酸酯(81b)
tert-butyl4-[(2S)-2-(tert-butoxycarbonylamino)-3-[2-[[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]oxycarbonyloxy]ethoxy]-3-oxo-propyl]imidazole-1-carboxylate
将(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]2-羟乙基碳酸酯(32a)(2.0g,4.6mmol)溶于二氯甲烷(25mL)中,加入(S)-3-(1-(叔丁氧羰基)-1H-咪唑4-基)-2-((叔丁氧羰基)氨基)丙酸(81a)(1.5g,5.8mmol)加入二环己基碳二亚胺(881mg,4.3mmol),4-二甲氨基吡啶(2.4g,6.9mmol)室温反应2小时,抽滤固体,减压浓缩干滤液,用硅胶柱层析分离纯化(石油醚/乙酸乙酯=2:1),得到白色固体的叔丁基4-[(2S)-2-(叔丁氧羰基氨基)-3-[2-[[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]氧基羰基氧基]乙氧基]-3-氧代-丙基]咪唑基-1-甲酸酯(81b)(2.5g,产率70%)。
第二步:2-[[(3S,8R,9S,10R,13S,14S)-10,13-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]氧基羰基氧基]乙基(2S)-2-氨基-3-(1H-咪唑-4-基)丙酸脂(化合物81)
2-[[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]oxycarbonyloxy]ethyl
(2S)-2-amino-3-(1H-imidazol-4-yl)propanoate
将叔丁基4-[(2S)-2-(叔丁氧羰基氨基)-3-[2-[[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]氧代羰基氧基]乙氧基]-3-氧代-丙基]咪唑基-1-甲酸酯(81b)(2.5g,3.4mmol)溶于盐酸乙酸乙酯(4mol/L,20mL)中,室温搅拌30分钟,过滤得到白色固体,加入饱和碳酸氢钠水溶液(20mL)碱化,无水硫酸铵干燥有机层,减压浓缩干,用硅胶柱层析分离纯化(二氯甲烷/甲醇=10:1),得到白色固体的2-[[(3S,8R,9S,10R,13S,14S)-10,13-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]氧代羰基氧基]乙基(2S)-2-氨基-3-(1H-咪唑-4-基)丙酸脂(化合物81)(600mg,产率31%)。
Msm/z(ESI):575.2[M+1]。
1HNMR(400MHz,MeOD)δ8.55(s,1H),8.41(d,J=4.8Hz,1H),7.87(s,1H),7.77(d,J=4.7Hz,1H),7.40(dd,J=7.9,4.9Hz,1H),7.07(s,1H),6.11(s,1H),5.47(s,1H),4.51–4.20(m,5H),3.20(ddd,J=22.8,15.3,6.4Hz,3H),2.48–2.25(m,3H),2.12(dd,J=27.1,11.6Hz,3H),1.96(d,J=10.1Hz,2H),1.86–1.48(m,7H),1.27–0.99(m,8H)。
实施例82
苯甲基2-[[(3S,8R,9S,10R,13S,14S)-10,13-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]氧基羰基氧基]乙基碳酸脂(化合物82)
Benzyl2-[[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]oxycarbonyloxy]ethylcarbonate
将(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]2-羟乙基碳酸酯(32a)(1.5g,3.4mmol)溶于二氯甲烷(15mL)中,氮气保护加入三乙胺(283.9mg,5.1mmol),加入氯甲酸苄酯(82a)(864.8mg,5.1mmol),室温反应5小时,抽滤固体,减压浓缩干滤液,用硅胶柱层析分离纯化(石油醚/乙酸乙酯=2:1),得到白色固体的苯甲基2-[[(3S,8R,9S,10R,13S,14S)-10,13-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]氧基羰基氧基]乙基碳酸脂(化合物82)(1.0g,产率52%)。
Msm/z(ESI):572.2[M+1]。
1HNMR(400MHz,CDCl3)δ8.62(d,1H),8.47(m,1H),7.69(d,1H),7.46–7.30(m,5H),7.25(d,1H),6.07–5.95(m,1H),5.46(s,1H),5.17(s,2H),4.55–4.44(m,1H),4.36(m,4H),2.42(m,2H),2.28(m,1H),2.16–2.05(m,4H),1.90(m,2H),1.79–1.44(m,7H),1.20–0.93(m,8H)。
生物测试例
药代动力学实验
雄性SD大鼠(购自北京维通利华实验动物中心,动物生产许可证号SCXK(京)2012-0001)180-220g,禁食给水过夜,3只大鼠口服灌胃100mg/kg(以阿比特龙原形药物计)。于给药前及给药后30分钟,1.0,2.0,4.0,6.0,8.0,12.0,24.0h由眼眶采血0.1ml,肝素抗凝,4℃3000rpm离心10分钟后分离血浆,于-80℃保存。取各时间点大鼠血浆30μL,加入内标含维拉帕米7.5ng/的乙腈溶液800μL混合后,涡旋混合1.5分钟,13000转/分钟离心10分钟,取上清液10μL进行LC-MS/MS(ABSCIEX公司,API4000+)分析。主要药代动力学参数用WinNonlin6.3软件非房室模型分析。测试结果见表1。
表1大鼠药代动力学实验结果
健康雄性恒河猴,3~5kg,适应观察5天后禁食给水过夜,胶囊口服给药醋酸阿比特龙50mg/kg或实施例化合物50mg/kg(以阿比特龙原形药物计),给药后5小时给食。于给药前及给药后15分钟,30分钟,1.0,2.0,4.0,6.0,8.0,12.0,24.0小时以肝素抗凝真空采血管静脉采血0.5ml,4℃3000rpm离心10分钟后分离血浆,于-80℃保存。各时刻血浆样品经乙腈沉淀蛋白处理后,进行LC-MS/MS(ABSCIEX公司,API4000+)分析,WinNonlin6.3(Pharsight公司)软件非房室模型计算主要药动学参数。测试结果见表2:
表2猴药代动力学实验结果
结论:在50mg/kg的剂量下,化合物25的暴露量约为醋酸阿比特龙的4.7倍,表明本发明化合物与醋酸阿比特龙相比具有更好的生物利用度。
Claims (9)
1.一种通式(I)所示化合物及其立体异构体或药学上可接受的盐,
其中:
A选自C(=O)R1或C(=O)XR2;
R1选自C10-20烷基、(CR1aR1b)nXC(=O)C1-6烷基、(CR1aR1b)nXC(=O)C1-6烷氧基、-(CR1aR1b)nC(=O)XC1-6烷基、CH(NH2)C1-6烷基-NH2、C2-8烯基、C2-8炔基、(CR1cR1d)m-C3-10环烷基、(CR1cR1d)n-C3-10碳环或者(CR1cR1d)q-3至10元杂环,所述的烷基、烷氧基、烯基、炔基、杂环或碳环任选进一步被0至4个选自H、F、Cl、Br、I、OH、NH2、C1-4烷基、C1-4烷氧基、-NHC(=O)C1-4烷氧基、C(=O)C1-4烷氧基、-NHC(=O)(CR1eR1f)NH2、R1g、C5-6碳环或4至6元杂环的取代基所取代,所述的杂环含有1至4个选自N、O或S的杂原子;
R1c和R1d各自独立的选自H、OH、氨基或C1-4烷基,所述烷基任选进一步被0至4个选自H、F、Cl、Br、I、OH、C1-4烷基或C1-4烷氧基的取代基所取代;
R1a、R1b、R1e、R1f和R1g各自独立的选自H、OH、C1-4烷基或氨基酸的侧链基团,所述烷基任选进一步被0至4个选自H、F、Cl、Br、I、OH、C1-4烷基或C1-4烷氧基的取代基所取代,所述氨基酸选自赖氨酸、精氨酸、组氨酸、脯氨酸、2,3-二氨基丙酸、2,4-二氨基丙酸、丙氨酸、缬氨酸、亮氨酸、异亮氨酸、苯丙氨酸、色氨酸、蛋氨酸、甘氨酸、丝氨酸、苏氨酸、半胱氨酸、酪氨酸、天冬酰胺、谷氨酰胺、天冬氨酸、门冬氨酸或者谷氨酸;
R2选自C1-6烷基、(CH2)nXC(=O)R2a、-(CH2)nXC(=O)OR2a、(CH2CH2O)nC(=O)R2a、C(=O)R2b、(CH2)nXR2c、(CH2)nS(=O)pC1-6烷基、C3-10碳环或(CH2)m3至10元杂环,所述的烷基、杂环和碳环任选进一步被0至4个选自H、F、Cl、Br、I、(=O)、OH、NH2、C1-4烷基、C1-4烷氧基、C1-4烷基-羟基或(CH2)nOC(=O)C1-6烷基的取代基所取代,所述的杂环含有1至4个选自N、O或S的杂原子;
R2a、R2b和R2c各自独立的选自C1-6烷基、C1-6烷氧基、C3-10碳环或3至10元杂环,所述的烷基、烷氧基、杂环和碳环任选进一步被0至4个选自H、F、Cl、Br、I、OH、NH2、C1-4烷基、C1-4烷氧基、-NHC(=O)C1-4烷氧基、C3-10碳环或3至10元杂环的取代基所取代,所述的杂环含有1至4个选自N、O或S的杂原子;
X各自独立的选自O、S或NRx;
Rx各自独立的选自H或C1-4烷基;
n选自1、2、3或4;
m选自0、1、2、3或4;
q选自1、2、3或4;
p选自0、1或2;
条件是,当A选自C(=O)OR2时,R2不为烷基取代的烷基、未取代的烷基或硝基取代的苯基。
2.根据权利要求1所述的化合物及其立体异构体或药学上可接受的盐,其中:
A选自C(=O)R1或C(=O)XR2;
R1选自C12-16烷基、-(CR1aR1b)nXC(=O)C1-4烷基、-(CR1aR1b)nC(=O)XC1-4烷基、CH(NH2)C1-6烷基-NH2、C3-5烯基、C3-5炔基、(CR1cR1d)m-C3-6环烷基、-(CR1cR1d)q-5至6元杂环或-(CR1cR1d)n-C3-6碳环,所述的烷基、烯基、炔基、杂环、碳环任选进一步被0至4个选自H、NH2、甲基、乙基、丙基、异丙基、-NHC(=O)OC(CH3)3、-C(=O)OC(CH3)3、-NHC(=O)(CR1eR1f)NH2、R1g、苯基或氮杂五元环的取代基所取代;
R1c和R1d各自独立的选自H、OH、氨基、甲基或羟甲基;
R1a、R1b、R1e、R1f和R1g各自独立的选自H、OH、甲基或氨基酸的侧链基团,所述氨基酸选自丙氨酸、缬氨酸、亮氨酸、异亮氨酸、苯丙氨酸或甘氨酸;
R2选自C1-4烷基、(CH2)nOC(=O)R2a、(CH2)nOC(=O)OR2a、(CH2CH2O)nC(=O)R2a、C(=O)R2b、(CH2)nS(=O)2C1-4烷基、C6-9碳环或(CH2)m5至8元杂环,所述的烷基、杂环和碳环任选进一步被0至4个选自H、F、Cl、Br、(=O)、OH、NH2、甲基、甲氧基、乙氧基、异丙氧基、羟甲基或乙酰氧基的取代基所取代;
R2a选自C1-4烷基、C5-6碳环或5至6元杂环,所述的烷基、碳环和杂环任选进一步被0至4个选自H、氨基、甲基、乙基、异丙基、-NHC(=O)OC(CH3)3、苯基或5至10元杂环的取代基所取代,所述的杂环含有1至4个选自N、O或S的杂原子;
R2b选自C6碳环。
3.根据权利要求2所述的化合物及其立体异构体或药学上可接受的盐,其中
A选自C(=O)R1、C(=O)XR2;
R1选自如下结构之一:
R1a、R1e和R1g各自独立的选自H、甲基或氨基酸的侧链基团,所述氨基酸选自丙氨酸、缬氨酸、亮氨酸、苯丙氨酸或甘氨酸;
R2选自如下结构之一:
X选自O、S或NH。
4.根据权利要求3所述的化合物及其立体异构体或药学上可接受的盐,其中
A选自C(=O)XR2;
R2选自如下结构之一:
5.根据权利要求1所示的化合物及其立体异构体或药学上可接受的盐,其中该化合物选自如下结构之一:
6.权利要求1~5所示的化合物及其立体异构体或药学上可接受的盐,其中所述的盐选自盐酸盐。
7.一种药物组合物,所述药物组合物含有治疗有效剂量的权利要求1~6中任意一项所述的化合物或其立体异构体或药学上可接受的盐,以及药学上可接受的载体和赋形剂。
8.权利要求1~6中任意一项所述的化合物及其立体异构体或药学上可接受的盐,以及权利要求7所述的组合物在制备治疗与癌症相关疾病药物中的用途。
9.根据权利要求8所述的用途,其中所述的癌症为前列腺癌。
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CN106977577A (zh) * | 2017-04-21 | 2017-07-25 | 湖南师范大学 | 两类阿比特龙衍生物的合成 |
CN109922809A (zh) * | 2016-10-11 | 2019-06-21 | 群·孙 | 阿比特龙衍生物及其制剂 |
CN110272465A (zh) * | 2019-07-15 | 2019-09-24 | 成都贝诺科成生物科技有限公司 | 阿比特龙衍生物、其制备方法与应用 |
CN113929727A (zh) * | 2020-09-28 | 2022-01-14 | 南京易腾药物研究院有限公司 | 阿比特龙酯类衍生物及其制备方法和应用 |
US11559534B2 (en) | 2019-03-06 | 2023-01-24 | Propella Therapeutics, Inc. | Abiraterone prodrugs |
WO2023025241A1 (zh) * | 2021-08-26 | 2023-03-02 | 苏州艾和医药科技有限公司 | 一种阿比特龙前体化合物及其制备方法和应用 |
US11957696B2 (en) | 2021-02-15 | 2024-04-16 | Propella Therapeutics, Inc. | Abiraterone prodrugs |
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WO2021100019A1 (en) * | 2019-11-22 | 2021-05-27 | Suven Life Sciences Limited | Prodrugs of abiraterone |
CN114560903B (zh) * | 2022-03-09 | 2023-08-01 | 绍兴市上虞区武汉理工大学高等研究院 | 一种阿比特龙衍生物的制备方法及其细胞毒性评价 |
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CN113929727A (zh) * | 2020-09-28 | 2022-01-14 | 南京易腾药物研究院有限公司 | 阿比特龙酯类衍生物及其制备方法和应用 |
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