CN112592252A - 柏木醇衍生物、其制备方法及其应用 - Google Patents
柏木醇衍生物、其制备方法及其应用 Download PDFInfo
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Abstract
Description
技术领域
本发明涉及合成药物技术领域,具体而言,涉及柏木醇衍生物、其制备方法及其应用。
背景技术
柏木醇(cedrol)又称柏木脑,是一种倍半萜醇,它具有愉快而持久的柏木香气,广泛用于木香、辛香和东方型香精中,也大量用作消毒剂、卫生用品的增香剂和香精的定香剂,它也是合成其他香料的中间体。研究表明,柏木醇对大肠杆菌、金黄色葡萄球菌、枯草芽孢杆菌、伤寒沙门氏菌等细菌均有较明显的抑制作用。柏木醇的药理活性有抗痉挛,镇痛、抗炎、抗癌、抗病毒和抗自由基氧化作用等。另外,柏木醇能呈剂量依赖关系加速皮肤成纤维细胞的生长,并且能增加胶原I型蛋白和弹性蛋白的产生。此外,健康人吸入柏木醇能增加副交感神经兴奋,并且降低交感神经兴奋,对心血管系统产生作用,能降低血压。柏木醇也具有抗白蚁能力。
流行性感冒(流感)是一种由流感病毒引起的急性呼吸道传染疾病,主要通过空气飞沫传播,具有爆发突然、蔓延迅速、传播面广的特点。20世纪曾爆发过3次世界范围内的流感大流行,造成了上千万人的死亡。即便到了今天,流感依旧威胁着人类的生命健康,据世界卫生组织(WHO)估算,每年全世界季节性流感导致300万~500万例重症病例,29万~65万例死亡病例。流感病毒包括人流感病毒和动物流感病毒,人流感病毒分为甲(A)、乙(B)、丙(C)3型,是流行性感冒的病原体,其中甲型流感病毒容易发生抗原性变异,并多次引发世界性流感大流行。目前对于流感的预防和治疗主要采用接种疫苗预防和开发抗病毒药物防治并重的应对手段。尽管接种疫苗可以预防同型流感病毒的感染,但需要在流感感染发生前就要开始生产。精确地预测即将传入的流感毒株仍是一个严峻的挑战,并且由于流感病毒存在抗原转变和漂移,流感疫苗每年都要重新生成,这些都给疫苗的生产带来了很大的困难。
鉴于流感的巨大威胁,针对流感的抗病毒药物研发成为一直以来的研究热点,神经氨酸酶抑制剂奥司他韦、帕拉米韦等基于结构的药物设计取得了巨大成功。然而,随着流感病毒的变异,已有的抗流感药物面临严峻的耐药形势,因此,开发新型的抗病毒药物迫在眉睫。
鉴于此,特提出本发明。
发明内容
本发明的目的在于提供柏木醇衍生物、其制备方法及其应用。本发明实施例提供一系列新的柏木醇衍生物,其对病毒、特别是流感病毒有良好的拮抗作用,继而扩大了柏木醇及其衍生物的应用范围,且扩大了柏木醇类衍生物的种类。
本发明是这样实现的:
第一方面,本发明提供一种柏木醇衍生物,其为以下结构式所示化合物中的任意一种、其互变异构体、水合物、溶剂化物或其药学上可接受的盐,
其中,R1、R2、R4、R11、R13、R18、R19、R22、R23和R26分别独立选自H或OH;
R3选自H、OH、醚键、取代或未取代酯基、氰基、取代或未取代烯烃基、取代或未取代炔烃基、取代或未取代烷基、氨基、胺基、砜基、糖基、取代或未取代芳香基、取代或未取代磺酰基、取代或未取代磺酸基和含杂原子的多元杂环中的任意一种;R5选自H、OH、醚键和酯基中的任意一种;R6选自H、OH、取代或未取代芳香基、取代或未取代烷基和氰基中的任意一种;R7选自H或铵基;
R8选择H、OH和卤素中的任意一种,R9选自O或N-R1′,R1′选自OH、取代或未取代磺酸基、酯基、酰胺基中的任意一种;R10选自H、OH、醚键、取代或未取代酯基、取代或未取代磺酸基和取代或未取代亚胺基中的一种;
R12选自H、OH、醚基、取代或未取代酯基和取代或未取代磺酸基中的任意一种;
R14选自取代或未取代烷基、羧酸基、酰胺基、酮基、醛基和含有杂原子的多元杂环中的任意一种;
当R15为=O时,R15′不存在,当R15不为=O时,R15′存在,此时,R15选自H、OH、取代或未取代芳香烃和取代或未取代亚胺基中的任意一种,R15′选自H、OH和取代或未取代芳香基中的任意一种;R16选自H、OH或醚基中的任意一种;
R17选自H或醚键;R19′为OH或=O;R20和R21分别独立为未取代烷基;R24和R25分别独立为酰基。
第二方面,本发明提供一种前述实施方式所述的柏木醇衍生物的制备方法,包括利用柏木醇为原料进行化学反应合成得到柏木醇衍生物。
第三方面,本发明提供一种前述实施方式所述的柏木醇衍生物在制备抗病毒药物中的应用。
本发明具有以下有益效果:本发明实施例提供一系列新的柏木醇衍生物,该柏木醇衍生物对于病毒有良好的治疗作用,特别是流感病毒,继而该柏木醇衍生物可以用与制备治疗病毒引起的疾病,扩大了柏木醇衍生物的应用范围,也扩大了柏木醇衍生物的种类。
具体实施方式
为使本发明实施例的目的、技术方案和优点更加清楚,下面将对本发明实施例中的技术方案进行清楚、完整地描述。实施例中未注明具体条件者,按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者,均为可以通过市售购买获得的常规产品。
本发明实施例提供一种柏木醇衍生物,其为式1-式14结构式所示化合物中的任意一种,或对应化合物的其互变异构体、水合物、溶剂化物或其药学上可接受的盐。具体地:
此时,R1、R2和R4分别独立选自H或OH;R3选自H、OH、醚键、取代或未取代酯基、氰基、取代或未取代烯烃基、取代或未取代炔烃基、取代或未取代烷基、氨基、胺基、砜基、糖基、取代或未取代芳香基、取代或未取代磺酰基、取代或未取代磺酸基和含杂原子的多元杂环中的任意一种;R5选自H、OH、醚键和酯基中的任意一种;R6选自H、OH、取代或未取代芳香基、取代或未取代烷基和氰基中的任意一种;R7选自H或铵基。
进一步地,R3选自H、-OH、-OCOR2′、-OSO2R3′、-O-R4′、未取代烷基、单卤素取代烷基、双卤素取代烷基、三卤素取代烷基、炔基取代烷基、烯烃基取代烷基、取代或未取代苯基、取代糖基、-OR6′、-OCONHR7′、-NH2、-NH-R5′、-OTs、-OTf和-OTMS中的任意一种;其中,R2′选自H、CnH2n+1、取代烷基、取代或未取代芳香基、取代酰基、取代或未取代六元氮杂环、取代或未取代五元环和金刚烷基中的任意一种,R3′为氨基或碱金属离子、R4′为取代或未取代烷基、-C=S-R、取代五元杂环、取代6元杂环和取代亚胺基中的任意一种,R为五元杂原子环,R5′选自CnH2n+1、COCnH2n+1、取代磺酰基和取代磺酸基中的任意一种;R7′为CnH2n+1、(CnH2n+1)2、取代磺酰基和取代磺酸基,n为整数;
进一步地,R3选自H、OH、-OCnH2n+1、-CXH2、-CX2H、-CX3、-OTs、-OTf、-OCOH、-OCF2H、-OCCOF3、-OCOCnH2n+1、-OCONHTs、-OCONHCnH2n+1、-OCON(CnH2n+1)2、-OSO2NH2、-OSO2Na、-NH2、NHTs、NHTf、-NHCnH2n+1、-N(CnH2n+1)2、NHCOCnH2n+1、CnH2n+1、-CH2CH=CH2、-CN、-OTMS、-CH2C≡CH、-OCH2C≡CH、 以及中的任意一种,其中,n为1-18之间的任意整数,A为C或N,B选自C、N、O和S中的任意一种,Ra选自H、X和CnH2n+1中的任意一种,Rb选自H、X和CnH2n+1中的任意一种,Rc选自H、X和CnH2n+1中的任意一种,X为卤素原子。
R5选自H、OH、-OCnH2n+1以及-OCOCnH2n+1的任意一种,R6选自H、OH、-CH2CH=CH2、-CN和中的任意一种,R7选自H或其中,n为1-18之间的任意整数,Rc选自H、X和CnH2n+1中的任意一种,X为卤素原子。
此时,R8选择H、OH和卤素中的任意一种,R9选自O或N-R1′,R1′选自OH、取代或未取代磺酸基、酯基、酰胺基中的任意一种;R10选自H、OH、醚键、取代或未取代酯基、取代或未取代磺酸基和取代或未取代亚胺基中的一种;R11选自H或OH;
进一步地,R9选自O、NOH、NOCnH2n+1、NOCOCnH2n+1、NOTs、NOTf和N-NHCONH2中的任意一种;
R10选自H、OH、-OCnH2n+1、OCOCnH2n+1、-OTs、-OTf、=NOH、=NOCnH2n+1、和中的任意一种,其中,n为1-18之间的任意整数,A为C或N,B选自C、N、O和S中的任意一种,Ra选自H、X和CnH2n+1中的任意一种,Rb选自H、X和CnH2n+1中的任意一种,X为卤素原子。
此时,当R15为=O时,R15′不存在,当R15不为=O时,R15′存在,此时,R15选自H、OH、取代或未取代芳香烃和取代或未取代亚胺基中的任意一种,R15′选自H、OH和取代或未取代芳香基中的任意一种;R16选自H、OH或醚基中的任意一种。
进一步地,R14选自-CnH2n+1、-CH2OH、-COH、-COOH、-CH2OCOCnH2n+1、-CH2OCnH2n+1、-COCnH2n+1、-CHOHCnH2n+1、-CONHCnH2n+1、-COOCnH2n+1、-CON(CnH2n+1)2以及-CHOHCH2C≡CH中的任意一种,其中,n为1-18之间的任意整数;优选地,当R15不为=O时,R15选自H、OH、=NOH、=NOCOCnH2n+1以及-Ph中的任意一种,R15′选自H、OH和-CH2-Ph中的任意一种。
需要说明的是,(1)本发明实施例记载的卤素或卤素原子为F、Cl、Br、I中的任意一种,而本发明实施例中记载了含有明确卤素原子的基团中的卤素原子也可以替换为其他卤素原子,例如-OCF2H也可以采用-OCBr2H,此处发明人不再进行详述。
(2)本发明实施例记载的n为1-18之间的任意整数,n可以为1、2、3、4、5、6、7、8、9、10、11、12、13、15、15、16、17以及18中的任意一种,继而得到对应碳数的烷基,例如甲基、乙基以及丙基等。
本发明实施例还提供上述柏木醇衍生物的制备方法,包括利用柏木醇为原料进行化学反应合成得到上述柏木醇衍生物。具体地,利用柏木醇参照下述合成路径中的至少一步合成所需的柏木醇:
以及
上述合成路径缺少引入糖基的合成路径,糖基的引入的合成方法为现有的方法,例如可以参考Ref:JOC,2019,84,589,例如,可采用的过程如下:
本发明实施例还提供一种上述柏木醇衍生物在制备抗病毒药物中的应用,特别地,该病毒为流感病毒。
需要说明的是:本发明实施例采用的1H-和13C-NMR由Bruker AVANCE III-600、DRX-500或AM-400测定,内标为TMS,其中1H NMR在400MHz,500MHz和600MHz下测定,13C NMR在100MHz,125MHz和150MHz下测定;质谱HREI-MS和EI-MS由Finnigan-MAT 90质谱仪测定;HRESI-MS和ESI-MS由API QSTAR Pulsar i质谱仪测定;旋转蒸发仪:Buchi R-200、R-201;DLSB 5110型低温反应冷却液循环泵,IKA RCT basic(安全控制型)加热磁力搅拌器。
柱色谱材料:柱层析用硅胶(80-100目和200-300目)与预制GF254 TLC板均为青岛海洋化工厂生产;Sephadex LH-20为瑞典Amersham Biosciences公司产品;ChromatorexC-18(40-75μm)为日本Fuji Silysia化学公司产品。HPLC:Agilent 1100,Zorbax SB-C18column,5μm,4.6mm×150mm;Prep-HPLC:Agilent 1200,Zorbox SB-C18 column,5μm,9.4mm×150mm。显色方法为荧光灯下波长254、365nm处观察荧光,I2蒸气显色,10%硫酸香草醛处理后加热显色。
其它试剂来自于Sigma Aldrich,J&K百灵威,北京伊诺凯公司或安耐吉试剂公司,均为商品化的分析纯或化学纯试剂,本发明实验部分所采用的无水试剂(如无水THF、DCM、Toluene、DMF等)均按无水溶剂标准处理程序制备。
以下结合实施例对本发明的特征和性能作进一步的详细描述。
实施例1
本实施例提供该柏木醇衍生物的制备方法:在反应容器中加入0.1mmol柏木醇(编号为化合物1),对甲苯磺酸0.1mmol,然后加入2mL乙腈,50℃反应0.5小时后,反应结束后,反应溶液加入水或饱和盐溶液洗涤淬灭反应,然后用有机溶剂萃取,干燥,减压蒸馏浓缩除去溶剂,粗产品经柱色谱分离,即得目标产物,产率96%。
化合物2的表征数据如下:Colorless oil,96%,1H NMR(600MHz,CDCl3)δ5.23-5.22(m,1H),2.19-2.15(m,1H),1.86-1.57(m,11H),1.40-1.34(m,3H),1.02(s,3H),0.95(s,3H),0.85(d,3H,J=7.3Hz);13C NMR(150MHz,CDCl3)δ140.59,119.21,58.92,54.80,53.85,48.17,41.45,40.65,38.81,36.06,27.67,25.61,24.79,15.45.
实施例2
本实施例提供该柏木醇衍生物的制备方法:在反应容器中加入实施例1制备得到的0.1mmol化合物2溶于2mLTHF中,加入0.5mmol BH3.DMS反应4h后,然后加入1eq.的NaOH和H2O2,反应3小时后,反应结束后,反应溶液加入水或饱和盐溶液洗涤淬灭反应,然后用有机溶剂萃取,干燥,减压蒸馏浓缩除去溶剂,粗产品经重结晶,即得目标产物,产率81%。
化合物3的表征数据如下:White salt,81%,m.p.143-145℃.1H NMR(600MHz,CDCl3)δ3.79-3.78(m,1H),1.99-1.95(m,1H),1.85-1.83(m,1H),1.75-1.71(m,3H),1.62-1.48(m,5H),1.40-1.24(m,3H),1.20-1.18(m,2H),1.16(d,3H,J=7.4Hz),1.13(s,3H),0.94(s,3H),0.85(d,3H,J=6.8Hz);13C NMR(150MHz,CDCl3)δ72.16,57.28,54.11,53.92,45.87,45.27,42.99,42.83,40.73,35.70,27.85,26.87,24.72,16.83,14.55.
实施例3
本实施例提供该柏木醇衍生物的制备方法:在反应容器中加入0.1mmol实施例2提供的化合物3溶于2mL二氯甲烷:水(1:1)中,加入3.8mmol TMSCF2Br和7.6mmol KHF2,室温条件下反应2h,反应结束后,反应溶液加入水或饱和盐溶液洗涤淬灭反应,然后用有机溶剂萃取,干燥,减压蒸馏浓缩除去溶剂,粗产品经柱色谱分离,即得目标产物,产率72%左右。
化合物4的表征数据如下:White salt,72%,m.p.135-136℃.1H NMR(600MHz,CDCl3)δ6.39-6.13(m,1H),4.26-4.21(m,1H),1.99-1.96(m,1H),1.85-1.82(m,1H),1.75-1.70(m,2H),1.68-1.66(m,2H),1.62-1.57(m,2H),1.52-1.49(m,2H),1.22-1.18(m,2H),1.15(d,3H,J=6.9Hz),1.12(s,3H),0.94(s,3H),0.85(d,3H,J=6.9Hz);13C NMR(150MHz,CDCl3)δ117.11,115.40,113.69,72.14,57.28,54.11,53.92,45.88,45.26,42.99,42.83,40.73,35.70,27.85,26.87,24.72,16.83,14.55.
实施例4
本实施例提供该柏木醇衍生物的制备方法:在反应容器中加入0.1mmol化合物3溶于2mL二氯甲烷中,加入0.11mmol PCC,室温条件下反应3h,反应结束后,减压蒸馏浓缩除去溶剂,粗产品经柱色谱分离,即得目标产物,产率84%左右。
化合物5的表征数据如下:Colorless oil,84%,1H NMR(600MHz,CDCl3)δ2.67-2.65(m,1H),2.35(d,1H,J=1.6.2Hz),2.22-2.18(m,1H),1.89-1.83(m,3H),1.73-1.66(m,2H),1.63-1.56(m,2H),1.44-1.27(m,2H),1.12(d,3H,J=7.5Hz),0.97(s,3H),0.95(s,3H),0.83(d,3H,J=6.9Hz);13C NMR(150MHz,CDCl3)δ215.92,57.46,54.63,54.17,48.75,45.89,41.73,40.57,36.55,35.74,25.96,25.87,24.72,17.18,14.34.HR-EI-MS(positive)m/z 221.18999[M+H]+(calcd for C15H25O 221.18272).
实施例5
本实施例提供该柏木醇衍生物的制备方法:在反应容器中加入0.1mmol实施例2制备得到的化合物2溶于2mL乙酸酐,加入0.12mmol过氧碳酸钠,放入超声波反应器中室温反应8h,反应结束后,反应溶液慢慢加入水淬灭反应,然后用有机溶剂萃取,干燥,减压蒸馏浓缩除去溶剂,粗产品经柱色谱分离,即得目标产物,产率93%。
化合物6的表征数据如下:Colorless oil,93%,1H NMR(600MHz,CDCl3)δ3.00(d,1H,J=4.6Hz),1.94-1.76(m,4H),1.68-1.56(m,5H),1.42-1.40(m,4H),1.30-1.23(m,2H),1.18(s,3H),0.99(s,3H),0.80(d,3H,J=6.9Hz);13C NMR(150MHz,CDCl3)δ61.10,60.94,58.37,53.66,52.03,43.08,41.50,36.78,35.92,35.82,30.12,27.51,25.02,23.74,15.58.HR-EI-MS(positive)m/z 221.18999[M+H]+(calcd for C15H25O 221.18272).
实施例6
本实施例提供该柏木醇衍生物的制备方法:本实施例提供该柏木醇衍生物的制备方法与实施例3提供的制备方法相同,区别在于将将原料TMSCF2Br和KHF2替换为三氟乙酸酐和Et3N。
化合物7的表征数据如下:White salt,86%,m.p.125-127℃.1H NMR(600MHz,CDCl3)δ5.25-5.21(m,1H),2.09-2.06(m,1H),1.99-1.96(m,1H),1.88-1.72(m,5H),1.58-1.55(m,1H),1.43-1.38(m,2H),1.33-1.26(m,2H),1.19(s,3H),1.07(d,3H,J=7.0Hz),0.98(s,3H),0.86(d,3H,J=7.6Hz);13C NMR(150MHz,CDCl3)δ157.63,157.35,157.08,117.53,115.63,113.74,111.84,81.31,58.21,55.08,54.86,46.43,43.90,42.49,41.77,39.13,36.73,28.72,28.03,25.79,17.35,15.50.
实施例7
本实施例提供该柏木醇衍生物的制备方法:在反应容器中加入0.1mmol实施例4制备得到化合物5溶于2mL无水THF中,0℃加入0.12mmol烯丙基溴格试试剂,加完之后室温条件下反应12h,反应结束后,反应溶液加入饱和NH4Cl溶液或饱和盐溶液洗涤淬灭反应,然后用有机溶剂萃取,干燥,减压蒸馏浓缩除去溶剂,粗产品经柱色谱分离,即得目标产物,产率73%左右。
化合物8的表征数据如下:Colorless oil,73%,1H NMR(600MHz,CDCl3)δ5.89-5.82(m,1H),5.15-5.08(m,2H),2.48-2.45(m,1H),2.35-2.31(m,1H),2.10-2.07(m,1H),1.83-1.76(m,3H),1.70-1.59(m,2H),1.62-1.59(m,2H),1.51-1.49(m,1H),1.41-1.35(m,2H),1.29(s,3H),1.27-1.25(m,1H),1.13(d,3H,J=7.6Hz),0.93(s,3H),0.81(d,3H,J=6.9Hz);13C NMR(150MHz,CDCl3)δ133.32,117.72,72.14,54.65,53.02,51.59,48.27,46.21,45.88,45.02,42.99,40.94,34.39,28.12,27.19,24.09,14.57,13.81.
实施例8
本实施例提供该柏木醇衍生物的制备方法:在反应容器中加入0.1mmol化合物5溶于2mL乙醇中,加入0.12mmol盐酸羟胺,用30%NaOH溶液调pH值至中性,加完之后室温条件下反应12h,反应结束后,反应溶液加入水或饱和盐溶液洗涤淬灭反应,然后用有机溶剂萃取,干燥,减压蒸馏浓缩除去溶剂,粗产品经柱色谱分离,即得目标产物,产率56%左右。
化合物9的表征数据如下:White salt,56%,m.p.101-103℃.1H NMR(600MHz,CDCl3)δ9.37-9.31(m,1H),3.18-3.15(m,1H),2.54-2.52(m,1H),1.89-1.86(m,2H),1.80-1.75(m,3H),1.63-1.60(m,1H),1.54-1.48(m,2H),1.37-1.33(m,2H),1.29(d,3H,J=7.0Hz),1.11(s,3H),0.93(d,6H,J=7.0Hz);13C NMR(150MHz,CDCl3)δ161.86,59.89,56.14,54.65,46.56,43.97,43.76,42.21,37.25,34.34,28.40,27.94,25.76,16.64,15.55.HR-EI-MS(positive)m/z 236.20084[M+H]+(calcd for C15H26ON236.19361).
实施例9
本实施例提供该柏木醇衍生物的制备方法:在反应容器中加入0.1mmol化合物9溶于2mL无水THF中,加入0.1mmol氢化铝锂,加热回流反应12h,反应结束后,反应溶液慢慢加入水淬灭反应,然后用有机溶剂萃取,干燥,减压蒸馏浓缩除去溶剂,粗产品经柱色谱分离,即得目标产物,产率70%。
化合物10的表征数据如下:White salt,70%,m.p.129-130℃.1H NMR(600MHz,CDCl3)δ2.09-2.08(m,1H),1.81-1.71(m,4H),1.67-1.65(m,1H),1.59-1.56(m,3H),1.39(s,3H),1.38-1.36(m,1H),1.27-1.25(m,3H),1.20(s,3H),0.97(s,3H),0.93-0.91(m,1H),0.76(d,3H,J=7.3Hz);13C NMR(150MHz,CDCl3)δ60.72,52.97,52.12,43.64,41.64,40.05,37.14,36.72,36.16,35.71,30.56,27.65,26.59,24.90,15.52.HR-EI-MS(positive)m/z220.20576[M+H]+(calcd for C15H26N 220.21435).
实施例10
本实施例提供该柏木醇衍生物的制备方法:在反应容器中加入0.1mmol化合物10溶于2mL MeOH中,加入0.12mmol CH3I和1.5mmol Na2CO3,反应结束后,减压蒸馏浓缩除去溶剂,粗产品经柱色谱分离,即得目标产物,产率83%。
化合物11的表征数据如下:Colorless oil,83%,1H NMR(600MHz,CDCl3)δ2.28(s,3H),1.96-1.93(m,1H),1.83-1.70(m,3H),1.64-1.51(m,4H),1.40-1.36(m,1H),1.30(s,3H),1.28-1.23(m,3H),1.22(s,3H),1.18-1.14(m,1H),0.97(s,3H),0.77(d,3H,J=7.0Hz);13C NMR(150MHz,CDCl3)δ60.94,54.81,51.79,45.21,43.74,41.65,39.75,36.42,36.40,35.65,30.71,27.90,24.87,16.09,15.56.HR-EI-MS(positive)m/z 234.22147[M+H]+(calcd for C16H28N 234.23000).
实施例11
本实施例提供该柏木醇衍生物的制备方法:该合成方法与实施例7的制备方法相同,区别在于将丙烯溴格氏试剂替换为对氯苯格氏试剂。
化合物12的表征数据如下:Colorless oil,51%,1H NMR(600MHz,CDCl3)δ7.19(d,2H,J=8.6Hz),6.77(d,2H,J=8.6Hz),5.15(brs,1H),2.79-2.76(m,1H),2.45-2.42(m,1H),2.24-2.21(m,1H),1.94-1.86(m,3H),1.71-1.55(m,8H),1.46(s,3H),1.43-1.39(m,1H),1.33-1.28(m,2H),1.01(s,3H),1.00(s,3H),0.86(d,3H,J=7.0Hz);13C NMR(150MHz,CDCl3)δ154.22,129.49,125.54,116.65,61.44,58.64,55.44,48.66,41.32,40.95,38.92,37.01,29.00,28.78,25.66,24.09,15.61.HR-EI-MS(positive)m/z331.18500[M+H]+(calcd for C21H28OCl 331.19069).
实施例12
本实施例提供该柏木醇衍生物的制备方法:本该合成方法与实施例3的制备方法相同,区别在于为使用草酰氯。
化合物13的表征数据如下:Colorless oil,87%,1H NMR(600MHz,CDCl3)δ8.11(s,1H),5.20-5.15(m,1H),2.04-2.00(m,1H),1.87-1.68(m,7H),1.59-1.52(m,2H),1.40-1.37(m,1H),1.33-1.22(m,4H),1.18(s,3H),1.05(d,3H,J=7.5Hz),0.96(s,3H),0.84(d,3H,J=7.5Hz);13C NMR(150MHz,CDCl3)δ160.19,74.78,57.13,54.06,53.73,45.60,42.87,41.62,40.78,38.84,35.73,27.75,26.99,24.74,16.57,14.46.
实施例13
本实施例提供该柏木醇衍生物的制备方法:该合成方法与实施例3的制备方法相同,区别在于使用对甲苯磺酸酐。
化合物14的表征数据如下:White salt,87%,m.p.74-76℃.1H NMR(600MHz,CDCl3)δ7.82-7.80(m,2H),7.33-7.32(m,2H),4.70-4.65(m,1H),2.43(s,3H),1.96-1.92(m,1H),1.83-1.79(m,2H),1.71-1.61(m,4H),1.52-1.48(m,1H),1.43-1.33(m,2H),1.25-1.22(m,1H),1.17-1.15(m,1H),1.06(s,3H),0.91(s,3H),0.85(d,3H,J=7.5Hz),0.75(d,3H,J=7.5Hz);13C NMR(150MHz,CDCl3)δ143.37,133.66,128.59,126.78,84.67,57.11,54.22,53.86,45.23,42.75,42.00,40.60,40.07,35.59,27.64,26.96,24.70,20.60,16.45,14.36.
实施例14
本实施例提供该柏木醇衍生物的制备方法:在反应容器中加入0.1mmol实施例4制备得到的化合物5溶于2mL无水DMSO:CH3OH(10:1)中,加入0.1mmol叔丁醇钾,室温反应5h,反应结束后,反应溶液慢慢加入水淬灭反应,然后用有机溶剂萃取,干燥,减压蒸馏浓缩除去溶剂,粗产品经柱色谱分离,即得目标产物,化合物15产率80%。
化合物15的表征数据如下:Colorless oil,80%,1H NMR(600MHz,CDCl3)δ2.78-2.75(m,1H),2.44-2.42(m,1H),2.23-2.20(m,1H),1.93-1.88(m,3H),1.70-1.66(m,5H),1.45(s,3H),1.32-1.29(m,3H),1.01(s,3H),0.99(s,3H),0.86(d,3H,J=7.3Hz);13C NMR(150MHz,CDCl3)δ210.45,60.41,57.60,54.39,47.61,40.30,39.91,37.91,35.99,27.96,27.77,24.63,23.05,14.59.HR-EI-MS(positive)m/z237.18481[M+H]+(calcd for C15H25O2237.17763).
实施例15
本实施例提供一种柏木醇衍生物(编号为化合物16),名为:(3R,3aR,6S,7S,8aS)-3,6,8,8-四甲基八氢-1H-3a,7-雪松烷-5-基2-((苯基)氨基)-2-氧乙酸甲酯,其结构式如下:
本实施例提供该柏木醇衍生物的制备方法:该合成方法与实施例3的制备方法相同,区别在于使用草酰氯和甲基苯胺。
化合物16的表征数据如下:Colorless oil,67%,1H NMR(600MHz,CDCl3)δ7.39-7.37(m,2H),7.34-7.33(m,1H),7.27-7.26(m,2H),4.91-4.80(m,1H),3.35(s,3H),1.80-1.77(m,1H),1.72-1.62(m,4H),1.59-1.58(m,1H),1.56-1.52(m,1H),1.47-1.43(m,1H),1.33-1.29(m,1H),1.22-1.18(m,1H),1.07(s,3H),0.90(s,3H),0.83(d,3H,J=7.3Hz),0.71(d,3H,J=7.3Hz);13C NMR(150MHz,CDCl3)δ162.80,162.21,141.48,129.56,128.33,126.67,78.01,57.97,55.09,54.52,46.44,43.73,42.33,41.76,38.70,36.72,36.06,28.69,27.90,25.71,17.29,15.58.HR-EI-MS(positive)m/z 406.23505[M+Na]+(calcdfor C24H33O3NNa 406.23581).
实施例16
本实施例提供一种柏木醇衍生物(编号为化合物17),名为:O-((3R,3aR,6S,7S,8aS)-3,6,8,8-四甲基八氢-1H-3a,7-雪松烷-5-基)1H-咪唑-1-甲硫醇酯,其结构式如下:
本实施例提供该柏木醇衍生物的制备方法:该合成方法与实施例3的制备方法相同,区别在于使用硫代羰基二咪唑。
化合物17的表征数据如下:Colorless oil,91%,1H NMR(600MHz,CDCl3)δ8.35(s,1H),7.65(s,1H),7.03(s,1H),5.93-5.88(m,1H),2.26-2.23(m,1H),2.15-2.12(m,1H),1.89-1.76(m,4H),1.60(m,1H),1.44-1.31(m,4H),1.25(s,3H),1.13-1.11(m,3H),1.00(s,3H),0.87-0.85(m,3H);13C NMR(150MHz,CDCl3)δ184.36,136.78,130.67,117.92,86.58,58.38,55.20,54.93,46.53,43.89,42.95,41.82,38.45,36.82,28.81,28.03,25.86,17.51,15.53.HR-EI-MS(positive)m/z 333.19928[M+H]+(calcd forC19H29ON2S333.19223).
实施例17
本实施例提供该柏木醇衍生物的制备方法:该合成方法与实施例3的制备方法相同,区别在于使用三氯乙腈。
化合物18的表征数据如下:Colorless oil,83%,1H NMR(600MHz,CDCl3)δ8.20(s,1H),5.22-5.17(m,1H),2.24-2.20(m,1H),2.03-2.00(m,1H),1.86-1.70(m,6H),1.60-1.53(m,1H),1.41-1.38(m,1H),1.33-1.28(m,4H),1.21(s,3H),1.15(d,3H,J=7.5Hz),0.97(s,3H),0.85(d,3H,J=7.5Hz);13C NMR(150MHz,CDCl3)δ161.59,91.09,80.22,57.14,54.20,53.71,45.62,42.90,42.14,40.86,37.26,35.71,27.75,27.03,24.74,16.68,14.52.HR-EI-MS(positive)m/z 366.11539[M+H]+(calcd forC17H27ONCl3 366.10800).
实施例18
本实施例提供该柏木醇衍生物的制备方法:该合成方法与实施例7的制备方法相同,区别在于使用TMSCN。
化合物19的表征数据如下:Colorless oil,63%,1H NMR(600MHz,CDCl3)δ2.43-2.33(2H),2.10-1.08(m,1H),2.01-1.89(m,1H),1.73-1.68(m,2H),1.60-1.58(m,2H),1.55(s,3H),1.27-1.23(m,3H),1.16(d,3H,J=7.5Hz),1.15-1.14(m,3H),1.08-1.06(m,2H),0.97(d,3H,J=7.5Hz);13C NMR(150MHz,CDCl3)δ120.86,75.85,68.94,63.11,54.37,49.17,46.94,43.25,39.40,33.44,28.57,27.16,26.75,25.04,24.61,23.27,14.25。
实施例19
本实施例提供该柏木醇衍生物的制备方法:该制备方法与实施例14的制备方法相同,柱分离得到化合物15和化合物20,化合物20的产率为38%。。
化合物20的表征数据如下:Colorless oil,38%,1H NMR(600MHz,CDCl3)δ3.95-3.94(m,1H),3.66-3.50(m,1H),3.27-3.20(m,1H),2.59-2.56(m,1H),2.08-2.05(m,1H),1.93-1.87(m,2H),1.67-1.48(m,4H),1.43(s,3H),1.43-1.40(m,1H),1.29-1.25(m,1H),1.03(s,3H),0.94(s,3H),0.93(d,3H,J=7.5Hz);13C NMR(150MHz,CDCl3)δ207.68,80.87,80.85,79.36,60.73,60.51,53.72,42.12,39.04,35.12,32.05,28.85,28.33,24.53,23.18,23.16,15.25.HR-EI-MS(positive)m/z 219.17410[M+H]+(calcd for C15H23O219.16707)。
实施例20
本实施例提供一种柏木醇衍生物(编号为化合物21),名为:(3R,3aR,6S,7S,8aS)-3,6,8,8-四甲基-5-((三甲基甲硅烷基)氧基)八氢-1H-3a,7-雪松烷-5-腈,其结构式如下:
本实施例提供该柏木醇衍生物的制备方法:该合成方法与实施例18的制备方法相同,区别在于使用了LiOMe。
化合物21的表征数据如下:Colorless oil,85%,1H NMR(600MHz,CDCl3)δ2.26-2.23(m,1H),1.85-1.75(m,4H),1.70-1.68(m,1H),1.63-1.57(m,5H),1.41-1.34(m,3H),1.01(s,3H),0.93(s,3H),0.84(d,3H,J=7.5Hz),0.18(s,9H);13C NMR(150MHz,CDCl3)δ142.83,118.08,58.96,55.13,54.14,48.57,43.60,41.30,41.21,36.05,27.96,25.79,24.85,17.90,15.59,1.07.HR-EI-MS(positive)m/z334.25586[M+H]+(calcd forC20H36ONSi 334.23314)。
实施例21
本实施例提供该柏木醇衍生物的制备方法:该合成方法与实施例3的制备方法相同,区别在于使用TsCl。
化合物22的表征数据如下:White salt,87%,m.p.85-87℃.1H NMR(600MHz,CDCl3)δ7.83-7.81(m,2H),7.31-7.30(m,2H),3.11-3.10(m,1H),2.43(s,3H),2.02-2.01(m,1H),1.89-1.88(m,1H),1.87(s,3H),1.77-.174(m,1H),1.63-1.54(m,5H),1.42-1.40(m,1H),1.30-1.23(m,3H),1.00(s,3H),0.92(s,3H),0.87(d,3H,J=7.5Hz);13C NMR(150MHz,CDCl3)δ143.29,139.47,129.47,129.46,126.96,60.73,56.90,54.04,51.76,46.08,43.96,41.12,36.77,35.26,34.84,30.68,27.83,24.77,21.61,19.41,15.47.HR-EI-MS(positive)m/z 374.21478[M+H]+(calcd for C22H32O2NS 374.22320).
实施例22
本实施例提供一种柏木醇衍生物(编号为化合物23),名为:(E)-2-((3R,3aR,6S,7S,8aS)-3,6,8,8-四甲基六氢-1H-3a,7-雪松烷-5(4H)-基烯)肼-1-羧酰胺,其结构式如下:
本实施例提供该柏木醇衍生物的制备方法:该合成方法与实施例8的制备方法相同,区别在于使用盐酸肼甲酰胺。
化合物23的表征数据如下:White salt,42%,m.p.75-77℃.1H NMR(600MHz,CDCl3)δ8.24-8.21(m,1H),6.17(brs,1H),5.04(brs,1H),2.51-2.47(m,2H),1.90-1.87(m,2H),1.84-1.78(m,4H),1.52-1.45(m,3H),1.33-1.30(m,2H),1.27(d,3H,J=7.5Hz),1.25-1.24(m,1H),1.04(s,3H),0.93(s,3H),0.91(d,3H,J=7.5Hz);13C NMR(150MHz,CDCl3)δ158.29,154.81,60.25,55.95,55.02,46.28,45.22,43.97,42.05,37.15,36.15,28.30,27.99,25.70,16.81,15.53.HR-EI-MS(positive)m/z 278.22244[M+H]+(calcd forC16H28ON3 278.21541).
实施例23
本实施例提供该柏木醇衍生物的制备方法:该合成方法与实施例3的制备方法相同,区别在于使用乙酸酐。
化合物24的表征数据如下:Colorless oil,83%,1H NMR(600MHz,CDCl3)δ5.07-5.02(m,1H),2.05(s,3H),2.04-1.97(m,1H),1.86-1.79(m,3H),1.76-1.71(m,2H),1.66-1.65(m,1H),1.55-1.50(m,1H),1.40-1.34(m,1H),1.30-1.25(m,1H),1.22-1.19(m,2H),1.18(s,3H),1.03(d,3H,J=7.5Hz),0.95(s,3H),0.81(d,3H,J=7.5Hz);13C NMR(150MHz,CDCl3)δ171.05,75.70,58.09,55.14,54.70,46.74,43.88,42.85,41.90,39.85,36.82,28.82,27.99,25.79,21.39,17.65,15.52.
实施例24
本实施例提供该柏木醇衍生物的制备方法:该合成方法与实施例3的制备方法相同,区别在于使用了羰基二咪唑。
化合物25的表征数据如下:Colorless oil,93%,1H NMR(600MHz,CDCl3)δ8.12(s,1H),7.42-7.41(m,1H),7.05-7.04(m,1H),5.24-5.20(m,1H),2.17-2.13(m,1H),2.00-1.97(m,1H),1.84-1.72(m,5H),1.57-1.54(m,1H),1.42-11.38(m,2H),1.31-1.26(m,2H),1.20(s,3H),1.11(d,3H,J=7.5Hz),0.97(s,3H),0.84(d,3H,J=7.5Hz);13C NMR(150MHz,CDCl3)δ148.69,137.05,130.52,117.12,81.36,58.20,55.12,54.85,46.51,43.92,42.77,41.78,39.63,36.75,28.76,28.02,25.80,17.66,15.52.HR-EI-MS(positive)m/z317.22223[M+H]+(calcd for C19H29O2N2 317.21508).
实施例25
本实施例提供该柏木醇衍生物的制备方法:该合成方法与实施例11的制备方法相同,为该反应的第二个产物。
化合物26的表征数据如下:White salt,31%,m.p.102-103℃.1H NMR(600MHz,CDCl3)δ3.15(d,1H,J=14.7Hz),2.66-2.64(m,1H),2.34-2.31(m,2H),2.09(s,3H),2.05-2.01(m,1H),1.92-1.86(m,2H),1.69-1.66(m,1H),1.60-1.55(m,1H),1.43-1.40(m,1H),1.35-1.30(m,1H),1.06(s,3H),1.05(s,3H),0.88(d,3H,J=7.5Hz);13C NMR(150MHz,CDCl3)δ205.27,73.65,62.45,58.99,55.50,47.15,44.49,44.40,41.41,36.71,30.02,29.61,28.37,25.52,15.57.HR-EI-MS(positive)m/z 299.07349[M+H]+(calcd forC15H24OBr 299.09323).
实施例26
本实施例提供该柏木醇衍生物的制备方法:该合成方法与实施例7的制备方法相同,区别在于使用苯基格氏试剂。
化合物27的表征数据如下:Colorless oil,34%,1H NMR(600MHz,CDCl3)δ7.49-7.48(m,2H),7.35-7.32(m,2H),7.23-7.20(m,1H),2.68-2.65(m,1H),2.33-2.31(m,1H),2.03-1.99(m,2H),1.86-1.81(m,2H),1.77-1.74(m,2H),1.63-1.55(m,3H),1.49-1.46(m,1H),1.38(s,3H),1.35-1.25(m,2H),1.01(s,3H),0.90(d,3H,J=7.5Hz),0.77(d,3H,J=7.5Hz);13C NMR(150MHz,CDCl3)δ150.92,127.94,126.17,125.06,55.17,54.83,52.57,52.18,48.68,47.14,44.31,41.95,35.22,29.34,28.37,25.20,15.65,14.27.
实施例27
本实施例提供一种柏木醇衍生物(编号为化合物28),名为:(3R,3aR,6S,7S,8aS)-3,6,8,8-四甲基八氢-1H-3a,7-雪松烷-5-基(3S,5S,7S)-金刚烷-1-羧酸酯,其结构式如下:
本实施例提供该柏木醇衍生物的制备方法:该合成方法与实施例3的制备方法相同,区别在于使用金刚烷-1-羧酸酰氯。
化合物28的表征数据如下:Colorless oil,88%,1H NMR(600MHz,CDCl3)δ5.05-5.02(m,1H),2.02-2.00(m,1H),1.97-1.93(m,1H),1.90-1.85(m,8H),1.84-1.80(m,2H),1.75-1.65(m,10H),1.54-1.51(m,1H),1.39-1.30(m,1H),1.29-1.25(m,1H),1.18(s,3H),1.01(d,3H,J=7.5Hz),0.95(s,3H),0.83(d,3H,J=7.5Hz);13C NMR(150MHz,CDCl3)δ177.61,74.83,58.13,55.19,54.74,46.78,43.88,42.94,41.93,40.69,39.67,38.89,38.85,36.82,36.59,36.50,28.84,28.03,27.93,25.79,17.66,15.54.HR-EI-MS(positive)m/z 408.30863[M+Na+H]+(calcd for C26H41O2Na 408.29260).
实施例28
本实施例提供该柏木醇衍生物的制备方法:该合成方法与实施例7的制备方法相同,区别在于使用对氟苯基格氏试剂。
化合物29的表征数据如下:Colorless oil,57%,1H NMR(600MHz,CDCl3)δ7.46-7.42(m,2H),7.02-6.98(m,2H),2.65-2.62(m,1H),2.33-2.24(m,1H),2.09-1.97(m,2H),1.90-1.80(m,2H),1.78-1.69(m,3H),1.62-1.54(m,2H),1.50-1.45(m,1H),1.37(s,3H),1.34-128(m,2H),1.01(s,3H),0.90(d,3H,J=7.3Hz),0.77(d,3H,J=7.3Hz);13C NMR(150MHz,CDCl3)δ162.13,160.51,146.61,146.59,126.75,126.69,114.61,114.47,55.11,54.82,52.56,52.27,48.79,47.15,44.29,41.89,35.18,29.33,28.36,25.19,15.63,14.17.
实施例29
本实施例提供一种柏木醇衍生物(编号为化合物30),名为:(2R,3R,4S,5R,6R)-3,4,5-三(苄氧基)-2-((苄氧基)甲基)-6-(((3R,3aR,6S,7S,8aS)-3,6,8,8-四甲基八氢-1H-3a,7-雪松烷-5-基)氧)四氢-2H-吡喃,其结构式如下:
本实施例提供该柏木醇衍生物的制备方法:在反应容器中加入0.1mmol的化合物3溶于2mL无水DCM中,加入0.1mmol(3R,4S,5R,6R)-3,4,5-三(苄氧基)-6-((苄氧基)甲基)四氢-2H-吡喃-2-基3-苯基丙酸酯,0.3mmol氯化金,和10%4A分子筛,45度反应3h,反应结束后,反应溶液慢慢加入水淬灭反应,然后用有机溶剂萃取,干燥,减压蒸馏浓缩除去溶剂,粗产品经柱色谱分离,即得目标产物,化合物30产率28%。
化合物30的表征数据如下:White salt,28%,m.p.105-107℃.1H NMR(600MHz,CDCl3)δ7.35-7.24(m,18H),7.20-7.19(m,2H),5.00(d,1H,J=11Hz),4.91(d,1H,J=11Hz),4.82(d,1H,J=11Hz),4.79(d,1H,J=11Hz),4.73(d,1H,J=11Hz),4.60(s,2H),4.56(d,1H,J=11Hz),4.53(d,1H,J=11Hz),3.79-3.73(m,2H),3.68-3.63(m,2H),3.58-3.54(m,1H),3.50-3.44(m,2H),2.13-2.10(m,1H),1.85-1.80(m,2H),1.73-1.65(m,2H),1.62-1.56(m,2H),1.49-1.43(m,2H),1.37-1.33(m,1H),1.25-1.21(m,2H),1.20(d,3H,J=7.5Hz),1.13(s,3H),0.9s(s,3H),0.83(d,3H,J=7.5Hz);13C NMR(150MHz,CDCl3)δ138.68,138.48,138.38,138.18,128.42,128.37,128.36,128.33,128.13,128.03,127.86,127.77,127.64,127.60,127.58,127.53,104.72,85.00,83.57,82.75,78.11,75.77,75.13,74.98,73.72,58.15,55.29,54.76,46.62,44.66,43.97,42.88,41.96,36.74,28.85,28.17,25.77,18.36,15.65.
实施例30
本实施例提供一种柏木醇衍生物(编号为化合物31),名为:(2R,3R,4S,5R,6S)-3,4,5-三(苄氧基)-2-((苄氧基)甲基)-6-(((3R,3aR,6S,7S,8aS)-3,6,8,8-四甲基八氢-1H-3a,7-雪松烷-5-基)氧)四氢-2H-吡喃,其结构式如下:
本实施例提供该柏木醇衍生物的制备方法:合成与化合物30合成方法一样,分离得到的第二个产物。
化合物31的表征数据如下:Colorless oil,69%,1H NMR(600MHz,CDCl3)δ7.37-7.23(m,18H),7.14-7.13(m,2H),5.01-4.99(m,2H),4.83-4.80(m,3H),4.66(d,1H,J=11Hz),4.60(d,1H,J=11Hz),4.47(d,1H,J=11Hz),4.44(d,1H,J=11Hz),3.98-3.92(m,2H),3.86-3.85(m,1H),3.72-3.70(m,1H),3.64-3.55(m,3H),2.05-2.02(m,1H),1.94-1.90(m,1H),1.87-1.84(m,1H),1.77-1.69(m,2H),1.65-1.62(m,2H),1.56-1.46(m,2H),1.38-1.34(m,1H),1.29-1.25(m,3H),1.13(d,3H,J=7.5Hz),1.09(s,3H),0.93(s,3H),0.89(d,3H,J=7.5Hz);13C NMR(150MHz,CDCl3)δ138.96,138.33,138.20,138.02,128.45,128.43,128.37,128.33,128.28,127.99,127.95,127.93,127.91,127.70,127.63,127.59,93.07,82.29,79.70,78.06,76.04,75.72,75.08,73.54,73.47,70.30,68.72,58.18,55.66,54.41,46.41,43.85,42.89,42.02,38.59,36.90,28.85,27.84,25.83,19.33,15.67.
实施例31
本实施例提供该柏木醇衍生物的制备方法:该制备方法与实施例3提供的制备方法相同,区别在于使用TsNCO。
化合物32的表征数据如下:Colorless oil,87%,1H NMR(600MHz,CDCl3)δ7.93-7.91(m,2H),7.47-7.46(m,1H),7.35-7.34(m,2H),4.94-4.89(m,1H),2.45(s,3H),1.93-1.90(m,1H),1.82-1.78(m,1H),1.75-1.70(m,4H),1.63-1.62(m,1H),1.50-1.47(m,1H),1.37-1.32(m,1H),1.26-1.22(m,1H),1.16-1.12(m,2H),1.11(s,3H),0.92(s,3H),0.91(d,3H,J=7.5Hz),0.78(d,3H,J=7.5Hz);13C NMR(150MHz,CDCl3)δ150.40,144.95,135.70,129.59,128.36,79.69,58.02,55.04,54.68,46.53,43.80,42.75,41.76,39.55,36.72,28.72,27.90,25.73,21.69,17.36,15.45.
实施例32
本实施例提供一种柏木醇衍生物(编号为化合物33),名为:(2R,3S,4S,5R,6S)-2-(羟甲基)-6-(((3R,3aR,6S,7S,8aS)-3,6,8,8-四甲基八氢-1H-3a,7-雪松烷-5-基)氧)四氢-2H-吡喃-3,4,5-三醇,其结构式如下:
本实施例提供该柏木醇衍生物的制备方法:在反应容器中加入0.1mmol的化合物30溶于2mL MeOH中,加入10%的Pd/C在氢气氛围下,室温反应12h,反应结束后,反应溶液过滤,减压蒸馏浓缩除去溶剂,粗产品经柱色谱分离,即得目标产物,化合物33产率85%。
化合物33的表征数据如下:Colorless oil,85%,1H NMR(600MHz,CD3OD)δ5.03(d,1H,J=4Hz),3.95-3.91(m,2H),3.80-3.61(m,4H),3.41-3.38(m,1H),3.28-3.26(m,1H),2.13-2.10(m,1H),1.89(s,2H),1.87-1.82(m,1H),1.80-1.72(m,4H),1.64-1.63(m,1H),1.55-1.52(m,1H),1.44-1.41(m,1H),1.32-1.25(m,5H),1.18(d,3H,J=7.5Hz),1.17(s,3H),0.97(s,3H),0.88(d,3H,J=7.5Hz);13C NMR(150MHz,CD3OD)δ94.13,75.20,75.17,73.70,72.42,72.06,70.50,61.29,57.93,55.61,54.29,46.41,43.54,43.36,42.09,38.15,36.45,27.95,27.00,25.34,18.31,14.50.HR-EI-MS(positive)m/z 407.24023[M+Na]+(calcd for C21H36O3Na 407.25119).
实施例33
本实施例提供该柏木醇衍生物的制备方法:该制备方法与实施例3提供的制备方法相同,区别在于使用胺基磺酰氯。
化合物34的表征数据如下:White salt,61%,m.p.114-116℃.1H NMR(600MHz,CDCl3)δ4.90-4.85(brs,2H),4.78-4.73(m,1H),2.27-2.23(m,1H),1.91-1.84(m,2H),1.78-1.70(m,4H),1.55-1.52(m,2H),1.41-1.37(m,1H),1.33-1.28(m,1H),1.25-1.23(m,1H),1.19(d,3H,J=7.5Hz),1.18(s,3H),0.96(s,3H),0.86(d,3H,J=7.5Hz);13C NMR(150MHz,CDCl3)δ86.82,58.16,55.28,54.92,46.41,43.88,43.22,41.80,40.75,36.73,28.72,28.10,25.81,17.77,15.53.HR-EI-MS(positive)m/z 324.16025[M+Na]+(calcdfor C15H27O3NSNa 324.16093).
实施例34
本实施例提供一种柏木醇衍生物(编号为化合物35),名为:(2R,3R,4S,5R)-3,4-双(苄氧基)-2-((苄氧基)甲基)-5-(((3R,3aR,6S,7S,8aS)-3,6,8,8-四甲基八氢-1H-3a,7-雪松烷-5-基)氧)四氢呋喃,其结构式如下:
本实施例提供该柏木醇衍生物的制备方法:该制备方法与实施例30提供的制备方法相同,区别在于使用(3S,4R,5R)-3,4-双(苄氧基)-5-((苄氧基)甲基)四氢呋喃-2-基3-苯基丙酸酯。
化合物35的表征数据如下:Colorless oil,84%,1H NMR(600MHz,CDCl3)δ7.35-7.31(m,4H),7.30-7.23(m,11H),5.21(s,1H),4.62-4.44(m,6H),4.25-4.23(m,1H),4.03-4.02(m,1H),3.90-3.89(m,1H),3.74-3.60(m,3H),2.10-2.06(m,1H),1.82-1.66(m,5H),1.62-1.60(m,1H),1.51-1.47(m,1H),1.37-1.33(m,2H),1.26-1.24(m,1H),1.23-1.20(m,1H),1.15(d,3H,J=7.5Hz),1.14(s,3H),0.93(s,3H),0.81(d,3H,J=7.5Hz);13C NMR(150MHz,CDCl3)δ138.23,137.97,137.64,128.50,128.36,128.31,127.97,127.91,127.88,127.72,127.70,127.53,107.79,88.82,83.88,81.33,79.77,73.25,72.17,72.01,69.74,58.09,55.24,54.70,46.66,44.19,43.93,42.60,41.96,36.79,28.89,28.04,25.82,18.35,15.56.HR-EI-MS(positive)m/z 647.37042[M+Na]+(calcd for C41H52O5Na647.38147).
实施例35
本实施例提供一种柏木醇衍生物(编号为化合物36),名为:(2R,3R,4S,5S)-3,4-双(苄氧基)-2-((苄氧基)甲基)-5-(((3R,3aR,6S,7S,8aS)-3,6,8,8-四甲基八氢-1H-3a,7-雪松烷-5-基)氧)四氢呋喃,其结构式如下:
本实施例提供该柏木醇衍生物的制备方法:该制备方法与实施例34提供的制备方法相同。
化合物36的表征数据如下:Colorless oil,12%,1H NMR(600MHz,CDCl3)δ7.37-7.27(m,15H),5.19-5.18(m,1H),4.72-4.49(m,6H),4.11-4.07(m,3H),3.88-3.84(m,1H),3.62-3.58(m,2H),2.04-2.01(m,1H),1.85-1.78(m,2H),1.74-1.70(m,2H),1.66-1.62(m,2H),1.58-1.57(m,1H),1.51-1.47(m,1H),1.38-1.36(m,1H),1.27-1.24(m,2H),1.22-1.15(m,2H),1.14(s,3H),1.09(d,3H,J=7.5Hz),0.94(s,3H),0.85(d,3H,J=7.5Hz);13C NMR(150MHz,CDCl3)δ138.30,138.10,137.84,128.44,128.36,128.05,127.87,127.84,127.75,127.63,97.16,83.79,83.47,79.56,73.39,72.94,72.52,72.28,58.08,55.35,54.41,46.61,43.93,43.25,41.93,39.30,36.77,28.82,28.00,25.75,18.78,15.63.HR-EI-MS(positive)m/z647.37042[M+Na]+(calcd for C41H52O5Na 647.38147).
实施例36
本实施例提供一种柏木醇衍生物(编号为化合物37),名为:(2R,3S,4S,5R,6R)-2-(羟甲基)-6-(((3R,3aR,6S,7S,8aS)-3,6,8,8-四甲基八氢-1H-3a,7-雪松烷-5-基)氧)四氢-2H-吡喃-3,4,5-三醇,其结构式如下:
本实施例提供该柏木醇衍生物的制备方法:该制备方法与实施例32提供的制备方法相同。
化合物37的表征数据如下:White salt,87%,m.p.134-136℃.1H NMR(600MHz,CDCl3)δ5.49(brs,1H),5.10(brs,1H),4.61(brs,1H),4.42-4.40(m,1H),3.86-3.79(m,2H),3.73-3.59(m,5H),3.45-3.42(m,1H),3.33-3.30(m,1H),2.02-1.99(m,1H),1.85-1.78(m,2H),1,73-1.65(m,3H),1.60-1.59(m,1H),1.52-1.51(m,1H),1.41-1.36(m,2H),1.29-1.25(m,2H),1.18(d,3H,J=7.5Hz),1.14(s,3H),0.94(s,3H),0.85(d,3H,J=7.5Hz);13CNMR(150MHz,CDCl3)δ104.48,84.50,76.35,75.28,73.62,69.58,61.85,58.03,55.16,54.78,46.53,44.24,43.98,42.68,41.78,36.61,28.79,28.21,25.71,18.30,15.69.HR-EI-MS(positive)m/z 407.24023[M+Na]+(calcd for C21H36O3Na 407.25119).
实施例37
本实施例提供一种柏木醇衍生物(编号为化合物38),名为:(2R,3S,4S,5R)-2-(羟甲基)-5-(((3R,3aR,6S,7S,8aS)-3,6,8,8-四甲基八氢-1H-3a,7-雪松烷-5-基)氧)四氢呋喃-3,4-二醇,其结构式如下:
本实施例提供该柏木醇衍生物的制备方法:该制备方法与实施例32提供的制备方法相同。
化合物38的表征数据如下:White salt,83%,m.p.124-126℃.1H NMR(600MHz,CD3OD)δ5.01-5.00(m,1H),3.96-3.94(m,2H),3.83-3.80(m,1H),3.75-3.68(m,2H),3.64-3.62(m,1H),2.12-2.08(m,1H),1.88-1.85(m,1H),1.78-1.69(m,4H),1.62-1.61(m,1H),1.55-1.52(m,1H),1.44-1.40(m,1H),1.34-1.28(m,3H),1.21-1.19(m,1H),1.17(s,3H),1.15(d,3H,J=7.5Hz),0.97(s,3H),0.88(d,3H,J=7.5Hz);13C NMR(150MHz,CD3OD)δ109.69,83.74,82.34,81.11,77.35,61.62,58.13,55.26,54.56,46.47,44.50,43.58,42.35,41.97,36.46,27.97,27.12,25.36,17.14,14.51.HR-EI-MS(positive)m/z377.22985[M+Na]+(calcd for C20H34O5Na 377.24062).
实施例38
本实施例提供该柏木醇衍生物的制备方法:该制备方法与实施例3提供的制备方法相同,区别在于使用磺酰氯。
化合物39的表征数据如下:Colorless oil,87%,1H NMR(600MHz,Acetone-d6)δ4.50-4.45(m,1H),3.28-3.25(m,6H),2.95(brs,2H),2.34-2.30(m,1H),1.88-1.85(m,1H),1.78-1.67(m,4H),1.65-1.64(m,1H),1.56-1.53(m,1H),1.39-1.37(m,12H),1.30-1.28(m,2H),1.23-1.21(m,1H),1.20(s,3H),1.16(d,3H,J=7.5Hz),0.97(s,3H),0.85(d,3H,J=7.5Hz);13C NMR(150MHz,Acetone-d6)δ78.51,58.15,55.22,54.61,46.73,46.59,46.56,43.93,43.71,41.91,41.37,36.71,28.40,27.47,25.53,17.49,15.11,8.52,8.49.HR-EI-MS(negative)m/z 285.28607[M-H-Et3N]-(calcd for C15H25O3S 285.19299).
实施例39
本实施例提供该柏木醇衍生物的制备方法:在反应容器中加入0.1mmol化合物15溶于2mL无水DCM中,加入0.11mmol乙酰氯,0.11mmolEt3N,室温反应2h,反应结束后,反应溶液慢慢加入水淬灭反应,然后用有机溶剂萃取,干燥,减压蒸馏浓缩除去溶剂,粗产品经柱色谱分离,即得目标产物,化合物40产率13%。
化合物40的表征数据如下:Colorless oil,13%,1H NMR(600MHz,CDCl3)δ5.93(d,1H,J=2Hz),5.07(d,1H,J=2Hz),2.59(d,1H,J=4Hz),2.47-2.44(m,1H),2.35-.231(m,1H),2.01-1.97(m,1H),1.92-1.86(m,2H),1.71-1.63(m,3H),1.58(s,1H),1.51-1.47(m,1H),1.40-1.37(m,1H),1.25(s,2H),1.02(s,3H),0.88(s,3H),0.87(d,3H,J=7.4Hz);13CNMR(150MHz,CDCl3)δ201.79,148.57,120.92,59.13,57.78,54.36,51.56,43.51,42.35,41.78,36.59,28.64,25.87,25.68,15.42.HR-EI-MS(positive)m/z219.17441[M+H]+(calcd for C15H23O 219.16707).
实施例40
本实施例提供该柏木醇衍生物的制备方法:参照实施例3提供的制备方法合成该化合物。
化合物41的表征数据如下:Colorless oil,75%,1H NMR(400MHz,CDCl3)δ8.10-8.05(m,2H),7.80-7.56(m,1H),7.48-7.44(m,2H),5.17(s,1H),3.02(d,1H,J=12Hz),2.18-2.14(m,1H),2.01-1.92(m,2H),1.81-1.62(m,5H),1.50(s,3H),1.49-1.45(m,1H),1.28-1.27(m,1H),1.10(s,3H),1.04(s,3H),0.88(d,3H,J=7.5Hz);13C NMR(100MHz,CDCl3)δ204.11,165.48,133.24,129.81,129.79,128.50,128.45,81.43,78.55,61.00,60.18,53.50,42.26,39.63,35.18,33.57,28.68,28.41,24.51,24.10,15.23.HR-EI-MS(positive)m/z 379.18797[M+Na]+(calcd for C22H28O4Na 379.18853).
实施例41
本实施例提供该柏木醇衍生物的制备方法:在反应容器中加入0.1mmol实施例14制备得到的化合物15溶于2mL CH3OH中,加入0.12mmol硼氢化钠,室温反应0.5h,反应结束后,反应溶液慢慢加入水淬灭反应,然后用有机溶剂萃取,干燥,减压蒸馏浓缩除去溶剂,粗产品经柱色谱分离,即得目标产物,化合物产率95%。
化合物42的表征数据如下:White salt,95%,m.p.132-133℃.1H NMR(400MHz,CDCl3)δ3.73(d,1H,J=6.9Hz),2.39-2.35(m,1H),2.05-2.00(m,1H),1.86-1.82(m,2H),1.73-1.55(m,6H),1.48(s,3H),1.46-1.40(1H),1.34-1.32(m,1H),1.31(s,3H),1.04(s,3H),0.86(d,3H,J=7.5Hz);13C NMR(100MHz,CDCl3)δ76.34,74.46,74.44,61.13,61.10,53.41,53.39,52.99,43.08,41.68,41.67,40.23,40.04,35.54,29.52,29.05,27.48,25.18,15.59,15.57.HR-EI-MS(negative)m/z 237.18451[M-H]-(calcd forC15H25O2237.19328).
实施例42
本实施例提供一种柏木醇衍生物(编号为化合物43),名为:(3R,3aR,7S,8aS)-3,6,8,8-tetramethyl-1,2,3,7,8,8a-六氢-4H-3a,7-雪松烷-4-酮,其结构式如下:
本实施例提供该柏木醇衍生物的制备方法:在反应容器中加入0.1mmol实施例1制备得到的化合物2和0.3mmol PIDA溶于2mL乙酸乙酯,冷却至-20℃后加入0.4mmolTBHP,-20℃反应11h,反应结束后,反应溶液慢慢加入NaHCO3和Na2SO3溶液淬灭反应,然后用有机溶剂萃取,干燥,减压蒸馏浓缩除去溶剂,粗产品经柱色谱分离,即得目标产物,产率43%。
化合物43的表征数据如下:Colorless oil,43%,1H NMR(400MHz,CDCl3)δ5.86(s,1H),2.35-2.34(m,1H),1.99-1.94(m,6H),1.78-1.67(m,8H),1,54(s,1H),1.34(d,3H,J=7.5Hz),1.23-1.20(m,2H),1.12(s,3H),1.03(s,3H);13C NMR(100MHz,CDCl3)δ203.92,165.45,125.65,65.66,59.13,58.29,44.86,44.03,42.54,39.48,27.99,27.15,26.70,25.26,15.28.HR-EI-MS(positive)m/z 219.17410[M+H]+(calcd for C15H23O 219.16707).
实施例43
本实施例提供该柏木醇衍生物的制备方法:该方法参照实施例3的制备方法。
化合物44的表征数据如下:Colorless oil,78%,1H NMR(400MHz,CDCl3)δ4.91(d,1H,J=6.1Hz),2.38(q,2H,J=7.3Hz),2.24-2.19(m,1H),2.08-2.02(m,1H),1.93-1.44(m,12H),1.37(s,3H),1.31(brs,4H),1.28(brs,4H),1.20(t,3H,J=7.3Hz),1.06(s,3H),0.83(d,3H,J=7.3Hz);13C NMR(100MHz,CDCl3)δ173.42,75.38,74.91,60.95,53.51,52.76,42.91,41.63,39.67,37.71,35.65,29.69,29.48,28.63,28.26,27.35,25.17,15.50,9.17.HR-EI-MS(positive)m/z 295.22666[M+H]+(calcd for C18H31O3295.21949).
实施例44
本实施例提供该柏木醇衍生物的制备方法:在反应容器中加入0.1mmol实施例42制备得到的化合物43和0.22mmol SeO2溶于2mL1,4二氧六环,加热回流反应14h,反应结束后,过滤,反应溶液慢慢加入水淬灭反应,然后用有机溶剂萃取,干燥,减压蒸馏浓缩除去溶剂,粗产品经柱色谱分离,即得目标产物,产率70%。
化合物45的表征数据如下:White salt,70%,m.p.56-57℃.1H NMR(400MHz,CDCl3)δ9.75(s,1H),6.37(s,1H),3.06-3.04(m,1H),1.99-1.94(m,2H),1.90-1.53(m,5H),1.30(d,3H,J=7.4Hz),1.18(s,3H),0.84(s,3H);13C NMR(100MHz,CDCl3)δ203.49,193.35,157.80,140.02,67.87,57.78,49.45,43.95,43.78,42.59,39.31,27.96,26.57,26.44,14.97.HR-EI-MS(positive)m/z 233.15354[M+H]+(calcd for C15H21O2 233.14663).
实施例45
本实施例提供该柏木醇衍生物的制备方法:该合成方法参照实施例41的制备方法。
化合物46的表征数据如下:Colorless oil,68%,1H NMR(400MHz,CDCl3)δ5.10(s,1H),4.43(s,1H),2.27-2.23(m,1H),1.89-1.86(m,1H),1.81-1.80(m,1H),1.72-1.64(m,5H),1.58-1.56(m,2H),1.47-1.34(m,4H),1.07(d,3H,J=7.5Hz),1.01(s,3H),1.00(s,3H);13C NMR(100MHz,CDCl3)δ143.76,123.15,74.77,58.38,55.95,52.23,44.22,44.17,43.22,39.72,27.05,26.78,25.63,24.10,15.58.HR-EI-MS(positive)m/z 221.15362[M+H]+(calcd for C14H21O2 221.22967).
实施例46
本实施例提供该柏木醇衍生物的制备方法:该方法参照实施例3的制备方法,将原料换成化合物46。
化合物47的表征数据如下:Colorless oil,11%,1H NMR(400MHz,CDCl3)δ6.30(d,1H,J=9.8Hz),5.88(d,1H,J=9.8Hz),4.71(d,1H,J=2.1Hz),4.59(d,1H,J=9.8Hz),2.42-2.41(m,1H),2.03-1.98(m,2H),1.87-1.80(m,2H),1.68-1.65(m,2H),1.56(s,4H),1.54-1.51(m,1H),1.44-1.34(m,4H),1.04(s,3H),0.99(d,3H,J=7.3Hz),0.96(s,3H);13CNMR(100MHz,CDCl3)δ149.22,140.36,126.60,109.60,62.72,59.06,43.03,39.55,37.85,29.95,29.71,29.67,27.70,26.49,17.10.HR-EI-MS(positive)m/z 203.17951[M+H]+(calcd for C15H23 203.17215).
实施例47
本实施例提供该柏木醇衍生物的制备方法:该方法参照实施例3的制备方法,区别在于使用庚酰氯。
化合物48的表征数据如下:Colorless oil,83%,1H NMR(400MHz,CDCl3)δ5.10-5.03(m,1H),2.38(t,2H,J=7.5Hz),2.01-1.95(m,1H),1.85-1.49(m,10H),1.40-1.20(m,10H),1.18(s,3H),1.02(d,3H,J=7.5Hz),0.95(s,3H),0.89(t,3H,J=7.5Hz),0.82(d,3H,J=7.5Hz);13C NMR(100MHz,CDCl3)δ173.83,75.36,58.12,55.19,54.72,46.75,43.87,42.87,41.91,39.87,36.82,34.76,31.49,28.85,28.82,27.95,25.79,25.12,22.50,17.66,15.49,14.03.
实施例48
本实施例提供一种柏木醇衍生物(编号为化合物49),名为:(3R,3aR,7S,8aS)-4-苄基-3,6,8,8-四甲基-2,3,4,7,8,8a-六氢-1H-3a,7-雪松烷-4-醇,其结构式如下:
本实施例提供该柏木醇衍生物的制备方法:该方法参照实施例7的制备方法,区别在于使用化合物43和苄基格氏试剂。
化合物49的表征数据如下:Colorless oil,43%,1H NMR(500MHz,CDCl3)δ7.31-7.27(m,2H),7.25-7.22(m,3H),4.88(s,1H),3.25(d,1H,J=13.1Hz),3.01(d,1H,J=13.1Hz),2.32-2.30(m,1H),2.08-2.05(m,1H),1.89-1.68(m,6H),1.62(brs,3H),1.57-1.53(m,2H),1.42-1.38(m,2H),1.25(d,3H,J=7.4Hz),1.01(s,3H),0.95(s,3H);13C NMR(125MHz,CDCl3)δ140.00,138.11,131.10,127.85,126.68,126.06,78.55,63.90,52.87,49.81,46.41,43.84,41.15,38.65,34.48,27.90,25.65,24.13,23.74,18.62.HR-EI-MS(positive)m/z 311.23685[M+H]+(calcd for C22H31O 311.22967).
实施例49
本实施例提供该柏木醇衍生物的制备方法:该方法参照实施例3的制备方法,区别在于使用NaH和碘庚烷。
化合物50的表征数据如下:Colorless oil,81%,1H NMR(500MHz,CDCl3)δ3.65-3.61(m,1H),3.40-3.31(m,2H),2.04-2.00(m,1H),1.86-1.81(m,1H),1.74-1.47(m,9H),1.40-1.23(m,10H),1.21-1.16(m,2H),1.15(s,3H),1.11(d,3H,J=7.5Hz),0.94(s,3H),0.89(t,3H,J=7.5Hz),0.85(d,3H,J=7.5Hz);13C NMR(125MHz,CDCl3)δ80.63,69.25,58.33,55.15,54.51,46.77,44.20,43.95,42.01,40.16,36.80,31.89,30.39,29.20,28.87,27.95,26.22,25.79,22.65,18.21,15.57,14.13.HR-EI-MS(positive)m/z321.31522[M+H]+(calcd for C22H41O 321.30792).
实施例50
本实施例提供该柏木醇衍生物的制备方法:该方法参照实施例3的制备方法,区别在于使用NaH和碘戊烷。
化合物51的表征数据如下:Colorless oil,85%,1H NMR(500MHz,CDCl3)δ3.65-3.61(m,1H),3.40-3.31(m,2H),2.03-2.00(m,1H),1.85-1.82(m,1H),1.73-1.48(m,8H),1.39-1.24(m,6H),1.20-1.18(m,2H),1.14(s,3H),1.11(d,3H,J=7.5Hz),0.93(s,3H),0.88(t,3H,J=7.5Hz),0.84(d,3H,J=7.5Hz);13C NMR(125MHz,CDCl3)δ80.63,69.25,58.33,55.15,54.51,46.77,44.20,43.95,42.01,40.15,36.79,30.07,28.86,28.44,27.95,25.79,22.58,18.20,15.57,14.10.HR-EI-MS(positive)m/z 293.19315[M+H]+(calcd for C20H37O 293.19772).
实施例51
本实施例提供该柏木醇衍生物的制备方法:该方法参照实施例3的制备方法,区别在于使用NaH和碘庚烷。
化合物52的表征数据如下:Colorless oil,35%,1H NMR(500MHz,CDCl3)δ2.50-2.45(m,1H),2.09-2.00(m,2H),1.79-1.75(m,1H),1.70-1.69(m,2H),1.64-1.51(m,8H),1.41-1.37(m,1H),1.35-1.23(m,14H),1.22(s,3H),1.15-1.12(m,1H),0.97(s,3H),0.88(t,3H,J=7.5Hz),0.77(d,3H,J=7.5Hz);13C NMR(125MHz,CDCl3)δ60.76,55.21,53.47,51.96,43.86,43.77,43.02,41.54,36.89,36.41,35.48,31.88,30.91,30.73,29.40,27.87,27.68,24.78,22.66,16.34,15.55,14.12.HR-EI-MS(positive)m/z319.31833[M+H]+(calcd for C22H42N 319.32392).
实施例52
本实施例提供该柏木醇衍生物的制备方法:该方法参照实施例8的制备方法,区别在于使用化合物43。
化合物53的表征数据如下:White salt,87%,m.p.65-68℃.1H NMR(500MHz,CDCl3)δ8.19(brs,1H),6.55(s,1H),2.15-2.14(m,1H),2.05-2.03(m,1H),1.97-1.89(m,6H),1.45-1.41(m,1H),1.28(d,3H,J=7.5Hz),1.06(s,3H),1.00(s,3H);13C NMR(125MHz,CDCl3)δ162.73,155.24,111.89,60.99,59.08,58.49,45.36,44.62,44.37,39.37,27.81,26.76,26.66,25.47,16.05.HR-EI-MS(positive)m/z 234.18512[M+H]+(calcd forC15H24ON 234.17796).
实施例53
本实施例提供该柏木醇衍生物的制备方法:在反应容器中加入0.1mmol实施例1制备得到的化合物2、0.11mmol Se粉、0.2mmolTsNClNa溶于2mL无水DCM溶液中,室温反应36h,反应结束后,过滤,滤液减压蒸馏浓缩除去溶剂,粗产品经柱色谱分离,即得目标产物,化合物54产率21%。
化合物54的表征数据如下:Colorless oil,21%,1H NMR(500MHz,CDCl3)δ9.43(s,1H),6.66-6.65(m,1H),2.66(d,1H,J=3.6Hz),2.53-2.48(m,1H),2.22-2.17(m,1H),1.90-1.78(m,4H),1.68-1.61(m,3H),1.45-1.38(m,2H),1.30-1.28(m,1H),1.01(s,3H),0.89(d,3H,J=7.5Hz),0.85(s,3H);13C NMR(125MHz,CDCl3)δ192.17,149.25,146.81,58.60,53.38,47.01,45.13,40.12,39.17,38.56,35.11,26.31,23.86,23.85,14.47.HR-EI-MS(positive)m/z 219.17427[M+H]+(calcd for C15H23O219.16707).
实施例54
本实施例提供该柏木醇衍生物的制备方法:参见实施例53,柱分离,得到不同产物,分别为化合物54和化合物55,化合物55产率52%。
化合物55的表征数据如下:Colorless oil,52%,1H NMR(500MHz,CDCl3)δ5.52-5.50(m,1H),4.04-3.93(m,2H),2.26-2.21(m,1H),1.94-1.90(m,1H),1.88-1.83(m,2H),1.78-1.67(m,3H),1.62-1.53(m,2H),1.42-1.35(m,3H),0.99(s,3H),0.96(s,3H),0.85(d,3H,J=7.5Hz);13C NMR(125MHz,CDCl3)δ144.04,120.30,67.06,59.04,54.24,50.36,48.36,41.41,40.60,38.59,36.08,27.68,25.47,24.79,15.42.HR-EI-MS(positive)m/z221.18982[M+H]+(calcd for C15H25O 221.18272).
实施例55
本实施例提供一种柏木醇衍生物(编号为化合物56),名为:(3R,3aR,7S,8aS,E)-3,6,8,8-四甲基-1,2,3,7,8,8a-六氢-4H-3a,7-雪松烷-4-酮O-庚酰基肟,其结构式如下:
本实施例提供该柏木醇衍生物的制备方法:该方法参照实施例3的制备方法,区别在于使用化合物53和庚酰氯。
化合物56的表征数据如下:Colorless oil,72%,1H NMR(500MHz,CDCl3)δ6.38(s,1H),2.47-2.44(m,2H),2.20-2.19(m,1H),2.06-2.03(m,1H),1.97-1.90(m,6H),1.82-1.65(m,7H),1.51-1.45(m,1H),1.37(d,3H,J=7.5Hz),1.31-1.29(m,1H),1.08(s,3H),1.00(s,3H),0.88(t,3H,J=7.5Hz);13C NMR(125MHz,CDCl3)δ172.68,167.72,159.09,112.32,60.46,59.92,58.40,45.07,44.40,44.38,39.00,33.22,31.54,28.95,27.84,26.77,26.59,25.64,24.80,22.53,16.38,14.07.HR-EI-MS(positive)m/z346.27296[M+H]+(calcd for C22H36O2N 346.26678).
实施例56
本实施例提供一种柏木醇衍生物(编号为化合物57),名为:(3R,3aS,7R,8aS,Z)-6-((庚氧基)亚甲基)-3,8,8-三甲基-2,3,6,7,8,8a-六氢-1H-3a,7-雪松烷,其结构式如下:
本实施例提供该柏木醇衍生物的制备方法:该方法参照实施例3的制备方法,区别在于使用NaH和碘庚烷和化合物55。
化合物57的表征数据如下:Colorless oil,32%,1H NMR(500MHz,CDCl3)δ6.03(d,1H,J=9.6Hz),6.01(s,1H),3.69(d,1H,J=9.6Hz),3.75-3.65(m,2H),2.84-2.83(m,1H),2.02-1.94(m,2H),1.85-1.75(m,3H),1.61-1.150(m,9H),1.34-1.25(m,14H),1.05(s,3H),0.98(s,3H),0.96(d,3H,J=7.6Hz),0.88(t,3H,J=7.5Hz);13C NMR(125MHz,CDCl3)δ142.21,134.84,123.67,121.68,72.35,64.07,56.37,49.53,43.33,41.67,39.54,37.68,31.78,29.84,29.01,28.99,27.20,26.08,25.83,22.59,17.02,14.09.HR-EI-MS(positive)m/z 317.28374[M+H]+(calcd for C22H37O 317.27662).
实施例57
本实施例提供一种柏木醇衍生物(编号为化合物58),名为:(3R,3aS,7R,8aS,E)-6-((庚氧基)亚甲基)-3,8,8-三甲基-2,3,6,7,8,8a-六氢-1H-3a,7-雪松烷,其结构式如下:
本实施例提供该柏木醇衍生物的制备方法:该方法参照实施例3的制备方法,区别在于使用NaH和碘庚烷和化合物55。
化合物58的表征数据如下:Colorless oil,30%,1H NMR(500MHz,CDCl3)δ6.22(d,1H,J=8.9Hz),6.13(d,1H,J=8.9Hz),5.64(s,1H),3.70(t,2H,J=7.5Hz),2.14-2.13(m,1H),2.04-1.94(m,3H),1.85-1.80(m,2H),1.66-1.57(m,11H),1.40-1.25(m,15H),0.99(s,3H),0.97(d,3H,J=7.5Hz),0.96(s,3H),0.88(t,3H,J=7.5Hz);13C NMR(125MHz,CDCl3)δ139.54,136.75,120.12,119.55,72.36,63.39,56.43,54.22,43.37,42.48,39.66,37.80,31.77,30.11,29.80,29.06,27.39,26.38,25.77,22.60,17.07,14.09.HR-EI-MS(positive)m/z 317.28374[M+H]+(calcd for C22H37O 317.27662).
实施例58
本实施例提供该柏木醇衍生物的制备方法:该方法参照实施例3的制备方法,区别在于使用庚酰氯和化合物55。
化合物59的表征数据如下:Colorless oil,87%,1H NMR(500MHz,CDCl3)δ5.56-5.54(m,1H),4.50-4.42(m,2H),2.32(q,2H,J=7.4Hz),2.27-2.23(m,1H),1.92-1.84(m,3H),1.78-1.59(m,6H),1.41-1.27(m,9H),1.02(s,3H),0.96(s,3H),0.88(t,3H,J=7.4Hz),0.84(d,3H,J=7.4Hz);13C NMR(125MHz,CDCl3)δ173.83,139.16,123.49,67.99,59.05,54.03,50.61,48.48,41.40,40.42,38.65,36.09,34.42,31.48,28.85,27.65,25.48,24.98,24.80,22.51,15.41,14.05.HR-EI-MS(positive)m/z 333.27890[M+H]+(calcd for C22H37O2 333.27153).
实施例59
本实施例提供一种柏木醇衍生物(编号为化合物60),名为:2-苯基-1-((3R,3aS,7R,8aS)-3,8,8-三甲基-2,3,4,7,8,8a-六氢-1H-3a,7-雪松烷-6-基)乙醇-1-醇,其结构式如下:d/r=3:1。
本实施例提供该柏木醇衍生物的制备方法:该制备方法参照实施例7。区别在于使用原料化合物54和苄基格氏试剂。
化合物60的表征数据如下:Colorless oil,78%,1H NMR(500MHz,CDCl3)δ7.31-7.29(m,3H),7.25-7.22(m,4H),5.59-5.58(m,0.38H),5.57-5.53(m,1H),4.17-4.14(m,2H),2.96-2.84(m,2H),2.61-2.57(m,0.4H),2.27-2.20(m,2H),1.94-1.87(m,3H),1.82-1.77(m,3H),1.72-1.69(m,2H),1.61-1.59(m,2H),1.51-1.50(m,1H),1.44-1.38(m,4H),1.06(s,1H),1.03(s,3H),1.00(s,3H),0.99(s,1H),0.87(d,1H,J=7.4Hz),0.85(d,3H,J=7.4Hz);13C NMR(125MHz,CDCl3)δ146.95,145.25,139.22,138.56,129.56,129.48,128.44,128.35,126.42,126.32,121.35,118.16,75.94,75.38,59.40,59.02,54.25,53.97,51.79,50.39,48.63,48.61,43.27,41.97,41.51,41.36,40.99,40.41,38.84,38.48,36.17,36.08,28.26,27.59,25.69,25.65,24.85,15.47,15.45.HR-EI-MS(positive)m/z311.22810[M+H]+(calcd for C22H31O 311.22967).
实施例60
本实施例提供该柏木醇衍生物的制备方法:在反应容器中加入0.1mmol实施例44制备得到的化合物45、1mmol NaClO2、0.8mmolNaH2PO4和2.5mmol异戊烯溶于2mL水:叔丁醇(1:1)溶液中,室温反应19h,反应结束后,反应溶液慢慢加入水淬灭反应,然后用有机溶剂萃取,干燥,减压蒸馏浓缩除去溶剂,粗产品经柱色谱分离,即得目标产物,产率80%。
化合物61的表征数据如下:Colorless oil,80%,1H NMR(500MHz,CDCl3)δ6.72(s,1H),3.08(d,1H,J=3.9Hz),2.00-1.94(m,3H),1.88-1.80(m,2H),1.76-1.66(m,2H),1.59-1.53(m,1H),1.30(d,3H,J=7.5Hz),1.18(s,3H),0.98(s,3H);13C NMR(125MHz,CDCl3)δ203.31,171.74,151.36,134.91,67.11,57.70,52.31,44.33,43.74,43.14,39.34,27.73,26.70,26.57,15.01.The spectroscopic data werefound to be consistent withreported literature 3.
实施例61
本实施例提供该柏木醇衍生物的制备方法:在反应容器中加入0.1mmol的化合物2、0.5mmolNaIO4、2.5%RuCl3溶于2mL水:CH3CN:CCl4(4:3:3)溶液中,60度反应12h,反应结束后,反应溶液慢慢加入水淬灭反应,然后用有机溶剂萃取,干燥,减压蒸馏浓缩除去溶剂,粗产品经柱色谱分离,即得目标产物,产率85%。
化合物62的表征数据如下:Colorless oil,85%,1H NMR(500MHz,CDCl3)δ2.71(m,1H),2.41(d,1H,J=14.6Hz),2.33(d,1H,J=14.6Hz),2.26(t,1H,J=13.2Hz),2.13(s,3H),2.06(t,1H,J=9.1Hz),1.78-1.72(m,1H),1.69(m,1H),1.65-1.54(m,2H),1.35(m,1H),1.18(m,1H),1.11(s,3H),0.97(d,3H,J=6.7Hz),0.88(s,3H);13C NMR(125MHz,CDCl3)δ210.42,179.39,61.05,59.04,50.45,46.45,43.77,41.43,37.98,33.32,31.58,28.57,25.01,24.82,13.97.
实施例62
本实施例提供该柏木醇衍生物的制备方法:该方法参照实施例60的制备方法,区别在于将原料替换为化合物54。
化合物63的表征数据如下:White salt,87%,m.p.90-93 ℃.1H NMR(500MHz,CDCl3)δ7.02-7.01(m,1H),2.84(d,1H,J=3.8Hz),2.42-2.39(m,1H),2.10-2.05(m,1H),1.89-1.87(m,1H),1.82-1.77(m,2H),1.69-1.61(m,2H),1.44-1.33(m,3H),1.01(s,3H),0.98(s,3H),0.88(d,3H,J=7.4Hz);13C NMR(125MHz,CDCl3)δ172.70,141.24,136.12,59.52,53.66,48.77,48.47,41.11,39.91,39.59,36.11,27.13,25.14,24.87,15.49.Thespectroscopic data were found to be consistent with reported literature 4.
实施例63
本实施例提供一种柏木醇衍生物(编号为化合物64),名为:2-苯基-1-((3R,3aS,7R,8aS)-3,8,8-三甲基-2,3,4,7,8,8a-六氢-1H-3a,7-雪松烷-6-基)乙烷-1酮,其结构式如下:
本实施例提供该柏木醇衍生物的制备方法:该方法参照实施例4的制备方法,区别在于将原料替换为化合物60。
化合物64的表征数据如下:Colorless oil,90%,1H NMR(500MHz,CDCl3)δ7.31-7.28(m,2H),7.24-7.19(m,3H),6.91-6.90(m,1H),3.97(s,2H),2.82(d,1H,J=4.2Hz),2.48-2.43(m,1H),2.14-2.09(m,1H),1.90-1.75(m,3H),1.64-1.59(m,3H),1.43-1.36(m,2H),1.27-1.24(m,2H),0.98(s,3H),0.88(d,3H,J=7.3Hz),0.77(s,3H);13C NMR(125MHz,CDCl3)δ197.53,145.30,139.86,135.64,129.34,128.48,126.55,59.70,53.71,48.37,47.19,44.17,41.08,39.90,39.77,36.11,27.20,25.15,24.89,15.54.
实施例64
本实施例提供该柏木醇衍生物的制备方法:在反应容器中加入0.1mmol的化合物62、0.3mmolCuBr2溶于2mL二甘醇二甲醚溶液中,150度反应24h,反应结束后,冷却后,反应溶液慢慢加入水淬灭反应,然后用有机溶剂萃取,干燥,减压蒸馏浓缩除去溶剂,粗产品经柱色谱分离,即得目标产物,产率81%。
化合物65的表征数据如下:Colorless oil,81%,1H NMR(500MHz,CDCl3)δ2.57(d,1H,J=18.2Hz),2.55(d,1H,J=18.2Hz),2.43(m,1H),2.31(s,3H),1.98-1.87(m,3H),1.73(m,1H),1.58(m,1H),1.53(m,1H),1.42(m,1H),1.21(s,3H),0.89(d,3H,J=7.3Hz),0.84(s,3H);13C NMR(150MHz,CDCl3)δ205.35,170.16,100.09,60.20,48.88,48.75,43.07,41.58,40.23,35.92,27.56,25.71,25.29,22.99,15.22.The spectroscopic data werefound to be consistent with reported literature 3.
实施例65
本实施例提供该柏木醇衍生物的制备方法:该合成方法与实施例3的制备方法相同,区别在于使用丙炔溴。
化合物66的表征数据如下:Colorless oil,86%,1H NMR(500MHz,CDCl3)δ4.27-4.16(m,2H),3.68-3.63(m,1H),2.41(s,1H),2.06-2.02(m,1H),1.86-1.81(m,1H),1.74-1.61(m,5H),1.54-1.48(m,1H),1.41-1.34(m,1H),1.29-1.25(m,2H),1.20-1.18(m,2H),1.15(s,3H),1.14(d,3H,J=7.3Hz),0.94(s,3H),0.86(3H,J=7.3Hz);13C NMR(125MHz,CDCl3)δ80.88,79.75,73.61,58.33,56.02,55.18,54.54,46.70,43.93,43.87,41.95,39.53,36.78,28.84,27.99,25.80,18.07,15.57.HR-EI-MS(positive)m/z261.22119[M+H]+(calcd for C18H29O 261.21402).
实施例66
本实施例提供一种柏木醇衍生物(编号为化合物67),名为:(3R,3aS,7R,8aS)-N,N-二庚基-3,8,8-三甲基-2,3,4,7,8,8a-六氢-1H-3a,7-雪松烷-6-羧酰胺,其结构式如下:
本实施例提供该柏木醇衍生物的制备方法:在反应容器中加入0.1mmol的化合物63、0.12mmolNH(C7H15)2,0.12mmol EDCI,0.12mmol DMAP和0.2mmol Et3N溶于2mL DCM溶液中,室温反应1h,反应结束后,冷却后,反应溶液慢慢加入水淬灭反应,然后用有机溶剂萃取,干燥,减压蒸馏浓缩除去溶剂,粗产品经柱色谱分离,即得目标产物,产率84%。
化合物67的表征数据如下:Colorless oil,84%,1H NMR(500MHz,CDCl3)δ5.74-5.72(m,1H),3.19(brs,4H),2.30-2.20(m,2H),2.00-1.96(m,1H),1.89-1.76(m,4H),1.41-1.38(m,3H),1.28-1.23(m,17H),1.09(s,3H),0.95(s,3H),0.88-0.85(m,9H);13C NMR(125MHz,CDCl3)δ172.56,141.48,127.02,59.24,54.03,52.50,49.01,41.44,40.56,38.96,36.10,31.79,29.05,28.17,25.66,24.83,22.61,15.39,14.08.HR-EI-MS(positive)m/z 430.40402[M+H]+(calcd for C29H51ON 430.39707).
实施例67
本实施例提供该柏木醇衍生物的制备方法:在反应容器中加入0.1mmol化合物1、0.11mmolPIDA、0.04mmolI2溶于2mL环已烷溶液中,放入72w的蓝光反应器中室温反应0.5h,关闭反应蓝光反应器,加入1mmolAc2O和0.2mmolH3PO4反应0.5h,反应结束后,反应溶液慢慢加入NaHCO3和Na2S2O3溶液淬灭反应,然后用有机溶剂萃取,干燥,减压蒸馏浓缩除去溶剂,粗产品经柱色谱分离,即得目标产物,化合物68产率54%。
化合物68的表征数据如下:Colorless oil,54%,1H NMR(500MHz,CDCl3)δ5.27-5.24(m,1H),4.00(d,1H,J=4.0Hz),3.91(d,1H,J=4.0Hz),2.20-2.15(m,1H),2.04(s,3H),1.96(d,1H,J=1.9Hz),1.87-1.55(m,10H),1.46-1.37(m,3H),1.00(s,3H),0.85(d,3H,J=7.2Hz);13C NMR(125MHz,CDCl3)δ171.46,138.95,120.58,72.27,55.67,53.23,52.16,51.43,41.13,40.16,38.64,36.16,25.23,24.03,21.04,20.45,15.38.
实施例68
本实施例提供该柏木醇衍生物的制备方法:与实施例67的制备方法相同,柱分离得到两个产物,一个为化合物68,一个为化合物69,且化合物69的收率为45%。
化合物69的表征数据如下:Colorless oil,45%,1H NMR(500MHz,CDCl3)δ4.02-3.99(m,1H),2.48-2.43(m,2H),2.14(s,3H),2.01-1.91(m,2H),1.84-1.81(m,1H),1.70-1.58(m,5H),1.49-1.46(m,1H),1.24-1.12(m,2H),1.03(s,3H),0.95(d,3H,J=7.4Hz),0.92(s,3H);13C NMR(150MHz,CDCl3)δ208.81,54.44,52.98,47.51,45.88,44.29,40.88,40.02,33.79,31.01,30.12,28.77,28.53,23.35,14.28.HR-EI-MS(positive)m/z349.10220[M+H]+(calcd for C15H26OI 349.09501).
实施例69
本实施例提供该柏木醇衍生物的制备方法:在反应容器中加入0.1mmol化合物68、0.15mmolK2CO3溶于2mL甲醇溶液中,室温反应24h,反应结束后,滤液减压蒸馏浓缩除去溶剂,粗产品经柱色谱分离,即得目标产物,化合物42产率89%。
化合物70的表征数据如下:Colorless oil,89%,1H NMR(500MHz,CDCl3)δ5.26-5.24(m,1H),3.54-3.46(m,2H),2.20-2.16(m,1H),1.92-1.91(m,1H),1.89-1.66(m,9H),1.63-1.57(m,1H),1.46-1.37(m,4H),1.02(s,3H),0.84(d,3H,J=7.4Hz);13C NMR(125MHz,CDCl3)δ139.50,120.25,70.90,54.89,53.67,53.33,52.05,41.05,40.26,38.64,36.11,25.40,24.26,20.25,15.39.The spectroscopic data were found to be consistentwith reported literature 3.
实施例70
本实施例提供一种柏木醇衍生物(编号为化合物71),名为:(3R,3aR,7R,8aS)-N,N-二庚基-3,8,8-三甲基-4-氧-2,3,4,7,8,8a-六氢-1H-3a,7-雪松烷-6-羧酰胺,其结构式如下:
本实施例提供该柏木醇衍生物的制备方法:在反应容器中加入0.1mmol化合物21、0.11mmolNH(C7H15)2、0.12mmol EDCI和0.12mmolDMAP、0.2mmolEt3N溶于2mL无水DCM中,室温反应4h,反应结束后,减压蒸馏浓缩除去溶剂,粗产品经柱色谱分离,即得目标产物,产率87%。
化合物71的表征数据如下:Colorless oil,87%,1H NMR(500MHz,CDCl3)δ5.79(s,1H),3.42-3.14(m,4H),2.60(brs,1H),2.09-1.90(m,4H),1.80-1.66(m,4H),1.55-1.52(m,5H),1.31(d,3H,J=5.9Hz);1.29-1.24(m,17H),1.15(s,3H),1.14(s,3H),0.87(d,3H,J=7.3Hz);13C NMR(125MHz,CDCl3)δ202.70,169.67,159.19,126.93,66.59,58.38,56.48,48.40,45.79,44.33,44.22,43.60,39.45,31.82,31.67,29.05,28.94,28.81,27.33,27.23,26.95,26.78,26.68,22.58,15.12,14.08,14.06.HR-EI-MS(positive)m/z444.38266[M+H]+(calcd for C29H50O2N 444.37633).
实施例71
本实施例提供一种柏木醇衍生物(编号为化合物72),名为:1-((3R,3aS,7R,8aS)-3,8,8-三甲基-2,3,4,7,8,8a-六氢-1H-3a,7-雪松烷-6-基)丁-3-炔-1-醇,其结构式如下:d/r=10:9。
本实施例提供该柏木醇衍生物的制备方法:该制备方法参照实施例7。区别在于使用丙炔基格氏试剂。
化合物72的表征数据如下:Colorless oil,60%,1H NMR(500MHz,CDCl3)δ5.69-5.68(m,1H),5.57-5.55(m,1H),4.14-4.09(m,2H),2.56-2.51(m,3H),2.32-2.22(m,4H),2.05(brs,1H),1.94-1.75(m,8H),1.72-1.68(m,3H),1.62-1.57(m,3H),1.43-1.36(m,6H),1.05(s,3H),1.03(s,2.9H),0.99(s,2.9H),0.97(s,3H),0.87(d,3H,J=7.3Hz),0.85(d,2.9H,J=7.3Hz);13C NMR(125MHz,CDCl3)δ145.47,144.15,121.71,118.92,81.55,81.23,72.64,72.46,70.63,70.50,59.37,59.04,54.20,53.93,51.45,50.18,48.64,48.62,41.47,41.34,40.88,40.42,38.73,38.39,36.16,36.09,28.16,27.53,27.04,25.63,25.61,25.54,24.84,15.44,15.42.HR-EI-MS(positive)m/z 259.20566[M+H]+(calcd forC18H27O 259.19837).
实施例72
本实施例提供一种柏木醇衍生物(编号为化合物73),名为:(3R,3aR,7R,8aS)-N-十二烷基-3,8,8-三甲基-4-氧-2,3,4,7,8,8a-六氢-1H-3a,7-雪松烷-6-羧酰胺,其结构式如下:
本实施例提供该柏木醇衍生物的制备方法:该制备方法参照实施例70。区别在于使用C12H25NH2。
化合物73的表征数据如下:Colorless oil,83%,1H NMR(500MHz,CDCl3)δ6.56-6.52(m,1H),6.11(s,1H),3.37-3.29(m,2H),3.17-3.16(m,1H),1.96-1.78(m,6H),1.69-1.52(m,5H),1.31-1.24(m,20H),0.95(s,3H),0.85(t,3H,J=7.3Hz);13C NMR(125MHz,CDCl3)δ204.30,167.12,157.98,126.93,66.91,58.58,53.22,44.75,43.86,42.93,40.04,39.47,31.92,29.65,29.63,29.58,29.54,29.43,29.35,29.28,27.98,26.94,26.76,26.64,22.70,15.05,14.14.HR-EI-MS(positive)m/z 416.35202[M+H]+(calcdforC27H46O2N 416.34503).
实施例73
本实施例提供一种柏木醇衍生物(编号为化合物74),名为:(3R,3aR,7R,8aS)-3,8,8-三甲基-N-((3-甲基氧杂环丁烷-3-基)甲基)-4-氧-2,3,4,7,8,8a-六氢-1H-3a,7-雪松烷-6-羧酰胺,其结构式如下:
本实施例提供该柏木醇衍生物的制备方法:该制备方法参照实施例70。区别在于使用(3-甲基氧杂环丁-3-基)甲胺。
化合物74的表征数据如下:White salt,85%,m.p.142-144 ℃.1H NMR(500MHz,CDCl3)δ7.16-7.09(brs,1H),6.18(s,1H),4.50(d,2H,J=6.2Hz),4.38(d,2H,J=6.2Hz),3.54(d,2H,J=5.7Hz),3.18(d,1H,J=4.5Hz),2.03-1.77(m,6H),1.71-1.51(m,3H),1.31(s,3H),1.25(d,3H,J=7.2Hz),1.16(s,3H),0.98(s,3H);13C NMR(125MHz,CDCl3)δ204.45,167.89,157.75,127.24,80.28,80.22,66.98,58.55,53.28,46.14,44.77,43.83,42.96,40.39,39.47,27.96,26.77,26.60,22.02,15.08.HR-EI-MS(positive)m/z 332.22174[M+H]+(calcd for C20H30O3N 332.21474).
实施例74
本实施例提供该柏木醇衍生物的制备方法:该合成方法与实施例3的制备方法相同,区别在于使用化合物70和庚酰氯。
化合物75的表征数据如下:Colorless oil,92%,1H NMR(500MHz,CDCl3)δ5.26-5.25(m,1H),4.00(d,1H,J=10.1Hz),3.90(d,1H,J=10.1Hz),2.30(t,2H,J=7.6Hz),2.20-2.16(m,1H),1.98-1.96(m,1H),1.87-1.57(m,12H),1.46-1.38(m,3H),1.33-1.25(m,7H),1.00(s,3H),0.89(t,3H,J=7.3Hz),0.84(d,3H,J=7.1Hz);13C NMR(125MHz,CDCl3)δ174.15,138.99,120.55,72.02,55.65,53.25,52.20,51.52,41.11,40.16,38.64,36.13,34.57,31.49,28.89,25.24,25.02,24.08,22.53,20.48,15.38,14.05.HR-EI-MS(positive)m/z 333.27878[M+H]+(calcd for C22H37O2 333.27153).
实施例75
本实施例提供一种柏木醇衍生物(编号为化合物76),名为:(3R,3aS,7S,8aR)-8-((heptyloxy)methyl)-3,6,8-三甲基基-2,3,4,7,8,8a-六氢-1H-3a,7-雪松烷e,其结构式如下:
本实施例提供该柏木醇衍生物的制备方法:该合成方法与实施例3的制备方法相同,区别在于使用化合物70和庚碘烷。。
化合物76的表征数据如下:Colorless oil,86%,1H NMR(500MHz,CDCl3)δ5.22-5.21(m,1H),3.37-3.31(m,2H),3.28(d,1H,J=7.8Hz),3.10(d,1H,J=7.8Hz),2.19-2.15(m,1H),1.97-1.96(m,1H),1.86-1.84(m,1H),1.79-1.74(m,2H),1.67-1.63(m,4H),1.59-1.51(m,5H),1.44-1.23(m,14H),1.03(s,3H),0.87(t,3H,J=7.3Hz),0.84(d,3H,J=7.5Hz);13C NMR(125MHz,CDCl3)δ140.21,119.52,78.77,71.20,55.74,52.96,52.68,51.96,41.12,40.30,38.71,36.10,31.89,29.73,29.20,26.25,25.19,23.89,22.66,20.76,15.42,14.13.HR-EI-MS(positive)m/z 319.29947[M+H]+(calcd forC22H39O319.29227).
实施例76
本实施例提供一种柏木醇衍生物(编号为化合物77),名为:2-(1-甲苯磺酰-1H-1,2,3-三唑-4-基)-1-((3R,3aS,7R,8aS)-3,8,8-三甲基基-2,3,4,7,8,8a-六氢-1H-3a,7-雪松烷-6-基)乙烷-1-醇,其结构式如下:d/r=5:1。
本实施例提供该柏木醇衍生物的制备方法:在反应容器中加入0.1mmol化合物72、0.12mmolTsN3、0.05mmol CuTC溶于2mL无水Tol中,室温反应4h,反应结束后,减压蒸馏浓缩除去溶剂,粗产品经柱色谱分离,即得目标产物,产率80%。
化合物77的表征数据如下:Colorless oil,80%,1H NMR(500MHz,CDCl3)δ7.99-7.96(m,3H),7.37-7.36(m,2H),5.56(s,0.3H),5.49-5.47(m,1H),4.26-4.23(m,1H),3.05-3.04(m,0.3H),3.02-2.99(m,2H),2.77-2.72(m,0.6H),2.44(s,3H),2.20-2.12(m,2H),1.90-1.83(m,3H),1.76-1.71(m,2H),1.65-1.57(m,3H),1.40-1.34(m,3H),1.30-1.20(m,2H),1.00-0.93(m,8H),084-0.82(m,4H);13C NMR(125MHz,CDCl3)δ147.17,147.15,146.05,145.51,144.94,144.85,133.24,130.41,130.16,128.64,128.60,122.03,121.79,118.83,73.52,73.04,59.35,58.97,54.15,53.91,51.27,50.07,48.62,48.60,41.37,41.28,40.90,40.28,38.76,38.34,36.07,36.02,32.23,31.56,28.28,27.50,25.58,25.52,24.81,24.78,21.85,15.44,15.43,15.39.
实施例77
本实施例提供该柏木醇衍生物的制备方法:在反应容器中加入0.1mmol化合物63、0.3mmolSOCl2溶于2mL无水DCM中,室温反应4h后抽干溶剂,再加入0.12mmol Et3N和2mL无水DCM,室温反应4h,反应结束后,减压蒸馏浓缩除去溶剂,粗产品经柱色谱分离,即得目标产物86%。
化合物78的表征数据如下:Colorless oil,86%,1H NMR(500MHz,CDCl3)δ7.00-6.99(m,1H),2.69(d,1H,J=3.8Hz),2.45-2.41(m,1H),2.13-2.08(m,1H),1.91-1.79(m,3H),1.71-1.60(m,2H),1.45-1.35(m,3H),1.02(s,3H),1.00(s,3H),0.87(d,3H,J=7.4Hz);13C NMR(125MHz,CDCl3)δ163.45,143.01,136.57,59.67,53.75,48.85,41.17,39.92,39.90,36.22,27.27,25.24,24.99,15.60.HR-EI-MS(positive)m/z 473.30228[M+Na]+(calcd for C30H42O3Na 473.30316).
实施例78
本实施例提供该柏木醇衍生物的制备方法:在反应容器中加入0.1mmol化合物1、0.11mmolPIDA、0.04mmol I2溶于2mL环已烷溶液中,放入72w的蓝光反应器中室温反应0.5h,关闭反应蓝光反应器,反应结束后,反应溶液慢慢加入NaHCO3和Na2S2O3溶液淬灭反应,然后用有机溶剂萃取,干燥,减压蒸馏浓缩除去溶剂,粗产品经柱色谱分离,即得目标产物,化合物79产率83%。
化合物79的表征数据如下:Colorless oil,83%,1H NMR(500MHz,CDCl3)δ3.56(d,1H,J=7.9Hz),3.45(d,1H,J=7.9Hz),1.88-1.77(m,2H),1.76-1.70(m,3H),1.69-1.62(m,2H),1.56-1.44(m,2H),1.42-1.35(m,2H),1.34-1.27(m,2H),1.16(s,3H),0.98(s,3H),0.82(d,3H,J=7.1Hz);13C NMR(125MHz,CDCl3)δ84.68,78.04,59.95,59.37,53.89,53.03,41.93,35.48,34.88,31.65,30.27,28.13,25.16,18.82,15.76.The spectroscopic datawere found to be consistent with reported literature 5.
实施例79
本实施例提供一种柏木醇衍生物(编号为化合物80),名为:4-((((3R,3aR,6S,7S,8aS)-3,6,8,8-四甲基八氢-1H-3a,7-雪松烷-5-基)氧)甲基)-1-甲苯磺酰-1H-1,2,3-三唑,其结构式如下:
本实施例提供该柏木醇衍生物的制备方法:该合成方法与实施例3的制备方法相同,区别在于使用化合物3。
化合物80的表征数据如下:Colorless oil,87%,1H NMR(500MHz,CDCl3)δ8.09(s,1H),7.98(d,2H,J=8.5Hz),7.36(d,2H,J=8.5Hz),4.81(d,1H,J=11.1Hz),4.60(d,1H,J=11.1Hz),3.57-3.51(m,1H),2.44(s,3H),2.05-2.02(m,1H),1.84-1.81(m,1H),1.72-1.67(m,4H),1.62-1.59(m,2H),1.51-1.47(m,1H),1.38-1.34(m,1H),1.28-1.16(m,5H),1.06(s,3H),1.05(d,3H,J=7.2Hz),0.92(s,3H),0.82(d,3H,J=7.2Hz);13C NMR(125MHz,CDCl3)δ147.27,146.30,133.11,130.42,128.70,122.06,81.07,62.16,58.26,55.07,54.53,46.67,43.95,43.92,41.91,39.78,36.73,28.81,27.93,25.76,21.85,18.17,15.56.HR-EI-MS(positive)m/z 458.24704[M+H]+(calcd for C25H36O3N3S 458.23991).
实施例80
本实施例提供该柏木醇衍生物的制备方法:该合成方法与实施例2的制备方法相同,区别在于使用化合物68。
化合物81的表征数据如下:White salt,78%,m.p.96-97℃.1H NMR(500MHz,CDCl3)δ4.15(d,1H,J=10.6Hz),3.97(d,1H,J=10.7Hz),3.73(td,1H,J=10.0,6.5Hz),2.04(s,3H),2.01-1.94(m,1H),1.88-1.80(m,2H),1.79-1.70(m,3H),1.68-1.58(m,2H),1.51(m,1H),1.41(m,1H),1.34-1.28(m,1H),1.29-1.21(m,2H),1.08(d,3H,J=7.2Hz),1.02(s,3H),0.86(d,3H,J=7.1Hz);13C NMR(125MHz,CDCl3)δ171.41,72.83,71.20,54.63,54.50,53.49,47.60,46.40,45.57,43.53,41.56,36.67,26.30,23.34,21.01,17.76,15.48.The spectroscopic data were found to be consistent with reportedliterature 3.
实施例81
本实施例提供该柏木醇衍生物的制备方法:该合成方法与实施例2的制备方法相同,区别在于使用化合物69。
化合物82的表征数据如下:White salt,20%,m.p.169-170℃.1H NMR(500MHz,CD3OD)δ3.71-3.66(m,1H),3.63(d,1H,J=11.1Hz),3.54(d,1H,J=11.1Hz),1.96-1.92(m,1H),1.89-1.72(m,5H),1.60-1.53(m,2H),1.47-1.43(m,1H),1.36-1.31(m,1H),1.26-1.21(m,2H),1.11(d,3H,J=7.3Hz),1.05(s,3H),0.89(d,3H,J=7.3Hz);13C NMR(125MHz,CD3OD)δ72.00,68.69,54.49,54.19,53.37,49.86,46.31,45.59,43.33,41.60,36.35,26.28,22.20,17.04,14.53.HR-EI-MS(positive)m/z 239.20036[M+H]+(calcd forC15H27O2 239.19328).
实施例82
本实施例提供一种柏木醇衍生物(编号为化合物83),名为:(3R,3aS,7S,8R,8aR)-8-(甲氧基甲基)-3,6,8-三甲基基-2,3,4,7,8,8a-六氢-1H-3a,7-雪松烷,其结构式如下:
本实施例提供该柏木醇衍生物的制备方法:在反应容器中加入0.1mmol化合物1、0.11mmol PIDA、0.04mmolI2溶于2mL环已烷溶液中,放入72w的蓝光反应器中室温反应0.5h,反应结束后,反应溶液慢慢加入NaHCO3和Na2S2O3溶液淬灭反应,然后用有机溶剂萃取,干燥,减压蒸馏浓缩除去溶剂。
粗产品溶于2mLDCM中,再加入0.2mmol三甲基氧鎓四氟硼酸盐和0.2mmol质子海绵加热回流反应12h,滤液减压蒸馏浓缩除去溶剂,粗产品经柱色谱分离,即得目标产物,化合物83产率78%。
化合物83的表征数据如下:Colorless oil,78%,1H NMR(500MHz,CDCl3)δ5.23(m,1H),3.29(s,3H),3.26(d,1H,J=8.4Hz),3.10(d,1H,J=8.4Hz),2.17(m,1H),1.96(d,1H,J=3.8Hz),1.90-1.82(m,1H),1.81-1.72(m,2H),1.66(q,3H,J=1.9Hz),1.64(m,1H),1.60-1.53(m,2H),1.46-1.33(m,3H),1.03(s,3H),0.84(d,3H,J=7.1Hz);13C NMR(125MHz,CDCl3)δ140.01,119.73,81.05,58.82,55.57,53.01,52.53,51.93,41.05,40.27,38.69,36.06,25.12,23.82,20.68,15.41.
实施例83
本实施例提供一种柏木醇衍生物(编号为化合物84),名为:4-((((3R,3aR,6S,7S,8aS)-3,6,8,8-四甲基八氢-1H-3a,7-雪松烷-5-yl)oxy)methyl)-1H-1,2,3-triazole,其结构式如下:
本实施例提供该柏木醇衍生物的制备方法:在反应容器中加入0.1mmol化合物80、0.11mmol苯胺溶于2mL乙醇溶液中,室温反应0.5h,反应结束后,反应溶液用有机溶剂萃取,干燥,减压蒸馏浓缩除去溶剂,粗产品经柱色谱分离,即得目标产物,化合物84产率67%。
化合物84的表征数据如下:Colorless oil,67%,1H NMR(500MHz,CDCl3)δ7.74(s,1H),4.85(d,1H,J=12.9Hz),4.67(d,1H,J=12.9Hz),3.62-3.56(m,1H),2.10-2.06(m,1H),1.85-1.82(m,1H),1.76-1.70(m,3H),1.64-1.59(m,2H),1.52-1.48(m,1H),1.39-1.34(m,1H),1.30-1.18(m,4H),1.09(s,3H),1.08(d,3H,J=7.3Hz),0.92(s,3H),0.85(d,3H,J=7.3Hz);13C NMR(125MHz,CDCl3)δ144.72,131.32,80.83,61.78,58.30,55.10,54.54,46.66,43.92,41.91,39.78,36.72,28.80,27.94,25.75,18.15,15.57.HR-EI-MS(positive)m/z 304.23828[M+H]+(calcd for C18H30ON3 304.23106).
实施例84
本实施例提供该柏木醇衍生物的制备方法:在反应容器中加入0.1mmol化合物63、0.11mmolSOCl2溶于2mL甲醇溶液中,室温反应0.5h,反应结束后,反应溶液用有机溶剂萃取,干燥,减压蒸馏浓缩除去溶剂,粗产品经柱色谱分离,即得目标产物,化合物84产率76%。
化合物85的表征数据如下:Colorless oil,76%,1H NMR(500MHz,CDCl3)δ6.96-6.85(m,1H),3.73(s,3H),2.64(d,1H,J=3.8Hz),2.39-2.35(m,1H),2.05-2.01(m,1H),1.89-1.75(m,3H),1.69-1.59(m,3H),1.44-1.32(m,3H),1.25(s,1H),1.00(s,3H),0.93(s,3H),0.87(d,3H,J=7.4Hz);13C NMR(125MHz,CDCl3)δ166.70,137.32,135.49,58.42,52.68,50.52,47.77,47.69,40.10,38.92,38.35,35.06,26.03,24.13,23.81,14.44.HR-EI-MS(positive)m/z 249.18497[M+H]+(calcd for C16H25O2 249.17763).
实施例85
本实施例提供该柏木醇衍生物的制备方法:该合成方法与实施例2的制备方法相同,区别在于使用化合物69。
化合物86的表征数据如下:White salt,47%,m.p.84-86℃.1H NMR(500MHz,CDCl3)δ3.96-3.94(m,1H),3.56(d,1H,J=8.8Hz),3.43(d,1H,J=8.8Hz),3.32(s,3H),2.51-2.48(m,1H),1.99-1.97(m,1H),1.87-1.76(m,5H),1.71-1.66(m,3H),1.57-1.51(m,2H),1.43-1.39(m,5H),1.33-1.25(m,6H),1.09(d,3H,J=7.3Hz),0.99(s,3H),0.83(d,3H,J=7.3Hz);13C NMR(125MHz,CDCl3)δ79.71,69.45,58.49,53.02,52.79,48.62,48.04,47.30,43.52,43.03,41.70,35.62,29.71,29.68,25.50,23.85,16.50,15.62.
实施例86
本实施例提供该柏木醇衍生物的制备方法:该合成方法与实施例2的制备方法相同,区别在于使用化合物69。
化合物87的表征数据如下:Colorless oil,56%,1H NMR(500MHz,CDCl3)δ3.80-3.74(m,1H),3.35(d,1H,J=8.8Hz),3.29(s,3H),3.25(d,1H,J=8.8Hz),2.00-1.96(m,1H),1.85-1.66(m,6H),1.60-1.48(m,3H),1.43-1.40(m,1H),1.31-1.19(m,3H),1.09(d,3H,J=7.3Hz),1.02(s,3H),0.85(d,3H,J=7.3Hz);13C NMR(125MHz,CDCl3)δ79.95,72.98,58.82,54.53,54.37,53.19,48.74,46.56,45.99,43.79,41.51,36.57,26.20,23.62,17.38,15.56.
实施例87
本实施例提供该柏木醇衍生物的制备方法:该方法参照实施例4,区别在于使用化合物81。
化合物88的表征数据如下:Colorless oil,83%,1H NMR(500MHz,CDCl3)δ3.85(s,2H),2.58-2.53(m,1H),2.33(s,2H),2.18-2.04(m,1H),2.02(s,3H),1.92-1.87(m,2H),1.82-1.69(m,2H),1.59-1.54(m,1H),1.47-1.28(m,2H),1.24(s,1H),1.11(d,3H,J=7.3Hz),1.00(s,3H),0.87(d,3H,J=7.3Hz);13C NMR(125MHz,CDCl3)δ212.20,170.98,70.84,55.91,55.64,54.69,51.56,51.37,47.81,45.90,41.48,37.00,26.21,22.82,20.91,15.48,14.12.
实施例88
本实施例提供一种柏木醇衍生物(编号为化合物89),名为:(3R,3aR,6S,7S,8aS,Z)-4-(乙氧基亚氨基)-3,6,8,8-四甲基六氢-1H-3a,7-雪松烷-5(4H)-酮,其结构式如下:
本实施例提供该柏木醇衍生物的制备方法:在反应容器中加入0.1mmol化合物5、0.11mmoltBuONO、0.15mmol tBuOK溶于2mL乙醇溶液中,室温反应5h,反应结束后,反应溶液用有机溶剂萃取,干燥,减压蒸馏浓缩除去溶剂,粗产品经柱色谱分离,即得目标产物,化合物89产率23%。
化合物89的表征数据如下:Colorless oil,23%,1H NMR(500MHz,CDCl3)δ4.14-4.06(m,2H),2.71-2.67(m,1H),2.36-2.23(m,3H),2.13(s,3H),2.06-2.05(m,1H),1.74-1.53(m,6H),1.35-1.29(m,1H),1.26(t,3H,J=7.3Hz),1.21-1.15(m,1H),1.10(s,3H),0.94(d,3H,J=7.3Hz),0.85(s,3H);13C NMR(125MHz,CDCl3)δ210.25,172.98,60.82,60.19,59.03,50.58,46.41,43.83,41.57,37.98,33.32,31.58,28.59,25.12,24.85,14.19,13.94.HR-EI-MS(positive)m/z 278.21134[M+H]+(calcd forC17H28O2N278.20418).
实施例89
本实施例提供该柏木醇衍生物的制备方法:在反应容器中加入0.1mmol化合物5溶于2mL无水CH3OH中,加入0.12mmol叔丁醇钾和0.12mmol亚硝酸叔丁酯,室温反应5h,反应结束后,反应溶液慢慢加入水淬灭反应,然后用有机溶剂萃取,干燥,减压蒸馏浓缩除去溶剂,粗产品经柱色谱分离,即得目标产物,化合物90产率53%。
化合物90的表征数据如下:Colorless oil,53%,1H NMR(500MHz,CDCl3)δ4.13-4.05(m,2H),2.48-2.45(m,1H),2.35-2.32(m,1H),2.26-2.18(m,3H),2.07-2.03(m,1H),1.87(s,3H),1.73-1.68(m,1H),1.62-1.56(m,3H),1.38-1.30(m,1H),1.26(t,3H,J=7.3Hz),1.19-1.13(m,1H),0.97(s,3H),0.91(d,3H,J=7.3Hz),0.81(s,3H);13C NMR(125MHz,CDCl3)δ173.34,158.28,60.32,60.03,51.87,50.79,46.25,43.86,41.68,37.51,33.43,28.74,25.38,24.65,14.47,14.30,13.98.HR-EI-MS(positive)m/z296.22186[M+H]+(calcd for C17H30O3N 296.21474).
实施例90
本实施例提供一种柏木醇衍生物(编号为化合物91),名为:((1R,3aS,4S,5S,6S,7R,8aR)-1,4,6-三甲基六氢-1H,4H-3a,7-环氧-5,8a-雪松烷-4-基)醋酸甲酯,其结构式如下:
本实施例提供该柏木醇衍生物的制备方法:在反应容器中加入0.1mmol化合物81、0.3mmol PIDA、0.1mmolI2溶于2mL二氯甲烷溶液中,放入72w的蓝光反应器中5℃室温反应1h,反应结束后,反应溶液慢慢加入NaHCO3和Na2S2O3溶液淬灭反应,然后用有机溶剂萃取,干燥,减压蒸馏浓缩除去溶剂,粗产品经柱色谱分离,即得目标产物,化合物91产率81%。
化合物91的表征数据如下:Colorless oil,81%,1H NMR(500MHz,CDCl3)δ4.53(d,1H,J=11.3Hz),4.37(d,1H,J=11.3Hz),4.13(d,1H,J=4.7Hz),2.12-2.11(m,1H),2.04(s,3H),1.94-1.90(m,1H),1.87-1.81(m,2H),1.77-1.60(m,6H),1.53(d,1H,J=11.3Hz),1.43-1.40(m,1H),1.13(d,3H,J=7.3Hz),0.96(s,3H),0.92(d,3H,J=7.3Hz);13C NMR(125MHz,CDCl3)δ171.36,101.60,82.78,70.01,62.77,54.50,48.11,43.39,42.62,41.83,40.46,36.09,28.54,22.62,21.06,19.66,14.79.
实施例91
本实施例提供一种柏木醇衍生物(编号为化合物92),名为:(1S,3R,4S,4aS,5aR,6R,8aR,8bR)-4,6,8b-三甲基十氢-3,5a-甲烷甲烷[1,2-c]吡喃-1-基醋酸酯,其结构式如下:
本实施例提供该柏木醇衍生物的制备方法:该制备方法与实施例91相同,柱分离得到2个产物,一个为化合物91,一个为化合物92,化合物92的收率为4%。
化合物92的表征数据如下:Colorless oil,4%,1H NMR(500MHz,CDCl3)δ4.06(d,1H,J=4.7Hz),3.07(brs,1H),1.99(s,3H),1.93-1.83(m,4H),1.72(s,3H),1.71-1.61(m,4H),1.57(s,5H),1.52(d,1H,J=11.3Hz),1.34-1.25(m,1H),1.15(d,3H,J=7.4Hz),0.92(d,3H,J=7.4Hz);13C NMR(125MHz,CDCl3)δ169.59,100.64,89.07,82.83,61.50,53.43,43.05,42.03,41.40,41.24,35.89,25.67,22.20,18.68,18.55,14.64.HR-EI-MS(positive)m/z 301.17719[M+Na]+(calcd for C17H26O3Na 301.17796).
实施例92
本实施例提供一种柏木醇衍生物(编号为化合物93),名为:((3R,3aS,7R,8aS)-3,8,8-三甲基基-2,3,4,7,8,8a-六氢-1H-3a,7-雪松烷-6-yl)methyl acetate,其结构式如下:
本实施例提供该柏木醇衍生物的制备方法:该制备方法与实施例5相同,柱分离得到2个产物,一个为化合物93,一个为化合物94,化合物94的收率为61%。
化合物93的表征数据如下:Colorless oil,14%,1H NMR(500MHz,CDCl3)δ5.57-5.55(m,1H),4.50-4.41(m,2H),2.27-2.23(m,1H),2.07(s,3H),1.93-1.83(m,1H),1.79-1.69(m,4H),1.63-1.57(m,2H),1.43-1.35(m,3H),1.02(s,3H),0.96(s,3H),0.85(d,3H,J=7.4Hz);13C NMR(125MHz,CDCl3)δ171.11,139.00,123.78,68.32,59.05,54.01,50.61,48.50,41.38,40.44,38.66,36.08,27.65,25.47,24.80,21.10,15.41.HR-EI-MS(positive)m/z 285.18250[M+Na]+(calcd for C17H26O2Na 285.18305).
实施例93
本实施例提供该柏木醇衍生物的制备方法:该制备方法与实施例92相同。
化合物94的表征数据如下:Colorless oil,61%,1H NMR(500MHz,CDCl3)δ4.59(d,1H,J=11.4Hz),4.01(d,1H,J=11.4Hz),3.17(d,1H,J=5.4Hz),2.08(s,3H),2.06(d,1H,J=4.4Hz),1.97(d,1H,J=15.2Hz),1.83(m,2H),1.70-1.60(m,4H),1.43-1.40(m,1H),1.33-1.28(M,1H),1.20(s,3H),1.00(s,3H),0.81(d,3H,J=7.4Hz);13C NMR(125MHz,CDCl3)δ170.94,67.02,61.55,60.93,55.08,52.26,48.75,43.33,41.46,36.29,35.79,35.37,29.56,27.34,25.00,20.85,15.52.HR-EI-MS(positive)m/z279.19540[M+H]+(calcd for C17H27O3 279.18819).
实施例94
本实施例提供该柏木醇衍生物的制备方法:在反应容器中加入0.1mmol化合物6、0.2mmol乙二胺溶于2mL水溶液中,加热回流反应20h,反应结束后,有机溶剂萃取,干燥,减压蒸馏浓缩除去溶剂,粗产品经柱色谱分离,即得目标产物,化合物95产率38%。
化合物95的表征数据如下:Colorless oil,38%,1H NMR(500MHz,CDCl3)δ4.99(t,1H,J=2.4Hz),4.75(t,1H,J=2.4Hz),4.36-4.32(m,1H),2.35(d,1H,J=4.2Hz),2.16-2.12(m,1H),1.89-1.82(m,1H),1.81-1.74(m,2H),1.61-1.54(m,3H),1.47-1.41(m,1H),1.36-1.31(m,1H),1.29-1.17(m,4H),0.97(s,3H),0.94(s,3H),0.86(d,3H,J=7.2Hz);13CNMR(125MHz,CDCl3)δ154.19,106.50,70.22,60.35,57.01,54.90,45.01,44.99,42.31,41.62,36.73,29.72,26.72,26.15,25.87,15.53.HR-EI-MS(positive)m/z221.19002[M+H]+(calcd for C15H25O 221.18272).
实施例95
本实施例提供该柏木醇衍生物的制备方法:该制备方法参见实施例5。
化合物96的表征数据如下:Colorless oil,25%,1H NMR(500MHz,CDCl3)δ3.81(s,2H),3.29(d,1H,J=4.8Hz),2.03-1.96(m,3H),1.83-1.77(m,2H),1.68-1.57(m,4H),1.43-1.39(m,1H),1.35-1.28(m,2H),1.15(s,3H),0.99(s,3H),0.80(d,3H,J=7.3Hz);13C NMR(125MHz,CDCl3)δ64.38,64.14,60.89,55.60,52.59,49.77,49.75,43.13,41.50,36.60,35.85,35.49,29.72,27.25,25.02,15.55.HR-EI-MS(positive)m/z 237.18483[M+H]+(calcd for C15H25O2 237.17763).
实验例
病毒株:流感病毒株H1N1 PR8由本实验室扩增保存。
细胞模型:狗肾细胞系MDCK,本实验室传代保存。培养条件:DMEM+10%胎牛血清、37℃、5%CO2。
采用CellTiter-GloTM(Promega)试剂盒检测样品对细胞的毒性作用。
细胞毒性实验原理:CellTiter-Glo试剂盒通过对ATP进行定量测定来检测培养物中活细胞数目。有代谢活性细胞的呼吸作用和其他生命活动过程可以产生ATP,试剂盒中使用萤光素酶生成的稳定辉光型信号,发光过程中萤光素酶需要ATP的参与。向细胞培养基中加入CellTiter-Glo试剂测量发光值,光信号和体系中ATP量成正比,而ATP量和活细胞数呈正相关,因此光信号值可以反映活细胞的数目。
细胞毒性试验步骤:将MDCK细胞接种于96孔细胞培养板中,细胞贴壁后备用。化合物1-96分别用DMEM培养基从2倍最高检测浓度起连续3倍梯度稀释8个梯度。将化合物及适量培养基加入到细胞中,于37℃的CO2培养箱中培养。加药培养24h后,显微镜下观察药物引起的细胞病变效应(CPE),加入CellTiter-Glo检测细胞存活率。药物对细胞的毒性以细胞的活性表示。
计算公式:细胞活性(%)=药物组数值/细胞对照组平均值*100
抗病毒活性实验原理:实验采用测定流感病毒蛋白表达水平来检测病毒的复制水平。流感病毒的结构蛋白的表达水平与病毒的复制成正比;实验采用高灵敏度的试剂检测流感病毒蛋白的表达,通过荧光强度的变化反应出来。
抗病毒活性检测步骤:MDCK细胞接种于96孔细胞培养板中,37℃培养过夜后备用。MDCK细胞中同时加入对应的化合物及H1N1病毒液。置于37℃细胞培养箱培养24h后,取培养液上清进行检测。
实验设空白对照孔(正常细胞),病毒对照孔(病毒感染后未加药物),阳性药物对照孔(感染后加利巴韦林)。
抑制率(%)=100-(样品孔数值-空白对照数值)/(病毒对照数值-空白对照数值)*100
检测结果如下表。
根据上述表格可以看出,本发明实施例提供的系列柏木醇衍生物具有良好的抗病毒效果,可以用于制备具有抗病毒的药物。
以上所述仅为本发明的优选实施例而已,并不用于限制本发明,对于本领域的技术人员来说,本发明可以有各种更改和变化。凡在本发明的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (10)
1.一种柏木醇衍生物,其特征在于,其为以下结构式所示化合物中的任意一种、其互变异构体、水合物、溶剂化物或其药学上可接受的盐,
其中,R1、R2、R4、R11、R13、R18、R19、R22、R23和R26分别独立选自H或OH;
R3选自H、OH、醚键、取代或未取代酯基、氰基、取代或未取代烯烃基、取代或未取代炔烃基、取代或未取代烷基、氨基、胺基、砜基、糖基、取代或未取代芳香基、取代或未取代磺酰基、取代或未取代磺酸基和含杂原子的多元杂环中的任意一种;R5选自H、OH、醚键和酯基中的任意一种;R6选自H、OH、取代或未取代芳香基、取代或未取代烷基和氰基中的任意一种;R7选自H或铵基;
R8选择H、OH和卤素中的任意一种,R9选自O或N-R1′,R1′选自OH、取代或未取代磺酸基、酯基、酰胺基中的任意一种;R10选自H、OH、醚键、取代或未取代酯基、取代或未取代磺酸基和取代或未取代亚胺基中的一种;
R12选自H、OH、醚基、取代或未取代酯基和取代或未取代磺酸基中的任意一种;
R14选自取代或未取代烷基、羧酸基、酰胺基、酮基、醛基和含有杂原子的多元杂环中的任意一种;
当R15为=O时,R15′不存在,当R15不为=O时,R15′存在,此时,R15选自H、OH、取代或未取代芳香烃和取代或未取代亚胺基中的任意一种,R15′选自H、OH和取代或未取代芳香基中的任意一种;R16选自H、OH或醚基中的任意一种;
R17选自H或醚键;R19′为OH或=O;R20和R21分别独立为未取代烷基;R24和R25分别独立为酰基。
2.根据权利要求1所述的柏木醇衍生物,其特征在于,R3选自H、-OH、-OCOR2′、-OSO2R3′、-O-R4′、未取代烷基、单卤素取代烷基、双卤素取代烷基、三卤素取代烷基、炔基取代烷基、烯烃基取代烷基、取代或未取代苯基、取代糖基、-OR6′、-OCONHR7′、-NH2、-NH-R5′、-OTs、-OTf和-OTMS中的任意一种;
其中,R2′选自H、CnH2n+1、取代烷基、取代或未取代芳香基、取代酰基、取代或未取代六元氮杂环、取代或未取代五元环和金刚烷基中的任意一种,R3′为氨基或碱金属离子、R4′为取代或未取代烷基、-C=S-R、取代五元杂环、取代6元杂环和取代亚胺基中的任意一种,R为五元杂原子环,R5′选自CnH2n+1、COCnH2n+1、取代磺酰基和取代磺酸基中的任意一种;R7′为CnH2n+1、(CnH2n+1)2、取代磺酰基和取代磺酸基,n为整数;
优选地,R3选自H、OH、-OCnH2n+1、-CXH2、-CX2H、-CX3、-OTs、-OTf、-OCOH、-OCF2H、-OCCOF3、-OCOCnH2n+1、-OCONHTs、-OCONHCnH2n+1、-OCON(CnH2n+1)2、-OSO2NH2、-OSO2Na、-NH2、NHTs、NHTf、-NHCnH2n+1、-N(CnH2n+1)2、NHCOCnH2n+1、CnH2n+1、-CH2CH=CH2、-CN、-OTMS、-CH2C≡CH、-OCH2C≡CH、 以及中的任意一种,其中,n为1-18之间的任意整数,A为C或N,B选自C、N、O和S中的任意一种,Ra选自H、X和CnH2n+1中的任意一种,Rb选自H、X和CnH2n+1中的任意一种,Rc选自H、X和CnH2n+1中的任意一种,X为卤素原子;
4.根据权利要求1所述的柏木醇衍生物,其特征在于,R12选自H、OH、OCnH2n+1、OCOCnH2n+1、-OTs和-OTf中的任意一种,其中,n为1-18之间的任意整数。
5.根据权利要求1所述的柏木醇衍生物,其特征在于,R14选自-CnH2n+1、-CH2OH、-COH、-COOH、-CH2OCOCnH2n+1、-CH2OCnH2n+1、-COCnH2n+1、-CHOHCnH2n+1、-CONHCnH2n+1、-COOCnH2n+1、-CON(CnH2n+1)2以及CHOHCH2C≡CH中的任意一种,其中,n为1-18之间的任意整数;
优选地,当R15不为=O时,R15选自H、OH、=NOH、=NOCOCnH2n+1以及-Ph中的任意一种,R15′选自H、OH和-CH2-Ph中的任意一种。
6.根据权利要求1所述的柏木醇衍生物,其特征在于,R16选自H、OH或-OCnH2n+1中的任意一种,R17选自H或-OCnH2n+1,R20和R21分别独立为CnH2n+1;其中,n为1-18之间的任意整数。
7.一种权利要求1所述的柏木醇衍生物的制备方法,其特征在于,包括利用柏木醇为原料进行化学反应合成得到柏木醇衍生物。
9.一种权利要求1所述的柏木醇衍生物在制备抗病毒药物中的应用。
10.根据权利要求9所述的应用,其特征在于,所述病毒为流感病毒;
优选地,所述药物中所述柏木醇衍生物的质量含量为0.1-99%,优选为0.5-90%。
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Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101182299A (zh) * | 2006-07-31 | 2008-05-21 | 赛德玛公司 | 新的酪胺衍生物,其制备方法及其化妆品或皮肤药物组合物 |
TW201121558A (en) * | 2009-10-09 | 2011-07-01 | School Juridical Person Kitasato Inst | Anti-influenza virus agent |
EP2368547A1 (en) * | 2010-03-26 | 2011-09-28 | Cesa Alliance S.A. | Antiviral compositions comprising geraniol and carvone |
CN111050855A (zh) * | 2017-08-25 | 2020-04-21 | 西姆莱斯有限公司 | 包含对映纯Ambrocenide*的混合物 |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10106475B1 (en) * | 2013-06-27 | 2018-10-23 | The United States Of America As Represented By The Secretary Of The Navy | High density turbine and diesel fuels from tricyclic sesquiterpenes |
-
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Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101182299A (zh) * | 2006-07-31 | 2008-05-21 | 赛德玛公司 | 新的酪胺衍生物,其制备方法及其化妆品或皮肤药物组合物 |
TW201121558A (en) * | 2009-10-09 | 2011-07-01 | School Juridical Person Kitasato Inst | Anti-influenza virus agent |
EP2368547A1 (en) * | 2010-03-26 | 2011-09-28 | Cesa Alliance S.A. | Antiviral compositions comprising geraniol and carvone |
CN111050855A (zh) * | 2017-08-25 | 2020-04-21 | 西姆莱斯有限公司 | 包含对映纯Ambrocenide*的混合物 |
Non-Patent Citations (5)
Title |
---|
BRAULIO M.FRAGA,ET AL: "iotransformation of cedrol and related compounds by Mucor plumbeus", 《PHYTOCHEMISTRY》 * |
COLUMBUS,OHIO: "US REGISTRY[Online]", 《REGISTRY》 * |
KEVIN HUNG,ET AL: "Development of a Terpene Feedstock-Based Oxidative Synthetic Approach to the Illicium Sesquiterpenes", 《J. AM. CHEM. SOC》 * |
KIYOHARA H ,ET AL.: "Patchouli alcohol: in vitro direct anti-influenza virus sesquiterpene in Pogostemon cablin Benth", 《J NAT MED》 * |
SHRINIVAS P,ET AL: "Hydroboration of terpenes. VI. Hydroboration of .alpha.- and .beta.- cedrenes. Configurational assignments for the related cedrane derivatives", 《J. ORG. CHEM.》 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN116874544A (zh) * | 2023-06-13 | 2023-10-13 | 中国科学院昆明植物研究所 | 化合物Artemeriosides A-F及其药物组合物和其制备方法 |
CN116874544B (zh) * | 2023-06-13 | 2024-04-19 | 中国科学院昆明植物研究所 | 化合物Artemeriosides A-F及其药物组合物和其制备方法 |
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