CN106946968A - 一种异黄芪甲苷的合成方法 - Google Patents
一种异黄芪甲苷的合成方法 Download PDFInfo
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- CN106946968A CN106946968A CN201710188497.8A CN201710188497A CN106946968A CN 106946968 A CN106946968 A CN 106946968A CN 201710188497 A CN201710188497 A CN 201710188497A CN 106946968 A CN106946968 A CN 106946968A
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- 238000000034 method Methods 0.000 claims abstract description 10
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
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Abstract
本发明公开了一种异黄芪甲苷的合成方法,包括以下步骤:将环黄芪醇的3位羟基以保护基R1保护,6位和16位羟基以保护基R2保护后得到化合物3,将化合物3进行糖苷化反应,后脱除3位保护基R1,继续进行发生糖苷化反应,得到化合物8,所有保护基脱除,得到异黄芪甲苷1,本发明是高效、高立体选择性的异黄芪甲苷合成方法,为异黄芪甲苷的研究及应用提供足够的原料,为异黄芪苷类化合物的合成提供参考,填补现有技术的空白,将大大推进黄芪皂苷类化合物的活性机理研究及其药物开发的进程。
Description
技术领域
本发明属于化学合成领域,更具体的涉及一种异黄芪甲苷的制备方法。
背景技术
黄芪为补药之首,属于豆科黄芪属植物。近年来随着现代分离和鉴定技术的发展,从黄芪中分离出了大量三萜皂苷、黄酮类化合物以及多糖类成分。后期的生物生化实验表明黄芪的药用功效主要通过黄芪皂苷表现出来。近期研究表明,黄芪皂苷在免疫调节,降糖,改善胰岛素抵抗活性,抗肿瘤,对心血管***调节以及抗病毒,抗氧化活性等方面都表现出了极为可喜的药用前景,并且在众多黄芪皂苷中,以黄芪甲苷和异黄芪甲苷的活性最好。
尽管黄芪皂苷广泛的应用前景促使人们对其研究不断深入,但目前用于活性测试的黄芪皂苷多为从黄芪中分离提取所得,由于黄芪中所含皂苷种类繁多,且结构类似,这给分离提纯带来很大困难。还有一些黄芪皂苷为次生皂苷,在黄芪中的含量很低,要得到足够量以供活性测试之用更是不易,这已成为制约黄芪皂苷活性研究深入的瓶颈,到目前为止几乎没有关于黄芪皂苷的化学合成研究报道。
异黄芪甲苷在黄芪中的含量特别少,其分子结构式如下:
其皂苷部分为环黄芪醇,由于环黄芪醇(化合物1)的3位,6位,16位及25位含有4个惰性OH,特别是25位羟基为叔羟基活性低,糖苷化反应困难,并且4个惰性OH相互之前的反应活性难以区分,选择性的糖苷化其中部分羟基更为困难。
环黄芪醇的羟基保护反应进行困难且产物复杂多变,有文献报道,在过量乙酰化试剂作用下,60℃,长达50天的反应时间下,仅能得到56%收率的全乙酰化的环黄芪醇。缩短反应时间或降低反应温度导致反应产物十分复杂,为4个羟基中随机的1或2个羟基被保护的环黄芪醇。由此可见异黄芪甲苷合成困难,国内外至今未见成功的报道。
参考文献:a)Mamedova,R.P.;Agzamova,M.A.;Isaev,M.I.Chem.Nat.Compd.2001,37,533-536.b)Isaev,I.M.;Iskenderov,D.A.;Isaev,M.I.Chem.Nat.Compd.2009,45,381-384.c)Isaev,I.M.;Iskenderov,D.A.;Isaev,M.I.Chem.Nat.Compd.2010,46,407-411.d)Procopiou,P.A.;Baugh,S.P.D.;Flack,S.S.;Inglis,G.G.J.Org.Chem.1998,63,2342-2347.
发明内容
本发明提供一种异黄芪甲苷的合成方法,能高效、高选择性的合成异黄芪甲苷,为异黄芪甲苷的研究及应用提供足够的原料,为异黄芪苷类化合物的合成提供参考。
本发明通过以下步骤来实现的:
一种异黄芪甲苷的合成方法,包括以下步骤:
(1)将环黄芪醇的3位羟基以保护基R1保护,得到化合物2;
(2)将化合物2的6位和16位羟基以保护基R2保护,得到化合物3;
(3)将化合物3与糖基给体化合物4发生糖苷化反应,得到化合物5;
(4)将化合物5的3位保护基R1脱除,得到化合物6;
(5)将化合物6与糖基给体化合物7发生糖苷化反应,得到化合物8;
(6)将化合物8的所有保护基脱除,得到异黄芪甲苷;
其中,所述R1选自取代或非取代的C1-C9烷硅基;所述R2选自取代或非取代的C2-C6烷酰基;所述R3或R4各自独立的选自C1-C6芳酰基;X选自取代或非取代的炔苯甲酰氧基。
所述X为
上述步骤(1)中,所述保护的方法包括以下步骤:室温下,将环黄芪醇溶于第一溶剂中,再加入卤代硅烷和咪唑,将反应温度缓慢升至室温后搅拌直到TLC跟踪显示环黄芪醇反应完全;所述第一溶剂为二氯甲烷、二氯乙烷、氯仿、四氯化碳、1,2-二氯乙烷、DMF、甲苯、苯、二氧六环、吡啶、冰醋酸、四氢呋喃、三乙胺、乙酸乙酯、丙酮、甲醇、乙醇、DMSO或***中的一种或多种,所述环黄芪醇、卤代硅烷和咪唑的摩尔比为1:1:1~1:5:10,优选为1:2:3~1:4:6,所述环黄芪醇在第一溶剂中的浓度为0.1~1mol/L,优选为0.45~0.5mol/L,所述卤代硅烷为TBSCl、TESCl、TBDMSCl、TBDPSCl、DIPSCl、DPSCl或TIPDSCl。
上述步骤(2)中,所述保护的方法包括以下步骤:0℃以下,将化合物2溶于第二溶剂中,再加入特戊酰氯,将反应温度缓慢升至室温后再加热到50℃,继续搅拌直到TLC跟踪显示化合物2反应完全,所述第二溶剂为二氯甲烷、氯仿、四氯化碳、1,2-二氯乙烷、DMF、甲苯、苯、二氧六环、吡啶、四氢呋喃、三乙胺、乙酸乙酯、丙酮、甲醇、乙醇、DMSO或***中的一种或多种;所述化合物2和特戊酰氯的摩尔比为1:2~1:20,优选为1:2~1:10;所述化合物2在第二溶剂中的浓度为0.1~1mol/L,优选为0.108~0.5mol/L。
上述步骤(3)中,所述糖苷化反应包括以下步骤:在惰性气体保护下,将化合物3和糖基给体化合物4溶于第三溶剂中,并加入干燥剂,在室温下搅拌0.5~2小时再加入催化剂,继续在室温下搅拌直到TLC跟踪显示化合物2反应完全;所述第三溶剂为二氯甲烷、氯仿、四氯化碳、1,2-二氯乙烷、DMF、甲苯、苯、二氧六环、吡啶、冰醋酸、四氢呋喃、三乙胺、乙酸乙酯、丙酮、甲醇、乙醇、DMSO或***中的一种或多种,所述催化剂为一价金的络合物,优选为PPh3AuNTf2或PPh3AuOTf;所述化合物3、糖基给体化合物4和所述催化剂的摩尔比为1:1:0.1~1:5:0.8,优选为1:1:0.1~1:2:0.5;所述化合物3在第三溶剂中的浓度为0.001~1mol/L,优选为0.006~0.05mol/L;所述干燥剂为分子筛,优选为分子筛或酸洗的分子筛,更优选为4A分子筛。
上述步骤(4)中,所述保护基R1脱除的方法包括以下步骤:室温下,将化合物5溶于第四溶剂中,再加入樟脑磺酸,搅拌直到TLC跟踪显示化合物5反应完全;所述第四溶剂为二氯甲烷、氯仿、四氯化碳、1,2-二氯乙烷、DMF、甲苯、苯、二氧六环、吡啶、冰醋酸、四氢呋喃、三乙胺、乙酸乙酯、丙酮、甲醇、乙醇、DMSO或***中的一种或多种,所述化合物5和樟脑磺酸的摩尔比1:1~1:10,优选为1:1~1:4;所述化合物5在第四溶剂中的浓度为0.001~1mol/L,优选为0.001~0.004mol/L。
上述步骤(5)中,所述糖苷化反应包括以下步骤:将化合物6和糖基给体化合物7溶于第五溶剂中,并加入干燥剂,在室温下搅拌0.5~2小时再加入催化剂,继续在室温下搅拌直到TLC跟踪显示化合物6反应完全,所述第五溶剂为二氯甲烷、氯仿、四氯化碳、1,2-二氯乙烷、DMF、甲苯、苯、二氧六环、吡啶、冰醋酸、四氢呋喃、三乙胺、乙酸乙酯、丙酮、甲醇、乙醇、DMSO或***中的一种或多种;所述化合物6、糖基给体化合物7和所述催化剂的摩尔比为1:1:0.1~1:5:0.8,优选为1:1:0.1~1:2.5:1;所述化合物6在第五溶剂中的浓度为0.001~1mol/L,优选为0.001~0.003mol/L;所述催化剂为一价金的络合物,优选为PPh3AuNTf2或PPh3AuOTf;所述干燥剂为分子筛,优选为分子筛或酸洗的分子筛,更优选为4A分子筛。
上述步骤(6)中,所述保护基脱除的反应包括以下步骤:将化合物8溶于第六溶剂中,再加入还原剂,室温下搅拌直到TLC跟踪显示化合物8反应完全;所述还原剂为硼氢化钠,氢化铝锂,硼烷;所述第八溶剂为二氯甲烷、氯仿、四氯化碳、1,2-二氯乙烷、DMF、甲苯、苯、二氧六环、吡啶、冰醋酸、四氢呋喃、三乙胺、乙酸乙酯、丙酮、甲醇、乙醇、DMSO或***中的一种或多种,优选为甲醇。
优选的,上述步骤(1)~(6)中的任一步骤均在惰性气体保护条件下进行,所述惰性气体选自氮气、氩气或氦气。
步骤(1)中,当环黄芪醇,TBSCl和咪唑的摩尔比为1:20:20时,得到的是环黄芪醇3位和6位羟基全部保护的化合物,当环黄芪醇,TBSCl和咪唑的摩尔比为1:2:2时,其他反应参数相同,反应收率只有40%。
本发明的技术效果是:本发明是高效、高立体选择性的异黄芪甲苷合成方法,为异黄芪甲苷的研究及应用提供足够的原料,为异黄芪苷类化合物的合成提供参考,填补现有技术的空白,将大大推进黄芪皂苷类化合物的活性机理研究及其药物开发的进程。
具体实施方式
根据下述实施例,可以更好地理解本发明,然而,本领域的技术人员容易理解,实施例所描述的内容仅用于说明本发明,而不应当也不会限制权利要求书中所详细描述的本发明。
Bz保护的糖4和7按照本领域常规方法合成:
化合物4-1的合成方法如下:
在氮气保护,将异头位羟基裸露的全Bz葡萄糖(100mg,0.17mmol)溶于干燥的二氯甲烷(4mL)中,再向体系中加入邻炔基苯甲酸(37.4mg,0.2mmol),DMAP(28.1mg,0.23mmol),EDCI(43.9mg,0.23mmol),DIPEA(74μL),室温下搅拌过夜直到TLC跟踪显示原料反应完全,将反应体系用二氯甲烷萃取,并依次用1mol/l HCl、饱和碳酸氢钠、饱和NaCl洗,无水硫酸钠干燥,抽滤,减压浓缩粗产品,然后柱层析得到白色固体化合物4-1(121mg,93%):1H NMR(400MHz,CDCl3)δ1H NMR(400MHz,CDCl3)δ8.07(d,J=7.5Hz,2H),7.92-7.87(m,6H),7.44-7.28(m,17H),6.94(d,J=3.3Hz,1H),6.38(dd,J=9.6,9.9Hz,1H),5.94(dd,J=9.9,10.2Hz,1H),5.76(dd,J=3.3,9.9Hz,1H),4.80-4.66(m,2H),4.54(dd,J=3.3,6.0Hz,1H),1.56(m,1H),0.84(d,J=6.6Hz,4H).
化合物7-1的合成方法如下:
类似于合成化合物4-1,从异头位羟基裸露的全Bz木糖得到白色固体化合物7-1(612mg,89%):[α]D 25=0.02(c 1.0,CHCl3);1H NMR(400MHz,CDCl3)δ8.04-7.98(m,6H),7.90(dd,J=1.2,8.0Hz,1H),7.58-7.51(m,3H),7.49-7.42(m,2H),7.38-7.30(m,6H),7.21(td,J=1.6,7.6Hz,1H),6.42(d,J=7.6Hz,1H),5.81(t,J=5.2Hz,1H),5.58(dd,J=4.0,5.2Hz,1H),5.36-5.32(m,1H),4.63(dd,J=3.6,12.8Hz,1H),4.06(dd,J=4.8,12.4Hz,1H),1.54-1.47(m,1H),0.90-0.84(m,4H);13C NMR(100MHz,CDCl3)δ164.9,164.4,164.3,163.3,133.7,132.8,129.9,129.7,129.4,129.3,128.5,128.3,127.8(2C),126.3,124.7,99.7,91.4,73.6,67.8,67.6,67.2,60.9,8.2,-0.0;HRMS(ESI-TOF)m/z:[M+H]+calcd forC38H31O9 631.1968;found 631.1966.
实施例1
异黄芪甲苷的合成,
(1)3位羟基保护的环黄芪醇衍生物2的合成,
在氮气保护下,环黄芪醇(400mg,0.82mmol)溶于干燥的DMF再向体系中加入TBSCl(489mg,3.3mmol),咪唑(333mg,4.9mmol),在室温搅拌直到TLC跟踪显示原料反应完全,将反应体系用乙酸乙酯萃取,并依次用1mol/l HCl、饱和碳酸氢钠、饱和NaCl洗,无水硫酸钠干燥,抽滤,减压浓缩粗产品,然后柱层析得到白色固体化合物2(76.8%):[α]D 25=30.5(c=1,CHCl3);1H NMR(400MHz,CDCl3)δ4.67(dd,J=7.6,14.4Hz,1H),3.72(dd,J=6.0,8.0Hz,1H),3.51(td,J=3.6,9.6Hz,1H),3.25(dd,J=4.8,10.0Hz,1H),2.59(dd,J=10.4,21.6Hz,1H),2.31(d,J=8.0Hz,1H),2.00-1.92(m,4H),1.76(dd,J=4.0,12.0Hz,1H),1.25(s,3H),1.21(s,3H),1.17(s,3H),1.13(s,3H),1.11(s,3H),1.09(s,3H),0.91(s,3H),0.89(s,3H),0.85(s,9H),0.47(d,J=4.0Hz,1H),0.31(d,J=4.4Hz,1H),0.00(s,3H),-0.005(s,3H);13C NMR(100MHz,CDCl3)δ87.1,81.4,78.8,73.4,71.8,68.9,57.5,53.7,46.9,46.5,46.0,45.0,42.1,37.7,34.4,33.0,32.1,31.4,30.8,29.4,28.6,27.9,27.7,26.4,25.9(2C),25.8,21.4,20.5,20.0,18.1,15.8;HRMS(ESI)calcd for C36H65O5Si[M+H]+605.4596,found 605.4599;
(2)3,6和16位羟基保护的环黄芪醇衍生物3的合成,
在氮气保护,0摄氏度条件下,将化合物2(300mg,0.5mmol)溶于干燥的吡啶(2ml)中,再向体系中加入PivCl(50μL,4.96mmol),缓慢升至室温后加热到50度,搅拌直到TLC跟踪显示原料反应完全,将反应体系用乙酸乙酯萃取,并依次用1mol/l HCl、饱和碳酸氢钠、饱和NaCl洗,无水硫酸钠干燥,抽滤,减压浓缩粗产品,然后柱层析得到白色固体化合物3(94.9%):[α]D 25=72.9(c=1,CHCl3);1H NMR(400MHz,CDCl3)δ5.31-5.26(m,1H),4.74-4.69(m,1H),3.74(t,J=7.2Hz,1H),3.24(dd,J=4.8,10.0Hz,1H),2.37(d,J=8.0Hz,1H),2.08-2.00(m,2H),1.36(s,3H),1.31(s,3H),1.18(s,3H),1.16(s,9H),1.13(s,9H),1.07(s,3H),0.96(s,3H),0.85(s,12H),0.80(s,3H),0.54(d,J=4.8Hz,1H),0.21(d,J=4.8Hz,1H);13C NMR(100MHz,CDCl3)δ178.2,177.7,85.5,83.3,78.5,75.7,71.2,69.7,57.5,49.2,46.7,46.2,45.1,43.0,41.9,38.6,38.2,32.5,31.9,31.4,27.8,27.4,27.3,27.2,27.1(2C),26.6,26.2,26.0,25.9,25.4,24.5,20.7,19.8,19.6,18.1,15.4;HRMS(ESI)calcdfor C64H81O7Si[M+H]+773.5746,found 773.5743;
(3)25位糖苷化产物5的合成,
在氮气保护下,将化合物3和葡萄糖炔酯给体4-1溶于干燥的二氯甲烷中,并加入4A分子筛,在室温下搅拌半个小时再加入催化剂Ph3PAuNTf2(0.2eq),继续在室温下搅拌直到TLC跟踪显示原料反应完全,减压浓缩粗产品,然后柱层析得到白色固体化合物5(91.6%):[α]D 25=40.3(c=1,CHCl3);1H NMR(400MHz,CDCl3)δ8.02-7.96(m,4H),7.91(dd,J=1.2,8.0Hz,2H),7.86(dd,J=1.2,8.4Hz,2H),7.54-7.48(m,4H),7.43-7.34(m,7H),7.31(t,J=8.0Hz,1H),5.90(t,J=9.6Hz,1H),5.53(dd,J=9.2,10.0Hz,1H),5.48(dd,J=7.6,9.2Hz,1H),5.35(d,J=8.0Hz,1H),5.23-5.18(m,1H),4.76(dd,J=6.8,14.4Hz,1H),4.60(dd,J=2.8,12.0Hz,1H),4.44(dd,J=7.2,12.0Hz,1H),4.13-4.08(m,1H),3.72(dd,J=4.8,8.4Hz,1H),3.20(m,1H),2.42(d,J=7.6Hz,1H),2.14-2.06(m,2H),1.37(s,3H),1.33(s,3H),1.18(s,9H),1.17(s,9H),1.16(s,3H),1.13(s,3H),0.98(s,3H),0.86(s,12H),0.80(s,3H),0.56(d,J=4.8Hz,1H),0.27(d,J=4.8Hz,1H);13C NMR(100MHz,CDCl3)δ178.0,177.7,165.9,165.8,165.4,164.9,134.2,134.1,133.5,133.2,133.1(2C),129.8(2C),129.7(2C),129.6,129.3,129.2,129.0,128.8,128.4,128.3(2C),96.2,86.0,84.1,80.1,78.3,76.1,73.1,72.1(2C),70.5,69.8,63.9,57.8,49.1,46.8,46.3,45.2,43.2,41.9,38.6,38.5,38.2,32.6,32.1,31.2,30.5,27.8,27.4,27.2(2C),25.9,25.5,24.0,21.7,20.6,19.7,19.6,18.1,15.4,-3.9,-4.9;HRMS(ESI)calcd for C80H107O16Si[M+H]+1351.73229,found 1351.73310;
(4)3位羟基裸露产物6的合成,
在氮气保护下,将化合物5(20mg,0.03mmol)溶于干燥的甲醇(2.0mL)中,在室温下加入樟脑磺酸(26mg,0.11mmol),搅拌直到TLC跟踪显示原料反应完全,减压浓缩粗产品,然后柱层析得到白色固体化合物6(82.9%):[α]D 25=20.5(c=1,CHCl3);1H NMR(400MHz,CDCl3)δ8.00-7.96(m,4H),7.91(dd,J=1.2,8.0Hz,2H),7.85(dd,J=1.2,8.0Hz,2H),7.54-7.49(m,3H),7.45-7.33(m,7H),7.31-7.27(m,2H),5.91(t,J=9.6Hz,1H),5.54(t,J=10.1Hz,1H),5.48(dd,J=8.0,9.6Hz,1H),5.27(d,J=8.0Hz,1H),5.23-5.18(m,1H),4.78-4.73(m,1H),4.59(dd,J=3.2,12.0Hz,1H),4.44(dd,J=7.2,11.6Hz,1H),4.14-4.08(m,1H),3.72(dd,J=4.8,8.4Hz,1H),3.24(dd,J=4.8,11.6Hz,1H),2.43(d,J=8.0Hz,1H),2.16(dd,J=7.6,13.6Hz,1H),2.05-2.01(m,1H),1.36(s,3H),1.33(s,3H),1.18(s,12H),1.17(s,9H),1.11(s,3H),1.00(s,3H),0.91(s,3H),0.89(s,3H),0.56(d,J=4.8Hz,1H),0.30(d,J=4.4Hz,1H);13C NMR(100MHz,CDCl3)δ178.1,177.7,166.0,165.8,165.4,164.9,133.5,133.2(2C),133.1,129.8(2C),129.7(2C),129.6(2C),128.9,128.8,128.4,128.3(2C),96.2,86.0,84.1,80.1,77.9,76.1,73.1,72.1,72.0,70.4,69.9,63.9,57.8,49.2,46.8,46.3,45.4,43.7,41.3,38.6,38.5,38.3,32.3(2C),31.3,30.0,28.0,27.3,27.2,27.1,26.9,26.1,25.9,25.6,23.8,22.0,20.8,19.8,19.7,15.0;HRMS(ESI)calcdfor C74H93O16[M+H]+1237.64581,found 1237.64675;
(5)3,25位糖苷化产物8的合成,
在氮气保护下,将化合物6和木糖炔酯给体7溶于干燥的二氯甲烷中,并加入4A分子筛,在室温下搅拌半个小时再加入催化剂Ph3PAuNTf2(0.2eq),继续在室温下搅拌直到TLC跟踪显示原料反应完全,减压浓缩粗产品,然后柱层析得到白色固体化合物8(83.2%):[α]D 25=25.2(c=0.3,CHCl3);1H NMR(400MHz,CDCl3)δ8.02-7.94(m,10H),7.92(dd,J=1.2,8.0Hz,2H),7.86(dd,J=1.2,8.0Hz,2H),7.55-7.43(m,7H),7.41-7.27(m,14H),5.91(t,J=10.0Hz,1H),5.80(t,J=8.0Hz,1H),5.52-5.42(m,3H),5.32-5.27(m,2H),5.23-5.18(m,1H),4.80(d,J=6.4Hz,1H),4.65-4.58(m,2H),4.42-4.33(m,2H),4.14-4.09(m,1H),3.73(dd,J=4.8,8.4Hz,1H),3.62(dd,J=7.6,12.0Hz,1H),3.15(dd,J=4.4,11.2Hz,1H),2.44(d,J=7.6Hz,1H),2.13-2.03(m,2H),1.35(s,3H),1.33(s,3H),1.19(s,3H),1.17(s,9H),1.13(s,3H),1.08(s,9H),0.97(s,3H),0.78(s,3H),0.64(s,3H),0.52(d,J=4.8Hz,1H),0.26(d,J=4.8Hz,1H);13C NMR(100MHz,CDCl3)δ178.0,177.5,166.0,165.9,165.6(2C),165.4,165.1,164.9,133.6,133.4,133.3,133.2(2C),133.1,129.9,129.8,129.7(2C),129.6(2C),129.4,129.2,129.1,128.9,128.8,128.5,128.4(2C),128.3(2C),102.6,96.2,88.6,86.1,84.2,80.2,76.1,73.1,72.1(2C),71.2,71.0,70.4,69.6,69.3,63.9,61.7,57.8,49.2,46.8,46.3,45.2,42.9,41.4,38.5,38.3,32.5,31.8,31.1,28.6,27.4,27.2,27.1,26.6,26.2,25.9,25.6,24.0,21.9,20.7,19.7,19.6,15.6;HRMS(ESI)calcd for C100H116O23N[M+NH4]+1699.79666,found 1699.79904;
(6)异黄芪甲苷的合成,
在氮气保护0摄氏度的条件下,将化合物13(70mg,0.042mmol)溶于干燥的THF中,往体系中缓慢加入锂铝氢(25mg,0.67mmol),再缓慢升至室温搅拌直到TLC跟踪显示原料反应完全,减压浓缩粗产品,然后柱层析得到白色固体化合物异黄芪甲苷(收率:75.6%)::[α]D 25=7.9(c=0.25,CH3OH);1H NMR(400MHz,C5D5N)δ5.08(d,J=7.6Hz,1H),4.93(d,J=7.2Hz,1H),4.45(dd,J=3.6,11.6Hz,1H),4.40(dd,J=4.8,11.2Hz,1H),4.32(dd,J=4.8,11.6Hz,1H),4.25-4.15(m,4H),4.09-4.00(m,3H),3.92-3.88(m,2H),3.81-3.72(m,2H),3.64-3.61(m,1H),2.85(dd,J=11.6,19.6Hz,1H),2.48(d,J=7.6Hz,1H),2.00(s,3H),1.67(s,3H),1.42(s,3H),1.35(s,3H),1.33(s,3H),1.29(s,3H),0.94(s,3H),0.56(d,J=3.2Hz,1H),0.28(d,J=4.0Hz,1H);13C NMR(100MHz,C5D5N)δ107.4,98.6,88.4,87.0,81.8,78.3,77.8,75.4,75.0,73.3,71.1,71.0,67.7,66.8,62.5,57.9,53.8,46.6,45.9,45.8,45.0,42.5,38.4,34.8,33.2,32.2,30.3,30.1,29.3,28.7,27.6,26.0,25.7,25.4,22.8,21.3,20.7,19.8,16.4;HRMS(ESI)calcd for C41H68O14Na[M+Na]+807.4501,found807.4498。
对比例1:步骤(3)或(5)中,用三氯乙酰亚胺酯给体代替炔酯给体进行糖苷化反应时反应体系很杂,产物少,说明炔酯给体在合成异黄芪甲苷时更具优越性。
对比例2:步骤(1)中,所述环黄芪醇、卤代硅烷和咪唑的摩尔比为1:20:20时,其他反应参数相同,反应为3,6位羟基同时保护的产物。
对比例3:步骤(1)中,当环黄芪醇,TBSCl和咪唑的摩尔比为1:2:2时,其他反应参数相同,反应收率只有40%。
对比例4:步骤(2)中,化合物2的浓度为0.001mol/L时,其他反应参数相同,化合物2只有6羟基得到保护。
Claims (8)
1.一种异黄芪甲苷的合成方法,其特征在于,包括以下步骤:
(1)将环黄芪醇的3位羟基以保护基R1保护,得到化合物2;
(2)将化合物2的6位和16位羟基以保护基R2保护,得到化合物3;
(3)将化合物3与糖基给体化合物4发生糖苷化反应,得到化合物5;
(4)将化合物5的3位保护基R1脱除,得到化合物6;
(5)将化合物6与糖基给体化合物7发生糖苷化反应,得到化合物8;
(6)将化合物8的所有保护基脱除,得到异黄芪甲苷。
其中,所述R1选自取代或非取代的C1-C9烷硅基;所述R2选自取代或非取代的C2-C6烷酰基;所述R3或R4各自独立的选自C1-C6芳酰基;X选自取代或非取代的炔苯甲酰氧基。
2.根据权利要求1所述的一种异黄芪甲苷的合成方法,其特征在于,步骤(1)中,所述保护的方法包括以下步骤:室温下,将环黄芪醇溶于第一溶剂中,再加入卤代硅烷和咪唑,将反应温度缓慢升至室温后搅拌直到TLC跟踪显示环黄芪醇反应完全;所述第一溶剂为二氯甲烷、二氯乙烷、氯仿、四氯化碳、1,2-二氯乙烷、DMF、甲苯、苯、二氧六环、吡啶、冰醋酸、四氢呋喃、三乙胺、乙酸乙酯、丙酮、甲醇、乙醇、DMSO或***中的一种或多种,所述卤代硅烷为TBSCl、TESCl、TBDMSCl、TBDPSCl、DIPSCl、DPSCl或TIPDSCl。所述环黄芪醇、卤代硅烷和咪唑的摩尔比为1:1:3~1:5:10;所述环黄芪醇在第一溶剂中的浓度为0.1~1mol/L。
3.根据权利要求1所述的一种异黄芪甲苷的合成方法,其特征在于,步骤(2)中,所述保护的方法包括以下步骤:0℃以下,将化合物2溶于第二溶剂中,再加入特戊酰氯,将反应温度缓慢升至室温后再加热到50℃,继续搅拌直到TLC跟踪显示化合物2反应完全,所述第二溶剂为二氯甲烷、氯仿、四氯化碳、1,2-二氯乙烷、DMF、甲苯、苯、二氧六环、吡啶、四氢呋喃、三乙胺、乙酸乙酯、丙酮、甲醇、乙醇、DMSO或***中的一种或多种;所述化合物2和特戊酰氯的摩尔比为1:2~1:20;所述化合物2在第二溶剂中的浓度为0.1~1mol/L。
4.根据权利要求1所述的一种异黄芪甲苷的合成方法,其特征在于,步骤(3)中,所述糖苷化反应包括以下步骤:在惰性气体保护下,将化合物3和糖基给体化合物4溶于第三溶剂中,并加入干燥剂,在室温下搅拌0.5~2小时再加入催化剂,继续在室温下搅拌直到TLC跟踪显示化合物2反应完全;所述第三溶剂为二氯甲烷、氯仿、四氯化碳、1,2-二氯乙烷、DMF、甲苯、苯、二氧六环、吡啶、冰醋酸、四氢呋喃、三乙胺、乙酸乙酯、丙酮、甲醇、乙醇、DMSO或***中的一种或多种,化合物3、糖基给体化合物4和所述催化剂的摩尔比为1:1:0.1~1:5:0.8;所述化合物3在第三溶剂中的浓度为0.001~1mol/L;所述催化剂选自一价金的络合物;所述干燥剂选自分子筛。
5.根据权利要求1所述的一种异黄芪甲苷的合成方法,其特征在于,步骤(4)中,所述保护基R1脱除的方法包括以下步骤:室温下,将化合物5溶于第四溶剂中,再加入樟脑磺酸,搅拌直到TLC跟踪显示化合物5反应完全;所述第四溶剂为二氯甲烷、氯仿、四氯化碳、1,2-二氯乙烷、DMF、甲苯、苯、二氧六环、吡啶、冰醋酸、四氢呋喃、三乙胺、乙酸乙酯、丙酮、甲醇、乙醇、DMSO或***中的一种或多种,所述化合物5和樟脑磺酸的摩尔比1:1~1:10;所述化合物5在第四溶剂中的浓度为0.001~1mol/L。
6.根据权利要求1所述的一种异黄芪甲苷的合成方法,其特征在于,步骤(5)中,所述糖苷化反应包括以下步骤:将化合物6和糖基给体化合物7溶于第五溶剂中,并加入干燥剂,在室温下搅拌0.5~2小时再加入催化剂,继续在室温下搅拌直到TLC跟踪显示化合物6反应完全,所述第五溶剂为二氯甲烷、氯仿、四氯化碳、1,2-二氯乙烷、DMF、甲苯、苯、二氧六环、吡啶、冰醋酸、四氢呋喃、三乙胺、乙酸乙酯、丙酮、甲醇、乙醇、DMSO或***中的一种或多种;所述化合物6、糖基给体化合物7和所述催化剂的摩尔比为1:1:0.1~1:5:0.8;所述化合物6在第五溶剂中的浓度为0.001~1mol/L;所述催化剂选自一价金的络合物;所述干燥剂选自分子筛。
7.根据权利要求1所述的一种异黄芪甲苷的合成方法,其特征在于,步骤(6)中,所述保护基脱除的反应包括以下步骤:将化合物8溶于第六溶剂中,再加入还原剂,室温下搅拌直到TLC跟踪显示化合物8反应完全;所述还原剂为硼氢化钠,氢化铝锂,硼烷;所述第八溶剂为二氯甲烷、氯仿、四氯化碳、1,2-二氯乙烷、DMF、甲苯、苯、二氧六环、吡啶、冰醋酸、四氢呋喃、三乙胺、乙酸乙酯、丙酮、甲醇、乙醇、DMSO或***中的一种或多种。
8.根据权利要求1所述的异黄芪甲苷的合成方法,其特征在于,步骤(1)~(6)中的任意步骤在惰性气体保护条件下进行。
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