CN107501267B - 一种不对称烯丙基氨化反应合成手性非环核苷类似物的方法 - Google Patents
一种不对称烯丙基氨化反应合成手性非环核苷类似物的方法 Download PDFInfo
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Abstract
本发明公开了一种不对称烯丙基氨化反应合成手性非环核苷类似物的方法,属于有机合成技术领域。将反应溶剂、嘌呤化合物1、添加剂、SKP双膦配体和金属钯混合,接着加入MBH加合物2,保温反应后得到非环核苷3。本发明具有原料易得,操作简单,反应条件温和,反应可以达到中等到优异的区域选择性(高达99%B/L)和优异的对应选择性(高达99%ee)的的手性支链N‑烯丙基化产物。
Description
技术领域
本发明属于有机合成技术领域,具体涉及一种不对称烯丙基氨化反应合成手性非环核苷类似物的方法。
背景技术
核苷类化合物因为其潜在的优秀的抗病毒活性和抗癌活性得到科研工作者的青睐,核苷类化合物可以分为非环状类化合物和环核苷类化合物,其中环状核苷药物代表性的有Entecavir,Carbovir,Abacavir,Lamivudine等,非环核苷药物有Acyclovir,(S)-DHPA,(S)-HPMFA,Tenofovir等。
目前传统的合成步骤过于复杂,多数使用手性辅剂诱导和手性源合成手性核苷类似物,例如2005年,Yokomatsu课题组用手性羟基烯烃作为手性源,经过多步反应得到具有潜在抗血栓的脲苷酸酮糖类似物,可能具有治疗糖尿病或抗血栓作用,使其发展得到极大的限制,寻找方便快捷的合成手性药物是需要科研工作者不断努力。
其中化学反应中的不对称催化可以分为:金属催化和小分子催化反应,其反应特点是条件温和、效率高,不对称催化反应以手性催化剂来控制产物的立体选择性,使用非手性的产物转化成手性产物,可以实现手性增殖和手性放大。2017年,Bernhard Breit[20]课题组使用过度金属Rh/Josiphos 003-1催化连烯和嘌呤的不对称烯丙基氨化反应,反应可以很好控制在7位和9位的支链产物上,但是在对映选择性的结果并不好,使用金属钯催化反应时基本没有B型产物生成,而且在Z型和E型结构上最高只能达到90:10。
综上所述,对于嘌呤类化合物的不对称催化反应后得到手性非环核苷类似物仍然缺乏有效的途径。
发明内容
为了解决现有技术的不足,寻求到一种新的合成路径,并通过简便、绿色、高效的不对称烯丙基氨化反应合成手性非环核苷类似物,立足于解决此类化合物合成过程中过程控制复杂等问题,为核苷类药物的合成及应用提供参考价值,为新型抗病毒及抗癌活性药物的研究提供了原料。
为了实现本发明的目的,拟采用如下技术方案:
一种不对称烯丙基氨化反应合成手性非环核苷类似物的方法,包括以下操作:将反应溶剂、嘌呤化合物1、添加剂、双膦配体和金属钯混合,接着加入MBH加合物2,保温反应后得到非环核苷3。其中,MBH是指Morita-Baylis-Hillman的简称。
反应方程式如下:
R1选自甲基、乙基、苄基、叔丁基、1-金刚烷、2-金刚烷基等,
R5选自氯、哌啶基、苄氧基、氢、丙琉基、二乙氨基、甲氧基等;
R6选自氢、氨基等;R3选自氢、C1-C5烷基、苯基、取代苯基、苯乙基或1-烯丁基等;
PG选自:乙酰基、叔丁氧羰基、苯甲酰基、丙酰基等。PG为保护基的英文简写。
进一步地,所述反应溶剂选自DCE(1,2-二氯乙烷)、DCM(二氯甲烷)、PhCF3、CHCl3、六氟苯、甲苯等。
进一步地,所述金属钯和双膦配体分别为1-3mol%和2-6mol%,优选比例分别为2.5mol%和5mol%。
进一步地,所述反应过程中,采用惰性气体保护,包括氮气和氩气;保温反应时,包括采用超声条件下反应。超声反应可以加快反应进度,仅对反应周期有缩短,对反应收率、对映选择性和区域选择性无影响。
进一步地,反应温度在-40℃至室温均可正常反应,低温对区域选择性和位置选择性有利。保温反应时优选反应温度-20℃至室温。
进一步地,所述金属钯选自Pd2(dba)3、[Pd(η3C3H5)Cl]2、Pd(dba)2等。
进一步地,所述添加剂选自碳酸钾、三乙烯二胺、4A分子筛、TBAT(四正丁基铵二氟代三苯基硅酸盐)等。
进一步地,双膦配体选自手性DIOP-L1,BINAP-L2,Trost配体-L3、配体-L4或SKP配体,优选SKP配体。以R或R,R型为例对应结构表示如下:
SKP结构配体,以(R,R,R)-构型为例代表性如下:
上述反应嘌呤和MBH的烯丙基胺化反应生成多种互变异构体,包括手性的支链产物(B)和非手性的支链产物(L);其中,非手性的支链产物中还包含有有Z型和E或型和而且嘌呤反应有N7 和N9 位的选择性,这使得我们的反应存在一定的难度,采用本发明的方法取得了高对映选择性和良好的区域选择性,通过二维谱和单晶衍射等测试手段测得的反应主要产物是和
发明的有益效果
本发明具有原料易得,操作简单,反应条件温和等优点。对R1取代为脂肪族和芳香族反应条件,得到不同的结果;脂肪族MBH加合物与亲核性较弱的嘌呤类化合物发生不对称烯丙基胺化反应,得到较高的产率、中等到优异的区域选择性(部分高达99%B/L)、优异的对应选择性(部分高达99%ee)的的手性支链N-烯丙基化产物。
具体实施方式
对比实施例1
配体在进行优化的过程中,以下面具体反应为例,采用不同配体对反应的区域选择性和对映选择性进行筛选,结果如下:
Entry | Ligand | Yield(%) | B/L | Ee(%)of B |
1 | (R,R)-DIOP | 31 | 40:60 | 23 |
2 | (R)-BINAP | 47 | 0:100 | --- |
3 | (R,R)-Trost ligand | 88 | 40:60 | 91 |
4 | (R,R,R)-SKP-Ph | 88 | 50:50 | 90 |
5 | (R,R,R)-SKP-Xyl | 90 | 50:50 | 92 |
6 | (R,R,R)-SKP-Tol | 77 | 40:60 | 82 |
从以上结果可以看出,实现良好区域选择性和对映选择性来自SKP类双膦配体,因而在上述反应中,优选SKP配体。
实施例1
取一休朗克反应管,加入1h(46.2mg,0.3mmol)、SKP(3.6mg,5mol%)和Pd2(dba)3(1.8mg,2.5mol%),盖上橡胶塞,反应多次置换氮气后,加入0.5mL DCM,室温反应30min,放到-20℃的超声中加入溶解在0.5mL DCM的2n(34.6mg,0.1mmol)后反应,TLC检测反应完全。后处理方法:反应完全后,用CH2Cl2(3×10mL)萃取,无水Na2SO4干燥,旋干,过柱得到无色油状物3hn。89%产率,79:21B/L,78:22N9/N7,98%ee。1H NMR(600MHz,CDCl3)δ(ppm)8.73(s,1H),8.27(s,1H),6.57(s,1H),6.11(s,1H),5.80-5.69(m,1H),5.65-5.55(m,1H),5.65-5.55(m,3H),2.60-2.47(m,1H),2.60-2.47(m,1H),2.05-1.90(m,5H),1.89-1.80(m,5H),1.79-1.70(m,4H),1.55(t,J=14.4Hz,2H).13C NMR(150MHz,CDCl3)δ(ppm)164.5,151.92,151.89,151.1,145.2,138.1,136.0,131.9,128.9,116.7,78.7,55.6,37.3,36.32,36.31,31.97,31.93,31.87,31.84,31.3,30.5,27.2,26.9.HRMS-ESI exact mass calcd.ForC23H28ClN4O2([M+H]+)requires m/z 427.1895,found m/z 427.1905.
实施例2
取一休朗克反应管,加入1j(49.2mg,0.3mmol)、SKP(3.6mg,5mol%)和Pd2(dba)3(1.8mg,2.5mol%)、K2CO3(41.4mg,0.3mmol),盖上橡胶塞,反应多次置换氮气后,加入0.5mL DCM,室温反应30min,放到-10℃的低温反应仪器中加入溶解在0.5mL DCM的2n(34.6mg,0.1mmol)后反应,TLC检测反应完全。后处理方法:反应完全后,用CH2Cl2(3×10mL)萃取,无水Na2SO4干燥,旋干,过柱得到无色油状物3jn。86%产率,82:18B/L,84:16N9/N7,96%ee。1H NMR(400MHz,CDCl3)δ(ppm)8.67(s,1H),8.06(s,1H),6.51(s,1H),6.00(s,1H),5.80-5.6(m,1H),5.58(dd,J=9.6,5.6Hz,1H),5.03-4.88(m,3H),3.35(t,J=7.2Hz,2H),2.54-2.25(m,1H),2.35-2.25(m,1H),2.02-1.86(m,5H),1.87-1.77(m,7H),1.76-.66(m,4H),1.53(t,J=11.6Hz,2H),1.07(t,J=7.2Hz,3H).13C NMR(100MHz,CDCl3)δ(ppm)164.6,161.5,151.9,148.5,142.3,138.8,136.3,131.7,128.2,116.5,78.5,55.0,37.3,36.4,36.3,31.99,31.93,31.88,31.85,31.58,30.7,30.5,27.2,27.0,23.0,13.6.HRMS-ESI exact mass calcd.For C26H34N4O2SNa([M+Na]+)requires m/z489.2295,found m/z 489.2303.
实施例3
取一休朗克反应管,加入1l(60.9mg,0.3mmol)、SKP(3.6mg,5mol%)和Pd2(dba)3(1.8mg,2.5mol%)、K2CO3(13.68mg,0.1mmol),盖上橡胶塞,反应多次置换氮气后,加入0.5mL甲苯,室温反应一段,然后放到-10℃的低温反应仪器中加入溶解在0.5mL甲苯的2n(34.6mg,0.1mmol)后反应,TCL检测反应完全。后处理方法:反应完全后,用CH2Cl2(3×10mL)萃取,无水Na2SO4干燥,旋干,过柱得到无色油状物3ln。88%产率,50:50B/L,N9/N7>95:5,91%ee。1H NMR(400MHz,CDCl3)δ(ppm)8.32(s,1H),7.85(s,1H),6.48(s,1H),5.91(s,1H),5.81-5.69(m,1H),5.56(dd,J=9.6,5.6Hz,1H),4.99-4.95(m,3H),4.24(br,4H),2.48-2.37(m,1H),2.33-2.25(m,1H),2.07-1.92(m,5H),1.89-1.81(m,4H),1.79-1.67(m,9H),1.65-1.48(m,4H).13C NMR(100MHz,CDCl3)δ(ppm)164.8,154.0,152.5,151.0,139.3,137.5,136.6,127.8,120.1,116.2,78.3,54.7,37.4,36.38,36.36,31.99,31.89,31.84,30.6,27.3,27.0,26.3,25.0.HRMS-ESI exact mass calcd.For C28H38N5O2([M+H]+)requires m/z 476.3020,found m/z 476.3024.
实施例4
取一休朗克反应管,加入1n(72.3mg,0.3mmol)、SKP(3.6mg,5mol%)和Pd2(dba)3(1.8mg,2.5mol%)、K2CO3(27.6mg,0.2mmol),盖上橡胶塞,反应多次置换氮气后,加入0.5mL DCM,室温反应一段时间,放到-20℃的超声中加入溶解在0.5mL DCM的2n(34.6mg,0.1mmol)后反应,TLC检测反应完全。后处理方法:反应完全后,用CH2Cl2(3×10mL)萃取,无水Na2SO4干燥,旋干,过柱得到无色油状物3nn。85%产率,52:48B/L,>95:5N9/N7,99%ee。1H NMR(600MHz,CDCl3)δ(ppm)7.69(s,1H),7.50(d,J=7.2Hz,2H),7.37-7.31(m,2H),7.30-7.27(m,1H),6.46(s,1H),5.83(s,1H),5.80-5.71(m,1H),5.55(s,2H),5.44(q,J=4.8Hz,1H),5.00-4.94(m,3H),4.91(s,2H),2.38-2.30(m,1H),2.26-2.18(m,1H),2.05-1.94(m,5H),1.88(d,J=12.6Hz,1H),1.86-1.78(m,4H),1.77-1.69(m,4H),1.58-1.49(m,2H).13C NMR(150MHz,CDCl3)δ(ppm)164.8,161.1,159.2,154.3,139.6,138.6,136.6,128.45,128.38,128.0,127.3,116.2,115.9,78.4,68.1,54.2,37.4,36.37,36.35,31.99,31.96,31.90,31.87,31.85,30.6,27.3,27.0.HRMS-ESI exact mass calcd.ForC30H36N5O3([M+H]+)requires m/z 514.2813,found m/z 514.2811.
实施例5
取一休朗克反应管,加入1l(51.0mg,0.3mmol)、SKP(3.6mg,5mol%)和[Pd(η3C3H5)Cl]2(2.5mol%)、K2CO3(41.4mg,0.3mmol),盖上橡胶塞,反应多次置换氮气后,加入0.5mL DCM,室温反应,放到0℃中加入溶解在0.5mL DCM的2n(34.6mg,0.1mmol)后反应,TLC检测反应完全。后处理方法:反应完全后,用CH2Cl2(3×10mL)萃取,无水Na2SO4干燥,旋干,过柱得到无色油状物3on。81%产率,89:11B/L,76:24N9/N7,99%ee。1H NMR(600MHz,CDCl3)δ(ppm)7.88(s,1H),6.52(s,1H),5.95(s,1H),5.84-5.68(m,1H),5.51-5.39(m,1H),5.07-4.96(m,5H),2.41-2.35(m,1H),2.28-2.22(m,1H),2.09-1.91(m,5H),1.89-1.82(m,4H),1.80-1.70(m,4H),1.65-1.50(m,3H).13C NMR(150MHz,CDCl3)δ(ppm)164.6,159.0,154.0,151.4,141.9,138.8,136.3,128.0,125.6,116.5,78.6,54.7,37.4,36.4,32.01,31.94,31.89,31.6,30.6,27.3,27.0.HRMS-ESI exact mass calcd.For C23H29ClN5O2([M+H]+)requires m/z 442.1999,found m/z442.2008
实施例6
取一休朗克反应管,加入1h(46.2mg,0.3mmol)、SKP(3.6mg,5mol%)和Pd2(dba)3(1.8mg,2.5mol%)、4A MS,盖上橡胶塞,反应多次置换氮气后,加入0.5mL THF,室温反应一段时间,加入溶解在0.5mL THF的2i(36.2mg,0.1mmol)后室温反应,TLC检测反应完全。后处理方法:反应完全后,用CH2Cl2(3×10mL)萃取,无水Na2SO4干燥,旋干,过柱得到无色油状物。89%产率,82:18B/L,73:27N9/N7,98%ee.
(3hi)1H NMR(400MHz,CDCl3)δ(ppm)8.73(s,1H),8.27(s,1H),6.56(s,1H),6.08(s,1H),5.61-5.58(m,1H),4.94(s,1H),2.46-2.16(m,2H),1.98-1.93(m,3H),1.86-1.82(m,4H),1.75-1.72(m,3H),1.60-1.51(m,3H),1.37-1.13(m,7H),0.84(t,J=7.2Hz,3H).13C NMR(150MHz,CDCl3)δ(ppm)164.5,152.0,151.9,151.0,144.9,138.4,131.8,128.6,78.6,56.3,37.3,36.33,36.31,32.4,31.97,31.92,31.88,31.84,31.2,27.2,27.0,26.2,22.4,14.0.HRMS-ESI exact mass calcd.For C24H32ClN4O2([M+H]+)requires m/z 443.2203,found m/z 443.2211.
(4hi1H NMR(600MHz,CDCl3)δ(ppm)8.73(s,1H),8.34(s,1H),7.18(t,J=7.7Hz,1H),5.16(s,2H),4.99(s,1H),2.60(q,J=7.6Hz,2H),1.99(s,2H),1.90-1.84(m,4H),1.82-1.75(m,3H),1.72(s,2H),1.61(s,1H),1.56(d,J=12.4Hz,2H),1.51-1.42(m,2H),1.37-1.29(m,4H),0.89(t,J=6.6Hz,3H).13C NMR(150MHz,CDCl3)δ(ppm)165.8,151.9,151.0,150.2,146.2,131.5,126.4,78.4,39.7,37.4,36.4,32.1,32.0,31.7,31.1,29.4,28.5,27.3,27.0,22.6,14.1.HRMS-ESI exact mass calcd.ForC24H31ClN4O2Na([M+Na]+)requires m/z465.2028,found m/z 465.2028.
(5hi)1H NMR(600MHz,CDCl3)δ(ppm)8.75(s,1H),8.28(s,1H),6.63(t,J=7.4Hz,1H),5.09(s,2H),5.03(s,1H),2.65(q,J=7.5Hz,2H),1.98(s,2H),1.90-1.83(m,4H),1.83-1.75(m,3H),1.73(s,2H),1.62-1.55(m,3H),1.51-1.45(m,2H),1.34-1.28(m,4H),0.88(t,J=6.6Hz,3H).13C NMR(150MHz,CDCl3)δ(ppm)165.6,152.0,151.6,151.1,145.9,125.9,79.0,48.0,37.4,36.5,32.1,32.0,31.7,31.1,30.2,28.8,27.2,27.0,22.6,14.1.HRMS-ESI exact mass calcd.For C24H32ClN4O2([M+H]+)requires m/z 443.2203,found m/z 443.2201.
(6hi)1H NMR(600MHz,CDCl3)δ(ppm)8.88(s,1H),8.41(s,1H),6.53(s,1H),6.05(t,J=7.2Hz,1H),5.62(s,1H),4.99(s,1H),2.30-2.23(m,1H),2.19-2.12(m,1H),2.00-1.90(m,3H),1.86-1.80(m,4H),1.77-1.71(m,4H),1.64-.153(m,3H),1.48-1.41(m,1H),1.37-1.27(m,5H),0.87(t,J=7.2,3H).13C NMR(150MHz,CDCl3)δ(ppm)164.2,162.0,152.6,147.2,143.3,140.0,127.2,122.6,78.8,57.7,37.3,36.4,34.0,32.1,31.98,31.95,31.4,27.2,27.0,26.1,22.5,14.0.HRMS-ESI exact mass calcd.ForC24H31ClN4O2Na([M+Na]+)requires m/z465.2028,found m/z 465.2023.
实施例7
取一休朗克反应管,加入1h(46.2mg,0.3mmol)、SKP(3.6mg,5mol%)和Pd2(dba)3(1.8mg,2.5mol%)、K2CO3(41.4mg,0.3mmol),盖上橡胶塞,反应多次置换氮气后,加入0.5mL DCM,室温反应一段时间,放到-10℃的超声中加入溶解在0.5mL DCM的2i(36.2mg,0.1mmol)后反应,TLC检测反应完全。后处理方法:反应完全后,用CH2Cl2(3×10mL)萃取,无水Na2SO4干燥,旋干,过柱得到无色油状物3hp。85%产率,69:31B/L,68:32N9/N7,99%ee。1H NMR(400MHz,CDCl3)δ(ppm)8.73(s,1H),8.24(s,1H),7.26-7.22(m,2H),7.21-7.16(m,1H),7.06(d,J=7.1Hz,2H),6.57(s,1H),6.13(s,1H),5.58(dd,J=9.7,4.7Hz,1H),4.94(s,1H),2.93-2.75(m,1H),2.69-2.48(m,3H),1.98-1.90(m,2H),1.88-1.79(m,5H),1.78-1.70(m,4H),1.59-1.52(m,3H).13C NMR(150MHz,CDCl3)δ(ppm)164.5,151.9,151.1,145.3,139.6,138.1,132.0,128.9,128.8,128.4,126.7,78.7,56.0,37.3,36.3,33.6,32.8,31.99,31.96,31.88,27.2,27.0.HRMS-ESI exact mass calcd.For C27H30ClN4O2([M+H]+)requires m/z 477.2046,found m/z 477.2058.
实施例8
取一休朗克反应管,加入1h(46.2mg,0.3mmol)、SKP-Xyl(3.8mg,5mol%)和Pd2(dba)3(1.8mg,2.5mol%)、Et3N(0.3mmol),盖上橡胶塞,反应多次置换氮气后,加入0.5mL三氟甲苯,室温反应一段时间后加入溶解在0.5mL三氟甲苯的2q(0.1mmol)后反应,TLC检测反应完全。后处理方法:反应完全后,用CH2Cl2(3×10mL)萃取,无水Na2SO4干燥,旋干,过柱得到无色油状物3hq。81%产率,53:47B/L,N9/N7>95:5,96%ee。1H NMR(600MHz,CDCl3)δ(ppm)8.77(s,1H),8.02(s,1H),7.41(d,J=7.6Hz,3H),7.26–7.23(m,2H),6.89(s,1H),6.54(s,1H),5.29(s,1H),1.30(s,9H).13C NMR(150MHz,CDCl3)δ(ppm)163.8,152.4,151.7,151.4,144.5,140.0,135.9,129.5,129.2,128.9,127.8,82.6,59.0,27.9.HRMS-ESIexact mass calcd.For C19H19ClN4O2Na([M+Na]+)requires m/z393.1089,found m/z393.1090.
实施例9
取一休朗克反应管,加入1h(46.2mg,0.3mmol)、SKP-Xyl(3.8mg,5mol%)和Pd2(dba)3(1.8mg,2.5mol%),盖上橡胶塞,反应多次置换氮气后,加入0.5mL DCE,室温反应一段时间,放到低温反应仪器中加入溶解在0.5mL DCE的2r(33.5mg,0.1mmol)后反应,TLC检测反应完全。后处理方法:反应完全后,用CH2Cl2(3×10mL)萃取,无水Na2SO4干燥,旋干过柱得到无色油状物3hr,81%产率,61:39B/L,N9/N7>95:5,94%ee。1H NMR(600MHz,CDCl3)δ(ppm)8.73(s,1H),8.25(d,J=8.4Hz,2H),8.11(s,1H),7.40(d,J=8.5Hz,2H),6.99(s,1H),6.63(s,1H),5.47(s,1H),1.33(s,9H).13C NMR(150MHz,CDCl3)δ(ppm)163.3,152.5,151.7,151.6,148.2,144.0,143.2,138.8,131.8,130.7,128.5,124.5,83.2,58.3,27.9.HRMS-ESI exact mass calcd.For C19H18ClN5O4Na([M+Na]+)requires m/z438.0940,found m/z 438.0948.
实施例10
按照与实施例1的操作方式相同的操作(仅反应底物进行改变),柱层析分离后,其它反应底物的结果如下:
以上显示和描述了本发明的基本原理和主要特征和本发明的优点。本行业的技术人员应该了解,本发明不受上述实施例的限制,上述实施例和说明书中描述的只是说明本发明的原理,在不脱离本发明精神和范围的前提下,本发明还会有各种变化和改进,这些变化和改进都落入要求保护的本发明范围内。本发明要求保护范围由所附的权利要求书及其等效物界定。
Claims (4)
1.一种不对称烯丙基氨化反应合成手性非环核苷类似物的方法,其特征在于,包括以下操作:将反应溶剂、嘌呤化合物1、添加剂、SKP双膦配体和金属钯混合,加入MBH加合物2,保温反应后得到非环核苷3,反应方程式如下:
R1选自甲基、乙基、苄基、叔丁基、1-金刚烷或2-金刚烷基;
R5选自氯、哌啶基、苄氧基、氢、丙琉基、二乙氨基或甲氧基;
R6选自氢或氨基;R3选自氢、C1-C5烷基、苯基、4-氟苯基、4-氯苯基、4-溴苯基、4-硝基苯基、3-氯苯基、3-溴苯基、苯乙基或1-烯丁基;
PG选自:乙酰基、叔丁氧羰基、苯甲酰基或丙酰基;
所述金属钯选自Pd2(dba)3、[Pd(η3C3H5)Cl]2或Pd(dba)2;SKP双膦配体选自SKP-Ph或SKP-Xyl;添加剂选自碳酸钾、三乙烯二胺、4A分子筛或TBAT。
2.根据权利要求1中一种不对称烯丙基氨化反应合成手性非环核苷类似物的方法,其特征在于:所述反应溶剂选自1,2-二氯乙烷、二氯甲烷、PhCF3、氯仿、六氟苯或甲苯。
3.根据权利要求1中一种不对称烯丙基氨化反应合成手性非环核苷类似物的方法,其特征在于:所述金属钯和双膦配体分别为1-3mol%和2-6mol%。
4.根据权利要求1中一种不对称烯丙基氨化反应合成手性非环核苷类似物的方法,其特征在于:反应过程采用氮气或氩气保护;保温反应时,反应温度选自-20℃至室温,包括采用超声条件下反应。
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