CN101125817A - 一种合成高对映选择性醛基取代小环胺类化合物和光学活性3-位取代内酰胺类化合物的方法 - Google Patents
一种合成高对映选择性醛基取代小环胺类化合物和光学活性3-位取代内酰胺类化合物的方法 Download PDFInfo
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Abstract
本发明提供了由消旋的醛基取代的小环胺类化合物高效高对映选择性的合成手性醛基取代的小环胺类化合物,同时合成有一定光学活性的3-位取代内酰胺类化合物的方法。与现有方法相比,该方法可适底物范围广,催化剂方便易得,反应条件温和,操作简便,而且反应效率高。而且该方法无需加入任何金属盐类化合物,从而有利于药物的生产和处理。
Description
技术领域
本发明涉及一种通过对消旋的醛基取代小环胺类化合物动力学拆分,高对映选择性的合成醛基取代小环胺类化合物和一定光学活性3-位取代内酰胺类化合物的方法。该方法是由手性氮杂环卡宾的前体盐与碱作用现场生成的手性氮杂环卡宾催化醛基取代的小环胺类化合物扩环的反应,也可以直接由手性氮杂环卡宾催化消旋的醛基取代的小环胺类化合物扩环的反应,通过核磁等手段跟踪反应,控制反应底物的转化率,来实现对消旋底物的动力学拆分,高对映选择性的合成醛基取代小环胺类化合物和一定光学活性3-位取代内酰胺类化合物。
背景技术
近年来,有机小分子催化由于其合成容易,结构修饰方便,无重金属残留等优点在全世界范围内引起了学术界和工业界的广泛关注[(a)Seayad,J.List,B.Org.Biomol.Chem.2005,3,719-724.(b)Dalko,P.I.Moisan,L.Angew.Chem.Int.Ed.2004,43,5138-5175.],其中由氮杂环卡宾为催化剂催化的有机反应在近年来更是取得了迅速的发展[a)H.Stetter,Angew.Chem.1976,88,695-704;Angew.Chem.Int.Ed.1976,15,639-647;b)M.S.Kerr,J.Read de Alaniz,T.Rovis,J.Am.Chem.Soc.2002,124,10298-10299;c)A.E.Mattson,A.R.Bharadwaj,K.A.Scheidt,J.Am.Chem.Soc.2004,126,2314-2315;d)M.S.Kerr,T.Rovis,J.Am.Chem.Soc.2004,126,8876-8877;e)J.Read de Alaniz,T.Rovis,J.Am.Chem.Soc.2005,127,6284-6289;f) Q.Liu,T.Rovis,J.Am.Chem.Soc.2006,128,2552-2553;g)Y.Hachisu,J.W.Bode,K.Suzuki,J.Am.Chem.Soc.2003,125,8432-8433;h)D.Enders,O.Niemeier,T.Balensiefer,Angew.Chem.2006,118,1491-1495;Angew.Chem.Int.Ed.2006,45,1463-1467;i)H.Takikawa,Y.Hachisu,J.W.Bode,K.Suzuki,Angew.Chem.2006,118,3572-3574;Angew.Chem.Int.Ed.2006,45,3492-3494;j)M.He,G.J.Uc,J.W.Bode,J.Am.Chem.Soc.2006,128,15088-15089;k)G.-Q.Li,L.-X.Dai,S.-L.You,Chem.Commun.2007,852-854],在这一领域中,我们最近发展了由手性氮杂环卡宾催化醛基取代的小环胺类化合物的扩环反应,通过对反应中底物转化率的控制,可以高对映选择性的合成醛基取代小环胺类化合物和一定光学活性3-位取代内酰胺类化合物,而这两类化合物均存在于大量的具有生物活性的天然和非天然产物中[a)N.C.Warshakoon;S.Wu;A.Boyer;R.Kawamoto;J.Sheville;S.Renock;K.Xu;M.Pokross;A.G.Evdokimov;R.Walter;M.Mekel.Bioorg.Med.Chem.Lett.2006,16,5598-5601;b)J.Uddin;K.Ueda;E.Siwu;M.Kita;D.Uemura Biorg.Med.Chem.2006,14,6954-6961;c)H.Ishikawa;G.I.Elliott;J.Velcicky;Y.Choi;D.Boger J.Am.Chem.Soc.2006,128,10596-10612;d)Hamlyn,Richard John;Rigoreau,Laurent JeanMartin;Raynham,Tony Michael;Priestley,Rachael Elizabeth;Soudy,ChristelleNicole Marguerite;Lyko,Frank;Bruckner,Bodo;Kern,Oliver Thomas.PCT Int.Appl.2007,71;e)Jacyno,John M.Lin,Nan-Horng;Holladay,Mark W.Sullivan,James P.Current Topics in Plant Physiology(1995),15(Phytochemicals and Health),294-6.f)J.A.Ferrendelli;H.J.Kupferberg Advances in Neurology 1980,27,587-96.g)J.F.Fisher;S.O.Meroueh;S.Mobashery Chem.Rev.2005,105,395.h)C.Birck;J.Y.Cha;J.Cross;C.Schulze-Briese;S.O.Meroueh;H.B.Schlegel;S.Mobashery;J.-P.Samama J.Am.Chem.Soc.2004,126,13945.i)C.WalshAntibiotics:Actions,Origins,Resistance;ASM Press:Washington,DC,2003.j)O.A.Mascaretti Bacteria Versus Antibacterial Agents;ASM Press:Washington,DC,2003.k)V.P.Sandanayaka;A.S.Prashad Curr.Med.Chem.2002,9,1145.1)T.K.Ritter;C.-H.Wong Angew.Chem.Int.Ed.2001,40,3508.m)B.G.Sprat Science 1994,264,388.n)J.Davies Science 1994,264,375.]
目前文献中对高对映选择性的合成醛基取代小环胺类化合物的报道还不多,其中绝大部分是在低温下(如-78℃),手性催化剂催化亚胺与烯酮之间的加成反应制得,反应条件比较苛刻,难以控制,操作困难。而对合成3-位取代的内酰胺化合物的报道虽然很多,但其中大多都有金属参与反应或者反应条件较苛刻,反应时间很长等缺点,因而发展一种操作方便,条件温和,而且效率高的高对映选择性合成醛基取代小环胺类化合物以及3-位取代内酰胺类化合物的方法是这方面的重点和难点。本发明人发展的利用手性氮杂环卡宾前体盐与碱作用,现场生成手性氮杂环卡宾或者直接用手性氮杂环卡宾这一有机小分子催化剂,通过对消旋的醛基取代小环内酰胺这一方便易得的底物扩环,控制反应转化率为50%,可以同时实现高对映选择性的合成醛基取代小环胺类化合物和一定光学活性3-位取代内酰胺类化合物,对这两类化合物的合成有着重要的意义。
发明内容
本发明目的是要提供一种高效的高对映选择性地合成醛基取代小环胺类化合物,同时合成一定光学活性3-位取代内酰胺类化合物的方法。
本发明的方法是一种高效的高对映选择性地合成醛基取代小环胺类化合物,同时合成一定光学活性3-位取代内酰胺类化合物方法。该方法是由手性氮杂环卡宾前体盐与碱作用现场生成手性氮杂环卡宾作为催化剂,也可以直接用手性氮杂环卡宾作为催化剂。
式中:R1或R2任意选自H、含C1-C16的烷基、氨基、烷氧基或卤素原子等;
本发明的手性醛基取代小环胺类化合物和手性3-位取代的内酰胺化合物均是以消旋的醛基取代的小环胺类化合物为原料,在有机溶剂的存在下,以手性氮杂环卡宾前体盐与碱的作用生成的手性氮杂环卡宾催化反应,通过控制反应转化率为50%时淬灭反应制得,也可以直接用手性氮杂环卡宾催化反应,控制反应转化率为50%,淬灭反应制得,可用下式表示:
R2任意选自H、含C1-C16的烷基、氨基、烷氧基或者卤素原子等;R3任意选自酰基、取代的芳基或者C1-C16的烷基的等;X为羰基或n=0、1或2;
当用手性氮杂环卡宾前体盐与碱作用现场生成手性氮杂环卡宾作为催化剂时,手性氮杂环卡宾的前体盐的结构式可以是任意光学纯的或其对映体,如下结构式,但不受图示所限:
当直接用手性氮杂环卡宾作为催化剂时,手性氮杂环卡宾的结构式可以是任意光学纯的或其对映体,如下结构式,但不受图示所限:
其中,R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、R15、R16或R17为H、C1-C16的烷基、芳基、取代芳基;所述取代的芳基上的取代基为烷基、烷氧基或取代的胺基,上述各取代基可单独成键或者相互之间成键形成C5-C7的环烷基、芳基、取代芳基、含N、O、S的杂芳基或杂环烷基;A1,A2,A3,A4为Cl-、Br-、BF4 -或ClO4 -。
所述的碱是三乙胺、1,8-二氮杂二环[5,4,0]十一碳-7-烯、1,5-二氮杂二环[4,3,0]壬-5-烯、碳酸铯、磷酸钾、二(三甲基硅基)氨基钠、二(三甲基硅基)氨基锂、二(三甲基硅基)氨基钾、叔丁醇钾、叔丁醇钠或二异丙基乙基胺;
所述的消旋的醛基取代小环胺类化合物、手性氮杂环卡宾前体盐或手性氮杂环卡宾、碱的摩尔比为1∶0.01-0.2∶0-0.2。
当用手性氮杂环卡宾前体盐与碱作用,现场生成手性氮杂环卡宾催化该反应时,所述的消旋的醛基取代的小环胺类化合物、手性氮杂环卡宾前体盐和碱的的摩尔比1∶0.01-0.2∶0.01-0.2。推荐摩尔比为1∶0.2∶0.2。尤其推荐反应的摩尔比为:醛基取代小环胺类化合物∶氮杂环卡宾前体盐∶碱=1∶0.05∶0.05。
当直接用手性氮杂环卡宾催化该反应时,所述的消旋的醛基取代的小环胺类化合物、手性氮杂环卡宾和碱的的摩尔比1∶0.01-0.2∶0。尤其推荐反应的摩尔比为:消旋的醛基取代小环胺类化合物∶手性氮杂环卡宾∶碱=1∶0.05∶0。
反应温度推荐为0℃至120℃,进一步推荐反应温度为:-78℃至50℃。
其中R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、R15、R16和R17同前所述。
本发明中所提到的烷基、烃氧基、酰基等,除非另外说明,均推荐碳数为1~18的基团,进一步推荐碳数为1~10的,尤其推荐碳数为1~5的。本发明中所提到的环烷基,除非另外说明,均指碳数为3~18的基团,进一步推荐碳数为3~10的,尤其推荐碳数为3~7的。本发明中所提到的芳基,除非另外说明,均指苯基、C5~C10的含N、O或S的杂环基,推荐为苯基。本发明中提到的杂芳基,推荐C5~C10的含N、O和S的杂环基。
本发明方法中,所述有机溶剂可以是极性或非极性溶剂。如苯、四氯化碳、石油醚、四氢呋喃、二甲基甲酰胺、二甲基乙酰胺、乙醚、二氯甲烷、三氯甲烷、甲苯、二甲苯、环己烷、正己烷、正庚烷、二氧六环或乙腈等。
采用本发明方法所得产物可以经过重结晶,薄层层析,柱层析减压蒸馏等方法加以分离。如用重结晶的方法,推荐溶剂为极性溶剂与非极性溶剂的混合溶剂。推荐溶剂可为二氯甲烷-正己烷、异丙醇-石油醚、乙酸乙酯-石油醚、乙酸乙酯-正己烷或异丙醇-乙酸乙酯-石油醚等混合溶剂。用薄层层析和柱层析方法,所用的展开剂为极性溶剂与非极性溶剂的混合溶剂。推荐溶剂可为异丙醇-石油醚、乙酸乙酯-石油醚、乙酸乙酯-正己烷或异丙醇-乙酸乙酯-石油醚等混合溶剂,其体积比可以分别是:极性溶剂∶非极性溶剂=1∶0.1-500。例如:乙酸乙酯∶石油醚=1∶0.1-50,异丙醇∶石油醚=1∶0.1-500。
本发明提供了一些新的手性醛基取代的小环胺类化合物其中例如R1为H;R2为甲基、苯基、氨基、烷氧基;R3为苯基、对甲基苯基、苄基、烷基。该类化合物可以经常规的反应将R3脱除以及将酰胺还原为氨基并上氨基保护基如苄氧羰基,或者将醛基与其他试剂反应等方式进行转化,从而具有广泛的应用。
本发明提供了一些新的手性3-位取代内酰胺化合物其中例如R1为H;R2为甲基或苯基;R3为苯基、对甲基苯基、苄基、烷基。该类化合物可以经常规的反应将R3脱除以及将酰胺还原为氨基并上氨基保护基如苄氧羰基,从而具有广泛的应用。
本发明提供了一种有效的由手性氮杂环卡宾前体盐与碱作用,现场生成的手性氮杂环卡宾或者直接用手性氮杂环卡宾作为催化剂,由消旋的醛基取代的小环胺类化合物同时高效率的合成手性醛基取代的小环胺类化合物和手性3-位取代内酰胺化合物的方法。与现有方法相比,该方法可适用于多种不同类型的消旋的醛基取代小环胺类化合物,反应条件温和,操作简便。另外,反应中无需加入任何金属盐类化合物,从而有利于药物的生产和处理。且反应的产率也较好。
具体实施方式
通过下述实施例将有助于理解本发明,但并不限制本发明的内容。
C1:
2-phenyl-6,10b-dihydro-4H,5aH-5-oxa-3,10cdiaza-2-azoniacyclopenta[c]fluor--ene tetrafluoroborate
MS(m/z,相对强度)337(M+,100),336(24),338(20).
C2:
2-Pentafluorophenyl-6,10b-dihydro-4H,5aH-5-oxa-3,10cdiaza-2-azoniacyclopenta[c]fluorene tetrafluoroborate
MS(m/z,相对强度)380(M+,100),381(20),382(2).
C3:2-(2,4,6-trimethylphenyl)-6,10b-dihydro-4H,5aH-5-oxa-3,10cdiaza--2-azoniacyclopenta[c]fluorene tetrafluoroborate
MS(m/z,相对强度)419(M+,100),418(25),420(24)。
实施例1:氮杂环卡宾催化醛基取代内酰胺化合物的动力学拆分
在氩气保护下,向一干燥反应管中依次加入手性氮杂环卡宾的前体盐(0.005mmol),二氯甲烷2.0mL,碱(0.005mmol),搅拌5分钟后,向体系中加4-醛-β-内酰胺化合物(0.5mmol)。反应体系在25℃下搅拌,核磁跟踪反应,当反应转化率为50%时,停止搅拌,减压除去溶剂,柱层析,淋洗剂:石油醚/乙酸乙酯=4/1,收集组分,得相应产物A和B。
在氩气保护下,向一干燥反应管中加B(0.1mmol),新蒸无水甲醇1.0mL,NaBH40.12mmol,室温搅拌,TLC跟踪反应。反应完毕后,向体系中加饱和NaHCO3溶液5.0mL,搅拌30分钟后,用二氯甲烷萃取体系(2×5mL),合并有机相,经饱和氯化钠溶液(2×5mL)洗涤后,无水Na2SO4干燥。旋掉溶剂后柱层析,淋洗剂:
石油醚/乙酸乙酯=4/1,收集组分,得相应产物C。
化合物A的ee值均有相应的还原产物C的ee值计算得到。
A1:
催化剂为C3(5mol%);乙酸乙酯/石油醚=1/4,v/v;白色固体,产率:94%,ee值:80%;1H NMR(CDCl3,300MHz)δ3.80(s,3H),4.72(dd,1H,J1=3.6Hz,J2=6.3Hz),4.71(d,1H,J=6.6Hz),6.88(m,2H),7.31-7.38(m,7H),9.37(d,1H,J=3.9Hz);13CNMR(75MHz,CDCl3):δ55.5,57.7,61.6,114.5,117.8,128.5,128.5,129.2,130.2,131.0,156.6,163.4,199.4.
A2:
催化剂为C3(5mol%);乙酸乙酯/石油醚=1/4,v/v;白色固体,产率:80%,ee值:99%;1H NMR(CDCl3,300MHz)δ2.28(s,3H),2.42(brs,6H),4.85(dd,1H,J1=3.3Hz,J2=3.3Hz),5.05(d,1H,J=3.3Hz),6.91(s,2H),7.26-7.42(m,5H),9.37(d,1H,J=3.3Hz);13C NMR(75MHz,CDCl3):δ18.9,18.9,20.8,58.1,64.6,128.2,128.3,128.5,128.9,128.9,129.1,129.3,130.3,130.6,138.4,165.6,198.6;IR(thin film):vmax(cm-1)=3033,2955,2925,1756,1487,1375,910,732,699;MS(EI,m/z,rel.intensity)161(M-132,100).HRMS(EI)计算值C19H19NO2(M+):
293.1416;实测值:293.1412;;m.p.59-60℃.
A3
催化剂为C3(5mol%);乙酸乙酯/石油醚=1/5,v/v;白色固体,产率:74%,ee值:38%;1H NMR(CDCl3,300MHz)δ1.00(d,3H,J=6.3Hz),1.24(d,3H,J=6.6Hz),2.15-2.22(m,1H),2.26(s,3H),2.29(brs,6H),3.50(dd,1H,J1=3.6Hz,J2=5.4Hz),4.59(dd,1H,J1=3.6Hz,J2=5.4Hz),6.88(s,2H),9.93(d,1H,J=3.6Hz);13C NMR(75MHz,CDCl3):δ18.8,20.6,20.9,22.0,26.1,62.2,63.6,129.4,130.3,138.4,167.3,199.3;IR(薄膜):vmax(cm-1)=2960,2871,2731,1760,1375,1104,855,683;MS(电子轰击,m/z,相对强度)146(100),259(M+,20);元素分析C17H15NO3:计算值:C,74.10;H,8.16;N,5.40;实测值:C,74.22;H,8.44;N,5.14;
A4:
催化剂为C3(5mol%);乙酸乙酯/石油醚=1/8,v/v;白色固体,产率:60%,ee值:36%;1H NMR(CDCl3,300MHz)δ0.89(t,3H,J=6.0Hz),1.30-1.43(m,6H),1.51-1.66(m,3H),1.77-1.83(m,1H),2.26(s,3H),2.31(brs,6H),3.71(m,1H),4.35(dd,1H,J1=2.7Hz,J2=5.7Hz),6.88(s,2H),9.86(d,1H,J=2.7Hz);IR(薄膜):vmax(cm-1)=3416,2957,2929,1760,1488,1378,1081,852;MS(电子轰击,m/z,相对强度)60(100),287(M+,11);HRMS(电子轰击)理论计算值C18H25NO2(M+):287.1885;实测值:2871892;
A5:
催化剂为C3(5mol%);乙酸乙酯/石油醚=1/8,v/v;产率:94%,ee值:99%;1H NMR and 13C NMR show the presence of rotamers about the carbamatebond in ca.4∶1 ratio.1H NMR(300MHz,CDCl3)δ1.95-2.10(m,2H),2.29(m,1H),2.46(m,1H),3.40-3.69(m,2H),3.80,3.81(s,3H),4.17,4.30(d,1H,J=2.2Hz),5.02-5.16(m,2H),6.80-6.92(m,2H),7.10-7.38(m,7H),9.34,9.83(d,1H,J=2.2Hz);13C NMR(75MHz,CDCl3)δ:22.4,23.1,34.7,36.2,47.7,48.5,55.4,67.6,68.5,70.9,71.2,77.1,77.4,114.5,114.5,117.7,117.8,127.8,128.1,128.3,128.4,128.4,130.5130.9,134.5,135.7,154.1,156.5,165.4,197.0,197.4;
B1:N-(对甲氧基苯基)-3-苯基琥珀酰亚胺
N-(4-methoxyphenyl)-3-phenylpyrrolidine-2,5-dione
催化剂为C3(5mol%);乙酸乙酯/石油醚=1/8,v/v;;白色固体,产率:99%,ee值:26%;[手性柱AD-H,正己烷/异丙醇=70/30,0.7ml·min-1,λ=230nm,t(major)=39.40min,t(minor)=19.10min];[α]D 20=+4.6(c 1.0,CHCl3);1H NMR(CDCl3,300MHz)δ2.97(dd,1H,J1=4.8Hz,J2=18.3Hz),3.35(dd,1H,J1=9.9Hz,J2=18.6Hz),3.82(s,3H),4.16(dd,1H,J1=4.8Hz,J2=9.9Hz),6.98(d,2H,J=9.0Hz),7.23(d,2H,J=9.0Hz),7.29-7.42(m,5H);13C NMR(75MHz,CDCl3):δ37.2,45.9,55.4,114.5,124.4,127.3,127.6,128.0,129.2,137.2,159.5,175.4,176.9;IR(薄膜):vmax(cm-1)=3007,2953,2834,1705,1513,1250,1198,777,703,670;MS(电子轰击,相对强度)293(M+,50),161(100);元素分析C17H15NO3:计算值:C,72.58;H,5.37;N,4.98;实测值:C,72.42;H,5.26;N,4.83;熔点:161-162℃.
B2:N-(均三甲基)-3-苯基琥珀酰亚胺
N-mesityl-3-phenylpyrrolidine-2,5-dione
催化剂为C3(5mol%);乙酸乙酯/石油醚=1/8,v/v;;白色固体,78%产率;ee值:27%;[手性柱OD-H(15cm),正己烷/异丙醇=70/30,0.5ml·min-1,λ=214nm,t(最大保留时间)=24.29min,t(最小保留时间)=14.21min];[α]D 20=+5.8(c1.0,CHCl3).1H NMR(300MHz,CDCl3)δ2.09(s,3H),2.11(s,3H),2.30(s,3H),3.05(dd,1H,J1=5.1Hz,J2=18.6Hz),3.43(dd,1H,J1=9.9Hz,J2=18.6Hz),4.24(dd,1H,J1=5.1Hz,J2=9.9Hz),6.97(d,2H,J=4.5Hz),7.31-7.44(m,5H);13CNMR(75MHz,CDCl3)δ17.6,17.8,21.0,37.2,46.2,127.3,127.4,127.9,129.1,129.3,129.3,135.1,135.2,137.0,139.3,175.1,176.4;IR(压片):vmax(cm-1)=3466,3028,2919,1773,1712,1488,1372,1184,863,785,667;MS(电子轰击,m/z,相对强度)293(M+,30),161(100);HRMS(电子轰击)C19H19N02(M+):计算值:293.1416实测值:293.1412;m.p.137-138℃.
B3:
催化剂为C3(5mol%);乙酸乙酯/石油醚=1/5,v/v;白色固体,产率:68%,ee值:10%;[手性柱OD-H,正己烷/异丙醇=85/15,1.0ml·min-1,λ=230nm,t(最大保留时间)=13.85min,t(最小保留时间)=10.73min];1H NMR(300MHz,CDCl3)δ1.01(d,3H,J=6.6Hz),1.07(d,3H,J=7.2Hz),2.04(s,3H),2.07(s,3H),2.29(s,3H),2.42-2.48(m,1H),2.67(dd,1H,J1=5.4Hz,J2=18.6Hz),2.87(dd,1H,J1=9.3Hz,J2=18.6Hz),3.02(m,1H),6.95(s,2H);13C NMR(75MHz,CDCl3)δ17.4,17.6,17.9,20.2,21.28.4,3.2,46.0,127.5,129.3,135.1,135.1,139.2,175.8,178.2;
B4:
催化剂为C3(5mol%);乙酸乙酯/石油醚=1/5,v/v;白色固体,产率:58%,ee值:3%
B5:
催化剂为C3(5mol%);乙酸乙酯/石油醚=1/3,v/v;白色泡沫状固体,92%产率99.9%ee,[手性柱AD-H,正己烷/异丙醇=70/30,1.0ml·min-1,λ=220nm,t(最大保留时间)=19.67分钟,t(最小保留时间)=15.12分钟];[α]D 20=-46.5(c 1.0,CHCl3).1H NMR和13C NMR显示体系存在旋转异构体,其物质的量比为2∶1。.1H NMR(300MHz,CDCl3)δ1.90-2.18(m,2H),2.78(AB,1H,JAB=17.7Hz),3.12,3.27(AB,1H,JBA=18.0Hz),3.60-3.71(m,2H),3.77,3.79(s,3H),5.06-5.18(m,2H),6.62,6.96(d,2H,J=9.0Hz),6.79,7.26(d,2H,J=9.0Hz),7.24-7.34(m,5H);13C NMR(75Hz,CDCl3)δ:23.1,23.9,38.2,40.0,41.4,42.4,47.4,48.3,55.3,55.3,64.2,65.1,67.2,68.1,114.1,114.3,123.9,124.5,127.3,127.8,127.8,128.0,128.4,128.5,128.6,128.7,135.1,135.9,153.0,154.1,159.2,159.4,173.1,173.6,177.4,177.7;IR(压片):vmax(cm-1)=2957,2883,2840,1718,1696,1514,1417,1253,1213,1166;MS(电子轰击,m/z,相对强度)394(M+,27),91(100);HRMS(电子轰击)计算值:C22H22N2O5(M+):394.1529实测值:394.1535;m.p.107-108℃.
C1:
催化剂为C3(5mol%);乙酸乙酯/石油醚=1/5,v/v;白色固体,98%产率80%ee,[手性柱AD-H,正己烷/异丙醇=85/15,1.0ml·min-1,λ=230nm,t(最大保留时间)=26.19分钟,t(最小保留时间)=18.11分钟];1H NMR(300MHz,CDCl3)δ1.46(brs,1H),3.58(dd,1H,J1=6.0Hz,J2=12.0Hz),3.74-3.78(m,1H),3.79(s,3H),3.43(m,1H),4.71(dd,1H,J1=2.4Hz,J2=6.0Hz),6.88(d,2H,J=9.0Hz),7.30-7.40(m,5H),7.52(d,2H,J=9.0Hz);13C NMR(75MHz,CDCl3)δ55.5,56.2,57.1,61.3,114.3,118.2,128.0,128.8,128.9,131.1,132.3,156.3;IR(薄膜):vmax(cm-1)=3469,2960,1715,1516,1396,1260,1250,1047,839,831,697;MS(电子轰击,m/z,相对强度)149(100).HRMS(电子轰击)理论计算值C17H17NO3(M+):283.1208实测值:283.1204;熔点:168-169℃.
C2:
催化剂为C3(5mol%);乙酸乙酯/石油醚=1/3,v/v;白色泡沫状固体,92%产率99.9%ee,[手性柱AD-H,正己烷/异丙醇=85/15,1.0ml·min-1,λ=230nm,t(最大保留时间)=21.40分钟,t(最小保留时间)=16.40分钟];1H NMR(300MHz,CDCl3)δ0.90(t,1H,J=6.0Hz),2.28(s,3H),2.32(s,3H),2.40(s,3H),3.56(m,1H),4.48(dd,1H,J1=5.7Hz,J2=11.7Hz),4.83(d,1H,J=5.4Hz),6.91(d,2H,J=10.2Hz),7.34-7.38(m,1H),7.42(d,4H,J=4.2Hz);13CNMR(75MHz,CDCl3)δ18.6,19.0,20.9,55.9,59.6,61.9,127.8,128.7,128.9,129.2,129.3,130.3,132.5,135.0,136.0,138.1,166.6;IR(薄膜):vmax(cm-1)=3415,2928,2894,1716,1486,1390,1062,738,697;MS(电子轰击,m/z,相对强度)161(100).HRMS(电子轰击)理论计算值C19H21NO2(M+):295.1572实测值:293.1576;熔点:168-169℃.
C3:
催化剂为C3(5mol%);乙酸乙酯/石油醚=1/4,v/v;白色固体,94%产率38%ee,[手性柱OD-H,己烷/异丙醇=85/15,1.0ml·min-1,λ=230nm,t(最大保留时间)=9.44分钟,t(最小保留时间)=7.89分钟];1H NMR(300MHz,CDCl3)δ1.03(d,3H,J=6.0Hz),1.24(d,3H,J=6.0),1.52(brs,1H),2.14-2.20(m,1H),2.22(s,3H),2.26(s,3H),2.28(s,3H),3.10(dd,1H,J1=3.6Hz,J2=10.5Hz),3.83-3.88(m,1H),3.92-4.00(m,1H),4.23(m,1H),6.84(s,1H),6.87(s,IH);13CNMR(75MHz,CDCl3)δ18.5,18.7,20.9,21.1,22.6,25.8,58.3,59.2,61.5,129.1,129.2,130.4,135.0,136.1,137.7,168.7;IR(薄膜):vmax(cm-1)=3392,2962,2933,2878,1718,1488,1389,1075,1062,853,825;MS(电子轰击,m/z,相对强度)146(100),261(M+,43).HRMS(电子轰击)理论计算值C16H23NO2(M+):261.1729实测值:261.1730.
C4:
催化剂为C3(5mol%);乙酸乙酯/石油醚=1/5,v/v;白色固体,95%产率36%ee[手性柱OD-H,正己烷/异丙醇=85/15,1.0ml·min-1,λ=230nm,t(最大保留时间)=7.77min,t(最小保留时间)=6.77min]。
Claims (6)
1.一种合成高对映选择性醛基取代小环胺类化合物和一定光学活性3-位取代内酰胺类化合物的方法,其特征是在有机溶剂的存在下和-78℃~50℃下,以消旋的醛基取代β-内酰胺类化合物为原料,以手性氮杂环卡宾前体盐与碱作用生成的手性氮杂环卡宾作为催化剂,通过核磁等跟踪反应,控制反应转化率在50%时,淬灭反应,可同时制得高对映选择性的醛基取代β-内酰胺类化合物和一定光学活性的3-位取代的内酰胺化合物;
所述的消旋的醛基取代小环胺类化合物、手性氮杂环卡宾前体盐或手性氮杂环卡宾、碱的摩尔比为1∶0.01-0.2∶0-0.2;
所述的手性氮杂环卡宾的前体盐具有如下结构式:
所述的手性氮杂环卡宾具有如下结构式:
所述的碱是三乙胺、1,8-二氮杂二环[5,4,0]十一碳-7-烯、1,5-二氮杂二环[4,3,0]壬-5-烯、碳酸铯、磷酸钾、二(三甲基硅基)氨基钠、二(三甲基硅基)氨基锂、二(三甲基硅基)氨基钾、叔丁醇钾、叔丁醇钠或者二异丙基乙基胺;
其中R1或R2任意选自H,C1-C16的烷基、C3-C16的环烷基、氨基或取代的胺基、烷氧基或者卤素原子;R1或R2可以单独成键或者相互成键;R3任意选自酰基、C5~C10的含N、O或S的杂环基或者杂芳基、取代的芳基或者C1-C16的烷基;X为羰基或者n=0,1,2;
R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、R15、R16或R17为H、C1-C16的烷基、C5~C10的含N、O或S的杂环基、芳基或取代芳基;各取代基可单独成键或者相互成键形成C5-C7的环烷基、芳基、取代芳基、含N、O、S的杂芳基或杂环烷基;
所述取代的芳基上的取代基为烷基、烷氧基碳数为1~18;取代的胺基上的取代基为C1-C16的烷基、芳基、取代芳基或者C5~C10的含N、O或S的杂环芳基或者杂环烷基;A1、A2、A3或、A4任意为Cl-、Br-、BF4 -或ClO4 -;所述的烷基、烃氧基或酰基的碳数为1~18;所述的芳基是苯基、C5~C10的含N、O或S的杂环基或C5~C10的含N、O和S的杂芳基。
2.根据权利要求1所述的合成具高对映选择性的醛基取代的小环胺类化合物和有光学活性3-位取代内酰胺类化合物的方法,其特征是所述的醛基取代小环胺类化合物、氮杂环卡宾前体盐、碱的摩尔比为1∶0.01-0.2∶0.01-0.2。
3.根据权利要求1所述的合成具高对映选择性的醛基取代的小环胺类化合物和有光学活性3-位取代内酰胺类化合物的方法,其特征是所述的消旋的醛基取代小环胺类化合物、手性氮杂环卡宾、碱的摩尔比为1∶0.01-0.2∶0。
5.如权利要求1所述的合成具高对映选择性的醛基取代的小环胺类化合物和有光学活性3-位取代内酰胺类化合物的方法,其特征是所述有机溶剂是苯、四氯化碳、石油醚、四氢呋喃、二甲基甲酰胺、二甲基乙酰胺、乙醚、二氯甲烷、三氯甲烷、甲苯、二甲苯、环己烷、正己烷、正庚烷、二氧六环或乙腈。
6.如权利要求1所述的合成合成具高对映选择性的醛基取代的小环胺类化合物和有光学活性3-位取代内酰胺类化合物的方法,其特征是所得产物经过重结晶,薄层层析或柱层析减压蒸馏加以分离。
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US11578072B2 (en) | 2018-01-31 | 2023-02-14 | Aptinyx Inc. | Spiro-lactam NMDA receptor modulators and uses thereof |
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