CN105330608B - 脲唑类轴手性化合物及其催化不对称合成方法 - Google Patents
脲唑类轴手性化合物及其催化不对称合成方法 Download PDFInfo
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 65
- UDATXMIGEVPXTR-UHFFFAOYSA-N 1,2,4-triazolidine-3,5-dione Chemical compound O=C1NNC(=O)N1 UDATXMIGEVPXTR-UHFFFAOYSA-N 0.000 title claims abstract description 22
- 238000000034 method Methods 0.000 title abstract description 32
- 238000011914 asymmetric synthesis Methods 0.000 title abstract description 5
- 230000003197 catalytic effect Effects 0.000 title description 2
- 238000006243 chemical reaction Methods 0.000 claims abstract description 104
- 239000003054 catalyst Substances 0.000 claims abstract description 91
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 19
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 18
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 16
- 150000002367 halogens Chemical class 0.000 claims abstract description 16
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 14
- 239000001257 hydrogen Substances 0.000 claims abstract description 14
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 12
- 238000010189 synthetic method Methods 0.000 claims abstract description 11
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 72
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- -1 substituted-phenyl Chemical group 0.000 claims description 20
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- 125000003172 aldehyde group Chemical group 0.000 abstract 1
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- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
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- 229910001868 water Inorganic materials 0.000 description 6
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- 125000001033 ether group Chemical group 0.000 description 5
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- 238000004293 19F NMR spectroscopy Methods 0.000 description 4
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
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- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 3
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- 238000002360 preparation method Methods 0.000 description 3
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
- C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D249/12—Oxygen or sulfur atoms
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
- B01J31/0234—Nitrogen-, phosphorus-, arsenic- or antimony-containing compounds
- B01J31/0235—Nitrogen containing compounds
- B01J31/0244—Nitrogen containing compounds with nitrogen contained as ring member in aromatic compounds or moieties, e.g. pyridine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/32—Oxygen atoms
- C07D209/38—Oxygen atoms in positions 2 and 3, e.g. isatin
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- C07—ORGANIC CHEMISTRY
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- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
- B01J2231/30—Addition reactions at carbon centres, i.e. to either C-C or C-X multiple bonds
- B01J2231/34—Other additions, e.g. Monsanto-type carbonylations, addition to 1,2-C=X or 1,2-C-X triplebonds, additions to 1,4-C=C-C=X or 1,4-C=-C-X triple bonds with X, e.g. O, S, NH/N
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- Catalysts (AREA)
Abstract
本发明公开了一类脲唑类轴手性化合物,其具有式I或式II,其中,R1a选自烷基、卤素、苯基、取代苯基、 R5选自卤素、烷基和烷氧基,R6、R7各自独立地选自脂肪族取代基和芳香族取代基;R1b、R1c、R1d和R1e各自独立地选自氢、卤素、苯基、取代苯基、烷基、烷氧基、羟基、酯基、醛基、氰基和酰胺;R为无取代基或有一个或多个取代基的芳基;R’为氢或烷基。本发明还公开了这类化合物的不对称合成方法。本发明在温和的反应条件下,以高产率、高ee值合成得到脲唑类轴手性化合物;合成方法具有很好的底物适应性,能够在减少催化剂用量的情况下实现克以上规模的合成。本发明的化合物可以作为某些不对称反应的催化剂或者配体。
Description
技术领域
本发明涉及一类脲唑类轴手性化合物及其催化不对称合成方法。
背景技术
脲唑是重要的杂环化合物,由于化学合成简单,且易于优化反应条件,脲唑在医药和蛋白质化学修饰领域具有潜在的应用价值。此外,脲唑的氧化可以为多功能转换提供一类持续的环肼自由基。因此,脲唑类化合物有广阔的应用前景。
酪氨酸的点击反应提供了一个简单的策略在温和的条件下合成这类化合物,Barbas课题组用偶氮二碳酰胺(三氮唑二酮)化合物选择性地、迅速地和酪氨酸的酚侧链反应得到脲唑,并用于生物共轭化学。
目前还有其他一些合成这类化合物的方法,但是还没有催化对映选择性直接构建手性脲唑的报道。双功能有机催化剂在不对称催化领域有广泛的应用,可以用于催化多种不对称反应,催化剂的酸性和碱性中心同时充当氢键供体和受体,在一个合适的空间构象同时活化亲核试剂和亲电试剂。
发明内容
本发明的目的是提供一类新型的脲唑类轴手性化合物。
本发明的另一目的是提供该类化合物的催化不对称合成方法。
本发明的另一目的是提供该类化合物的用途。
为达到上述目的之一,本发明采用以下技术方案:
脲唑类轴手性化合物,其具有式I或式II:
其中,R1a选自烷基、卤素、苯基、取代苯基、 和R5选自卤素、烷基和烷氧基,R6、R7各自独立地选自脂肪族取代基和芳香族取代基;
R1b、R1c、R1d和R1e各自独立地选自氢、卤素、苯基、取代苯基、烷基、烷氧基、羟基、酯基、醛基、氰基和酰胺;
R为芳基,所述芳基无取代基或有一个或多个取代基;R’为氢或烷基。
进一步地,所述R6、R7各自独立地选自烷基、苯基和取代苯基;
所述R1b、R1c、R1d和R1e各自独立地选自氢、烷基、苯基、取代苯基和卤素;
所述R选自苯基、萘基、吲哚基和喹啉基。
进一步地,所述R5选自甲基、甲氧基和卤素,R6、R7各自独立地选自甲基、乙基、异丙基、环己基、苯基和取代苯基;
所述R选自和其中,R2为羟基或烷氧基,R2a、R2b、R3、R4a、R4b各自独立地选自氢、卤素、苯基、取代苯基、烷基、烷氧基、羟基、酯基、醛基、氰基和酰胺。
进一步地,R1a选自溴、碘、苯基和取代苯基;所述R2为羟基或甲氧基,所述R2a、R2b各自独立地选自氢、溴、苯基、甲氧基、氰基和对甲基苯基,所述R3选自叔丁基和苯基,R4a选自苯基、对氟苯基、对氯苯基、异丙基和甲基,所述R4b选自氢、溴和苯基;所述R’为氢或甲基。
进一步地,脲唑类轴手性化合物,选自以下化合物:
和
前面所述脲唑类轴手性化合物的合成方法,其至少包含以下步骤:在有机溶剂中,以手性硫脲或手性磷酸为催化剂,芳环化合物与式III或者式IV化合物反应得到产物:
R1a选自烷基、卤素、苯基、取代苯基、 和R5选自卤素、烷基和烷氧基,R6、R7各自独立地选自脂肪族取代基和芳香族取代基;
R1b、R1c、R1d和R1e各自独立地选自氢、卤素、苯基、取代苯基、烷基、烷氧基、羟基、酯基、醛基、氰基和酰胺;所述芳环化合物无取代基或有一个或多个取代基。
进一步地,所述手性硫脲选自具有以下结构式的化合物:
所述手性磷酸选自具有以下结构式的化合物:
最优选的手性硫脲是C7;最优选的手性磷酸是CP5。
进一步地,所述有机溶剂为二氯甲烷、甲苯和乙醚中的一种或两种。
进一步地,所述有机溶剂为二氯甲烷和乙醚按照体积比1:1混合而成。
进一步地,所述催化剂相对于芳环化合物的用量是1~20mol%。
进一步地,所述芳环化合物与式III化合物的摩尔比是1:1~2,所述芳环化合物与式IV化合物的摩尔比是1:1~2;最优选的摩尔比是1:1.2。
进一步地,所述式I化合物和式II化合物反应的温度是-78~-40℃;最优选的温度是-78℃。
前面所述的脲唑类轴手性化合物在不对称反应中可以作为催化剂或者配体:
由于化合物3a~3r、6a~6h、6k~6r、5a~5m具有类似3a的轴手性结构,因此这些化合物也可以作为不对称反应的配体。经过反应条件的筛选,ee值可进一步提高。显而易见的是,本发明的脲唑类轴手性化合物还可以作为其他不对称反应的配体或者催化剂。
本发明具有以下有益效果:
本发明在温和的反应条件下,使用简单、容易制备的原料,以高产率合成得到脲唑类轴手性化合物;本发明的合成方法具有很好的对映选择性,所得产物的对映体过量(ee)值大于90%;本发明的合成方法具有很好的底物适应性,芳环化合物作为亲核试剂,可以是萘酚、苯酚、吲哚、喹啉等,萘酚上可以有吸电子取代基或者供电子取代基,吲哚环取代基的电性、位阻、位置对反应的顺利进行也没有影响,化合物III和IV的取代基也可以是多种多样的,R1a可以是溴或碘,所得产物方便进行一系列转变,比如在过渡金属催化的反应中,溴或碘是非常好的活化基团;本发明的合成方法反应速度快,大多数底物可以在5min~2h内完成反应;本发明合成方法所用催化剂来源方便,没有重金属污染,能够在减少催化剂用量的情况下实现克以上规模的合成,可以实现工业化制备。
本发明合成的脲唑类轴手性化合物具有很好的稳定性,在溶剂(甲苯或乙腈)中长时间(12h)加热(80℃)后,其ee值没有变化;本发明通过实验证明,这类脲唑类轴手性化合物可以作为某些不对称反应的催化剂或者配体,对产物进行简单的衍生化可以得到两对对映异构体,为产物的进一步修饰提供了新途径,因此这类化合物在医药、不对称催化领域具有非常广阔的应用前景。
具体实施方式
以下所用化学试剂均购自商业化产品,除有特别说明外,无需进一步纯化。薄层色谱分析(TLC)使用60F254硅胶板,在254nm的UV光下显色。硅胶柱层析使用青岛海洋硅胶(60,颗粒0.040-0.063mm)。NMR图谱使用Bruker 400核磁共振仪表征,1H NMR为400MHz,13CNMR为100MHz,19F NMR为376MHz,溶剂为氘代氯仿或氘代丙酮。化学位移的单位是ppm,耦合常数的单位是Hz。高分辨质谱(HRMS)使用LC-TOF光谱仪测定。对映体过量用Agilent HPLC测定,使用大赛璐手性柱。
化合物3a~3h、3k~3r的核磁图谱比较混乱,峰的裂分不清楚,因此将其衍生成化合物6a~6h、6k~6r,进行核磁图谱表征。
化合物3a~3r、6a~6h、6k~6r的通用合成步骤为:
在舒仑克管中将0.12mmol的化合物2与手性催化剂溶于有机溶剂,所得溶液在-78℃搅拌10min,然后加入0.10mmol化合物1,反应至红色消失,用TLC监测反应完成后,反应液用6N盐酸酸化,经浓缩、硅胶柱层析(CH2Cl2~CH2Cl2/丙酮=10/1)纯化后得到产物3。
室温下,将0.2mmol化合物3和2.0mmol碘甲烷溶于1mL 1,4-二氧六环,加入0.4mmol碳酸钾,所得溶液在室温下搅拌5h,经硅胶柱层析(EA/PE=1:2)得到产物6。
化合物5a~5m的通用合成步骤为:
在舒仑克管中将0.12mmol的化合物2与手性催化剂溶于有机溶剂,所得溶液在-78℃搅拌10min,然后加入0.10mmol化合物4,反应至紫色消失,用TLC监测反应完成后,反应液用6N盐酸酸化经浓缩、硅胶柱层析(CH2Cl2/丙酮=20/1)纯化后得到产物5。
以上方法,根据所合成产物的不同,可以对溶剂种类和用量、催化剂种类和用量、反应温度、纯化方法进行适当调整和变化,下面结合具体实施例对本发明做进一步的说明:
实施例1
在舒仑克管中将0.12mmol的化合物2a与手性催化剂C7(5mol%,0.005mmol)溶于2mL乙醚,所得溶液在-78℃搅拌10min,然后加入0.10mmol化合物1a,反应30min至红色消失,用TLC监测反应完成后,反应液用6N盐酸酸化,经浓缩、硅胶柱层析(CH2Cl2~CH2Cl2/丙酮=10/1)纯化后得到产物3a。
室温下,将0.2mmol化合物3a和2.0mmol碘甲烷溶于1mL 1,4-二氧六环,加入0.4mmol碳酸钾,所得溶液在室温下搅拌5h,经硅胶柱层析(EA/PE=1:2)得到产物6a。
化合物3a:82%产率;99%ee;
HPLC条件:Daicel CHIRALPAK AD-H柱,hexane(正己烷)/i-PrOH=85/15,0.8mL/min,T=25℃,λ=230nm,tR(major)=10.2min,tR(minor)=17.4min;
HRMS(ESI)calcd for C22H21N3O3Na+(M+Na)+398.1475,found 398.1473;
化合物6a:1H NMR(400MHz,CDCl3)δ8.15(d,J=8.8Hz,1H),8.04(d,J=8.8Hz,1H),7.88(d,J=8.4Hz,1H),7.67-7.61(m,2H),7.47(t,J=7.6Hz,2H),7.39(m,2H),7.42-7.36(d,J=7.6Hz,1H),4.07(s,3H),3.09(s,3H),1.52(s,9H);
13C NMR(100MHz,CDCl3)δ155.4,154.6,154.1,149.6,134.2,132.7,131.8,130.3,129.3,129.1,128.7,128.5,127.7,125.8,124.9,121.6,113.6,112.1,57.1,36.2,32.0,31.7。
实施例2
按实施例1的方法,溶剂为二氯乙烷,催化剂用量为10mmol%,催化剂为C1,5min内完成反应。化合物3a:57%产率;25%ee。
实施例3
按实施例1的方法,溶剂为二氯乙烷,催化剂用量为10mmol%,催化剂为C2,5min内完成反应。化合物3a:59%产率;5%ee。
实施例4
按实施例1的方法,溶剂为二氯乙烷,催化剂用量为10mmol%,催化剂为C3,5min内完成反应。化合物3a:68%产率;75%ee。
实施例5
按实施例1的方法,溶剂为二氯乙烷,催化剂用量为10mmol%,催化剂为C4,5min内完成反应。化合物3a:65%产率;11%ee。
实施例6
按实施例1的方法,溶剂为二氯乙烷,催化剂用量为10mmol%,催化剂为C5,5min内完成反应。化合物3a:63%产率;-9%ee。
实施例7
按实施例1的方法,溶剂为二氯乙烷,催化剂用量为10mmol%,催化剂为C6,5min内完成反应。化合物3a:61%产率;-45%ee。
实施例8
按实施例1的方法,溶剂为二氯乙烷,催化剂用量为10mmol%,催化剂为C7,5min内完成反应。化合物3a:68%产率;91%ee。
实施例9
按实施例1的方法,溶剂为二氯乙烷,催化剂用量为10mmol%,催化剂为C8,5min内完成反应。化合物3a:66%产率;-43%ee。
实施例10
按实施例1的方法,0.12mmol化合物2a,溶剂为二氯乙烷,催化剂用量为5mmol%,催化剂为C7,5min内完成反应。化合物3a:70%产率;98%ee。
实施例11
按实施例1的方法,0.20mmol化合物2a,溶剂为二氯乙烷,催化剂用量为5mmol%,催化剂为C7,5min内完成反应。化合物3a:87%产率;96%ee。
实施例12
按实施例1的方法,溶剂为甲苯,催化剂用量为10mmol%,催化剂为C7,90min完成反应。化合物3a:65%产率;90%ee。
实施例13
按实施例1的方法,溶剂为乙醚,催化剂用量为10mmol%,催化剂为C7,25min完成反应。化合物3a:73%产率;97%ee。
实施例14
按实施例1的方法,溶剂为乙醚,催化剂用量为3mmol%,催化剂为C7,90min完成反应。化合物3a:70%产率;98%ee。
实施例15
化合物3b:15min完成反应;85%产率;99%ee;
HPLC条件:Daicel CHIRALPAK AD-H柱,hexane/i-PrOH=85/15,1.0mL/min,T=25℃,λ=230nm,tR(major)=7.8min,tR(minor)=23.0min;
HRMS(ESI)calcd for C22H20BrN3O3Na+(M+Na)+476.0580,found 476.0579;
化合物6b:1H NMR(400MHz,CDCl3)δ8.24(s,1H),7.95(d,J=9.2Hz,1H),7.70(d,J=8.4Hz,1H),7.64(dd,J=8.0,1.2Hz,1H),7.50(dd,J=4.8,1.6Hz,1H),7.47-7.42(m,1H),7.37-7.33(m,2H),7.17(dd,J=7.6,1.2Hz,1H),4.03(s,3H),3.07(s,3H),1.51(s,9H);
13C NMR(100MHz,CDCl3)δ156.0,154.2,153.9,149.4,135.0,132.5,131.4,130.1,130.0,129.6,128.9,128.2,127.4,127.3,123.5,123.4,115.6,113.7,56.9,36.0,31.8,31.6。
实施例16
化合物3c:15min完成反应;81%产率;99%ee;
HPLC条件:Daicel CHIRALPAK AD-H柱,hexane/i-PrOH=85/15,1.0mL/min,T=25℃,λ=230nm,tR(major)=9.6min,tR(minor)=17.4min;
HRMS(ESI)calcd for C22H20BrN3O3 +(M+Na)+476.0580,found 476.0581;
化合物6c:1H NMR(400MHz,CDCl3)δ8.04(s,1H),8.03(d,J=8.8Hz,1H),7.94(d,J=8.8Hz,1H),7.70-7.65(m,2H),7.47(td,J=7.0,1.6Hz,1H),7.42(d,J=9.2Hz,1H),7.37(td,J=9.0,1.2Hz,1H),7.18(dd,J=7.6,1.2Hz,1H),4.06(s,3H),3.07(s,3H),1.51(s,9H);
13C NMR(100MHz,CDCl3)δ155.3,154.4,153.9,149.3,132.6,131.8,131.5,131.4,130.1,130.1,130.0,129.5,128.9,127.5,123.2,118.4,117.0,114.5,56.9,35.9,31.7,31.6。
实施例17
化合物3d:20min完成反应;61%产率;98%ee;
HPLC条件:Daicel CHIRALPAK IC柱,hexane/i-PrOH=70/30,1.0mL/min,T=25℃,λ=240nm,tR(minor)=33.6min,tR(major)=43.4min;
HRMS(ESI)calcd for C23H20N4O3Na+(M+Na)+423.1428,found 423.1429;
化合物6d:1H NMR(400MHz,CDCl3)δ8.28(s,1H),8.26(d,J=8.8Hz,1H),8.12(d,J=9.2Hz,1H),7.76(dd,J=8.8,1.2Hz,1H),7.66(dd,J=8.4,1.2Hz,1H),7.53(d,J=9.2Hz,1H),7.47(td,J=8.0,1.6Hz,1H),7.37(td,J=7.6,1.6Hz,1H),7.16(dd,J=7.6,1.6Hz,1H),4.12(s,3H),3.08(s,3H),1.50(s,9H);
13C NMR(100MHz,CDCl3)δ157.4,154.5,154.0,149.2,135.6,134.5,133.2,131.3,130.2,129.4,129.0,128.9,127.6,127.5,122.7,118.9,117.2,115.1,108.1,57.0,35.9,31.9,31.7。
实施例18
化合物3e:60min完成反应;76%产率;97%ee;
HPLC条件:Daicel CHIRALPAK AD-H柱,hexane/i-PrOH=85/15,1.0mL/min,T=25℃,λ=254nm,tR(major)=7.7min,tR(minor)=18.3min;
HRMS(ESI)calcd for C28H25N3O3Na+(M+Na)+474.1788,found 474.1789;
化合物6e:1H NMR(400MHz,CDCl3)δ8.22(d,J=0.8Hz,1H),8.03(d,J=9.2Hz,1H),7.92(d,J=8.4Hz,1H),7.73-7.67(m,3H),7.63(dd,J=8.4,1.6Hz,1H),7.55-7.51(m,2H),7.46-7.42(m,2H),7.38-7.33(m,2H),7.27(dd,J=8.0,1.6Hz,1H),4.02(s,3H),3.10(s,3H),1.52(s,9H);13C NMR(100MHz,CDCl3)δ155.3,154.1,152.7,149.6,141.4,141.0,134.5,132.4,131.9,130.0,129.0,128.8,128.5,128.1,127.9,127.7,127.5,124.5,119.3,115.3,112.8,56.2,35.7,31.6,31.4。
实施例19
化合物3f:60min完成反应;71%产率;99%ee;
HPLC条件:Daicel CHIRALPAK AD-H柱,hexane/i-PrOH=85/15,1.0mL/min,T=25℃,λ=260nm,tR(major)=7.5min,tR(minor)=26.5min;
HRMS(ESI)calcd for C29H27N3O3Na+(M+Na)+488.1945,found 488.1943;
化合物6f:1H NMR(400MHz,CDCl3)δ8.22(s,1H),8.05(d,J=9.2Hz,1H),7.93(d,J=8.4Hz,1H),7.70(d,J=8.4Hz,1H),7.67-7.63(m,3H),7.46(t,J=7.6Hz,1H),7.40-7.35(m,4H),7.29(s,1H),4.04(s,3H),3.11(s,3H),2.48(s,3H),1.54(s,9H);
13C NMR(100MHz,CDCl3)δ155.2,154.1,152.7,149.6,141.3,138.1,137.8,134.5,132.3,131.9,130.0,129.7,128.7,128.5,128.0,127.5,124.5,119.0,115.2,112.7,56.2,35.7,31.6,31.4,21.2。
实施例20
化合物3g:30min完成反应;81%产率;97%ee;
HPLC条件:Daicel CHIRALPAK AD-H柱,hexane/i-PrOH=85/15,1.0mL/min,T=25℃,λ=230nm,tR(minor)=20.0min,tR(major)=25.5min;
HRMS(ESI)calcd for C23H23N3O4Na+(M+Na)+428.1581,found 428.1576;
化合物6g:1H NMR(400MHz,CDCl3)δ7.90(d,J=9.2Hz,1H),7.74(d,J=9.2Hz,1H),7.63(dd,J=8.0,0.8Hz,1H),7.46-7.42(m,1H),7.37-7.34(m,2H),7.21-7.18(m,2H),7.08(dd,J=8.8,2.8Hz,1H),4.01(s,3H),3.93(s,3H),3.07(s,3H),1.50(s,9H);
13C NMR(100MHz,CDCl3)δ159.9,155.9,153.6,153.5,149.1,135.6,132.1,131.6,130.0,129.6,128.9,127.5,124.6,117.4,114.8,110.4,99.5,56.7,55.3,35.9,31.7,31.2。
实施例21
化合物3h:30min完成反应;70%产率;98%ee;
HPLC条件:Daicel CHIRALPAK AD-H柱,hexane/i-PrOH=85/15,1.0mL/min,T=25℃,λ=230nm,tR(minor)=18.1min,tR(major)=25.4min;
HRMS(ESI)calcd for C23H23N3O4Na+(M+Na)+428.1581,found 428.1580;
化合物6h:1H NMR(400MHz,CDCl3)δ8.05(d,J=9.2Hz,1H),7.91(d,J=9.2Hz,1H),7.65(dd,J=8.0,1.2Hz,1H),7.46(td,J=8.0,1.6Hz,1H),7.39-7.35(m,2H),7.31(dd,J=9.2,2.4Hz,1H),7.20(dd,J=7.6,1.6Hz,1H),7.17(d,J=2.4Hz,1H),4.03(s,3H),3.95(s,3H),3.08(s,3H),1.51(s,9H);
13C NMR(100MHz,CDCl3)δ156.8,154.4,153.8,153.4,149.3,131.5,130.8,130.1,130.0,129.7,129.3,128.8,127.4,123.0,121.4,117.1,114.1,106.1,56.9,55.4,35.9,31.7,31.4。
实施例22
50min完成反应;51%产率;94%ee;
HPLC条件:Daicel CHIRALPAK AD-H柱,hexane/i-PrOH=95/5,1.2mL/min,T=25℃,λ=214nm,tR(major)=10.9min,tR(minor)=19.9min;
HRMS(ESI)calcd for C22H27N3O3Na+(M+Na)+404.1945,found 404.1944;
1H NMR(400MHz,CDCl3)δ7.65(d,J=8.0Hz,1H),7.49(t,J=7.6Hz,1H),7.35-7.33(m,2H),7.23(d,J=8.8Hz,1H),7.11(d,J=7.6Hz,1H),6.99(d,J=8.4Hz,1H),1.40(s,9H),1.23(s,9H);13C NMR(100MHz,CDCl3)δ154.1,151.0,149.2,146.0,144.6,131.3,130.7,129.1,127.8,127.6,125.9,123.6,119.6,118.1,35.9,34.3,31.6,31.3。
实施例23
50min完成反应;60%产率;90%ee;
HPLC条件:Daicel CHIRALPAK AD-H柱,hexane/i-PrOH=85/15,1.0mL/min,T=25℃,λ=254nm,tR(major)=6.1min,tR(minor)=9.8min;
HRMS(ESI)calcd for C24H24N3O3 +(M+H)+402.1812,found 402.1815;
1H NMR(400MHz,CDCl3)δ7.65(dd,J=8.0,1.2Hz,1H),7.60(d,J=2.0Hz,1H),7.52-7.44(m,4H),7.40-7.33(m,4H),7.15(d,J=8.4Hz,1H),7.13(d,J=8.0Hz,1H),1.37(s,9H);13C NMR(100MHz,CDCl3)δ154.2,151.6,149.1,147.7,139.6,134.9,131.2,130.8,129.2,128.9,127.7,127.6,127.4,127.3,126.8,124.9,120.7,119.3,35.9,31.6。
实施例24
在100mL圆底烧瓶中将3.84mmol的化合物2a与手性催化剂C7(5mol%,0.16mmol)溶于65mL乙醚,所得溶液在-78℃搅拌20min,然后加入3.20mmol化合物1a,继续在-78℃搅拌反应至红色消失,用TLC监测反应完成后,反应液用6N盐酸酸化,经浓缩、硅胶柱层析(CH2Cl2~CH2Cl2/丙酮=10/1)纯化后得到白色固体产物3a(1.02g)。反应时间4h,85%收率,98%ee。本实施例证明本发明的合成方法能实现克以上规模的合成,实现工业化制备。
实施例25
化合物3k:30min完成反应;70%产率;99%ee;
HPLC条件:Daicel CHIRALPAK AD-H柱,hexane/i-PrOH=85/15,0.8mL/min,T=25℃,λ=230nm,tR(major)=9.1min,tR(minor)=34.1min;
HRMS(ESI)calcd for C22H20BrN3O3 +(M+Na)+476.0580,found 476.0579;
化合物6k:1H NMR(400MHz,CDCl3)δ8.11(d,J=8.8Hz,1H),8.05(d,J=9.2Hz,1H),7.89(d,J=8.0Hz,1H),7.77(d,J=2.4Hz,1H),7.63(td,J=6.8,1.2Hz,1H),7.52(dd,J=8.4,2.4Hz,1H),7.47(td,J=7.8,1.2Hz,1H),7.40(d,J=9.2Hz,1H),7.07(d,J=8.43Hz,1H),4.06(s,3H),3.08(s,3H),1.50(s,9H);
13C NMR(100MHz,CDCl3)δ155.1,153.8,153.3,151.7,133.9,133.2,132.6,132.2,130.7,129.0,128.9,128.5,128.3,124.7,124.4,121.2,116.2,113.3,56.9,36.1,31.5,31.3。
实施例26
化合物3l:30min完成反应;64%产率;98%ee;
HPLC条件:Daicel CHIRALPAK AD-H柱,T=25℃,λ=230nm,hexane/i-PrOH=80/20,1mL/min,tR(major)=5.6min,tR(minor)=17.9min;
HRMS(ESI)calcd for C28H25N3O3Na+(M+Na)+474.1788,found 474.1790;
化合物6l:1H NMR(400MHz,CDCl3)δ8.14(d,J=10Hz,1H),8.06(d,J=9.2Hz,1H),7.89(d,J=8.4Hz,1H),7.83(d,J=2.0Hz,1H),7.66-7.62(m,3H),7.57(dd,J=8.0,2.0Hz,1H),7.51-7.39(m,5H),7.34(d,J=8.0Hz,1H),4.05(s,3H),3.09(s,3H),1.58(s,9H);13CNMR(100MHz,CDCl3)δ154.9,154.1,152.6,149.7,143.0,141.0,134.2,132.6,132.2,129.2,129.0,128.8,128.5,128.2,127.8,127.6,127.5,126.4,124.6,121.5,115.1,112.9,56.2,35.99,31.6,31.4。
实施例27
化合物3m:90min完成反应;68%产率;91%ee;
HPLC条件:Daicel CHIRALPAK AD-H柱,hexane/i-PrOH=85/15,1mL/min,T=25℃,λ=230nm,tR(major)=15.0min,tR(minor)=21.3min;
HRMS(ESI)calcd for C20H16IN3O3Na+(M+Na)+496.0129,found 496.0131;
化合物6m:1H NMR(400MHz,CDCl3)δ8.05(d,J=9.2Hz,1H),8.00(d,J=8.8Hz,1H),7.89(d,J=8.0Hz,1H),7.68(s,1H),7.62(td,J=7.6,1.2Hz,1H),7.46(td,J=7.6,0.8Hz,1H),7.42(d,J=9.2Hz,1H),7.16(s,1H),4.06(s,3H),3.10(s,3H),2.43(s,3H),2.35(s,3H);
13C NMR(100MHz,CDCl3)δ156.0,152.0,151.0,141.9,138.8,138.5,134.1,133.0,132.3,130.7,129.3,128.7,128.6,124.8,121.4,115.1,113.8,99.5,57.1,31.8,21.0,19.3。
实施例28
化合物3n:120min完成反应;70%产率;90%ee;
HPLC条件:Daicel CHIRALPAK IC柱,hexane/i-PrOH=70/30,1mL/min,T=25℃,λ=240nm,tR(minor)=18.3min,tR(major)=24.8min;
HRMS(ESI)calcd for C19H13BrIN3O3Na+(M+Na)+559.9077,found 559.9077;
化合物6n:1H NMR(400MHz,CDCl3)δ8.19(d,J=8.4Hz,1H),8.06(d,J=9.2Hz,1H),7.98(d,J=2.0Hz,1H),7.89(d,J=8.4Hz,1H),7.64(t,J=7.6Hz,1H),7.53(d,J=1.2Hz,1H),7.47(t,J=7.2Hz,1H),7.41(d,J=9.2Hz,1H),4.01(s,3H),3.10(s,3H),2.47(s,3H);
13C NMR(100MHz,CDCl3)δ1550,151.3,150.2,141.0,139.4,134.0,134.0,133.6,132.7,128.9,128.6,128.2,124.7,124.4,121.4,115.2,113.0,100.8,56.4,31.6,18.7。
实施例29
化合物3o:90min完成反应;70%产率;98%ee;
HPLC条件:Daicel CHIRALPAK AD-H柱,hexane/i-PrOH=85/15,1mL/min,T=25℃,λ=230nm,tR(major)=17.1min,tR(minor)=25.3min;
HRMS(ESI)calcd for C19H14IN3O3Na+(M+Na)+481.9972,found 481.9974;
化合物6o:1H NMR(400MHz,CDCl3)δ8.06(d,J=9.2Hz,1H),8.01(d,J=8.4Hz,1H),7.89(d,J=8.0Hz,1H),7.85(d,J=7.6Hz,1H),7.63(t,J=7.6Hz,1H),7.47(td,J=7.6,0.8Hz,1H),7.43(d,J=9.2Hz,1H),7.35(d,J=7.6Hz,1H),7.11(t,J=7.6Hz,1H),4.07(s,3H),3.11(s,3H),2.48(s,3H);13C NMR(100MHz,CDCl3)δ155.7,151.5,150.5,139.3,137.8,133.8,133.1,132.8,131.3,131.1,129.0,128.5,128.4,124.6,121.1,114.7,113.5,99.5,56.8,31.5,19.1。
实施例30
化合物3p:60min完成反应;70%产率;93%ee;
HPLC条件:Daicel CHIRALPAK AD-H柱,hexane/i-PrOH=85/15,1mL/min,T=25℃C,λ=230nm,tR(major)=21.2min,tR(minor)=28.2min;
HRMS(ESI)calcd for C19H14BrN3O3Na+(M+Na)+434.0111,found 434.0111;
化合物6p:37%产率;85%ee;
HPLC条件:Daicel CHIRALPAK ID柱,hexane/i-PrOH=60/40,1mL/min,T=25℃,λ=230nm,tR(minor)=34.9min,tR(major)=44.6min;
1H NMR(400MHz,CDCl3)δ8.07(d,J=4.4Hz,1H),8.05(d,J=4.8Hz,1H),7.89(d,J=8.4Hz,1H),7.65-7.61(m,2H),7.46(td,J=8.0,1.2Hz,1H),7.42(d,J=9.2Hz,1H),7.34(d,J=7.2Hz,1H),7.29(t,J=8.0Hz,1H),4.05(s,3H),3.10(s,3H),2.47(s,3H);
13C NMR(100MHz,CDCl3)δ155.8,152.0,151.5,140.1,134.2,133.0,131.6,131.2,130.4,129.9,129.3,128.7,128.6,124.8,124.3,121.4,115.5,113.7,57.0,31.8,19.0。
经过对化合物6p’的X射线衍射分析,确定化合物3p的绝对构型为aS。
化合物6p’:55%产率;91%ee;
HPLC条件:Daicel CHIRALPAK IC柱,hexane/i-PrOH=70/30,1mL/min,T=25℃,λ=230nm,tR(major)=19.7min,tR(minor)=28.7min;
1H NMR(400MHz,CDCl3)δ8.19(d,J=8.8Hz,1H),8.05(d,J=8.8Hz,1H),7.88(d,J=8.4Hz,1H),7.64(t,J=7.6Hz,1H),7.60((d,J=7.6Hz,1H)),7.47(t,J=7.2Hz,1H),7.41-7.39(m,1H),7.34(d,J=7.6Hz,1H),7.27(t,J=7.6Hz,1H),4.02(s,3H),3.10(s,3H),2.49(s,3H);
13C NMR(100MHz,CDCl3)δ155.1,152.0,151.7,140.2,134.0,132.6,131.0,130.1,129.6,129.3,129.0,128.5,128.2,124.7,124.3,121.5,115.7,113.1,56.5,31.7,18.4。
实施例31
化合物3q:60min完成反应;73%产率;95%ee;
HPLC条件:Daicel CHIRALPAK IC柱,hexane/i-PrOH=70/30,1mL/min,T=25℃,λ=230nm,tR(major)=8.5min,tR(minor)=23.2min;
HRMS(ESI)calcd for C25H19N3O3Na+(M+Na)+432.1319,found 432.1319;
化合物6q:1H NMR(400MHz,CDCl3)δ7.99(d,J=9.2Hz,1H),7.86(d,J=8.8Hz,2H),7.59(t,J=8.0Hz,1H),7.54-7.52(m,2H),7.48-7.39(m,6H),7.34-7.30(m,2H),3.76(s,3H),2.89(s,3H),2.49(s,3H);13C NMR(100MHz,CDCl3)δ155.8,153.1,150.6,142.8,139.3,137.6,133.3,132.5,130.3,129.7,129.1,128.95,128.9,128.4,128.4,128.1,128.0,127.2,124.6,121.1,114.1,113.7,56.8,31.5,18.2。
实施例32
化合物3r:60min完成反应;62%产率;92%ee;
HPLC条件:Daicel CHIRALPAK AD-H柱,hexane/i-PrOH=75/25,1mL/min,T=25℃,λ=254nm,tR(minor)=11.8min,tR(major)=32.0min;
HRMS(ESI)calcd for C22H13BrIN3O3Na+(M+Na)+595.9077,found 595.9075;
化合物6r:1H NMR(400MHz,CDCl3)δ8.36(s,1H),8.32(d,J=8.0Hz,1H),8.27(d,J=8.4Hz,1H),8.08(d,J=9.2Hz,1H),8.04(d,J=8.0Hz,1H),7.90(d,J=8.0Hz,1H),7.74-7.65(m,3H),7.49(t,J=7.6Hz,1H),7.45(d,J=9.2Hz,1H),4.15(s,3H),3.17(s,3H);
13C NMR(100MHz,CDCl3)δ155.0,151.7,138.2,134.1,132.8,132.7,132.6,131.0,129.1,128.9,128.6,128.4,128.2,128.2,128.1,125.7,124.8,123.4,121.5,115.9,113.2,98.2,56.8,31.7。
实施例33
在舒仑克管中将0.12mmol的化合物2a与手性催化剂CP5(5mol%,0.005mmol)溶于2mL溶剂(二氯甲烷和乙醚按体积比1:1组成),所得溶液在-78℃搅拌10min,然后加入0.10mmol化合物4a,继续在-78℃反应10min至紫色消失,用TLC监测反应完成后,反应液用经浓缩、硅胶柱层析(CH2Cl2/丙酮=20/1)纯化后得到产物5a。
化合物3r:96%产率;97%ee;
HPLC条件:Daicel CHIRALPAK IC柱,hexane/i-PrOH=80/20,1.0mL/min,T=25℃,λ=230nm,tR(minor)=16.4min,tR(major)=25.2min;
HRMS(ESI)calcd for C26H24N4O2Na+(M+Na)+447.1791,found 447.1791;
1H NMR(400MHz,Acetone-d6)δ10.97(s,1H),9.80(brs,1H),7.94-7.92(m,2H),7.70(dd,J=8.0,1.2Hz,1H),7.69(d,J=7.6Hz,1H),7.57-7.45(m,5H),7.39(td,J=7.6,1.6Hz,1H),7.32(dd,J=8.0,1.6Hz,1H),7.27(td,J=7.2,1.2Hz,1H),7.20(td,J=7.6,0.8Hz,1H),1.49(s,9H);
13C NMR(100MHz,Acetone-d6)δ153.9,153.2,149.2,136.8,134.9,132.2,130.6,130.3,129.8,128.9,128.6,128.5,127.6,127.2,125.5,123.0,120.6,117.9,112.0,108.1,35.6,31.2。
实施例34
按实施例33的方法,溶剂为乙醚,催化剂用量为10mmol%,催化剂为C6,48h完成反应。化合物5a:69%产率;5%ee。
实施例35
按实施例33的方法,溶剂为DCM/Et2O=1/1,催化剂用量为10mmol%,催化剂为C6,30min完成反应。化合物5a:73%产率;5%ee。
实施例36
按实施例33的方法,溶剂为DCM,催化剂用量为10mmol%,催化剂为C6,5min内完成反应。化合物5a:76%产率;3%ee。
实施例37
按实施例33的方法,溶剂为DCM,催化剂用量为10mmol%,催化剂为C7,5min内完成反应。化合物5a:78%产率;-19%ee。
实施例38
按实施例33的方法,溶剂为乙醚,催化剂用量为10mmol%,催化剂为C7,24h完成反应。化合物5a:74%产率;-15%ee。
实施例39
按实施例33的方法,溶剂为DCM/Et2O=1/1,催化剂用量为10mmol%,催化剂为C7,30min完成反应。化合物5a:78%产率;-71%ee。
实施例40
按实施例33的方法,溶剂为乙醚,催化剂用量为10mmol%,催化剂为CP1,10h完成反应。化合物5a:96%产率;89%ee。
实施例41
按实施例33的方法,溶剂为二氯甲烷,催化剂用量为10mmol%,催化剂为CP1,5min内完成反应。化合物5a:99%产率;68%ee。
实施例42
按实施例33的方法,溶剂为甲苯,催化剂用量为10mmol%,催化剂为CP1,60min完成反应。化合物5a:94%产率;60%ee。
实施例43
按实施例33的方法,溶剂为DCM/Et2O=1/1,催化剂用量为10mmol%,催化剂为CP1,10min完成反应。化合物5a:99%产率;95%ee。
实施例44
按实施例33的方法,溶剂为DCM/Et2O=1/2,催化剂用量为10mmol%,催化剂为CP1,20min完成反应。化合物5a:98%产率;95%ee。
实施例45
按实施例33的方法,溶剂为DCM/Et2O=1/1,催化剂用量为10mmol%,催化剂为CP2,10min完成反应。化合物5a:99%产率;95%ee。
实施例46
按实施例33的方法,溶剂为DCM/Et2O=1/1,催化剂用量为10mmol%,催化剂为CP3,10min完成反应。化合物5a:98%产率;37%ee。
实施例47
按实施例33的方法,溶剂为DCM/Et2O=1/1,催化剂用量为10mmol%,催化剂为CP4,10min完成反应。化合物5a:99%产率;85%ee。
实施例48
按实施例33的方法,溶剂为DCM/Et2O=1/1,催化剂用量为10mmol%,催化剂为CP5,10min完成反应。化合物5a:99%产率;97%ee。
实施例49
按实施例33的方法,溶剂为DCM/Et2O=1/1,催化剂用量为10mmol%,催化剂为CP6,10min完成反应。化合物5a:96%产率;-77%ee。
实施例50
按实施例33的方法,溶剂为DCM/Et2O=1/1,催化剂用量为10mmol%,催化剂为CP7,10min完成反应。化合物5a:96%产率;-47%ee。
实施例51
按实施例33的方法,溶剂为DCM/Et2O=1/1,催化剂用量为10mmol%,催化剂为CP8,10min完成反应。化合物5a:97%产率;-79%ee。
实施例52
按实施例33的方法,溶剂为DCM/Et2O=1/1,催化剂用量为10mmol%,催化剂为CP9,10min完成反应。化合物5a:98%产率;-95%ee。
实施例53
按实施例33的方法,溶剂为DCM/Et2O=1/1,催化剂用量为10mmol%,催化剂为CP10,10min完成反应。化合物5a:99%产率;-89%ee。
实施例54
按实施例33的方法,溶剂为DCM/Et2O=1/1,催化剂用量为3mmol%,催化剂为CP5,10min完成反应。化合物5a:99%产率;95%ee。
实施例55
按实施例33的方法,溶剂为DCM/Et2O=1/2,催化剂用量为1mmol%,催化剂为CP5,40min完成反应。化合物5a:99%产率;95%ee。
实施例56
在100mL圆底烧瓶中将3.6mmol的化合物2a与手性催化剂CP5(1mol%,0.03mmol)溶于60mL溶剂(二氯甲烷和乙醚按体积比1:2组成),所得溶液在-78℃搅拌20min,然后加入3.0mmol化合物4a,继续在-78℃反应至紫色消失,用TLC监测反应完成后,反应液用经浓缩、硅胶柱层析(CH2Cl2/丙酮=20/1)纯化后得到白色固体产物5a(1.22g)。反应时间40min,96%收率,95%ee。
本实施例证明本发明的合成方法能实现克以上规模的合成,实现工业化制备。
实施例57
15min完成反应;95%产率;96%ee;
HPLC条件:Daicel CHIRALPAK IC柱,hexane/i-PrOH=80/20,1.0mL/min,T=25℃,λ=230nm,tR(minor)=9.3min,tR(major)=15.8min;
HRMS(ESI)calcd for C26H24FN4O2 +(M+H)+443.1878,found 443.1879;
1H NMR(400MHz,Acetone-d6)δ10.98(s,1H),9.71(brs,1H),7.99-7.95(m,2H),7.70(dd,J=8.0,1.6Hz,1H),7.69(d,J=7.6Hz,1H),7.52(d,J=8.4Hz,1H),7.49(td,J=8.0,1.6Hz,1H),7.39(td,J=7.2,1.2Hz,1H),7.35-7.29(m,3H),7.27(td,J=7.2,1.2Hz,1H),7.21(td,J=7.6,1.2Hz,1H),1.49(s,9H);13C NMR(100MHz,Acetone-d6)δ162.8(d,JC-F=246Hz),153.9,153.3,149.2,135.9,134.9,132.2,130.2,129.8,129.7(d,3JC-F=8.4Hz),128.6,127.2,127.0(d,4JC-F=3.3Hz),125.3,123.0,120.7,117.9,115.8(d,2JC-F=21.8Hz),112.0,108.0,35.6,31.2;19F NMR(376MHz,Acetone-d6)δ-114.06(s,1F)。
实施例58
20min完成反应;95%产率;92%ee;
HPLC条件:Daicel CHIRALPAK IC柱,hexane/i-PrOH=80/20,1.0mL/min,T=25℃,λ=240nm,tR(minor)=9.1min,tR(major)=16.4min;
HRMS(ESI)calcd for C26H23ClN4O2Na+(M+Na)+481.1402,found 481.1403;
1H NMR(400MHz,Acetone-d6)δ11.04(s,1H),9.65(brs,1H),7.95-7.92(m,2H),7.71-7.70(m,2H),7.60-7.56(m,2H),7.53(d,J=8.0Hz,1H),7.50(td,J=8.0,1.6Hz,1H),7.39(td,J=8.0,1.6Hz,1H),7.33(td,J=8.0,1.6Hz,1H),7.28(td,J=7.6,0.8Hz,1H),7.21(td,J=7.6,0.8Hz,1H),1.49(s,9H);
13C NMR(100MHz,Acetone-d6)δ153.9,153.3,149.2,135.4,135.0,134.0,132.2,130.2,129.8,129.4,129.1,129.0,128.5,127.2,125.3,123.2,120.8,118.0,112.0,108.6,35.6,31.2。
实施例59
15min完成反应;94%产率;94%ee;
HPLC条件:Daicel CHIRALPAK IC柱,hexane/i-PrOH=85/15,1.0mL/min,T=25℃,λ=254nm,tR(minor)=10.8min,tR(major)=15.0min;
HRMS(ESI)calcd for C26H23BrN4O2Na+(M+Na)+525.0897,found 525.0899;
1H NMR(400MHz,Acetone-d6)δ11.17(s,1H),9.82(brs,1H),7.93-7.89(m,3H),7.70(dd,J=8.4,1.2Hz,1H),7.56(t,J=8.0Hz,2H),7.51-7.46(m,3H),7.41-7.34(m,3H),1.49(s,9H);13CNMR(100MHz,Acetone-d6)δ154.0,153.1,149.2,138.4,133.5,132.3,130.2,130.0,129.8,129.0,129.0,128.5,127.7,127.2,127.2,125.6,120.4,113.9,113.5,107.4,35.6,31.2。
实施例60
15min完成反应;90%产率;96%ee;
HPLC条件:Daicel CHIRALPAK IC柱,hexane/i-PrOH=85/15,1.0mL/min,T=25℃,λ=254nm,tR(major)=16.6min,tR(minor)=19.7min;
HRMS(ESI)calcd forC32H28N4O2Na+(M+Na)+523.2104,found 523.2105;
1H NMR(400MHz,Acetone-d6)δ11.08(s,1H),9.81(s,1H),7.96(d,J=8.8Hz,2H),7.95(s,1H)7.74(d,J=7.6Hz,2H),7.70(d,J=8.4Hz,1H),7.84-7.55(m,4H),7.51(t,J=8.0Hz,2H),7.49(t,J=8.0Hz,2H),7.41-7.36(m,3H),1.51(s,9H);13C NMR(100MHz,Acetone-d6)δ154.0,153.1,149.2,142.0,137.6,134.5,134.1,132.2,130.5,130.4,129.7,128.9,128.8,128.7,128.5,127.6,127.2,127.1,126.6,126.1,122.6,116.1,112.4,108.4,35.6,31.2。
实施例61
10min完成反应;92%产率;93%ee;
HPLC条件:Daicel CHIRALPAK IC柱,hexane/i-PrOH=80/20,1.0mL/min,T=25℃,λ=230nm,tR(minor)=13.5min,tR(major)=22.9min;
HRMS(ESI)calcd for C26H23BrN4O2Na+(M+Na)+525.0897,found 525.0892;
1H NMR(400MHz,Acetone-d6)δ11.04(s,1H),7.91(d,J=8.0Hz,2H),7.84(s,1H),7.69(d,J=8.0Hz,1H),7.59(d,J=8.4Hz,1H),7.56-7.51(m,3H),7.46(t,J=7.2Hz,1H),7.33(d,J=8.4Hz,1H),7.27(t,J=7.6Hz,1H),7.20(t,J=7.6Hz,1H),1.49(s,9H);
13C NMR(100MHz,Acetone-d6)δ153.4,152.8,152.0,136.9,134.9,134.3,131.6,130.5,130.4,129.8,128.9,128.7,127.6,125.5,123.5,123.0,120.7,117.9,112.0,107.8,35.8,30.9。
实施例62
室温下,将0.2mmol化合物5f和2.0mmol碘甲烷溶于1mL丙酮,加入0.4mmol碳酸钾,所得溶液在室温下搅拌5h,经硅胶柱层析(EA/Hexane=1/4)得到产物7f。
93%产率;93%ee;
HPLC条件:Daicel CHIRALPAK ID柱,hexane/i-PrOH=60/40,1.0mL/min,T=25℃,λ=230nm,tR(minor)=17.8min,tR(major)=25.7min;
1H NMR(400MHz,CD3CN)δ7.81(dd,J=7.2,2.4Hz,1H),7.72(d,J=8.0Hz,0.6H),7.65-7.50(m,7.4H),7.40(td,J=7.2,1.6Hz,1H),7.32-7.28(m,1.6H),6.88(d,J=8.4Hz,0.4H),3.74(s,1.7H),3.73(s,1.3H),2.90(s,3H),1.45(s,4H),1.24(s,5H);
13C NMR(100MHz,CD3CN)δ154.2,154.1,153.9,152.9,152.8,152.8,142.9,142.6,137.0,136.9,134.8,134.6,132.8,132.7,131.5,131.2,131.2,130.5,130.5,130.3,130.3,130.1,129.8,129.7,129.7,125.8,125.3,124.7,123.9,123.9,122.2,122.1,117.9,111.7,111.7,107.2,106.1,36.7,36.6,32.3,32.1,32.0,31.9,31.7,31.5。
经过对化合物7f的X射线衍射分析,确定化合物5f的绝对构型为aR。
实施例63
15min完成反应;92%产率;93%ee;
HPLC条件:Daicel CHIRALPAK IC柱,hexane/i-PrOH=80/20,1.0mL/min,T=25℃,λ=230nm,tR(minor)=8.5min,tR(major)=15.8min;
HRMS(ESI)calcd for C26H22BrFN4O2Na+(M+Na)+543.0802,found 543.0801;
1H NMR(400MHz,Acetone-d6)δ11.01(s,1H),9.79(brs,1H),7.97-7.84(m,2H),7.83(d,J=2.0Hz,1H),7.69(d,J=8.0Hz,1H),7.59(dd,J=8.0,2.0Hz,1H),7.52(d,J=8.0Hz,1H),7.35-7.29(m,3H),7.27(td,J=8.0,0.8Hz,1H),7.20(td,J=8.0,0.8Hz,1H)),1.49(s,9H);
13C NMR(100MHz,Acetone-d6)δ162.9(d,JC-F=245.7Hz),153.4,152.8,151.9,135.9,134.9,134.3,131.7,130.4,129.7(d,3JC-F=8.2Hz),129.7,126.9(d,4JC-F=3.3Hz),125.3,123.6,123.0,120.7,117.9,115.8(d,2JC-F=21.6Hz),112.0,107.8,35.8,30.9;
19F NMR(376MHz,Acetone-D6)δ-113.97(s,1F)。
实施例64
20min完成反应;93%产率;91%ee;
HPLC条件:Daicel CHIRALPAK IC柱,hexane/i-PrOH=80/20,1.0mL/min,T=25℃,λ=230nm,tR(minor)=8.4min,tR(major)=16.3min;
HRMS(ESI)calcd for C26H22BrClN4O2Na+(M+Na)+559.0507,found 559.0500;
1H NMR(400MHz,Acetone-d6)δ11.07(s,1H),9.72(brs,1H),7.93(d,J=8.4Hz,2H),7.84(d,J=2.4Hz,1H),7.70(d,J=7.6Hz,1H),7.61-7.56(m,3H),7.52(d,J=8.0Hz,1H),7.35(d,J=8.4Hz,1H),7.28(t,J=8.0Hz,1H),7.21(t,J=7.6Hz,1H),1.49(s,9H);
13C NMR(100MHz,Acetone-d6)δ153.4,152.8,151.9,135.5,135.0,134.3,134.0,131.7,130.4,129.6,129.2,129.1,129.0,125.2,123.6,123.3,120.8,118.0,112.1,108.1,35.8,30.9。
实施例65
10min完成反应;92%产率;94%ee;
HPLC条件:Daicel CHIRALPAK IC柱,hexane/i-PrOH=80/20,1.0mL/min,T=25℃,λ=230nm,tR(minor)=9.8min,tR(major)=25.9min;
HRMS(ESI)calcd for C32H28N4O2Na+(M+Na)+523.2104,found 523.2103;
1H NMR(400MHz,Acetone-d6)δ10.99(s,1H),9.78(brs,1H),7.96-7.94(m,2H),7.92(d,J=2.0Hz,1H),7.75-7.71(m,3H),7.65(dd,J=8.0,2.0Hz,1H),7.58-7.52(m,5H),7.50-7.41(m,3H),7.28(td,J=7.2,0.8Hz,1H),7.22(td,J=7.2,0.8Hz,1H),1.56(s,9H);
13C NMR(100MHz,Acetone-d6)δ153.8,153.2,149.7,142.4,140.6,136.8,134.9,132.8,130.6,129.6,128.9,128.6,127.7,127.6,127.3,127.2,125.8,125.5,123.0,120.6,117.9,112.0,108.1,35.8,31.2。
实施例66
20min完成反应;91%产率;95%ee;
HPLC条件:Daicel CHIRALPAK IC柱,hexane/i-PrOH=80/20,1.0mL/min,T=25℃,λ=230nm,tR(minor)=11.0min,tR(major)=33.8min;
HRMS(ESI)calcd for C32H27FN4O2Na+(M+Na)+541.2010,found 541.2010;
1H NMR(400MHz,Acetone-d6)δ11.00(s,1H),9.75(brs,1H),8.01-7.96(m,2H),7.92(d,J=2.0Hz,1H),7.75-7.71(m,3H),7.65(dd,J=8.1,2.0Hz,1H),7.52(t,J=7.2Hz,3H),7.44-7.41(m,2H),7.34(t,J=8.8Hz,2H),7.28(td,J=6.8,1.2Hz,1H),7.22(td,J=7.21.2Hz,1H),1.56(s,9H);13C NMR(100MHz,Acetone-d6)δ162.9(d,JC-F=245.5Hz),153.9,153.3,149.6,142.5,140.5,135.9,134.9,132.7,129.8(d,3JC-F=8.2Hz),129.5,128.9,127.7,127.3,127.2,127.0(d,4JC-F=3.2Hz),125.8,125.4,123.0,120.7,118.0,115.8(d,2JC-F=21.8Hz),112.0,108.1,35.8,31.2;19F NMR(376MHz,Acetone-D6)δ-114.06(s,1F)。
实施例67
20min完成反应;86%产率;92%ee;
HPLC条件:Daicel CHIRALPAK IC柱,hexane/i-PrOH=80/20,1.0mL/min,T=25℃,λ=230nm,tR(minor)=8.4min,tR(major)=25.7min;
HRMS(ESI)calcd for C32H27ClN4O2Na+(M+Na)+557.1715,found 557.1714;
1H NMR(400MHz,Acetone-d6)δ11.05(s,1H),9.80(brs,1H),7.96(d,J=8.8Hz,2H),7.93(d,J=2.0Hz,1H),7.76-7.72(m,3H),7.65(dd,J=8.0,2.0Hz,1H),7.59(d,J=8.8Hz,2H),7.55-7.50(m,3H),7.45-7.41(m,2H),7.29(td,J=7.2,1.2Hz,1H),7.22(t,J=7.2Hz,1H),1.56(s,9H);13C NMR(100MHz,Acetone-d6)δ153.9,153.3,149.6,142.5,140.5,135.4,135.0,134.0,132.8,129.4,129.3,129.1,129.0,128.9,127.8,127.3,127.3,125.8,125.3,123.2,120.8,118.0,112.1,108.5,35.8,31.2。
实施例68
5min内完成反应;95%产率;90%ee;
HPLC条件:Daicel CHIRALPAK IC柱,hexane/i-PrOH=80/20,1.0mL/min,T=25℃,λ=230nm,tR(minor)=7.5min,tR(major)=13.1min;
HRMS(ESI)calcd for C23H26N4O2Na+(M+Na)+413.1948,found 413.1945;
1H NMR(400MHz,Acetone-d6)δ10.50(brs,1H),9.69(brs,1H),7.69(dd,J=8.0,1.6Hz,1H),7.55(d,J=7.2Hz,1H),7.48(td,J=7.2,1.6Hz,1H),7.38(td,J=7.6,1.2Hz,2H),7.30(dd,J=7.6,1.6Hz,1H),7.17-7.09(m,2H),3.47-3.37(m,1H),1.49(s,9H),1.43(d,J=3.2Hz,3H),1.41(d,J=2.8Hz,3H);13C NMR(100MHz,Acetone-d6)δ154.0,152.8,149.2,144.7,134.4,132.2,130.4,129.7,128.5,127.1,124.8,121.6,120.0,117.1,111.5,106.5,35.6,31.2,25.6,21.5。
实施例69
5min内完成反应;95%产率;84%ee;
HPLC条件:Daicel CHIRALPAK IC柱,hexane/i-PrOH=70/30,1.0mL/min,T=25℃,λ=230nm,tR(minor)=6.6min,tR(major)=16.2min;
HRMS(ESI)calcd for C21H22N4O2Na+(M+Na)+385.1635,found 385.1635;
1H NMR(400MHz,Acetone-d6)δ10.44(s,1H),9.67(brs,1H),7.69(d,J=8.0Hz,1H),7.54(d,J=7.6Hz,1H),7.47(td,J=8.0,1.6Hz,1H),7.40-7.36(m,2H),7.30(dd,J=7.6,1.6Hz,1H),7.16-7.09(m,2H),2.48(s,3H),1.49(s,9H);
13C NMR(100MHz,Acetone-d6)δ154.1,152.7,149.2,135.0,134.3,132.2,130.4,129.6,128.5,127.1,124.7,121.5,120.0,117.0,111.3,108.6,35.5,31.2,10。
实施例70
在干燥、氩气保护的10mL烧瓶中将活化的分子筛(100mg/0.1mmol)、3a(0.012mmol)、Sc(OTf)3(0.01mmol)溶于干燥的乙腈(0.1mL),在25℃搅拌30min,加入1-甲基靛红9(0.1mmol),然后将N-甲基吲哚8(0.3mmol)用0.1mL乙腈溶解后加入,用TLC监测反应完成后,反应液经硅胶柱层析得到产物10。对反应的条件进行优化,得到表1:
表1
Sc(OTf)3(X mol%) | 3a(Y mol%) | T(℃) | 时间(h) | 收率(%) | ee(%) |
0 | 12 | 25 | 8 | 26 | 0 |
10 | 12 | 25 | 2 | 65 | 36 |
10 | 24 | 5 | 8 | 93 | 59 |
10 | 12 | 5 | 8 | 96 | 62 |
化合物10:
HPLC条件:Daicel CHIRALPAK AD-H柱,hexane/i-PrOH=70/30,1.0mL/min,T=25℃,λ=230nm,tR(major)=10.0min,tR(minor)=13.9min;
1H NMR(400MHz,CDCl3)δ7.64(d,J=8.0Hz,1H),7.49(d,J=7.6Hz,1H),7.34(t,J=7.6Hz,1H),7.24(s,1H),7.19(t,J=7.2Hz,1H),7.06(t,J=7.6Hz,2H),6.95(s,1H),6.89(d,J=8.0Hz,1H),3.67(s,3H),3.23(s,3H);
13C NMR(100MHz,CDCl3)δ177.3,143.2,137.8,131.2,129.8,127.7,125.4,124.9,123.3,122.1,120.8,119.8,113.8,109.6,108.6,75.6,32.8,26.5。
由于化合物3a~3r、6a~6h、6k~6r、5a~5m和3a具有类似的轴手性结构,因此这些化合物也可以作为不对称反应的配体。本实施例证明,本发明的脲唑类轴手性化合物可以作为不对称反应的催化剂或者配体,这类化合物在不对称催化领域具有非常广阔的应用前景。
实施例71
0.1mmol N-Boc吡咯和0.12mmol 2a,现在-78℃反应5h,后转至25℃反应3h。
61%产率;4%ee;
HPLC条件:Daicel CHIRALPAK IC柱,hexane/i-PrOH=80/20,1.0mL/min,T=25℃,λ=230nm,tR(major)=11.9min,tR(minor)=17.6min;
HRMS(ESI)calcd for C21H27N4O4 +(M+H)+399.2027,found 399.2025;
1H NMR(400MHz,Acetone-D6)δ9.65(s,1H),7.66(dd,J=8.0,1.2Hz,1H),7.48-7.44(m,1H),7.41-7.34(m,3H),6.56(dd,J=3.6,1.6Hz,1H),6.25(t,J=3.6Hz,1H),1.65(s,9H),1.43(s,9H);13C NMR(100MHz,Acetone-D6)δ154.6,154.4,149.3,147.5,131.9,130.6,129.7,128.2,127.1,124.7,122.3,115.7,109.2,84.7,35.4,31.1,27.2。
实施例72
化合物2a~2i可通过以下方法制备:
S1的合成:0℃将三光气(2.97g,10.0mmol,0.5equiv)溶于干燥DCE(50mL),加入三乙胺(0.03mL,0.01equiv),搅拌5min后,将芳香胺(20.0mmol)溶于干燥DCE(50mL)后滴入,2h滴完,反应液在氮气保护下回流并搅拌4h,冷却至室温,将混合物减压蒸发得到黄色固体S1。
S2的合成:氮气保护下甲基肼(1.8g,20.0mmol)溶于无水THF,在1~2min内加入芳基异氰酸酯S1(20.0mmol,1.0equiv),所得反应液在室温反应1h,经TLC监测反应完成后,过滤或蒸发至干得到白色固体S2。
S3的合成:中间体S2溶于甲醇,加入碳酸钾(2.0equiv),反应液回流过夜,经TLC监测反应完成后,将所得混合物浓缩并溶于小量的水,通过滴加1N盐酸将混合物的pH调节至3~4,经过简单过滤、冷的去离子水清洗、干燥得到产物S3。
S4的合成:中间体S3(10mmol))溶于150mL DCM,冰浴条件下加入NBS(20mmol),搅拌30min后,所得红色溶液用5次水提取,DCM层用MgSO4干燥、过滤、减压浓缩,得到产物S。
化合物2a:收率71%;
1H NMR(400MHz,CDCl3)δ7.64(dd,J=8.4,1.2Hz,1H),7.49(td,J=7.6,1.2Hz,1H),7.32(td,J=8.0,1.2Hz,1H),6.85(dd,J=7.6,1.2Hz,1H),1.23(s,9H);
13C NMR(100MHz,CDCl3)δ158.5,148.6,130.9,129.7,129.2,127.9,127.0,35.5,31.5。
化合物2b:收率61%;
1H NMR(400MHz,CDCl3)δ7.72(d,J=2.0Hz,1H),7.47(dd,J=8.4,2.0Hz,1H),6.73(d,J=8.4Hz,1H),1.23(s,9H);
13C NMR(100MHz,CDCl3)δ158.1,150.9,132.7,131.3,131.2,126.2,125.5,35.8,31.3。
化合物2c:收率40%;
1H NMR(400MHz,CDCl3)δ7.85(d,J=2.0Hz,1H),7.63-7.60(m,2H),7.55(dd,J=8.0,2.0Hz,1H),7.53-7.49(m,2H),7.46-7.43(m,1H),6.95(d,J=8.4Hz,1H),1.33(s,9H);
13C NMR(100MHz,CDCl3)δ158.5,148.9,144.0,139.9,130.1,128.9,128.2,128.1,127.3,126.6,126.0,35.7,31.5。
化合物2d:收率64%;
1H NMR(400MHz,CDCl3)δ7.60(s,1H),7.14(s,1H),2.33(s,3H),2.10(s,3H);
13C NMR(100MHz,CDCl3)δ156.4,143.0,138.2,137.4,132.2,127.6,97.0,20.6,18.5。
化合物2e:收率56%;
1H NMR(400MHz,CDCl3)δ7.92(s,1H),7.50(s,1H),2.13(s,3H);
13C NMR(100MHz,CDCl3)δ155.8,139.9,139.5,134.4,129.7,125.6,98.0,18.6。
化合物2f:收率52%;
1H NMR(400MHz,CDCl3)δ7.76(d,J=7.6Hz,1H),7.33(d,J=7.6Hz,1H),7.14(t,J=8.0Hz,1H),2.15(s,3H);
13C NMR(100MHz,CDCl3)δ156.2,138.2,137.7,132.3,131.4,130.3,97.3,18.6。
化合物2g:收率62%;
1H NMR(400MHz,CDCl3)δ7.56(dd,J=6.0,3.2Hz,1H),7.35-7.33(m,2H),2.18(s,3H);
13C NMR(100MHz,CDCl3)δ156.3,138.7,132.0,131.3,130.5,127.0,122.0,18.1。
化合物2h:收率56%;
1H NMR(400MHz,CDCl3)δ7.52(t,J=7.6Hz,1H),7.41(d,J=7.6Hz,1H),7.35-7.31(m,4H),7.14-7.11(m,2H),2.19(s,3H);13C NMR(100MHz,CDCl3)δ157.2,141.3,137.1,136.2,130.5,128.8,128.6,128.2,127.7,125.6,17.6。
化合物2i:收率44%;
1H NMR(400MHz,CDCl3)δ8.35(d,J=8.4Hz,1H),8.31(s,1H),7.77-7.73(m,1H),7.66-7.62(m,1H),7.33(d,J=8.4Hz,1H);13C NMR(100MHz,CDCl3)δ156.3,138.0,132.7,132.5,131.0,130.0,129.1,128.7,127.1,121.7,96.0。
以上所述,仅为本发明的具体实施方式,但本发明的保护范围并不局限于此,任何属于本技术领域的技术人员在本发明揭露的技术范围内,可轻易想到的变化或替换,都应涵盖在本发明的保护范围之内。因此,本发明的保护范围应该以权利要求的保护范围为准。
Claims (4)
1.脲唑类轴手性化合物,其特征在于,其选自以下化合物:
2.脲唑类轴手性化合物I或II的合成方法,其特征在于,其至少包含以下步骤:在有机溶剂中,以手性硫脲或手性磷酸为催化剂,芳环化合物与式III或者式IV化合物反应得到产物:
R1a选自烷基、卤素、苯基、取代苯基、 R5选自卤素、烷基和烷氧基;
R1b、R1c、R1d和R1e各自独立地选自氢、卤素、苯基、取代苯基、烷基、烷氧基、羟基、酯基、醛基、氰基和酰胺;
所述芳环化合物选自
R选自
其中,R2为羟基或烷氧基,R2a、R2b、R3、R4a、R4b各自独立地选自氢、卤素、苯基、取代苯基、烷基、烷氧基、羟基、酯基、醛基、氰基和酰胺;R’为氢;
所述手性硫脲选自具有以下结构式的化合物:
所述手性磷酸选自具有以下结构式的化合物:
3.根据权利要求2所述的合成方法,其特征在于,所述有机溶剂为二氯甲烷、甲苯和乙醚中的一种或两种。
4.根据权利要求2所述的合成方法,其特征在于,所述催化剂相对于芳环化合物的用量是1~20mol%。
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DE1153759B (de) * | 1960-07-20 | 1963-09-05 | Hoechst Ag | Verfahren zur Herstellung von blutdrucksenkenden Urazolen |
US6846525B2 (en) * | 1993-03-19 | 2005-01-25 | Xerox Corporation | Recording sheets containing purine, pyrimidine, benzimidazole, imidazolidine, urazole, pyrazole, triazole, benzotriazole, tetrazole, and pyrazine compounds |
ES2166328B1 (es) * | 2000-05-11 | 2003-09-16 | Consejo Superior Investigacion | Inhibidores heterociclicos del enzima gsk 3 utiles en el tratamiento de procesos neurodegenerativos e hiperproliferativos |
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