CN116375653A - 一种高对映选择性合成手性四氢喹唑啉类衍生物的方法 - Google Patents
一种高对映选择性合成手性四氢喹唑啉类衍生物的方法 Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 33
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- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 16
- 238000006243 chemical reaction Methods 0.000 claims abstract description 50
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 19
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- -1 1,3, 5-triazine compound Chemical class 0.000 claims abstract description 15
- 229910052741 iridium Inorganic materials 0.000 claims abstract description 15
- GKOZUEZYRPOHIO-UHFFFAOYSA-N iridium atom Chemical compound [Ir] GKOZUEZYRPOHIO-UHFFFAOYSA-N 0.000 claims abstract description 15
- 239000003054 catalyst Substances 0.000 claims abstract description 13
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000003446 ligand Substances 0.000 claims abstract description 10
- 238000007115 1,4-cycloaddition reaction Methods 0.000 claims abstract description 7
- 239000000654 additive Substances 0.000 claims abstract description 7
- 230000000996 additive effect Effects 0.000 claims abstract description 7
- 229910052786 argon Inorganic materials 0.000 claims abstract description 5
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical group OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 19
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 18
- 230000015572 biosynthetic process Effects 0.000 claims description 16
- ORBBTCHHNMWMCP-UHFFFAOYSA-K cycloocta-1,5-diene trichloroiridium Chemical group [Ir](Cl)(Cl)Cl.C1=CCCC=CCC1 ORBBTCHHNMWMCP-UHFFFAOYSA-K 0.000 claims description 16
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- JIHQDMXYYFUGFV-UHFFFAOYSA-N 1,3,5-triazine Chemical compound C1=NC=NC=N1 JIHQDMXYYFUGFV-UHFFFAOYSA-N 0.000 claims description 3
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 claims description 2
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 238000006555 catalytic reaction Methods 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 238000003756 stirring Methods 0.000 claims description 2
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- 150000003217 pyrazoles Chemical class 0.000 claims 1
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- UXDWYQAXEGVSPS-GFUIURDCSA-N (4s)-6-chloro-4-[(e)-2-cyclopropylethenyl]-4-(trifluoromethyl)-1,3-dihydroquinazolin-2-one Chemical compound C(/[C@]1(C2=CC(Cl)=CC=C2NC(=O)N1)C(F)(F)F)=C\C1CC1 UXDWYQAXEGVSPS-GFUIURDCSA-N 0.000 description 1
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- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/74—Quinazolines; Hydrogenated quinazolines with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to ring carbon atoms of the hetero ring
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Abstract
本发明公开了一种高对映选择性合成手性四氢喹唑啉类衍生物的方法。具体来说是通过铱催化剂和手性配体组合,催化消旋的2‑氨基苯基烯丙基醇和1,3,5‑三嗪化合物发生不对称[4+2]‑环加成反应制备一系列手性四氢喹唑啉类衍生物的方法,该方法属于有机合成领域。具体操作步骤为:在氩气保护下,向反应管中加入铱催化剂和手性配体,随后加入2‑氨基苯基烯丙基醇,1,3,5‑三嗪化合物和添加剂,然后在0℃下反应,待反应完全,淬灭纯化,得到手性四氢喹唑啉类衍生物。该方法具有底物适用性好,反应条件温和,区域选择性以及对映选择性高的优点。
Description
技术领域
本发明属于有机合成领域,具体涉及一种高对映选择性合成手性四氢喹唑啉类衍生物的方法。
背景技术
手性四氢喹唑啉类衍生物是一类常见的有机合成中间体,广泛存在于天然产物和各类医药中间体中。上市小分子药物诸如Afacifenacin,DPC-083等都具有手性四氢喹唑啉骨架单元。然而,已报道的合成手性四氢喹唑啉类衍生物的方法极少。2018年我们团队报道了铜催化4-乙炔基-3,1-苯并恶嗪-2-酮与1,3,5-三嗪的不对称[4+2]-环加成反应生成手性四氢喹唑啉化合物,在这工作中4-乙炔基-3,1-苯并恶嗪-2-酮底物是不容易合成的,且大部分反应收率和立体选择性偏低,且底物种类极有限(详见:Ji,D.;Wang,C.;Sun,J.Org.Lett.2018,20,3710-3713.)。
在前期工作基础上,我们一直寻找从易得的底物出发,发展更高效的构建手性四氢喹唑啉化合物的方法。因此,我们通过设计催化体系和条件筛查,实现了铱催化外消旋的2-氨基苯基烯丙基醇和1,3,5-三嗪化合物发生不对称[4+2]-环加成反应制备一系列手性四氢喹唑啉类衍生物。该方法具有底物适用性好,反应条件温和,区域选择性以及对映选择性高等优点。
发明内容
鉴于前面所发展的方法局限性。本发明利用不对称[4+2]-环加成策略,提供了一种易得的2-氨基苯基烯丙基醇和1,3,5-三嗪化合物为反应原料,高区域和对映选择性合成手性四氢喹唑啉类衍生物的方法。
为了实现本发明目的,所采用的技术方案为:
一种高对映选择性合成手性四氢喹唑啉类衍生物的方法,其特征在于:铱催化剂的催化作用下,外消旋的2-氨基苯基烯丙基醇和1,3,5-三嗪化合物发生不对称[4+2]-环加成反应制备一系列手性四氢喹唑啉类衍生物。所述外消旋的2-氨基苯基烯丙基醇的结构式为:
其中,R可以是H、甲基、甲氧基和卤素。氮上保护基PG可以是对甲苯磺酰基(Ts),对硝基磺酰基(Ns)和甲磺酰基(Ms)
进一步的,所述方法按照下述步骤进行:在氩气保护下,将铱催化剂和手性配体溶解于二氯乙烷溶剂并置于封管中,搅拌使铱催化剂中铱和手性配体充分配位(一般10分钟左右)。随后将2-氨基苯基烯丙基醇,1,3,5-三嗪化合物和添加剂依次加入上述封管,置换氩气,然后在0℃至室温下充分反应(一般24h左右),然后纯化,得到手性四氢喹唑啉类衍生物。
进一步的,所述1,3,5-三嗪化合物的结构式为:
其中,R1为烷基、苯环、对甲基苯基、对溴苯基或苄基。
具体的反应方程式如下(Scheme 1):
进一步的,所述2-氨基苯基烯丙基醇和1,3,5-三嗪化合物的摩尔比例为1:1-2:1,该摩尔比下的收率最高。
进一步的,所述铱催化剂的用量为2-氨基苯基烯丙基醇当量的2%-4%。
进一步的,所述的手性亚磷酰胺配体L为S-构型,使用量为铱催化剂摩尔量的400%。
进一步的,所述添加剂为三氟乙酸,当量为1,3,5-三嗪化合物当量的200%-400%。当其催化量为300%时已达到最高收率。
有益效果:
本发明方法利用不对称[4+2]-环加成策略,提供了一种利用易得的2-氨基苯基烯丙基醇和1,3,5-三嗪化合物为反应原料,高区域和对映选择性合成手性四氢喹唑啉类衍生物的方法。该方法具有底物适用性好,反应条件温和,区域选择性以及对映选择性高的优点。
附图说明
图1为实施例1中制备的纯化3aa的核磁共振氢谱图;
图2为实施例1中制备的纯化3aa的核磁共振碳谱图;
图3为化合物3aa的消旋高效液相色谱图(Racemic sample 3aa:HPLC(DaicelChiralpak IC column(hexane/iPrOH=90:10,flow rate:1.0mL/min,λ=254nm);
图4为手性的高效液相色谱图;
图5为实施例1中制备的纯化3aa的高分辨质谱图。
具体实施方式
下面结合实施例对本发明做进一步描述,但不限于此。以下实施例中反应时间的限定是为了保证反应充分,但并不表示反应充分至少需要24小时。关于反应温度,一般室温下反应ee值比0℃下反应的ee值至多低2%,以实施例1为例,其它条件不变,反应温度调整为室温,ee值最低为97%。
实施实例1:
(3aa)的合成:
氩气保护下向反应管中加入1,5-环辛二烯氯化铱二聚体(4.0mg,2-氨基苯基烯丙基醇摩尔量的3mol%),(S)-L(12.2mg,12mol%)及二氯乙烷(1.5mL),室温下搅拌10分钟。随后,1a(0.2mmol,60.6mg,1eq.)、2a(0.1mmol,35.6mg)和TFA(34.2mg,1.5eq.)。随后封管,反应在0℃下反应24h。处理,粗产物通过TLC制备板纯化得到3aa(73.6mg,99%ee,收率:91%).1H NMR(300MHz,CDCl3)δ7.71(dd,J=8.3,1.2Hz,1H),7.40-7.31(m,2H),7.32-7.15(m,3H),7.18-7.04(m,5H),6.99(td,J=7.5,1.3Hz,1H),6.87(dd,J=8.2,1.4Hz,1H),5.19-5.03(m,2H),4.91-4.83(m,1H),4.80(d,J=12.1Hz,1H),4.30(d,J=12.1Hz,1H),3.92(d,J=6.4Hz,1H),3.67(d,J=13.6Hz,1H),3.44(d,J=13.6Hz,1H),2.31(s,3H).13CNMR(75MHz,CDCl3)δ143.5,139.1,136.9,136.7,135.8,129.4,129.2,129.1,128.4,127.9,127.7,127.6,127.4,124.7,123.2,118.7,64.2,63.7,56.1,21.6.HRMS(ESI)m/zcalculated for C24H25N2O2S[M+H]+:405.1631,found:405.1637.HPLC:Daicel ChiralpakIC column(hexane/iPrOH=90:10,flow rate:1.0mL/min,λ=254nm,tR(major)=16.02min,tR(minor)=17.04min.ee=99%.
实施实例2:
(3ab)的合成:
氩气保护下向反应管中加入1,5-环辛二烯氯化铱二聚体(4.0mg,2-氨基苯基烯丙基醇摩尔量的3mol%),(S)-L(12.2mg,12mol%)及二氯乙烷(1.5mL),室温下搅拌10分钟。随后,1a(0.2mmol,60.6mg,1eq.)、2b(0.1mmol,31.6mg)和TFA(34.2mg,1.5eq.)。随后封管,反应在0℃下反应24h。处理,粗产物通过TLC制备板纯化得到3ab(60.1mg,96%ee,收率:77%).1H NMR(400MHz,CDCl3)δ7.84(dd,J=8.3,1.3Hz,1H),7.29-7.21(m,5H),7.15(td,J=7.5,1.3Hz,1H),7.09(dd,J=7.9,1.7Hz,1H),6.93-6.85(m,5H),5.62(d,J=13.3Hz,1H),5.46(ddd,J=17.0,10.2,6.8Hz,1H),5.11(d,J=10.2Hz,1H),4.98(d,J=17.1Hz,1H),4.87(d,J=13.3Hz,1H),4.83(d,J=6.8Hz,1H),2.26(s,3H).13C NMR(101MHz,CDCl3)δ146.7,143.5,136.7,136.1,135.7,129.3,129.0,128.7,128.5,127.8,127.6,125.5,124.7,120.4,118.2,116.9,60.8,60.1,21.6.HRMS(ESI)m/zcalculated for C23H23N2O2S[M+H]+:391.1475,found:391.1480.HPLC:Daicel Chiralpak IC column(hexane/iPrOH=70:30,flow rate:1.0mL/min,λ=225nm,tR(major)=10.23min,tR(minor)=8.53min.ee=96%.
实施实例3:
(3ac)的合成:
氩气保护下向反应管中加入1,5-环辛二烯氯化铱二聚体(4.0mg,3mol%),(S)-L(12.2mg,12mol%)及二氯乙烷(1.5mL),室温下搅拌10分钟。随后,1a(0.2mmol,60.6mg,1eq.)、2c(0.1mmol,35.6mg)和TFA(34.2mg,1.5eq.)。随后封管,反应在0℃下反应24h。处理,粗产物通过TLC制备板纯化得到3ac(68.5mg,96%ee,收率:85%).1H NMR(400MHz,CDCl3)δ7.84(dd,J=8.2,1.2Hz,1H),7.29-7.22(m,3H),7.14(td,J=7.5,1.3Hz,1H),7.09-7.03(m,3H),6.95(d,J=8.2Hz,2H),6.79-6.76(m,2H),5.44(dd,J=13.1,0.8Hz,1H),5.35(ddd,J=17.1,10.1,6.9Hz,1H),5.07(dt,J=10.1,1.2Hz,1H),4.94(dt,J=17.1,1.2Hz,1H),4.92(d,J=13.1Hz,1H),4.79(d,J=6.9Hz,1H),2.29(s,3H),2.28(s,3H).13C NMR(101MHz,CDCl3)δ144.6,143.5,137.2,136.1,135.6,130.4,129.8,129.0,128.8,128.7,127.9,127.5,125.4,124.6,118.2,118.1,61.9,61.0,21.6,20.7.HRMS(ESI)m/zcalculated for C24H25N2O2S[M+H]+:405.1631,found:405.1636.HPLC:DaicelChiralpak IC column(hexane/iPrOH=70:30,flow rate:1.0mL/min,λ=225nm,tR(major)=11.21min,tR(minor)=9.25min.ee=95%.
实施实例4:
(3ad)的合成:
氩气保护下向反应管中加入1,5-环辛二烯氯化铱二聚体(4.0mg,3mol%),(S)-L(12.2mg,12mol%)及二氯乙烷(1.5mL),室温下搅拌10分钟。随后,1a(0.2mmol,60.6mg,1eq.)、2d(0.1mmol,55.0mg)和TFA(34.2mg,1.5eq.)。随后封管,反应在0℃下反应24h。处理,粗产物通过TLC制备板纯化得到3ad(74.2mg,88%ee,收率:79%).1H NMR(600MHz,CDCl3)δ7.85(d,J=8.2Hz,1H),7.32-7.24(m,3H),7.21-7.15(m,3H),7.08(d,J=7.8Hz,1H),6.93(d,J=7.9Hz,2H),6.70(d,J=8.7Hz,2H),5.59(d,J=13.4Hz,1H),5.45(ddd,J=17.0,10.2,6.8Hz,1H),5.12(d,J=10.1Hz,1H),4.97(d,J=17.1Hz,1H),4.79(d,J=13.4Hz,1H),4.74(d,J=6.8Hz,1H),2.27(s,3H).13C NMR(150MHz,CDCl3)δ145.8,143.7,136.3,136.1,135.9,132.12,129.1,128.6,128.3,127.8,127.7,125.6,124.8,118.32,118.28,112.5,60.4,60.1,21.6.HRMS(ESI)m/z calculated for C23H21BrN2NaO2S[M+Na]+:491.0399,found:491.0406.HPLC:Daicel Chiralpak IC column(hexane/iPrOH=70:30,flow rate:1.0mL/min,λ=225nm,tR(major)=12.82min,tR(minor)=9.24min.ee=88%.
实施实例5:
(3ae)的合成:
氩气保护下向反应管中加入1,5-环辛二烯氯化铱二聚体(4.0mg,3mol%),(S)-L(12.2mg,12mol%)及二氯乙烷(1.5mL),室温下搅拌10分钟。随后,1a(0.2mmol,60.6mg,1eq.)、2e(0.1mmol,21.3mg)和TFA(34.2mg,1.5eq.)。随后封管,反应在0℃下反应24h。处理,粗产物通过TLC制备板纯化得到3ae(45.0mg,99%ee,收率:63%).1H NMR(400MHz,CDCl3)δ7.77(d,J=8.2Hz,1H),7.56-7.44(m,2H),7.25-7.10(m,3H),7.06(t,J=7.5Hz,1H),6.96(d,J=7.7Hz,1H),5.12-4.85(m,4H),4.22(d,J=12.0Hz,1H),3.92(d,J=5.6Hz,1H),2.49-2.41(m,1H),2.37-2.27(m,1H),2.34(s,3H),1.64-1.54(m,1H),1.53-1.40(m,1H),0.87(td,J=7.4,1.5Hz,3H).13C NMR(101MHz,CDCl3)δ143.4,139.3,136.6,135.9,129.04,128.98,128.6,128.1,127.3,124.9,123.6,118.3,65.4,64.6,53.6,21.6,20.2,12.0.HRMS(ESI)m/z calculated for C20H25N2O2S[M+H]+:357.1631,found:357.1634.HPLC:Daicel Chiralpak IC column(hexane/iPrOH=80:20,flow rate:1.0mL/min,λ=215nm,tR(major)=10.07min,tR(minor)=10.84min.ee=99%.
实施实例6:
(3af)的合成:
氩气保护下向反应管中加入1,5-环辛二烯氯化铱二聚体(4.0mg,3mol%),(S)-L(12.2mg,12mol%)及二氯乙烷(1.5mL),室温下搅拌10分钟。随后,1a(0.2mmol,60.6mg,1eq.)、2f(0.1mmol,25.6mg)和TFA(34.2mg,1.5eq.)。随后封管,反应在0℃下反应24h。处理,粗产物通过TLC制备板纯化得到3af(54.8mg,99%ee,收率:74%).1H NMR(400MHz,CDCl3)δ7.77(d,J=8.3Hz,1H),7.58(d,J=7.9Hz,2H),7.17(dd,J=12.3,7.5Hz,3H),7.04(t,J=7.5Hz,1H),6.97(d,J=7.7Hz,1H),5.33-5.25(m,1H),5.09(dd,J=10.0,1.6Hz,1H),4.95-4.90(m,1H),4.83(d,J=12.1Hz,1H),4.36(d,J=12.1Hz,1H),3.94(d,J=6.9Hz,1H),2.35(s,3H),2.27-2.15(m,2H),1.86-1.79(m,1H),0.89(d,J=6.7Hz,3H),0.84(d,J=6.7Hz,3H).13C NMR(101MHz,CDCl3)δ143.5,139.6,136.8,136.0,129.3,127.8,127.6,127.4,124.4,122.4,118.1,65.3,64.9,60.4,26.4,21.6,21.2,21.1.HRMS(ESI)m/zcalculated for C21H27N2O2S[M+H]+:371.1788,found:371.1793.HPLC:Daicel ChiralpakIB column(hexane/iPrOH=99:1,flow rate:1.0mL/min,λ=215nm,tR(major)=6.19min,tR(minor)=6.79min.ee=99%.
实施实例7:
(3ba)的合成:
氩气保护下向反应管中加入1,5-环辛二烯氯化铱二聚体(4.0mg,3mol%),(S)-L(12.2mg,12mol%)及二氯乙烷(1.5mL),室温下搅拌10分钟。随后,1b(0.2mmol,67mg,1eq.)、2d(0.1mmol,35.6mg)和TFA(34.2mg,1.5eq.)。随后封管,反应在0℃下反应24h。处理,粗产物通过TLC制备板纯化得到3ba(55.0mg,99%ee,收率:63%).1H NMR(400MHz,CDCl3)δ7.80(d,J=8.4Hz,1H),7.62(d,J=8.4Hz,2H),7.37-7.21(m,7H),7.16(t,J=8.2Hz,1H),7.06(d,J=8.0Hz,1H),5.74(ddd,J=17.4,10.4,4.3Hz,1H),5.19-4.89(m,2H),4.73(d,J=12.0Hz,1H),4.46-4.43(m,1H),4.36(d,J=17.4Hz,1H),3.82(d,J=13.4Hz,1H),3.52(d,J=13.4Hz,1H),2.38(s,3H).13C NMR(101MHz,CDCl3)δ144.2,137.8,137.4,136.7,136.3,134.5,129.7,129.1,128.6,128.3,127.7,127.3,124.5,122.2,118.8,118.5,63.8,58.8,56.6,21.7.HRMS(ESI)m/z calculated for C24H24ClN2O2S[M+H]+:439.1242,found:367.1250.HPLC:Daicel Chiralpak IC column(hexane/iPrOH=90:10,flow rate:1.0mL/min,λ=225nm,tR(major)=11.41min,tR(minor)=10.80min.ee=99%.
实施实例8:
(3ca)的合成:
氩气保护下向反应管中加入1,5-环辛二烯氯化铱二聚体(4.0mg,3mol%),(S)-L(12.2mg,12mol%)及二氯乙烷(1.5mL),室温下搅拌10分钟。随后,1c(0.2mmol,76.6mg,1eq.)、2d(0.1mmol,35.6mg)和TFA(34.2mg,1.5eq.)。随后封管,反应在0℃下反应24h。处理,粗产物通过TLC制备板纯化得到3ca(80.0mg,98%ee,收率:83%).1H NMR(400MHz,CDCl3)δ7.69(d,J=8.9Hz,1H),7.43(d,J=8.4Hz,2H),7.38-7.27(m,4H),7.20-7.16(m,4H),7.07(d,J=2.3Hz,1H),5.27-5.14(m,2H),4.96-4.91(m,1H),4.84(d,J=12.2Hz,1H),4.37(d,J=12.2Hz,1H),3.96(d,J=6.5Hz,1H),3.70(d,J=13.6Hz,1H),3.52(d,J=13.6Hz,1H),2.40(s,3H).13C NMR(101MHz,CDCl3)δ143.8,138.4,136.6,136.3,135.0,131.9,130.6,129.7,129.41,129.35,128.5,127.86,127.80,124.8,119.5,117.9,64.1,63.3,56.1,21.7.HRMS(ESI)m/z calculated for C24H24BrN2O2S[M+H]+:483.0736,found:483.0743.HPLC:Daicel Chiralpak IC column(hexane/iPrOH=90:10,flow rate:1.0mL/min,λ=254nm,tR(major)=14.45min,tR(minor)=15.13min.ee=98%.
实施实例9:
(3da)的合成:
氩气保护下向反应管中加入1,5-环辛二烯氯化铱二聚体(4.0mg,3mol%),(S)-L(12.2mg,12mol%)及二氯乙烷(1.5mL),室温下搅拌10分钟。随后,1d(0.2mmol,66.6mg,1eq.)、2d(0.1mmol,35.6mg)和TFA(34.2mg,1.5eq.)。随后封管,反应在0℃下反应24h。处理,粗产物通过TLC制备板纯化得到3da(71.3mg,91%ee,收率:82%).1H NMR(400MHz,CDCl3)δ7.72(d,J=9.1Hz,1H),7.46-7.25(m,5H),7.18-7.13(m,4H),6.78(dd,J=9.0,3.0Hz,1H),6.46(dd,J=2.9,0.8Hz,1H),5.19-5.08(m,1H),5.06-4.95(m,2H),4.87(d,J=12.1Hz,1H),4.17(d,J=12.1Hz,1H),3.92-3.90(m,1H),3.76-3.72(m,1H),3.74(s,3H),3.41(d,J=13.9Hz,1H),2.39(s,3H).13C NMR(101MHz,CDCl3)δ156.9,143.3,138.8,136.5,130.2,129.6,129.0,128.7,128.4,128.1,127.7,125.6,118.9,113.6,113.3,64.4,64.3,56.0,55.5,21.7.HRMS(ESI)m/z calculated for C25H27N2O3S[M+H]+:435.1737,found:435.1745.HPLC:Daicel Chiralpak IC column(hexane/iPrOH=80:20,flow rate:1.0mL/min,λ=215nm,tR(major)=17.06min,tR(minor)=18.03min.ee=91%.
实施实例10:
(3ea)的合成:
氩气保护下向反应管中加入1,5-环辛二烯氯化铱二聚体(4.0mg,3mol%),(S)-L(12.2mg,12mol%)及二氯乙烷(1.5mL),室温下搅拌10分钟。随后,1e(0.2mmol,63.0mg,1eq.)、2a(0.1mmol,35.6mg)和TFA(34.2mg,1.5eq.)。随后封管,反应在0℃下反应24h。处理,粗产物通过TLC制备板纯化得到3ea(67.0mg,96%ee,收率:80%).1H NMR(400MHz,CDCl3)δ7.36-7.28(m,3H),7.20-7.06(m,8H),6.80(dd,J=7.7,1.5Hz,1H),5.16-5.09(m,2H),4.98(d,J=11.7Hz,1H),4.27-4.11(m,1H),3.92-3.71(m,3H),3.26(d,J=13.8Hz,1H),2.54(s,3H),2.40(s,3H).13C NMR(100MHz,CDCl3)δ143.1,138.5,137.6,137.0,135.7,134.8,133.3,130.1,129.9,129.2,128.6,128.3,127.7,126.7,125.8,119.0,66.1,55.7,21.6,20.0.HRMS(ESI)m/z calculated for C25H27N2O2S[M+Na]+:419.1788,found:419.1794.HPLC:Daicel Chiralpak IC column(hexane/iPrOH=70:30,flow rate:1.0mL/min,λ=215nm,tR(major)=9.72min,tR(minor)=12.12min.ee=96%.
实施实例11:
(3fa)的合成:
氩气保护下向反应管中加入1,5-环辛二烯氯化铱二聚体(4.0mg,3mol%),(S)-L(12.2mg,12mol%)及二氯乙烷(1.5mL),室温下搅拌10分钟。随后,1f(0.2mmol,46.0mg,1eq.)、2a(0.1mmol,35.6mg)和TFA(34.2mg,1.5eq.)。随后封管,反应在0℃下反应24h。处理,粗产物通过TLC制备板纯化得到3fa(51.7mg,87%ee,收率:79%).1H NMR(400MHz,CDCl3)δ7.68(d,J=7.9Hz,1H),7.39-7.27(m,5H),7.25-7.09(m,3H),5.82(ddd,J=17.0,10.1,8.0Hz,1H),5.43(dd,J=10.1,1.5Hz,1H),5.34(dt,J=17.1,1.2Hz,1H),4.78(d,J=12.2Hz,1H),4.20(d,J=8.0Hz,1H),4.11(d,J=12.2Hz,1H),4.02(d,J=13.5Hz,1H),3.49(d,J=13.6Hz,1H),2.90(s,3H).13C NMR(101MHz,CDCl3)δ138.6,136.8,135.7,129.3,129.2,128.7,127.9,127.7,125.5,124.5,120.0,65.5,64.0,56.0,38.8.HRMS(ESI)m/zcalculated for C18H21N2O2S[M+H]+:329.1318,found:329.1325.HPLC:Daicel ChiralpakIB column(hexane/iPrOH=90:10,flow rate:1.0mL/min,λ=215nm,tR(major)=7.99min,tR(minor)=9.20min.ee=87%.
实施实例12:
(3ga)的合成:
氩气保护下向反应管中加入1,5-环辛二烯氯化铱二聚体(4.0mg,3mol%),(S)-L(12.2mg,12mol%)及二氯乙烷(1.5mL),室温下搅拌10分钟。随后,1g(0.2mmol,67.0mg,1eq.)、2a(0.1mmol,35.6mg)和TFA(34.2mg,1.5eq.)。随后封管,反应在0℃下反应24h。处理,粗产物通过TLC制备板纯化得到3ga(75.5mg,99%ee,收率:87%).1H NMR(400MHz,CDCl3)δ8.16-8.11(m,2H),7.80(dd,J=8.3,1.3Hz,1H),7.54-7.48(m,2H),7.41-7.33(m,3H),7.29-7.23(m,1H),7.18-7.12(m,3H),7.01(dt,J=7.7,1.2Hz,1H),5.21(dd,J=10.0,1.5Hz,1H),5.14-5.06(m,1H),4.99-4.85(m,2H),4.15(d,J=12.1Hz,1H),3.98(d,J=7.9Hz,1H),3.76(d,J=13.5Hz,1H),3.31(d,J=13.5Hz,1H).13C NMR(101MHz,CDCl3)δ149.9,144.8,138.3,136.3,134.8,129.8,129.33,129.29,129.16,128.6,128.0,127.7,126.1,124.5,123.5,119.8,65.2,64.4,55.9.HRMS(ESI)m/z calculated for C23H22N3O4S[M+H]+:436.1326,found:436.1331.HPLC:Daicel Chiralpak IC column(hexane/iPrOH=60:40,flow rate:1.0mL/min,λ=215nm,tR(major)=10.34min,tR(minor)=12.51min.ee=99%.
以下实例13-15为控制变量实验:
实施实例13:
(3aa)的合成:
氩气保护下向反应管中加入1,5-环辛二烯氯化铱二聚体(2.6mg,2mol%),(S)-L(8.8mg,8mol%)及二氯乙烷(1.5mL),室温下搅拌10分钟。随后,1a(0.2mmol,60.6mg,1eq.)、2a(0.1mmol,35.6mg)和TFA(34.2mg,1.5eq.)。随后封管,反应在0℃下反应24h。处理,粗产物通过TLC制备板纯化得到3aa(50.1mg,98%ee,收率:60%).
实施实例14:
(3aa)的合成:
氩气保护下向反应管中加入1,5-环辛二烯氯化铱二聚体(4.0mg,3mol%),(S)-L(12.2mg,12mol%)及甲苯(1.5mL),室温下搅拌10分钟。随后,1a(0.2mmol,60.6mg,1eq.)、2a(0.1mmol,35.6mg)和TFA(34.2mg,1.5eq.)。随后封管,反应在0℃下反应24h。处理,粗产物通过TLC制备板纯化得到3aa(49.8mg,78%ee,收率:60%),本实施例中影响对映体选择性的主要因素为溶剂选用。
实施实例14:
(3aa)的合成:
氩气保护下向反应管中加入1,5-环辛二烯氯化铱二聚体(4.0mg,3mol%),(S)-L(12.2mg,12mol%)及二氯乙烷(1.5mL),室温下搅拌10分钟。随后,1a(0.2mmol,60.6mg,1eq.)、2a(0.2mmol,71.2mg)和TFA(34.2mg,1.5eq.)。随后封管,反应在0℃下反应24h。处理,粗产物通过TLC制备板纯化得到3aa(67.4mg,86%ee,收率:81%).
所述实施例为本发明的优选的实施方式,但本发明并不限于上述实施方式,在不背离本发明的实质内容的情况下,本领域技术人员能够做出的任何显而易见的改进、替换或变型均属于本发明的保护范围。
Claims (9)
2.根据权利要求1所述的高对映选择性合成手性四氢喹唑啉类衍生物的方法,其特征在于:所述方法按照下述步骤进行:在氩气保护下,将铱催化剂和手性配体(S)-L溶解于二氯乙烷溶剂并置于封管中,搅拌使铱催化剂中铱和手性配体充分配位;随后将2-氨基苯基烯丙基醇,1,3,5-三嗪化合物和添加剂依次加入上述封管,置换氩气,然后在0℃至室温下充分反应,然后纯化,得到手性四氢喹唑啉类衍生物。
4.根据权利要求1至3中任一项所述的一种高对映选择性合成手性四氢喹唑啉类衍生物的方法,其特征在于:所述2-氨基苯基烯丙基醇和1,3,5-三嗪化合物的摩尔比例为1:1-2:1。
5.根据权利要求2所述的高对映选择性合成手性四氢喹唑啉类衍生物的方法,其特征在于:所述反应溶剂为二氯甲烷,二氯乙烷,甲苯或三氯甲烷。
6.根据权利要求2所述的高对映选择性合成手性四氢喹唑啉类衍生物的方法,其特征在于:所述铱催化剂为1,5-环辛二烯氯化铱二聚体;铱催化剂的用量为吡唑衍生物当量的2%-4%。
7.根据权利要求2所述的高对映选择性合成手性四氢喹唑啉类衍生物的方法,其特征在于:所述添加剂为三氟乙酸,添加剂当量为1,3,5-三嗪当量的200-400%。
8.根据权利要求7所述的高对映选择性合成手性四氢喹唑啉类衍生物的方法,其特征在于:添加剂当量为1,3,5-三嗪当量的300%。
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