CN109956946B - 一种铱催化二氢吡咯/吲哚[1,2-a]并吡嗪的不对称氢化合成手性胺的方法 - Google Patents
一种铱催化二氢吡咯/吲哚[1,2-a]并吡嗪的不对称氢化合成手性胺的方法 Download PDFInfo
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- 238000009876 asymmetric hydrogenation reaction Methods 0.000 title claims abstract description 20
- GXWNSJYVSIJRLS-UHFFFAOYSA-N 6-bromo-8-methylimidazo[1,2-a]pyrazine Chemical compound CC1=NC(Br)=CN2C=CN=C12 GXWNSJYVSIJRLS-UHFFFAOYSA-N 0.000 title claims abstract description 14
- 238000000034 method Methods 0.000 title claims abstract description 14
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- 125000003118 aryl group Chemical group 0.000 claims abstract description 15
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 11
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- ORBBTCHHNMWMCP-UHFFFAOYSA-K cycloocta-1,5-diene trichloroiridium Chemical class [Ir](Cl)(Cl)Cl.C1=CCCC=CCC1 ORBBTCHHNMWMCP-UHFFFAOYSA-K 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
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- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims description 2
- QYMGRIFMUQCAJW-UHFFFAOYSA-N 1,2-dihydropyrazine Chemical compound C1NC=CN=C1 QYMGRIFMUQCAJW-UHFFFAOYSA-N 0.000 claims 2
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- 230000000694 effects Effects 0.000 abstract 1
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- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 54
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 19
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- 229940093499 ethyl acetate Drugs 0.000 description 18
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
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- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
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- 238000004811 liquid chromatography Methods 0.000 description 3
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- 239000002253 acid Substances 0.000 description 2
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- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
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- 241000950577 Antilla Species 0.000 description 1
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- ZNORAFJUESSLTM-UHFFFAOYSA-N [4-[5-bis(3,5-ditert-butyl-4-methoxyphenyl)phosphanyl-1,3-benzodioxol-4-yl]-1,3-benzodioxol-5-yl]-bis(3,5-ditert-butyl-4-methoxyphenyl)phosphane Chemical compound C1=C(C(C)(C)C)C(OC)=C(C(C)(C)C)C=C1P(C=1C(=C2OCOC2=CC=1)C=1C(=CC=C2OCOC2=1)P(C=1C=C(C(OC)=C(C=1)C(C)(C)C)C(C)(C)C)C=1C=C(C(OC)=C(C=1)C(C)(C)C)C(C)(C)C)C1=CC(C(C)(C)C)=C(OC)C(C(C)(C)C)=C1 ZNORAFJUESSLTM-UHFFFAOYSA-N 0.000 description 1
- GDMCOFXEPNHXJT-UHFFFAOYSA-N [5-(6-diphenylphosphanyl-2,3-dihydro-1,4-benzodioxin-5-yl)-2,3-dihydro-1,4-benzodioxin-6-yl]-diphenylphosphane Chemical compound O1CCOC(C=2C=3C=4OCCOC=4C=CC=3P(C=3C=CC=CC=3)C=3C=CC=CC=3)=C1C=CC=2P(C=1C=CC=CC=1)C1=CC=CC=C1 GDMCOFXEPNHXJT-UHFFFAOYSA-N 0.000 description 1
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- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
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- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical compound C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 description 1
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- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
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- 150000003233 pyrroles Chemical class 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
本发明提供一种合成手性胺的方法，催化二氢吡咯/吲哚[1,2‑a]并吡嗪经不对称氢化反应制备，催化剂为铱的金属前体和手性双膦配体的配合物，铱的金属前体、手性双膦配体、底物的摩尔比为：0.01～0.05:0.022～0.11:1；
式中：R1为C1‑C6的烷基或芳基，芳基包括苯基、卤代芳基、卤代烷取代芳基、烷氧基取代芳基以及烷基取代芳基；R2为H或Br；R4为芳基或Br，芳基包括苯基或烷基取代芳基。本发明反应活性和对映选择性高，其对映体过量最多可达到95％；催化剂制备方便，反应操作简便实用；氢化反应条件温和。
Description
技术领域
本发明涉及一种应用铱的均相体系高度对映选择性催化二氢吡咯/吲哚[1,2-a]并吡嗪化合物的氢化合成手性胺的方法，属于手性化合物合成技术领域。
背景技术
杂环手性化合物广泛存在于生物活性分子和天然产物中，而通过不对称氢化合成该类化合物是一种简单、直接、高效的方法。四氢吡咯[1,2-a]并吡嗪的衍生物表现出广泛的药理活性，如抗衰老，抗过敏，抗心律不齐，抗病毒以及醛糖还原酶抑制活性等(参考文献一：(a)Peresada,V.P.；Medvedev,O.S.；Likhosherstov,A.M.；Skoldinov,A.P.Khim.Farm.Zh.1987,21,1054.(b)Seredenin,S.B.；Voronina,T.A.；Likhosherstov,A.M.；Peresada,Y.P.；Molodavkin,G.M.；Halikas,J.A.U.S.5378846,1995.(c)Seredenin,S.B.；Voronina,T.A.；Beshimov,A.；Peresada,V.P.；Likhosherstov,A.M.RU 2099055,1997；(d)Negoro,T.；Murata,M.；Ueda,S.；Fujitani,B.；Ono,Y.；Kuromiya,A.；Komiya,M.；Suzuki,K.；Matsumoto,J.-i.J.Med.Chem.1998,41,4118.(e)Likhosherstov,A.M.；Filippova,O.V.；Peresada,V.P.；Kryzhanovskii,S.A.；Vititnova,M.B.；Kaverina,N.V.；Reznikov,K.M.Pharm.Chem.J.2003,37,6.(f)Merla,B.；Christoph,T.；Oberboersch,S.；Schiene,K.；Bahrenberg,G.；Frank,R.；Kuehnert,S.；Schroeder,W.WO 2008046582,2008.(g)Zhu,B.；Marinelli,B.A.；Goldschmidt,R.；Foleno,B.D.；Hilliard,J.J.；Bush,K.；Macielag,M.Bioorg.Med.Chem.Lett.2009,19,4933.)。过去，合成该分子的方法主要是通过底物诱导的策略，比如通过对手性的二氢吡咯[1,2-a]并吡嗪酮还原可以实现手性的四氢吡咯[1,2-a]并吡嗪化合物的合成(参考文献二：(a)Li,G.；Rowland,G.B.；Rowland,E.B.；Antilla,J.C.Org.Lett.2007,9,4065.(b)Gualandi,A.；Cerisoli,L.；Monari,M.；Savoia,D.Synthesis 2011,909.(c)Bhowmik,S.；Kumar,A.K.S.；Batra,S.TetrahedronLett.2013,54,2251.)。使用聚合物负载的手性酰基异羟肟酸拆分试剂进行动力学拆分提供了另外一种合成途径(参考文献三：Kreituss,I.；Chen,K.-Y.；Eitel,S.H.；Adam,J.-M.；Wuitschik,G.；Fettes,A.；Bode,J.W.Angew.Chem.Int.Ed.2016,55,1553.)。直到2011年，首例催化不对称合成四氢吡咯[1,2-a]并吡嗪的方法才被Li和Antilla报道，该反应利用手性磷酸催化2-(1H-吡咯-1-基)乙胺与醛发生分子内氮杂傅克反应，取得了优异的反应活性和对映选择性(参考文献四：He,Y.；Lin,M.；Li,Z.；Liang,X.；Li,G.；Antilla,J.C.Org.Lett.2011,13,4490.)。最近，Kobayashi小组发展了一种非均相手性双功能催化剂，由金属纳米粒子和手性磷酸组成，实现了苄醇的有氧氧化-氮杂傅克反应合成四氢吡咯[1,2-a]并吡嗪的串联一锅反应，对映选择性最高为95％(参考文献五：Cheng,H.-G.；Miguélez,J.；Miyamura,H.；Yoo,W.-J.；Kobayashi,S.Chem.Sci.2017,8,1356.)。不对称氢化作为一种简单、直接、原子经济性的合成方法，广泛应用于手性胺的合成。2014年，Zhou小组采用底物活化的策略，实现了对1-取代吡咯[1,2-a]并吡嗪苄溴盐底物的不对称氢化，得到一系列的四氢吡咯[1,2-a]并吡嗪衍生物，反应体系中需要加入当量的碱中和反应产生的酸来抑制产物的消旋化(参考文献六：Huang,W.-X.；Yu,C.-B.；Shi,L.；Zhou,Y.-G.Org.Lett.2014,16,3324.)。随后，该小组成功实现了3-取代吡咯[1,2-a]并吡嗪的直接不对称氢化，值得注意的是，该体系不需要进行底物活化就能以最高96％的ee值得到目标分子(参考文献七：Hu,S.-B.；Chen,Z.-P.；Song,B.；Wang,J.；Zhou,Y.-G.Adv.Synth.Catal.2017,359,2762.)。考虑到四氢吡咯[1,2-α]并吡嗪结构单元在天然产物和生物活性分子中的重要性，并受到不对称氢化反应的研究启发，发展一种简单、直接的不对称氢化合成四氢吡咯[1,2-α]并吡嗪的方法仍非常具有意义。
发明内容
本发明的目的是提供一种合成手性胺的方法，为实现上述目的，本发明以铱的手性双膦P-P*配合物为催化剂，实现二氢吡咯/吲哚[1,2-a]并吡嗪的不对称氢化，采用的技术方案如下：催化二氢吡咯/吲哚[1,2-a]并吡嗪经不对称氢化反应制备，催化剂为铱的金属前体和手性双膦配体的配合物，铱的金属前体、手性双膦配体、底物的摩尔比为：0.01～0.05:0.022～0.11:1；
式中：R1为C1-C6的烷基或芳基，芳基包括苯基、卤代芳基、卤代烷取代芳基、烷氧基取代芳基以及烷基取代芳基。。
R2为H或Br。R4为芳基或Br，芳基为苯基或烷基取代芳基。
另一目的是提供一种合成手性胺的方法，催化二氢吡咯/吲哚[1,2-a]并吡嗪经不对称氢化反应制备，催化剂为铱的金属前体和手性双膦配体的配合物，铱的金属前体、手性双膦配体、底物的摩尔比为：0.01～0.05:0.022～0.11:1；
式中：R1为C1-C6的烷基或芳基，芳基包括苯基、卤代芳基、卤代烷取代芳基、烷氧基取代芳基以及烷基取代芳基；
R3和R4位点并一个苯环。
作为优选的技术方案，所述方法包括两个阶段：(1)催化剂制备：将铱的金属前体和手性双膦配体加入有机溶剂后反应得到催化剂；(2)底物不对称氢化：将催化剂、有机溶剂加入二氢吡咯/吲哚[1,2-a]并吡嗪底物中，通入氢气反应得到直接氢化的产物。
释放氢气，减压除去溶剂后直接柱层析分离得到纯的产物。
优选地，所述有机溶剂选自甲苯、1,4-二氧六环、苯、二氯甲烷、1,2-二氯乙烷、甲醇中的至少一种；更优选苯，最优选甲苯。有机溶剂的用量根据反应需要加入，没有特别限定。
优选地，铱金属前体选自1,5-环辛二烯氯化铱二聚体。
优选地，所述配体选自选自(R)-BINAP或(R)-DifluorPhos或(S)-SynPhos或(R)-MeO-Biphep或(Rax,S,S)-C3-TunePhos或Walphos(CAS号：387868-06-6)或Walphos(CAS号：388079-60-5)或(R)-DTBM-SegPhos或(R)-SegPhos或(R)-BTFM-GarPhos；更优选双膦配体Walphos(CAS号：388079-60-5)。
优选地，所述底物不对称氢化的反应压力为10～1000psi，更优选为500psi-800psi，反应温度为0～80℃，更优选为30～60℃，反应物浓度为0.025～0.5mmol/mL。
本发明有益效果
1.反应活性和对映选择性高，其对映体过量最多可达到95％；
2.催化剂制备方便，反应操作简便实用；
3.氢化反应条件温和。
4.合成方法操作简便实用易行，收率高，环境友好，催化剂商业可得，反应条件温和，具有潜在的实际应用价值。
具体实施方式
下面通过实施例详述本发明，但本发明并不限于下述的实施例。
铱的金属前体及双膦配体均为市售且无需任何处理。
实施例1-19氢化反应条件的优化
手套箱中，在反应瓶中投入1,5-环辛二烯氯化铱二聚体(底物用量的1mol％-5mol％)和手性双膦配体(底物用量的2.2mol％-11mol％)，加入有机溶剂(1.0-2.0mL)，室温搅拌5min后；然后用有机溶剂(1.0-2.0mL)将此溶液转到预先放有氢化底物1a(0.2mmol)的反应瓶中，移至反应釜中，通入氢气(10psi-1000psi)，0-80℃下反应12-48小时；释放氢气，减压除去溶剂后直接柱层析分离得到纯的产物，反应式和配体结构如下：
其产率为转化率，产物的对映体过量用手性液相色谱测定，详见表1。
表1.二氢吡咯[1,2-a]并吡嗪不对称氢化条件优化一a
实施例20-33二氢吡咯[1,2-a]并吡嗪不对称氢化合成手性胺2
手套箱中，在反应瓶中投入1,5-环辛二烯氯化铱二聚体(底物用量的1.5mol％)和手性双膦配体(底物用量的3.3mol％)，加入有机溶剂(1.0mL)，室温搅拌5min后将混合物用有机溶剂(2.0mL)转移至预先放有氢化底物1(0.3mmol)的反应瓶中，移至反应釜中，通入氢气(600psi)，40℃下反应48h；释放氢气，减压除去溶剂后直接柱层析分离得到纯的产物，反应式和配体结构如下：
其产率为分离收率，产物的对映体过量用手性液相色谱测定，见表2。
表2.二氢吡咯[1,2-a]并吡嗪不对称氢化a
实施例34-37二氢吲哚[1,2-a]并吡嗪不对称氢化合成手性胺4
手套箱中，在反应瓶中投入1,5-环辛二烯氯化铱二聚体(底物用量的1.5mol％)和手性双膦配体(底物用量的3.3mol％)，加入有机溶剂(1.0mL)，室温搅拌5min后将混合物用有机溶剂‘’(2.0mL)转移至预先放有氢化底物3(0.3mmol)的反应瓶中，移至反应釜中，通入氢气(600psi)，30℃下反应48h；释放氢气，减压除去溶剂后直接柱层析分离得到纯的产物，反应式和配体结构如下：
其产率为分离收率，产物的对映体过量用手性液相色谱测定，见表3。
表3.吲哚[1,2-a]并吡嗪的不对称氢化a
(+)-1-phenyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine(2a):59 mg,98％yield,91％ee,[α]20 D＝+56.6(c 0.89,CHCl3),known compound,white solid,Rf＝0.20(hexanes/ethyl acetate/dichloromethane 3/1/1).1H NMR(400 MHz,CDCl3)δ7.41(d,J＝7.2 Hz,2H),7.38–7.28(m,3H),6.62(s,1H),6.13(t,J＝3.0 Hz,1H),5.64–5.52(m,1H),5.10(s,1H),4.15–4.06(m,1H),4.01(dt,J＝11.7,3.8 Hz,1H),3.42–3.34(m,1H),3.33–3.23(m,1H),1.89(s,1H)；13C NMR(100 MHz,CDCl3)δ143.1,130.9,128.6,128.5,127.9,119.2,107.9,105.1,59.3,45.6,43.3.HPLC:Chiralpak IC column,230 nm,30℃,n-hexane/i-propanol＝70/30,flow＝0.7 mL/min,retention time 7.0 min and 7.6 min(maj).
(+)-1-(2-fluorophenyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine(2b):62 mg,95％yield,95％ee,[α]20 D＝+60.9(c 1.24,CHCl3),pale yellow oil,Rf＝0.50(ethyl acetate).1H NMR(400 MHz,CDCl3)δ7.33–7.23(m,2H),7.12–7.02(m,2H),6.60(s,1H),6.13(t,J＝3.0 Hz,1H),5.66–5.56(m,1H),5.49(s,1H),4.09–4.03(m,1H),3.99(dt,J＝11.7,4.2 Hz,1H),3.33(dt,J＝12.7,4.3 Hz,1H),3.29–3.19(m,1H),1.99(s,1H)；13CNMR(100 MHz,CDCl3)δ161.0(d,JF-C＝244.9 Hz),130.2(d,JF-C＝4.3 Hz),130.1,129.4(d,JF-C＝8.4 Hz),129.1,124.2(d,JF-C＝3.5 Hz),119.3,115.6(d,JF-C＝21.8 Hz),107.9,104.8,52.1(d,JF-C＝3.6 Hz),45.6,42.8；19F NMR(376 MHz,CDCl3)δ-119.7.HPLC:Chiralpak IC column,230 nm,30℃,n-hexane/i-propanol＝70/30,flow＝0.7 mL/min,retention time 7.0 min and 8.1min(maj).
(+)-1-(3-fluorophenyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine(2c):63 mg,97％yield,94％ee,[α]20 D＝+35.1(c 1.05,CHCl3),yellow solid,Rf＝0.50(ethylacetate).1H NMR(400 MHz,CDCl3)δ7.34–7.25(m,1H),7.15(dd,J＝23.0,8.8 Hz,2H),6.98(td,J＝8.4,2.3 Hz,1H),6.60(s,1H),6.11(t,J＝3.1 Hz,1H),5.63–5.49(m,1H),5.08(s,1H),4.12–4.02(m,1H),3.97(dt,J＝11.7,3.8 Hz,1H),3.34(dt,J＝12.6,4.1 Hz,1H),3.30–3.19(m,1H),1.90(s,1H)；13C NMR(100 MHz,CDCl3)δ163.1(d,J＝245.7 Hz),145.7(d,J＝6.8 Hz),130.0,129.9(d,J＝8.1 Hz),124.1(d,J＝2.8 Hz),119.3,115.3(d,J＝21.8 Hz),114.8(d,J＝21.2 Hz),107.9,105.1,58.6(d,J＝1.8 Hz),45.6,43.1；19F NMR(376 MHz,CDCl3)δ-113.1.HPLC:Chiralpak IA column,230 nm,30℃,n-hexane/i-propanol＝95/5,flow＝0.7mL/min,retention time 14.2 min(maj)and 16.6 min.
(+)-1-(4-fluorophenyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine(2d):60 mg,93％yield,90％ee,[α]20 D＝+52.0(c 0.99,CHCl3),yellow oil,Rf＝0.50(ethylacetate).1H NMR(400 MHz,CDCl3)δ7.37(dd,J＝8.3,5.6 Hz,2H),7.01(t,J＝8.6 Hz,2H),6.60(s,1H),6.11(t,J＝3.0 Hz,1H),5.52(s,1H),5.06(s,1H),4.12–4.03(m,1H),3.98(dt,J＝11.7,3.6 Hz,1H),3.40–3.31(m,1H),3.31–3.20(m,1H),1.85(s,1H)；13C NMR(100MHz,CDCl3)δ162.6(d,J＝245.7 Hz),138.9,130.8,130.1(d,J＝8.1 Hz),119.3,115.4(d,J＝21.3 Hz),107.9,105.1,58.7,45.6,43.4；19F NMR(376 MHz,CDCl3)δ-114.9.HPLC:Chiralpak IC column,230 nm,30℃,n-hexane/i-propanol＝85/15,flow＝0.7 mL/min,retention time 7.5 min and 8.1 min(maj).
(R)-1-(4-chlorophenyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine(2e):64 mg,92％yield,89％ee,[α]20 D＝+37.4(c 1.15,CHCl3),pale yellow solid,Rf＝0.50(ethyl acetate).1H NMR(400 MHz,CDCl3)δ7.35(q,J＝8.5 Hz,4H),6.62(s,1H),6.13(t,J＝2.9 Hz,1H),5.55(s,1H),5.08(s,1H),4.15–4.05(m,1H),4.00(dt,J＝11.7,3.5 Hz,1H),3.40–3.32(m,1H),3.32–3.22(m,1H),1.98(s,1H)；13C NMR(100 MHz,CDCl3)δ141.6,133.6,130.3,129.9,128.7,119.3,107.9,105.1,58.6,45.5,43.2.HPLC:Chiralpak ICcolumn,230 nm,30℃,n-hexane/i-propanol＝70/30,flow＝0.7 mL/min,retention time6.4min and 7.0 min(maj).
(+)-1-(4-bromophenyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine(2f):79mg,95％yield,89％ee,[α]20 D＝+31.8(c 0.89,CHCl3),pale yellow solid,Rf＝0.50(ethyl acetate).1H NMR(400 MHz,CDCl3)δ7.47(d,J＝8.3 Hz,2H),7.30(d,J＝8.2 Hz,2H),6.61(s,1H),6.12(t,J＝2.9 Hz,1H),5.59–5.50(m,1H),5.06(s,1H),4.14–4.04(m,1H),3.99(dt,J＝11.7,3.6 Hz,1H),3.40–3.32(m,1H),3.32–3.21(m,1H),1.93(s,1H)；13CNMR(100 MHz,CDCl3)δ142.1,131.7,130.2,121.8,119.3,107.9,105.1,58.6,45.6,43.2.HPLC:Chiralpak IC column,230 nm,30℃,n-hexane/i-propanol＝70/30,flow＝0.7mL/min,retention time 6.6 min and 7.4 min(maj).
(+)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine(2g):76 mg,95％yield,88％ee,[α]20 D＝+21.5(c 1.52,CHCl3),new compound,pale yellow solid,Rf＝0.30(hexanes/ethyl acetate 5/1).1H NMR(400 MHz,CDCl3)δ7.62(d,J＝8.2 Hz,2H),7.55(d,J＝8.1 Hz,2H),6.64(s,1H),6.14(t,J＝3.1 Hz,1H),5.60–5.49(m,1H),5.17(s,1H),4.15–4.07(m,1H),4.02(dt,J＝11.7,3.8 Hz,1H),3.41–3.34(m,1H),3.34–3.24(m,1H),1.97(s,1H)；13C NMR(100 MHz,CDCl3)δ147.1,130.3,130.3,129.8,128.8,125.5(q,J＝3.8 Hz),119.5,108.0,105.2,58.7,45.6,43.1；19F NMR(376MHz,CDCl3)δ-62.4.HPLC:Chiralpak IC column,230 nm,30℃,n-hexane/i-propanol＝95/5,flow＝0.7 mL/min,retention time 7.9 min and 8.7 min(maj).
(+)-1-(p-tolyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine(2h):58 mg,92％yield,90％ee,[α]20 D＝+48.3(c 1.15,CHCl3),known compound,pale yellow solid,m.p.＝99-100℃,Rf＝0.50(ethyl acetate).1H NMR(400 MHz,CDCl3)δ7.30(d,J＝7.8 Hz,2H),7.17(d,J＝7.8 Hz,2H),6.61(s,1H),6.13(t,J＝3.0 Hz,1H),5.57(d,J＝2.6 Hz,1H),5.07(s,1H),4.14–4.06(m,1H),4.00(dt,J＝11.7,3.6 Hz,1H),3.42–3.34(m,1H),3.32–3.23(m,1H),2.37(s,3H),1.91(s,1H)；13C NMR(100 MHz,CDCl3)δ140.2,137.6,131.1,129.2,128.4,119.1,107.8,105.0,59.0,45.6,43.3,21.3；HPLC:Chiralpak ICcolumn,230nm,30℃,n-hexane/i-propanol＝70/30,flow＝0.7 mL/min,retention time7.7 min and 9.2 min(maj).
(+)-1-(m-tolyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine(2i):59 mg,93％yield,90％ee,[α]20 D＝+56.2(c 1.17,CHCl3),new compound,white solid,m.p.＝117-118℃,Rf＝0.40(ethyl acetate).1H NMR(400 MHz,CDCl3)δ7.29–7.18(m,3H),7.15(d,J＝7.2 Hz,1H),6.63(s,1H),6.15(t,J＝3.0 Hz,1H),5.60(d,J＝1.2 Hz,1H),5.08(s,1H),4.16–4.07(m,1H),4.01(dt,J＝11.7,3.6 Hz,1H),3.43–3.35(m,1H),3.32–3.25(m,1H),2.38(s,3H),1.93(s,1H)；13C NMR(100 MHz,CDCl3)δ143.0,138.2,130.9,129.1,128.7,128.4,125.6,119.1,107.8,105.0,59.3,45.6,43.4,21.6.HPLC:Chiralpak ICcolumn,230 nm,30℃,n-hexane/i-propanol＝70/30,flow＝0.7 mL/min,retention time7.1 min and 7.9min(maj).HRMS Calculated for C14H17N2[M+H]+213.1386,found213.1386.
(+)-1-(3,5-dimethylphenyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine(2j):66 mg,98％yield,95％ee,[α]20 D＝+60.4(c 1.02,CHCl3),new compound,paleyellow solid,m.p.＝157-158℃,Rf＝0.30(ethyl acetate).1H NMR(400 MHz,CDCl3)δ7.03(s,2H),6.96(s,1H),6.62(s,1H),6.13(t,J＝3.0 Hz,1H),5.59(d,J＝1.3 Hz,1H),5.03(s,1H),4.11(td,J＝11.0,4.7 Hz,1H),4.00(dt,J＝11.7,3.5 Hz,1H),3.43–3.35(m,1H),3.34–3.23(m,1H),2.32(s,6H),1.87(s,1H)；13C NMR(100 MHz,CDCl3)δ143.0,138.1,131.0,129.6,126.3,119.1,107.8,105.0,59.4,45.6,43.5,21.5；HPLC:Chiralpak ICcolumn,230nm,30℃,n-hexane/i-propanol＝70/30,flow＝0.7 mL/min,retention time6.8 min and 7.7 min(maj).HRMS Calculated for C15H19N2[M+H]+227.1543,found227.1545.
(+)-1-cyclohexyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine(2k):56 mg,92％yield,86％ee,[α]20 D＝+98.5(c 0.46,CHCl3),colorless oil,Rf＝0.20(ethylacetate).1H NMR(400 MHz,CDCl3)δ6.56–6.50(m,1H),6.19–6.09(m,1H),5.89–5.80(m,1H),3.90–3.85(m,3H),3.33(dt,J＝12.9,3.7 Hz,1H),3.13–3.06(m,1H),1.84–1.63(m,7H),1.36–1.06(m,5H)；13C NMR(100 MHz,CDCl3)δ130.6,118.9,107.6,102.8,58.9,45.6,43.3,42.3,30.6,27.3,27.0,26.8,26.8.HPLC:Chiralcel OJ column,220nm,30℃,n-hexane/i-propanol＝95/5,flow＝0.6 mL/min,retention time 9.4 min(maj)and 11.3min.
(-)-6-bromo-1-phenyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine(2l):78mg,94％yield,89％ee,[α]20 D＝-26.6(c 0.50,CHCl3),new compound,yellow solid,m.p.＝100-101℃,Rf＝0.40(hexanes/ethyl acetate 1/1).1H NMR(400 MHz,CDCl3)δ7.49–7.27(m,5H),6.10(d,J＝3.7 Hz,1H),5.55(d,J＝3.7Hz,1H),5.01(s,1H),4.01–3.90(m,1H),3.91–3.79(m,1H),3.41(ddd,J＝12.7,4.7,3.2 Hz,1H),3.25(ddd,J＝12.8,10.1,4.5Hz,1H),1.88(s,1H)；13C NMR(100 MHz,CDCl3)δ142.3,132.5,128.6,128.5,128.1,109.6,106.3,100.0,59.5,44.8,43.1；HPLC:Chiralpak IC column,230 nm,30℃,n-hexane/i-propanol＝70/30,flow＝0.7 mL/min,retention time 6.3 min and 6.8 min(maj).HRMSCalculated for C13H14BrN2[M+H]+277.0335,found 277.0332(79Br)and 279.0315(81Br).
(-)-1,6-diphenyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine(2m):75 mg,91％yield,93％ee,[α]20 D＝-155.3(c 1.21,CHCl3),new compound,pale yellow solid,m.p.＝123-124℃,Rf＝0.30(hexanes/ethyl acetate 5/1).1H NMR(400 MHz,CDCl3)δ7.50–7.29(m,10H),6.23(d,J＝3.5 Hz,1H),5.67(d,J＝3.5 Hz,1H),5.21(s,1H),4.17–4.09(m,1H),4.05(dt,J＝11.9,3.5 Hz,1H),3.40(dt,J＝12.5,3.7 Hz,1H),3.31–3.21(m,1H),2.00(s,1H)；13C NMR(100 MHz,CDCl3)δ143.2,133.4,133.1,132.2,128.6,128.6,128.5,128.0,126.7,108.3,105.9,59.7,45.3,43.7.HPLC:Chiralpak IC column,230 nm,30℃,n-hexane/i-propanol＝95/5,flow＝0.7 mL/min,retention time 13.9 min and15.4 min(maj).HRMS Calculated for C19H19N2[M+H]+275.1543,found 275.1545.
(-)-1-phenyl-6-(p-tolyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine(2n):83 mg,95％yield,94％ee,[α]20 D＝-137.1(c 1.51,CHCl3),new compound,paleyellow solid,m.p.＝138-139℃,Rf＝0.40(hexanes/ethyl acetate 1/1).1H NMR(400MHz,CDCl3)δ7.47–7.42(m,2H),7.38–7.27(m,5H),7.20(d,J＝8.0 Hz,2H),6.15(d,J＝3.6Hz,1H),5.62(dd,J＝3.5,0.8 Hz,1H),5.15(s,1H),4.11–3.93(m,2H),3.40–3.29(m,1H),3.20(ddd,J＝12.6,10.1,4.2 Hz,1H),2.37(s,3H),1.91(s,1H)；13C NMR(100 MHz,CDCl3)δ143.2,136.4,133.1,131.9,130.5,129.3,128.6,128.5,127.9,107.9,105.7,59.7,45.2,43.7,21.3.HPLC:Chiralpak IC column,230 nm,30℃,n-hexane/i-propanol＝90/10,flow＝0.7mL/min,retention time 11.0 min and 11.7 min(maj).HRMS Calculated forC20H21N2[M+H]+289.1699,found 289.1698.
(-)-6,8-dibromo-1-phenyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine(2o):104 mg,97％yield,94％ee,[α]20 D＝-0.6(c 2.13,CHCl3),new compound,paleyellow solid,m.p.＝133-134℃,Rf＝0.50(ethyl acetate).1H NMR(400 MHz,CDCl3)δ7.42–7.30(m,5H),5.66(s,1H),4.97(s,1H),3.97–3.90(m,1H),3.90–3.82(m,1H),3.45–3.38(m,1H),3.31–3.22(m,1H),1.94(s,1H)；13C NMR(100 MHz,CDCl3)δ141.6,133.4,128.7,128.4,128.3,108.6,101.5,98.0,59.2,45.6,43.1.HPLC:Chiralpak IC column,230 nm,30℃,n-hexane/i-propanol＝70/30,flow＝0.7 mL/min,retention time 6.2min and 7.4min(maj).HRMS Calculated for C13H13Br2N2[M+H]+354.9440,found354.9442(79Br)and 356.9427(79Br and 81Br),358.9409(81Br).
(+)-1-phenyl-1,2,3,4-tetrahydropyrazino[1,2-a]indole(4a):67 mg,90％yield,94％ee,[α]20 D＝+25.5(c 1.34,CHCl3),new compound,yellow oil,Rf＝0.20(hexanes/ethyl acetate 2/1).1H NMR(400MHz,CDCl3)δ7.47(d,J＝7.8 Hz,1H),7.44–7.39(m,2H),7.37–7.26(m,4H),7.19–7.14(m,1H),7.08(t,J＝7.4 Hz,1H),5.87(s,1H),5.19(s,1H),4.16–4.08(m,1H),4.08–3.99(m,1H),3.52–3.42(m,1H),3.32(ddd,J＝12.6,10.1,4.6 Hz,1H),2.00(s,1H)；13C NMR(100 MHz,CDCl3)δ142.2,138.3,136.4,128.6,128.2,127.9,121.0,120.4,120.0,108.9,98.8,59.7,43.1,42.7.HPLC:Chiralpak IAcolumn,230 nm,30℃,n-hexane/i-propanol＝70/30,flow＝0.7 mL/min,retention time9.1 min(maj)and 10.5 min.HRMS Calculated for C17H17N2[M+H]+249.1386,found249.1384.
(+)-1-(4-bromophenyl)-1,2,3,4-tetrahydropyrazino[1,2-a]indole(4b):98mg,99％yield,92％ee,[α]20 D＝+18.3(c 1.71,CHCl3),new compound,white solid,m.p.＝146-147℃,Rf＝0.30(hexanes/ethyl acetate 2/1).1H NMR(400 MHz,CDCl3)δ7.53–7.45(m,3H),7.36–7.28(m,3H),7.22–7.16(m,1H),7.12–7.06(m,1H),5.86(s,1H),5.19(s,1H),4.22–4.13(m,1H),4.14–4.02(m,1H),3.50(ddd,J＝12.6,4.8,3.2 Hz,1H),3.37(ddd,J＝12.6,10.0,4.5 Hz,1H),1.92(s,1H)；13C NMR(100 MHz,CDCl3)δ141.3,137.7,136.5,131.8,130.4,127.9,122.1,121.3,120.5,120.2,109.0,98.9,59.1,43.0,42.8.HPLC:Chiralpak IA column,230 nm,30℃,n-hexane/i-propanol＝70/30,flow＝0.7 mL/min,retention time 9.9 min(maj)and 15.6 min.HRMS Calculated for C17H16BrN2[M+H]+327.0491,found 327.0492(79Br)and 329.0472(81Br).
(+)-1-(4-methoxyphenyl)-1,2,3,4-tetrahydropyrazino[1,2-a]indole(4c):83 mg,99％yield,93％ee,[α]20 D＝+29.9(c 1.32,CHCl3),new compound,yellow solid,m.p.＝120-121℃,Rf＝0.10(hexanes/ethyl acetate 2/1).1H NMR(400 MHz,CDCl3)δ7.48(d,J＝7.8 Hz,1H),7.37–7.28(m,3H),7.20–7.15(m,1H),7.09(dd,J＝11.0,3.9 Hz,1H),6.93–6.85(m,2H),5.88(s,1H),5.18(s,1H),4.17(ddd,J＝11.3,4.3,3.0 Hz,1H),4.06(td,J＝10.8,4.9 Hz,1H),3.81(s,3H),3.51(ddd,J＝12.5,4.8,2.9Hz,1H),3.36(ddd,J＝12.6,10.3,4.5 Hz,1H),1.93(s,1H)；13C NMR(100 MHz,CDCl3)δ159.5,138.8,136.5,134.5,129.8,128.0,121.0,120.4,120.0,114.0,108.9,98.7,59.2,55.5,43.2,42.8.HPLC:Chiralpak IA column,230 nm,30℃,n-hexane/i-propanol＝70/30,flow＝0.7 mL/min,retention time10.8 min(maj)and 20.0 min.HRMS Calculated forC18H19N2O[M+H]+279.1492,found 279.1493.
(-)-1-methyl-1,2,3,4-tetrahydropyrazino[1,2-a]indole(4d):54 mg,97％yield,56％ee,[α]20 D＝-45.0(c 1.08,CHCl3),new compound,colorless oil,Rf＝0.70(dichloromethane/methanol 10/1).1H NMR(400MHz,CDCl3)δ7.56(d,J＝7.7 Hz,1H),7.24(dd,J＝5.1,4.4 Hz,1H),7.12(dtd,J＝14.7,7.1,1.1 Hz,2H),6.23(s,1H),4.18(q,J＝6.4 Hz,1H),4.08(ddd,J＝11.4,4.5,1.7 Hz,1H),3.86(td,J＝11.4,5.0 Hz,1H),3.47(ddd,J＝13.1,4.9,1.8 Hz,1H),3.26(ddd,J＝13.1,11.4,4.6 Hz,1H),1.59(s,1H),1.53(d,J＝6.6 Hz,3H)；13C NMR(100 MHz,CDCl3)δ140.3,136.4,128.1,120.9,120.3,120.0,108.9,96.1,49.9,43.3,42.7,21.1.HPLC:Chiralpak AD-H column,210 nm,30℃,n-hexane/i-propanol＝70/30,flow＝0.7 mL/min,retention time 8.3 min and 11.1 min(maj).HRMS Calculated for C12H15N2[M+H]+187.1230,found 187.1230.
Claims (4)
1.一种合成手性胺的方法，其特征在于：所述手性胺结构如式2所示，催化二氢吡咯[1,2-a]并吡嗪类化合物1为底物经不对称氢化反应制备，催化剂为1,5-环辛二烯氯化铱二聚体和手性双膦配体L的配合物，1,5-环辛二烯氯化铱二聚体、手性双膦配体L、底物的摩尔比为：0.01～0.05:0.022～0.11:1；有机溶剂为甲苯；反应温度为40℃；
式中：R1为C1-C6的烷基、苯基、卤代芳基、卤代烷取代芳基、烷氧基取代芳基或烷基取代芳基；
R2为H或Br；R3为H；R4为苯基、烷基取代芳基或Br；L为
2.一种合成手性胺的方法，其特征在于：所述手性胺结构如式4所示，催化二氢吡嗪[1,2-a]并吲哚类化合物3为底物经不对称氢化反应制备，催化剂为1,5-环辛二烯氯化铱二聚体和手性双膦配体L的配合物，1,5-环辛二烯氯化铱二聚体、手性双膦配体L、底物的摩尔比为：0.01～0.05:0.022～0.11:1；有机溶剂为甲苯；反应温度为40℃；
式中：R1为C1-C6的烷基、苯基、卤代芳基、卤代烷取代芳基、烷氧基取代芳基或烷基取代芳基；
R2为H；R3和R4位点并一个苯环；L为
3.如权利要求1或2所述的方法，其特征在于：所述方法包括两个阶段：
(1)催化剂制备
将1,5-环辛二烯氯化铱二聚体和手性双膦配体L加入有机溶剂后反应得到催化剂；
(2)底物不对称氢化
将所述催化剂、所述有机溶剂加入所述二氢吡咯[1,2-a]并吡嗪类化合物1或二氢吡嗪[1,2-a]并吲哚类化合物3底物中，通入氢气反应得到直接氢化的产物。
4.如权利要求3所述的方法，特征在于：所述底物不对称氢化的反应压力为10～1000psi，底物浓度为0.025～0.5mmol/mL。
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1294119A (zh) * | 1999-08-27 | 2001-05-09 | 约翰逊马西有限公司 | 改进的催化方法 |
| CN101845016A (zh) * | 2009-03-25 | 2010-09-29 | 中国科学院大连化学物理研究所 | 一种铱催化不对称硅氢化合成手性四氢喹啉衍生物的方法 |
| CN101939323A (zh) * | 2008-02-01 | 2011-01-05 | 莫茨药物股份两合公司 | 吡唑并嘧啶,其制备方法及其用作药物的用途 |
| CN102336698A (zh) * | 2010-07-28 | 2012-02-01 | 中国科学院大连化学物理研究所 | 一种钯催化不对称氢化合成手性二氢吲哚的方法 |
| CA2819373A1 (en) * | 2010-12-09 | 2012-06-14 | Amgen Inc. | Bicyclic compounds as pim inhibitors |
-
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1294119A (zh) * | 1999-08-27 | 2001-05-09 | 约翰逊马西有限公司 | 改进的催化方法 |
| CN101939323A (zh) * | 2008-02-01 | 2011-01-05 | 莫茨药物股份两合公司 | 吡唑并嘧啶,其制备方法及其用作药物的用途 |
| CN101845016A (zh) * | 2009-03-25 | 2010-09-29 | 中国科学院大连化学物理研究所 | 一种铱催化不对称硅氢化合成手性四氢喹啉衍生物的方法 |
| CN102336698A (zh) * | 2010-07-28 | 2012-02-01 | 中国科学院大连化学物理研究所 | 一种钯催化不对称氢化合成手性二氢吲哚的方法 |
| CA2819373A1 (en) * | 2010-12-09 | 2012-06-14 | Amgen Inc. | Bicyclic compounds as pim inhibitors |
Non-Patent Citations (1)
| Title |
|---|
| "Concise Redox Deracemization of Secondary and Tertiary Amines with a Tetrahydroisoquinoline Core via a Nonenzymatic Process"及Supporting Information;Yue Ji等，;《J. Am. Chem. Soc.》;20150814;第137卷;第10496-10499页以及第S10页 * |
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