CN102964304A - 含吡唑烷酮结构的手性氨基氰化物的制备方法 - Google Patents
含吡唑烷酮结构的手性氨基氰化物的制备方法 Download PDFInfo
- Publication number
- CN102964304A CN102964304A CN2012103686131A CN201210368613A CN102964304A CN 102964304 A CN102964304 A CN 102964304A CN 2012103686131 A CN2012103686131 A CN 2012103686131A CN 201210368613 A CN201210368613 A CN 201210368613A CN 102964304 A CN102964304 A CN 102964304A
- Authority
- CN
- China
- Prior art keywords
- chiral
- add
- aminocyanide
- preparation
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- NDGRWYRVNANFNB-UHFFFAOYSA-N pyrazolidin-3-one Chemical group O=C1CCNN1 NDGRWYRVNANFNB-UHFFFAOYSA-N 0.000 title claims abstract description 10
- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- XZMCDFZZKTWFGF-UHFFFAOYSA-N Cyanamide Chemical compound NC#N XZMCDFZZKTWFGF-UHFFFAOYSA-N 0.000 title claims abstract 10
- 238000006243 chemical reaction Methods 0.000 claims abstract description 45
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 claims abstract description 42
- AUHZEENZYGFFBQ-UHFFFAOYSA-N mesitylene Substances CC1=CC(C)=CC(C)=C1 AUHZEENZYGFFBQ-UHFFFAOYSA-N 0.000 claims abstract description 19
- 239000003054 catalyst Substances 0.000 claims abstract description 11
- 239000000758 substrate Substances 0.000 claims abstract description 10
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 7
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims abstract description 5
- 238000006555 catalytic reaction Methods 0.000 claims abstract description 4
- 239000002904 solvent Substances 0.000 claims abstract description 4
- 239000000376 reactant Substances 0.000 claims abstract description 3
- LEIMLDGFXIOXMT-UHFFFAOYSA-N trimethylsilyl cyanide Chemical compound C[Si](C)(C)C#N LEIMLDGFXIOXMT-UHFFFAOYSA-N 0.000 claims abstract 3
- 125000001827 mesitylenyl group Chemical group [H]C1=C(C(*)=C(C([H])=C1C([H])([H])[H])C([H])([H])[H])C([H])([H])[H] 0.000 claims abstract 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 52
- -1 cyclic hydrazone Chemical class 0.000 claims description 39
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 37
- 239000003795 chemical substances by application Substances 0.000 claims description 17
- 239000000126 substance Substances 0.000 claims description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 4
- 238000004440 column chromatography Methods 0.000 claims description 3
- 238000004809 thin layer chromatography Methods 0.000 claims description 3
- 125000006276 2-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims description 2
- 125000006275 3-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C([H])C(*)=C1[H] 0.000 claims description 2
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 claims description 2
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 2
- 239000003208 petroleum Substances 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
- 229960005235 piperonyl butoxide Drugs 0.000 claims description 2
- 125000004591 piperonyl group Chemical group C(C1=CC=2OCOC2C=C1)* 0.000 claims description 2
- 238000000926 separation method Methods 0.000 claims description 2
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 claims 1
- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 claims 1
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 claims 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims 1
- 125000004199 4-trifluoromethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C(F)(F)F 0.000 claims 1
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 claims 1
- 239000011259 mixed solution Substances 0.000 claims 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims 1
- 150000007857 hydrazones Chemical class 0.000 abstract description 10
- 238000000034 method Methods 0.000 abstract description 10
- 150000002466 imines Chemical class 0.000 abstract description 6
- 239000002994 raw material Substances 0.000 abstract description 5
- 230000015572 biosynthetic process Effects 0.000 abstract description 4
- 238000003786 synthesis reaction Methods 0.000 abstract description 4
- 239000006227 byproduct Substances 0.000 abstract description 2
- 125000000524 functional group Chemical group 0.000 abstract description 2
- 238000007333 cyanation reaction Methods 0.000 abstract 2
- 231100000053 low toxicity Toxicity 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 32
- 150000001875 compounds Chemical class 0.000 description 27
- 239000000047 product Substances 0.000 description 17
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 16
- 238000005160 1H NMR spectroscopy Methods 0.000 description 16
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 16
- 241000353097 Molva molva Species 0.000 description 16
- 238000013375 chromatographic separation Methods 0.000 description 16
- 238000010790 dilution Methods 0.000 description 16
- 239000012895 dilution Substances 0.000 description 16
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 16
- 238000012746 preparative thin layer chromatography Methods 0.000 description 16
- 239000007787 solid Substances 0.000 description 16
- 238000003756 stirring Methods 0.000 description 16
- 238000007059 Strecker synthesis reaction Methods 0.000 description 10
- 230000000155 isotopic effect Effects 0.000 description 6
- 150000003934 aromatic aldehydes Chemical class 0.000 description 4
- 125000004093 cyano group Chemical group *C#N 0.000 description 3
- 0 *c1cccc([C@@](C#N)N(CC2)NC2=O)c1 Chemical compound *c1cccc([C@@](C#N)N(CC2)NC2=O)c1 0.000 description 2
- SQDFHQJTAWCFIB-UHFFFAOYSA-N n-methylidenehydroxylamine Chemical compound ON=C SQDFHQJTAWCFIB-UHFFFAOYSA-N 0.000 description 2
- HBENZIXOGRCSQN-VQWWACLZSA-N (1S,2S,6R,14R,15R,16R)-5-(cyclopropylmethyl)-16-[(2S)-2-hydroxy-3,3-dimethylpentan-2-yl]-15-methoxy-13-oxa-5-azahexacyclo[13.2.2.12,8.01,6.02,14.012,20]icosa-8(20),9,11-trien-11-ol Chemical compound N1([C@@H]2CC=3C4=C(C(=CC=3)O)O[C@H]3[C@@]5(OC)CC[C@@]2([C@@]43CC1)C[C@@H]5[C@](C)(O)C(C)(C)CC)CC1CC1 HBENZIXOGRCSQN-VQWWACLZSA-N 0.000 description 1
- PHDIJLFSKNMCMI-ITGJKDDRSA-N (3R,4S,5R,6R)-6-(hydroxymethyl)-4-(8-quinolin-6-yloxyoctoxy)oxane-2,3,5-triol Chemical compound OC[C@@H]1[C@H]([C@@H]([C@H](C(O1)O)O)OCCCCCCCCOC=1C=C2C=CC=NC2=CC=1)O PHDIJLFSKNMCMI-ITGJKDDRSA-N 0.000 description 1
- VPMIAOSOTOODMY-KJAPKAAFSA-N (4r)-6-[(e)-2-[6-tert-butyl-4-(4-fluorophenyl)-2-propan-2-ylpyridin-3-yl]ethenyl]-4-hydroxyoxan-2-one Chemical group C([C@H](O)C1)C(=O)OC1/C=C/C=1C(C(C)C)=NC(C(C)(C)C)=CC=1C1=CC=C(F)C=C1 VPMIAOSOTOODMY-KJAPKAAFSA-N 0.000 description 1
- QRDAPCMJAOQZSU-KQQUZDAGSA-N (e)-3-[4-[(e)-3-(3-fluorophenyl)-3-oxoprop-1-enyl]-1-methylpyrrol-2-yl]-n-hydroxyprop-2-enamide Chemical group C1=C(\C=C\C(=O)NO)N(C)C=C1\C=C\C(=O)C1=CC=CC(F)=C1 QRDAPCMJAOQZSU-KQQUZDAGSA-N 0.000 description 1
- JNPGUXGVLNJQSQ-BGGMYYEUSA-M (e,3r,5s)-7-[4-(4-fluorophenyl)-1,2-di(propan-2-yl)pyrrol-3-yl]-3,5-dihydroxyhept-6-enoate Chemical compound CC(C)N1C(C(C)C)=C(\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O)C(C=2C=CC(F)=CC=2)=C1 JNPGUXGVLNJQSQ-BGGMYYEUSA-M 0.000 description 1
- VAVHMEQFYYBAPR-ITWZMISCSA-N (e,3r,5s)-7-[4-(4-fluorophenyl)-1-phenyl-2-propan-2-ylpyrrol-3-yl]-3,5-dihydroxyhept-6-enoic acid Chemical compound CC(C)C1=C(\C=C\[C@@H](O)C[C@@H](O)CC(O)=O)C(C=2C=CC(F)=CC=2)=CN1C1=CC=CC=C1 VAVHMEQFYYBAPR-ITWZMISCSA-N 0.000 description 1
- MWVKLRSIDOXBSE-UHFFFAOYSA-N 5-(1-piperidin-4-ylpyrazol-4-yl)-3-(6-pyrrolidin-1-yl-1,3-benzoxazol-2-yl)pyridin-2-amine Chemical compound NC1=NC=C(C2=CN(N=C2)C2CCNCC2)C=C1C(OC1=C2)=NC1=CC=C2N1CCCC1 MWVKLRSIDOXBSE-UHFFFAOYSA-N 0.000 description 1
- HIHOEGPXVVKJPP-JTQLQIEISA-N 5-fluoro-2-[[(1s)-1-(5-fluoropyridin-2-yl)ethyl]amino]-6-[(5-methyl-1h-pyrazol-3-yl)amino]pyridine-3-carbonitrile Chemical compound N([C@@H](C)C=1N=CC(F)=CC=1)C(C(=CC=1F)C#N)=NC=1NC=1C=C(C)NN=1 HIHOEGPXVVKJPP-JTQLQIEISA-N 0.000 description 1
- VCUKKMIXURRDKL-UHFFFAOYSA-N 9-(dimethylamino)-3-(4-ethylphenyl)pyrido[1,2]thieno[3,4-d]pyrimidin-4-one Chemical compound C1=CC(CC)=CC=C1N1C(=O)C(SC=2C3=C(N(C)C)C=CN=2)=C3N=C1 VCUKKMIXURRDKL-UHFFFAOYSA-N 0.000 description 1
- REDUQXCPUSNJOL-UHFFFAOYSA-N C(C1=CC=CC=C1)NC(CN(C(C1=CC=C(C=C1)C(C)C)=O)CC1=CC=C(C=C1)C(NO)=O)=O Chemical group C(C1=CC=CC=C1)NC(CN(C(C1=CC=C(C=C1)C(C)C)=O)CC1=CC=C(C=C1)C(NO)=O)=O REDUQXCPUSNJOL-UHFFFAOYSA-N 0.000 description 1
- DGJMHKMYSDYOFP-MRXNPFEDSA-N C=CC(N(CCC1)C[C@@H]1N1N=C(C2=CN(CC(C3=CC=CC=C3)(F)F)N=N2)C2=C(N)N=CN=C12)=O Chemical compound C=CC(N(CCC1)C[C@@H]1N1N=C(C2=CN(CC(C3=CC=CC=C3)(F)F)N=N2)C2=C(N)N=CN=C12)=O DGJMHKMYSDYOFP-MRXNPFEDSA-N 0.000 description 1
- CYSWUSAYJNCAKA-FYJFLYSWSA-N ClC1=C(C=CC=2N=C(SC=21)OCC)OC1=CC=C(C=N1)/C=C/[C@H](C)NC(C)=O Chemical group ClC1=C(C=CC=2N=C(SC=21)OCC)OC1=CC=C(C=N1)/C=C/[C@H](C)NC(C)=O CYSWUSAYJNCAKA-FYJFLYSWSA-N 0.000 description 1
- QBXVXKRWOVBUDB-GRKNLSHJSA-N ClC=1C(=CC(=C(CN2[C@H](C[C@H](C2)O)C(=O)O)C1)OCC1=CC(=CC=C1)C#N)OCC1=C(C(=CC=C1)C1=CC2=C(OCCO2)C=C1)C Chemical group ClC=1C(=CC(=C(CN2[C@H](C[C@H](C2)O)C(=O)O)C1)OCC1=CC(=CC=C1)C#N)OCC1=C(C(=CC=C1)C1=CC2=C(OCCO2)C=C1)C QBXVXKRWOVBUDB-GRKNLSHJSA-N 0.000 description 1
- YUNTWDKKZKHSLO-KFJBMODSSA-N O=C(CC1)NN1[C@H](C1NC1)c(cc1)ccc1F Chemical compound O=C(CC1)NN1[C@H](C1NC1)c(cc1)ccc1F YUNTWDKKZKHSLO-KFJBMODSSA-N 0.000 description 1
- BEXZJJQVPWJPOA-VOTSOKGWSA-N [(e)-hept-2-enyl] 6-methyl-4-(4-nitrophenyl)-2-oxo-3,4-dihydro-1h-pyrimidine-5-carboxylate Chemical compound CCCC\C=C\COC(=O)C1=C(C)NC(=O)NC1C1=CC=C([N+]([O-])=O)C=C1 BEXZJJQVPWJPOA-VOTSOKGWSA-N 0.000 description 1
- HGDWHTASNMRJMP-UHFFFAOYSA-N [1-(hydroxyamino)-1-oxo-5-(3-phenoxyphenyl)pentan-2-yl]phosphonic acid Chemical compound ONC(=O)C(P(O)(O)=O)CCCC1=CC=CC(OC=2C=CC=CC=2)=C1 HGDWHTASNMRJMP-UHFFFAOYSA-N 0.000 description 1
- YLEIFZAVNWDOBM-ZTNXSLBXSA-N ac1l9hc7 Chemical group C([C@H]12)C[C@@H](C([C@@H](O)CC3)(C)C)[C@@]43C[C@@]14CC[C@@]1(C)[C@@]2(C)C[C@@H]2O[C@]3(O)[C@H](O)C(C)(C)O[C@@H]3[C@@H](C)[C@H]12 YLEIFZAVNWDOBM-ZTNXSLBXSA-N 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 238000007259 addition reaction Methods 0.000 description 1
- 150000004705 aldimines Chemical class 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 150000001345 alkine derivatives Chemical class 0.000 description 1
- SRVFFFJZQVENJC-IHRRRGAJSA-N aloxistatin Chemical group CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](CC(C)C)C(=O)NCCC(C)C SRVFFFJZQVENJC-IHRRRGAJSA-N 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- WARCRYXKINZHGQ-UHFFFAOYSA-N benzohydrazide Chemical compound NNC(=O)C1=CC=CC=C1 WARCRYXKINZHGQ-UHFFFAOYSA-N 0.000 description 1
- KSCRVOKQPYZBHZ-IXPOFIJOSA-N benzyl n-[(2s)-1-[[(2s)-1-[[(2s)-1-(1,3-benzothiazol-2-yl)-1-oxo-3-[(3s)-2-oxopyrrolidin-3-yl]propan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]carbamate Chemical group N([C@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C[C@H]1C(NCC1)=O)C(=O)C=1SC2=CC=CC=C2N=1)C(C)C)C(=O)OCC1=CC=CC=C1 KSCRVOKQPYZBHZ-IXPOFIJOSA-N 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 229910021538 borax Inorganic materials 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000006352 cycloaddition reaction Methods 0.000 description 1
- AVAACINZEOAHHE-VFZPANTDSA-N doripenem Chemical compound C=1([C@H](C)[C@@H]2[C@H](C(N2C=1C(O)=O)=O)[C@H](O)C)S[C@@H]1CN[C@H](CNS(N)(=O)=O)C1 AVAACINZEOAHHE-VFZPANTDSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 150000007975 iminium salts Chemical class 0.000 description 1
- JFOZKMSJYSPYLN-QHCPKHFHSA-N lifitegrast Chemical compound CS(=O)(=O)C1=CC=CC(C[C@H](NC(=O)C=2C(=C3CCN(CC3=CC=2Cl)C(=O)C=2C=C3OC=CC3=CC=2)Cl)C(O)=O)=C1 JFOZKMSJYSPYLN-QHCPKHFHSA-N 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- QAPTWHXHEYAIKG-RCOXNQKVSA-N n-[(1r,2s,5r)-5-(tert-butylamino)-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical group CC(=O)N[C@@H]1C[C@H](NC(C)(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 QAPTWHXHEYAIKG-RCOXNQKVSA-N 0.000 description 1
- GVOISEJVFFIGQE-YCZSINBZSA-N n-[(1r,2s,5r)-5-[methyl(propan-2-yl)amino]-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 GVOISEJVFFIGQE-YCZSINBZSA-N 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 150000003839 salts Chemical group 0.000 description 1
- 235000010339 sodium tetraborate Nutrition 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- BSVBQGMMJUBVOD-UHFFFAOYSA-N trisodium borate Chemical compound [Na+].[Na+].[Na+].[O-]B([O-])[O-] BSVBQGMMJUBVOD-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明公开了一种含吡唑烷酮结构的手性氨基氰化物的制备方法，其特征在于：以环状腙为反应物，在手性硫脲催化剂的催化下，以三甲基硅腈为氰基化试剂，以均三甲苯为溶剂，于–15℃条件下反应10-144小时，获得手性氨基氰化物。本发明所用催化剂均由工业化、廉价易得的原料制备，所用氰基化试剂毒性低，价格便宜；本发明所涉及到的反应条件温和，后处理简单方便，反应过程中无N–N键的断裂过程，无亚胺副产物生成；本发明适用的底物范围广，官能团兼容性高，立体选择性良好到优秀，为合成吡唑烷酮骨架的手性氨基氰化物提供了一种高效的方法。
Description
技术领域
本发明属于不对称催化合成领域，具体涉及一种通过不对称Strecker反应制备手性氨基氰化物的方法。
背景技术
不对称Strecker反应是合成手性氨基酸的重要方法。自从Lipton (M. S. Iye, K. M. Gigstad, N. D. Namdev, M. Lipton, J. Am. Chem. Soc. 1996, 118, 4910)和Jacobsen (M. S. Sigman, E. N. Jacobsen, J. Am. Chem. Soc. 1998, 120, 5315.)小组分别以有机小分子催化剂和金属催化剂报道亚胺的不对称Strecker反应以来，大量基于不同活化模式的催化体系的报道相继涌现出来。另外，目前以醛亚胺为底物的不对称Strecker反应已经相当成熟，酮亚胺的不对称Strecker反应在最近20里也获得了长足的发展。而亚胺等价物的不对称Strecker反应发展相对缓慢，其中比较成功的有芳香醛与苯甲酰肼衍生的链状腙的不对称Strecker反应。 a) J. M. Keith, E. N. Jacobsen, Org. Lett. 2004, 6, 153; b) A. Zamfir, S. B. Tsogoeva, Org. Lett. 2010, 12, 188. 而硝酮与亚胺盐的不对称Strecker反应却未有报道，此类亚胺等价物的手性Strecker反应产物往往是通过以手性硝酮以及手性亚胺盐为反应底物获得的。
芳香醛与吡唑烷酮缩合所得的环状腙是一种分子内的亚胺盐，作为1,3偶极子，该底物在与烯烃、炔烃的不对称环加成反应中得到了广泛的应用。Shitata 和Hayashi 教授分别开发了其作为亲电试剂与TMSCF3和四苯硼酸钠的单步加成反应。a) H. Kawai, A. Kusuda, S. Nakamura, M. Shiro, N. Shitata, Angew. Chem., Int. Ed. 2009, 48, 6324; b) R. Shintani, Y. T. Soh, T. Hayashi, Org. Lett. 2010, 12, 4106. 2007年，Jurij Svete课题组以手性的环状分子内盐形式的腙为底物，以现场生成的HCN为氰基化试剂发生反应。(L. Pezdirc, U. Groelj, A. Meden, B. Stanovnik, J. Svete. Tetrahedron Lett., 2007, 48, 5205.) 然而，在他们的反应条件下，氨基氰化物大都不能稳定存在，而是生成亚胺并伴随着N–N键的断裂，如下式所示：
考虑到吡唑烷酮在天然产物以及药物中的广泛存在，我们设想开发更加温和的条件以获得稳定存在的含吡唑烷酮结构的手性氨基氰化物，借以考察其可能拥有的生物活性。
发明内容
本发明的发明目的是提供一种手性氨基氰化物的制备方法，通过环状分子内亚胺盐的不对称Strecker反应实现。
为达到上述发明目的，本发明采用的技术方案是：一种手性氨基氰化物的制备方法，以环状腙为反应物，在手性硫脲催化剂的催化下，以三甲基硅腈为氰基化试剂，以均三甲苯为溶剂，于–15℃条件下反应10～144小时，获得手性氨基氰化物；
所述环状腙的化学结构式为：
，其中Ar选自：苯基、2-氟苯基、4-氟苯基、2-氯苯基、3-氯苯基、4-氯苯基、2-溴苯基、3-溴苯基、4-溴苯基、2-甲氧基苯基、4-甲氧基苯基、3,5-二甲氧基苯基、胡椒基、4-三氟甲基苯基、2-萘基或2-呋喃基中的一种；
所述手性硫脲催化剂的化学结构式为：
；
所述手性氨基氰化物的化学结构式为：
。
上述方法可以高达99%的收率，76–97%的对映选择性得到目标化合物。原料环状腙根据文献方法由相应的芳香醛与吡唑烷酮一步合成，原料便宜易得，合成方法简单。
上述技术方案中，所述催化剂用量为底物环状腙的1～10 mol%。
优选的技术方案，以物质的量计，三甲基硅腈用量为底物的１～1.2倍。
进一步的技术方案，反应结束后，加入二氯甲烷使反应体系呈均相，直接对反应体系进行制备薄层色谱或快速柱色谱分离，薄层色谱展开剂、柱色谱流动相为体积比1∶1的乙酸乙酯/石油醚。
由于上述技术方案运用，本发明与现有技术相比具有下列优点：
1、本发明的原料环状腙可以由相应的芳香醛与吡唑烷酮一步合成，相对于现有技术中的手性吡唑烷酮亚胺，原料便宜易得；三甲基硅腈是一种毒性相对低的氰基化试剂，安全有保障；催化剂为工业化、廉价易得的产品。
2、本发明所涉及到的strecker反应条件温和，反应体系不存在N–N键的断裂过程，可有效防止同类反应中亚胺副产物的生成。
3、本发明适用的底物范围广，官能团兼容性高，立体选择性良好等到优秀，为环状腙的不对称Strecker反应提供了一种有效的方法。
具体实施方式
下面结合实施例对本发明作进一步描述：
实施例1：
将化合物1a (0.2 mmol，34.84 mg)和手性硫脲Cat. (0.002 mmol，1.16 mg)置于具塞试管中，冷却至–15℃，小心加入三甲基硅腈(1.2 equiv, 30.54μL)，加入0.5 mL均三甲苯，在同样温度下搅拌18h。反应结束后，加入少许二氯甲烷稀释，反应体系直接用制备薄层色谱分离（展开剂为乙酸乙酯：石油醚=1：1）即可得到白色固体2a (39.04 mg)，收率为97%。
对产物进行分析，结果如下： 95.3% ee [Daicel Chiralcel AD-H, hexanes/i-PrOH = 93/7, flow rate: 1.0 mL·min-1, λ = 254.4 nm, t (major)= 40.098, t (minor)= 36.087]; [α]D 25 = -107.18 (c 0.59, CHCl3); 1H NMR (400 MHz, CDCl3) δ = 7.91 (s, 1H), 7.57 – 7.50 (m, 2H), 7.48 – 7.42 (m, 3H), 4.95 (s, 1H), 3.58 (s, 1H), 3.53 – 3.44 (m, 1H), 2.65 (s, 2H); 13C NMR (75 MHz, CDCl3) δ = 175.44, 131.07, 129.75, 129.15, 128.30, 116.99, 62.75, 49.27, 29.79 ppm; IR (KBr) nmax: 3451.3, 3189.5, 2200.1, 1692.3, 1072.1, 929.6, 699.9 cm-1; ESI-MS (%): m/z = 202.1 [M+H]+; HRMS (ESI): m/z = 202.0965 (calcd for C11H11N3O+H+ = 202.0975). 以上数据证明所得化合物确为化合物2a。
实施例2：
将化合物1b (0.2 mmol，38.43 mg)和手性硫脲Cat. (0.002 mmol，1.16 mg)置于具塞试管中，冷却至–15℃，小心加入三甲基硅腈(1.2 equiv, 30.54μL)，加入0.5 mL均三甲苯，在同样温度下搅拌3d。反应结束后，加入少许二氯甲烷稀释，反应体系直接用制备薄层色谱分离（展开剂为乙酸乙酯：石油醚=1：1)即可得到白色固体2b (42.97 mg)，收率为98%。
对产物进行分析，结果如下：91.5% ee [Daicel Chiralcel AD-H, hexanes/i-PrOH = 85/15, flow rate: 1.0 mL·min-1, λ = 254.4 nm, t (major)= 20.234, t (minor)= 13.614]; [α]D 25 = -89.57 (c 0.23, CHCl3); 1H NMR (400 MHz, CDCl3) δ = 7.64 (t, J = 7.32 Hz, 1H), 7.55 – 7.38 (m, 2H), 7.21 – 7.12 (m, 1H), 5.19 (s, 1H), 3.80 – 3.61 (m, 1H), 3.60 – 3.44 (m, 1H), 2.75 (s, 1H), 2.61 – 2.46 (m, 1H); 13C NMR (75 MHz, CDC3) δ = 175.74, 158.61, 132.20, 132.08, 130.18, 124.88, 118.91, 118.74, 116.39, 116.28, 116.00, 56.50, 49.96, 29.63 ppm; IR (KBr) nmax: 3460.3, 3158.1, 2848.9, 2114.2, 1697.3, 1494.7, 1094.7, 944.6, 804.9, 665.9 cm-1; ESI-MS (%): m/z = 220.1 [M+H]+; HRMS (ESI): m/z = 220.0881 (calcd for C11H10FN3O+H+ = 220.0881). 以上数据证明所得化合物确为化合物2b。
实施例3：
将化合物1c (0.2 mmol，38.43 mg)和手性硫脲Cat. (0.002 mmol，1.16 mg)置于具塞试管中，冷却至–15℃，小心加入三甲基硅腈(1.2 equiv, 30.54μL)，加入0.5 mL均三甲苯，在同样温度下搅拌23h。反应结束后，加入少许二氯甲烷稀释，反应体系直接用制备薄层色谱分离（展开剂为乙酸乙酯：石油醚=1：1）即可得到白色固体2c (41.65 mg)，收率为95%。
对产物进行分析，结果如下：94.8% ee [Daicel Chiralcel AD-H, hexanes/i-PrOH = 85/15, flow rate: 1.0 mL·min-1, λ = 254.4 nm, t (major)= 17.480, t (minor)= 23.212]; [α]D 25 = -106.25 (c 0.32, CHCl3); 1H NMR (400 MHz, CDCl3) δ = 7.61 – 7.42 (m, 2H), 7.12 (t, J = 8.44 Hz, 2H), 4.87 (s, 1H), 3.83 – 3.35 (m, 2H), 2.62 (s, 2H); 13C NMR (75 MHz, CDCl3) δ = 175.53, 164.99, 161.68, 130.29, 130.18, 127.01, 116.88, 116.38, 116.09, 62.12, 49.21, 29.75 ppm; IR (KBr) nmax: 3457.9, 3154.4, 2020.4, 1692.9, 1422.8, 1084.5, 862.4, 638.1 cm-1; ESI-MS (%): m/z = 220.1 [M+H]+; HRMS (ESI): m/z = 220.0886 (calcd for C11H10FN3O+H+ = 220.0881). 以上数据证明所得化合物确为化合物2c。
实施例4：
将化合物1d (0.2 mmol，41.72 mg)和手性硫脲Cat. (0.002 mmol，1.16 mg)置于具塞试管中，冷却至–15℃，小心加入三甲基硅腈(1.2 equiv, 30.54μL)，加入0.5 mL均三甲苯，在同样温度下搅拌10h。反应结束后，加入少许二氯甲烷稀释，反应体系直接用制备薄层色谱分离（展开剂为乙酸乙酯：石油醚=1：1）即可得到白色固体2d（46.17 mg)，收率为98%。
对产物进行分析，结果如下：88.5% ee [Daicel Chiralcel AD-H, hexanes/i-PrOH = 85/15, flow rate: 1.0 mL·min-1, λ = 254.4 nm, t (major)= 28.720, t (minor)= 16.028]; [α]D 25 = -100.27 (c 0.38, CHCl3); 1H NMR (400 MHz, CDCl3) δ = 7.73 – 7.65 (m, 1H), 7.49 – 7.43 (m, 1H), 7.42 – 7.34 (m, 2H), 5.33 (s, 1H), 3.74 – 3.57 (m, 1H), 3.55 – 3.38 (m, 1H), 2.86 – 2.69 (m, 1H), 2.67 – 2.45 (m, 1H); 13C NMR (75 MHz, CDCl3) δ = 175.72, 134.27, 131.38, 130.35, 130.30, 129.15, 127.61, 116.63, 59.76, 50.09, 29.67 ppm; IR (KBr) nmax: 3464.8, 3168.3, 2098.8, 1708.1, 1458.9, 1040.3, 942.0, 753.5, 650.6 cm-1; ESI-MS (%): m/z = 236.1 (100) and 238.1 (38) [M+H]+ for 35Cl and 37Cl isotopic pattern; HRMS (ESI): m/z = 236.0575 (calcd for C11H10ClN3O+H+ = 236.0585). 以上数据证明所得化合物确为化合物2d。
实施例5：
将化合物1e (0.2 mmol，41.72 mg)和手性硫脲Cat. (0.002 mmol，1.16 mg)置于具塞试管中，冷却至–15℃，小心加入三甲基硅腈(1.2 equiv, 30.54μL)，加入0.5 mL均三甲苯，在同样温度下搅拌10h。反应结束后，加入少许二氯甲烷稀释，反应体系直接用制备薄层色谱分离（展开剂为乙酸乙酯：石油醚=1：1）即可得到白色固体2e (46.17 mg)，收率为98%。
对产物进行分析，结果如下：96.7% ee [Daicel Chiralcel AD-H, hexanes/i-PrOH = 85/15, flow rate: 1.0 mL·min-1, λ = 254.4 nm, t (major)= 13.448, t (minor)= 11.605]; [α]D 25 = -105.28 (c 0.36, CHCl3); 1H NMR (400 MHz, CDCl3) δ = 8.09 (s, 1H), 7.55 (s, 1H), 7.47 – 7.36 (m, 3H), 4.94 (s, 1H), 3.79 – 3.32 (m, 2H), 2.69 (s, 2H); 13C NMR (75 MHz, CDCl3) δ = 175.50, 135.01, 133.09, 130.47, 129.97, 128.37, 126.44, 116.55, 62.22, 49.34, 29.76 ppm; IR (KBr) nmax: 3476.6, 3186.5, 2239.4, 1694.9, 1427.8, 1083.6, 1016.779, 892.2, 677.9, cm-1; ESI-MS (%): m/z = 236.1 (100) and 238.1 (38) [M+H]+ for 35Cl and 37Cl isotopic pattern; HRMS (ESI): m/z = 236.0582 (calcd for C11H10ClN3O+H+ = 236.0585). 以上数据证明所得化合物确为化合物2e。
实施例6：
将化合物1f (0.2 mmol，41.72 mg)和手性硫脲Cat. (0.002 mmol，1.16 mg)置于具塞试管中，冷却至–15℃，小心加入三甲基硅腈(1.2 equiv, 30.54μL)，加入0.5 mL均三甲苯，在同样温度下搅拌20h。反应结束后，加入少许二氯甲烷稀释，反应体系直接用制备薄层色谱分离（展开剂为乙酸乙酯：石油醚=1：1）即可得到白色固体2f (46.65 mg)，收率为99%。
对产物进行分析，结果如下：92.5% ee [Daicel Chiralcel AD-H, hexanes/i-PrOH = 85/15, flow rate: 1.0 mL·min-1, λ = 254.4 nm, t (major)= 28.720, t (minor)= 16.028]; [α]D 25 = -110.94 (c 0.32, CHCl3); 1H NMR (400 MHz, CDCl3) δ = 7.57 – 7.34 (m, 4H), 4.90 (s, 1H), 3.76 – 3.37 (m, 2H), 2.90 – 2.42 (s, 2H); 13C NMR (75 MHz, CDCl3) δ = 175.47, 135.96, 129.60, 129.43, 116.61, 62.29, 49.44, 29.71 ppm; IR (KBr) nmax: 3449.7, 3173.0, 2238.9, 1685.2, 1408.2 1088.1, 858.3, 685.3 cm-1; ESI-MS (%): m/z = 236.1 (100) and 238.1 (38) [M+H]+ for 35Cl and 37Cl isotopic pattern; HRMS (ESI): m/z = 236.0574 (calcd for C11H10ClN3O+H+ = 236.0585). 以上数据证明所得化合物确为化合物2f。
实施例7：
将化合物1g (0.2 mmol，50.62 mg)和手性硫脲Cat. (0.002 mmol，1.16 mg)置于具塞试管中，冷却至–15℃，小心加入三甲基硅腈(1.2 equiv, 30.54μL)，加入0.5 mL均三甲苯，在同样温度下搅拌72h。反应结束后，加入少许二氯甲烷稀释，反应体系直接用制备薄层色谱分离（展开剂为乙酸乙酯：石油醚=1：1）即可得到白色固体2g (55.44 mg)，收率为99%。
对产物进行分析，结果如下：95.4% ee [Daicel Chiralcel AD-H, hexanes/i-PrOH = 85/15, flow rate: 1.0 mL·min-1, λ = 210.8 nm, t (major)= 13.285, t (minor)= 11.663]; [α]D 25 = -50.57 (c 0.44, CHCl3); 1H NMR (400 MHz, CDCl3) δ = 7.94 (s, 1H), 7.70 (d, J = 7.68 Hz, 1H), 7.65 (d, J = 7.96 Hz, 1H), 7.48 – 7.38 (m, 1H), 7.37 – 7.28 (m, 1H), 5.30 (s, 1H), 3.76 – 3.58 (m, 1H), 3.53 – 3.35 (m, 1H), 2.90 – 2.68 (m, 1H), 2.66 – 2.43 (m, 1H); 13C NMR (75 MHz, CDCl3) δ = 175.59, 133.61, 131.45, 130.72, 130.32, 128.13, 124.51, 116.55, 61.99, 49.91, 29.58 ppm; IR (KBr) nmax: 3467.6, 3187.1, 2239.9, 1693.9, 1431.2, 1024.3, 943.8, 758.2 cm-1; ESI-MS (%): m/z = 280.0 (94) and 282.0 (100) [M+H]+ for 79Br and 81Br isotopic pattern; HRMS (ESI): m/z = 280.0072 (calcd for C11H10BrN3O+H+ = 280.0080). 以上数据证明所得化合物确为化合物2g。
实施例8：
将化合物1h (0.2 mmol，50.62 mg)和手性硫脲Cat. (0.002 mmol，1.16 mg)置于具塞试管中，冷却至–15℃，小心加入三甲基硅腈(1.2 equiv, 30.54μL)，加入0.5 mL均三甲苯，在同样温度下搅拌72h。反应结束后，加入少许二氯甲烷稀释，反应体系直接用制备薄层色谱分离（展开剂为乙酸乙酯：石油醚=1：1）即可得到白色固体2h (55.44 mg)，收率为99%。
对产物进行分析，结果如下：96.6% ee [Daicel Chiralcel AD-H, hexanes/i-PrOH = 85/15, flow rate: 1.0 mL·min-1, λ = 254.4 nm, t (major)= 12.783, t (minor)= 18.109]; [α]D 25 = -72.80 (c 0.50, CHCl3); 1H NMR (400 MHz, CDCl3) δ = 8.32 (bs, 1H), 7.69 (s, 1H), 7.56 (d, J = 7.52 Hz, 1H), 7.48 (d, J = 7.32 Hz, 1H), 7.39 – 7.29 (m, 1H), 4.93 (s, 1H), 3.81 – 3.26 (m, 2H), 2.68 (s, 2H); 13C NMR (75 MHz, CDCl3) δ = 175.36, 133.20, 132.84, 131.13, 130.61, 126.80, 123.02, 116.36, 62.10, 49.32, 29.67 ppm; IR (KBr) nmax: 3451.6, 3167.0, 2239.5, 1689.2, 1418.0, 1079.1, 936.9, 874.7, 785.5 cm-1; ESI-MS (%): m/z = 280.0 (94) and 282.0 (100) [M+H]+ for 79Br and 81Br isotopic pattern; HRMS (ESI): m/z = 280.0069 (calcd for C11H10BrN3O+H+ = 280.0080). 以上数据证明所得化合物确为化合物2h。
实施例9：
将化合物1i (0.2 mmol，50.62 mg)和手性硫脲Cat. (0.002 mmol，1.16 mg)置于具塞试管中，冷却至–15℃，小心加入三甲基硅腈(1.2 equiv, 30.54μL)，加入0.5 mL均三甲苯，在同样温度下搅拌72h。反应结束后，加入少许二氯甲烷稀释，反应体系直接用制备薄层色谱分离（展开剂为乙酸乙酯：石油醚=1：1）即可得到白色固体2i (55.32 mg)，收率为97%。
对产物进行分析，结果如下：96.6% ee [Daicel Chiralcel AD-H, hexanes/i-PrOH = 85/15, flow rate: 1.0 mL·min-1, λ = 254.4 nm, t (major)= 12.783, t (minor)= 18.109]; [α]D 25 = -96.36 (c 0.33, CHCl3); 1H NMR (400 MHz, CDCl3) δ = 8.72 (s, 1H), 7.56 (d, J = 8.28 Hz, 2H), 7.40 (d, J = 8.20 Hz, 2H), 4.92 (s, 1H), 3.84 – 3.20 (m, 2H), 2.63 (s, 2H); 13C NMR (101 MHz, CDCl3) δ = 175.67, 132.60, 130.39, 130.10, 124.35, 116.79, 62.57, 50.18, 29.92 ppm; IR (KBr) nmax: 3436.8, 3150.1, 2293.6, 1679.7, 1481.3, 1080.1, 937.5, 865.1, 718.5 cm-1; ESI-MS (%): m/z = 280.0 (94) and 282.0 (100) [M+H]+ for 79Br and 81Br isotopic pattern; HRMS (ESI): m/z = 280.0074 (calcd for C11H10BrN3O+H+ = 280.0080). 以上数据证明所得化合物确为化合物2i。
实施例10：
将化合物1j (0.2 mmol，40.85 mg)和手性硫脲Cat. (0.002 mmol，1.16 mg)置于具塞试管中，冷却至–15℃，小心加入三甲基硅腈(1.2 equiv, 30.54μL)，加入0.5 mL均三甲苯，在同样温度下搅拌5d。反应结束后，加入少许二氯甲烷稀释，反应体系直接用制备薄层色谱分离（展开剂为乙酸乙酯：石油醚=1：1）即可得到白色固体2j (44.51 mg)，收率为95%。
对产物进行分析，结果如下：90.1% ee [Daicel Chiralcel AD-H, hexanes/i-PrOH = 85/15, flow rate: 1.0 mL·min-1, λ = 254.4 nm, t (major)= 34.166, t (minor)= 16.694]; [α]D 25 = -114.38 (c 0.32, CHCl3); 1H NMR (400 MHz, CDCl3) δ = 7.54 (d, J = 7.40 Hz, 1H), 7.48 – 7.37 (m, 1H), 7.11 – 7.01 (m, 2H), 6.93 (d, J = 8.28 Hz, 1H), 5.29 (s, 1H), 3.87 (s, 3H), 3.71 – 3.58 (m, 1H), 3.55 – 3.41 (m, 1H), 2.69 (s, 1H), 2.59 – 2.40 (m, 1H); 13C NMR (75 MHz, CDCl3) δ = 175.45, 156.76, 131.52, 129.79, 120.97, 119.54, 117.33, 111.23, 56.43, 55.89, 49.99, 29.71 ppm; IR (KBr) nmax: 3491.6, 3168.8, 2835.1, 2032.4, 1706.6, 1471.0, 1095.6, 1021.8, 837.7, 749.8, 654.9 cm-1; ESI-MS (%): m/z = 232.1 [M+H]+; HRMS (ESI): m/z = 232.1072 (calcd for C12H13N3O2+H+ = 232.1081). 以上数据证明所得化合物确为化合物2j。
实施例11：
将化合物1k (0.2 mmol，40.85 mg)和手性硫脲Cat. (0.002 mmol，1.16 mg)置于具塞试管中，冷却至–15℃，小心加入三甲基硅腈(1.2 equiv, 30.54μL)，加入0.5 mL均三甲苯，在同样温度下搅拌6d。反应结束后，加入少许二氯甲烷稀释，反应体系直接用制备薄层色谱分离（展开剂为乙酸乙酯：石油醚=1：1）即可得到白色固体2k (44.44 mg)，收率为97%。
对产物进行分析，结果如下：82.7% ee [Daicel Chiralcel AD-H, hexanes/i-PrOH = 85/15, flow rate: 1.0 mL·min-1, λ = 254.4 nm, t (major)= 15.166, t (minor)= 23.874]; [α]D 25 = -96.99 (c 0.47, CHCl3); 1H NMR (400 MHz, CDCl3) δ = 8.25 (brs, 1H), 7.43 (d, J = 8.04 Hz, 2H), 6.94 (d, J = 8.00 Hz, 2H), 4.89 (s, 1H), 3.82 (s, 3H), 3.59 – 3.32 (m, 2H), 2.60 (s, 2H); 13C NMR (75 MHz, CDCl3) δ = 175.35, 160.60, 129.66, 122.96, 117.10, 114.50, 62.23, 55.39, 49.10, 29.74 ppm; IR (KBr) nmax: 3449.0, 3180.1, 2230.0, 1683.8, 1407.6, 1249.5, 1023.7, 841.1, 647.9 cm-1; ESI-MS (%): m/z = 232.1 [M+H]+; HRMS (ESI): m/z = 232.1075 (calcd for C12H13N3O2+H+ = 232.1081). 以上数据证明所得化合物确为化合物2k。
实施例12：
将化合物1l (0.2 mmol，46.85 mg)和手性硫脲Cat. (0.002 mmol，1.16 mg)置于具塞试管中，冷却至–15℃，小心加入三甲基硅腈(1.2 equiv, 30.54μL)，加入0.5 mL均三甲苯，在同样温度下搅拌6d。反应结束后，加入少许二氯甲烷稀释，反应体系直接用制备薄层色谱分离（展开剂为乙酸乙酯：石油醚=1：1）即可得到白色固体2l (51.21 mg)，收率为98%。
对产物进行分析，结果如下：90.1% ee [Daicel Chiralcel AD-H, hexanes/i-PrOH = 85/15, flow rate: 1.0 mL·min-1, λ = 254.4 nm, t (major)= 21.059, t (minor)= 24.922]; [α]D 25 = -80.44 (c 0.23, CHCl3); 1H NMR (400 MHz, CDCl3) δ = 6.66 (d, J = 1.36 Hz, 2H), 6.49 (s, 1H), 4.84 (s, 1H), 3.82 (s, 6H), 3.68 – 3.41 (m, 2H), 2.65 (s, 2H); 13C NMR (75 MHz, CDCl3) δ = 175.32, 161.23, 133.15, 116.80, 106.12, 101.57, 62.85, 55.53, 49.34, 29.76 ppm; IR (KBr) nmax: 3446.5, 3158.5, 2243.6, 1687.8, 1461.5, 1065.4, 834.4, 747.1, 690.9 cm-1; ESI-MS (%): m/z = 262.1 [M+H]+; HRMS (ESI): m/z = 262.1175 (calcd for C13H15N3O3+H+ = 262.1186). 以上数据证明所得化合物确为化合物2l。
实施例13：
将化合物1m (0.2 mmol，43.64 mg)和手性硫脲Cat. (0.002 mmol，1.16 mg)置于具塞试管中，冷却至–15℃，小心加入三甲基硅腈(1.2 equiv, 30.54μL)，加入0.5 mL均三甲苯，在同样温度下搅拌5d。反应结束后，加入少许二氯甲烷稀释，反应体系直接用制备薄层色谱分离（展开剂为乙酸乙酯：石油醚=1：1）即可得到白色固体2m (45.61 mg)，收率为93%。
对产物进行分析，结果如下：85.1% ee [Daicel Chiralcel AD-H, hexanes/i-PrOH = 85/15, flow rate: 1.0 mL·min-1, λ = 210.8 nm, t (major)= 20.523, t (minor)= 22.498]; [α]D 25 = -94.81 (c 0.14, CHCl3); 1H NMR (400 MHz, CDCl3) δ = 8.00 (bs, 1H), 7.06 – 6.92 (m, 2H), 6.83 (d, J = 7.68 Hz, 1H), 6.01 (s, 2H), 4.82 (s, 1H), 3.70 – 3.32 (m, 2H), 2.64 (s, 2H); 13C NMR (75 MHz, CDCl3) δ = 180.44, 148.90, 148.44, 124.69, 122.17, 116.84, 112.61, 108.46, 101.70, 62.55, 49.66, 29.66 ppm; IR (KBr) nmax: 3433.7, 3155.1, 2292.3, 1960.2, 1683.0, 1498.2, 1240.9, 1031.9, 921.4, 797.9 cm-1; ESI-MS (%): m/z = 246.1 [M+H]+; HRMS (ESI): m/z = 246.0868 (calcd for C12H11N3O3+H+ = 246.0873). 以上数据证明所得化合物确为化合物2m。
实施例14：
将化合物1n (0.2 mmol，48.44 mg)和手性硫脲Cat. (0.002 mmol，1.16 mg)置于具塞试管中，冷却至–15℃，小心加入三甲基硅腈(1.2 equiv, 30.54μL)，加入0.5 mL均三甲苯，在同样温度下搅拌20h。反应结束后，加入少许二氯甲烷稀释，反应体系直接用制备薄层色谱分离（展开剂为乙酸乙酯：石油醚=1：1）即可得到白色固体2n (48.46 mg)，收率为90%。
对产物进行分析，结果如下：90.3% ee [Daicel Chiralcel AD-H, hexanes/i-PrOH = 85/15, flow rate: 1.0 mL·min-1, λ = 210.8 nm, t (major)= 9.580, t (minor)= 12.821]; [α]D 25 = -78.18 (c 0.17, CHCl3); 1H NMR (400 MHz, CDCl3) δ = 8.68 (bs, 1H), 7.78 – 7.62 (m, 4H), 5.03 (s, 1H), 3.79 – 3.28 (m, 2H), 2.65 (s, 2H); 13C NMR (101 MHz, CDCl3) δ = 175.71, 135.18, 132.41, 132.08, 129.00, 128.93, 126.44, 126.41, 125.16, 122.45, 116.59, 62.80, 49.99, 29.85 ppm; IR (KBr) nmax: 3439.2, 3176.1, 2238.4, 1689.9, 1421.8, 1328.1, 1016.7, 937.6, 875.0, 808.2, 659.6 cm-1; ESI-MS (%): m/z = 270.1 [M+H]+; HRMS (ESI): m/z = 270.0840 (calcd for C12H10F3N3O+H+ = 270.0849). 以上数据证明所得化合物确为化合物2n。
实施例15：
将化合物1o (0.2 mmol，44.85 mg)和手性硫脲Cat. (0.002 mmol，1.16 mg)置于具塞试管中，冷却至–15℃，小心加入三甲基硅腈(1.2 equiv, 30.54μL)，加入0.5 mL均三甲苯，在同样温度下搅拌6d。反应结束后，加入少许二氯甲烷稀释，反应体系直接用制备薄层色谱分离（展开剂为乙酸乙酯：石油醚=1：1）即可得到白色固体2o (49.75 mg)，收率为99%。
对产物进行分析，结果如下：87.3% ee [Daicel Chiralcel AD-H, hexanes/i-PrOH = 85/15, flow rate: 1.0 mL·min-1, λ = 254.4 nm, t (major)= 14.979, t (minor)= 17.002]; [α]D 25 = -83.14 (c 0.26, CHCl3); 1H NMR (400 MHz, CDCl3) δ = 8.02 (s, 1H), 7.94 – 7.77 (m, 3H), 7.54 (d, J = 5.76 Hz, 3H), 5.07 (s, 1H), 3.83 – 3.29 (m, 2H), 2.62 (s, 2H); 13C NMR (75 MHz, CDCl3) δ = 175.38, 133.55, 132.88, 129.24, 128.46, 128.29, 127.93, 127.76, 127.30, 126.95, 125.12, 117.01, 62.98, 49.25, 29.75 ppm; IR (KBr) nmax: 33449.9, 3151.5, 3039.5, 2007.5, 1684.8, 1426.7, 1371.6, 1079.2, 859.2, 751.3, 632.9 cm-1; ESI-MS (%): m/z = 252.1 [M+H]+; HRMS (ESI): m/z = 252.1123 (calcd for C15H13N3O2+H+ = 252.1131). 以上数据证明所得化合物确为化合物2o。
实施例16：
将化合物1p (0.2 mmol，32.83 mg)和手性硫脲Cat.（0.02 mmol，11.57 mg)置于具塞试管中，冷却至–15℃，小心加入三甲基硅腈(1.2 equiv, 30.54μL)，加入0.5 mL均三甲苯，在同样温度下搅拌20h。反应结束后，加入少许二氯甲烷稀释，反应体系直接用制备薄层色谱分离（展开剂为乙酸乙酯：石油醚=1：1）即可得到白色固体2p (37.85 mg)，收率为99%。
对产物进行分析，结果如下：75.9% ee [Daicel Chiralcel AD-H, hexanes/i-PrOH = 85/15, flow rate: 1.0 mL·min-1, λ = 254.4 nm, t (major)= 16.289, t (minor)= 26.215]; [α]D 25 = -66.82 (c 0.22, CHCl3); 1H NMR (400 MHz, CDCl3) δ = 7.59 (s, 1H), 7.48 (s, 1H), 6.61 (d, J = 3.04 Hz, 1H), 6.48 – 6.39 (m, 1H), 4.93 (s, 1H), 3.64 (s, 1H), 3.59 – 3.48 (m, 1H), 2.50 (s, 2H); 13C NMR (75 MHz, CDCl3) δ = 175.74, 144.59, 144.03, 115.27, 111.98, 111.19, 56.17, 49.51, 29.57 ppm; IR (KBr) nmax: 3455.6, 3151.1, 1696.0, 1499.4, 1311.8, 1072.0, 954.8, 760., 607.1 cm-1; ESI-MS (%): m/z = 192.1 [M+H]+; HRMS (ESI): m/z = 192.0770 (calcd for C9H9N3O2+H+ = 192.0768). 以上数据证明所得化合物确为化合物2p。
Claims (4)
1.一种含吡唑烷酮结构的手性氨基氰化物的制备方法，其特征在于：以环状腙为反应物，在手性硫脲催化剂的催化下，以三甲基硅腈为氰基化试剂，以均三甲苯为溶剂，于–15℃条件下反应10～144小时，获得手性氨基氰化物；
所述环状腙的化学结构式为： 
，其中Ar选自：苯基、2-氟苯基、4-氟苯基、2-氯苯基、3-氯苯基、4-氯苯基、2-溴苯基、3-溴苯基、4-溴苯基、2-甲氧基苯基、4-甲氧基苯基、3,5-二甲氧基苯基、胡椒基、4-三氟甲基苯基、2-萘基或2-呋喃基中的一种；
所述手性硫脲催化剂的化学结构式为：
；
所述手性氨基氰化物的化学结构式为：
。
2.根据权利要求1所述手性氨基氰化物的制备方法，其特征在于：所述催化剂用量为底物环状腙的1～10 mol%。
3.根据权利要求1所述手性氨基氰化物的制备方法，其特征在于：以物质的量计，三甲基硅腈用量为底物的1～1.2倍。
4.根据权利要求1所述手性氨基氰化物的制备方法，其特征在于：反应结束后，加入二氯甲烷使反应体系呈均相，直接对反应体系进行制备薄层色谱或快速柱色谱分离，薄层色谱展开剂、柱色谱流动相为体积比1∶1的乙酸乙酯/石油醚混合液。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210368613.1A CN102964304B (zh) | 2012-09-28 | 2012-09-28 | 含吡唑烷酮结构的手性氨基氰化物的制备方法 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210368613.1A CN102964304B (zh) | 2012-09-28 | 2012-09-28 | 含吡唑烷酮结构的手性氨基氰化物的制备方法 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102964304A true CN102964304A (zh) | 2013-03-13 |
| CN102964304B CN102964304B (zh) | 2015-06-17 |
Family
ID=47794768
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201210368613.1A Expired - Fee Related CN102964304B (zh) | 2012-09-28 | 2012-09-28 | 含吡唑烷酮结构的手性氨基氰化物的制备方法 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102964304B (zh) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103508826A (zh) * | 2013-10-12 | 2014-01-15 | 苏州大学张家港工业技术研究院 | 手性三取代茚满化合物的制备方法 |
| CN104961670A (zh) * | 2015-07-01 | 2015-10-07 | 中国计量学院 | 一种n,o-双取代的酮亚胺衍生物的制备方法 |
| CN106188078A (zh) * | 2016-07-15 | 2016-12-07 | 苏州大学 | 一种手性螺环羟吲哚‑苯并吡喃‑酮并‑3,4‑二氢‑吡喃化合物的合成方法 |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008068423A2 (fr) * | 2006-11-20 | 2008-06-12 | Sanofi-Aventis | Derives de pyrrole, leur preparation et leur utilisation en therapeutique. |
| CN101805329A (zh) * | 2010-04-02 | 2010-08-18 | 上海师范大学 | 具有杀虫活性1,5-二取代六氢三嗪化合物及制备方法 |
-
2012
- 2012-09-28 CN CN201210368613.1A patent/CN102964304B/zh not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008068423A2 (fr) * | 2006-11-20 | 2008-06-12 | Sanofi-Aventis | Derives de pyrrole, leur preparation et leur utilisation en therapeutique. |
| CN101535250A (zh) * | 2006-11-20 | 2009-09-16 | 赛诺菲-安万特 | 吡咯的衍生物、它们的制备和它们在治疗中的用途 |
| CN101805329A (zh) * | 2010-04-02 | 2010-08-18 | 上海师范大学 | 具有杀虫活性1,5-二取代六氢三嗪化合物及制备方法 |
Non-Patent Citations (2)
| Title |
|---|
| LIDIJA PEZDIRC，等: "Unexpected cleavage of the N–N bond in the reactions of 3-pyrazolidinone-1-azomethine imines with HCN", 《TETRAHEDRON LETTERS》, vol. 48, 31 May 2007 (2007-05-31), pages 5205 - 5208, XP022132309, DOI: doi:10.1016/j.tetlet.2007.05.142 * |
| 邵友东: "亚胺的烯化和加成反应", 《中国科学技术大学博士学位论文》, 1 May 2012 (2012-05-01), pages 12 - 17 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103508826A (zh) * | 2013-10-12 | 2014-01-15 | 苏州大学张家港工业技术研究院 | 手性三取代茚满化合物的制备方法 |
| CN103508826B (zh) * | 2013-10-12 | 2015-04-08 | 苏州大学张家港工业技术研究院 | 手性三取代茚满化合物的制备方法 |
| CN104961670A (zh) * | 2015-07-01 | 2015-10-07 | 中国计量学院 | 一种n,o-双取代的酮亚胺衍生物的制备方法 |
| CN106188078A (zh) * | 2016-07-15 | 2016-12-07 | 苏州大学 | 一种手性螺环羟吲哚‑苯并吡喃‑酮并‑3,4‑二氢‑吡喃化合物的合成方法 |
| CN106188078B (zh) * | 2016-07-15 | 2018-04-03 | 苏州大学 | 一种手性螺环羟吲哚‑苯并吡喃‑酮并‑3,4‑二氢‑吡喃化合物的合成方法 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102964304B (zh) | 2015-06-17 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Zhang et al. | Recent development of synthetic preparation methods for guanidines via transition metal catalysis | |
| Huang et al. | Multi-site cyclization via initial C–H activation using a rhodium (III) catalyst: rapid assembly of frameworks containing indoles and indolines | |
| Kondoh et al. | Enantioselective formal [3+ 2] cycloaddition of epoxides with imines under Brønsted base catalysis: synthesis of 1, 3‐oxazolidines with quaternary stereogenic center | |
| Ni et al. | Thiourea‐Catalyzed Asymmetric Michael Addition of Carbazolones to 2‐Chloroacrylonitrile: Total Synthesis of 5, 22‐Dioxokopsane, Kopsinidine C, and Demethoxycarbonylkopsin | |
| Wu et al. | Zinc‐Catalyzed Enantioselective Formal (3+ 2) Cycloadditions of Bicyclobutanes with Imines: Catalytic Asymmetric Synthesis of Azabicyclo [2.1. 1] hexanes | |
| Kimmel et al. | Enantio-and diastereoselective addition of thioacetic acid to nitroalkenes via N-sulfinyl urea catalysis | |
| Chen et al. | Bicyclic guanidinium-catalyzed enantioselective phase-transfer alkylation: direct access to pyrroloindolines and furoindolines | |
| Tsubokura et al. | Direct guanylation of amino groups by cyanamide in water: catalytic generation and activation of unsubstituted carbodiimide by scandium (III) triflate | |
| Zhao et al. | Hydrosilane-assisted synthesis of urea derivatives from CO2 and amines | |
| Shi et al. | Phosphine-catalyzed [3+ 2] annulation of β-sulfonamido-substituted enones with sulfamate-derived cyclic imines | |
| Augustine et al. | Propylphosphonic anhydride (T3P®): A remarkably efficient reagent for the one-pot transformation of aromatic, heteroaromatic, and aliphatic aldehydes to nitriles | |
| Kong et al. | Multi-component solvent-free cascade reaction of 2-cyanoacetamides: regioselective synthesis of pyridin-2-ones bearing quaternary centers | |
| TW201529163A (zh) | 雙環烷基化合物及合成 | |
| Arava et al. | Strategies for the synthesis of N-arylammonium salts | |
| Derdau | New trends and applications in cyanation isotope chemistry | |
| Yu et al. | DBU-catalyzed tandem additions of electron-deficient 1, 3-conjugated enynes with 2-aminomalonates: a facile access to highly substituted 2-pyrrolines | |
| Jiang et al. | Synthesis of 6-aminophenanthridines via palladium-catalyzed insertion of isocyanides into N-sulfonyl-2-aminobiaryls | |
| Hazarika et al. | Facile, catalyst-free cascade synthesis of sulfonyl guanidines via carbodiimide coupling with amines | |
| Huang et al. | Asymmetric copper-catalyzed propargylic amination with amine hydrochloride salts | |
| Curti et al. | Exploring the Remote Reactivity of π-Extended Carbonyl Compounds: The Vinylogous Alkylidene Malononitrile Activation Strategy | |
| CN102964304A (zh) | 含吡唑烷酮结构的手性氨基氰化物的制备方法 | |
| Wakchaure et al. | Chiral Brønsted acids catalyze asymmetric additions to substrates that are already protonated: Highly enantioselective disulfonimide-catalyzed Hantzsch ester reductions of NH–imine hydrochloride salts | |
| Tong et al. | Alkenylazaarenes as dipolarophiles in 1, 3-dipolar cycloaddition of nitrones: regioselectivity-switchable and highly diastereoselective synthesis of multisubstituted isoxazolidines | |
| Liu et al. | PPh3-catalyzed [2+ 2+ 2] and [4+ 2] annulations: synthesis of highly substituted 1, 2-dihydropyridines (DHPs) | |
| Takamatsu et al. | Highly stereoselective Strecker synthesis induced by a slight modification of benzhydrylamine from achiral to chiral |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20150617 Termination date: 20180928 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |