CN114920702A - 不对称共轭加成合成光学活性咪唑酮类化合物的方法 - Google Patents
不对称共轭加成合成光学活性咪唑酮类化合物的方法 Download PDFInfo
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- CN114920702A CN114920702A CN202210591304.4A CN202210591304A CN114920702A CN 114920702 A CN114920702 A CN 114920702A CN 202210591304 A CN202210591304 A CN 202210591304A CN 114920702 A CN114920702 A CN 114920702A
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- optically active
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- imidazolone
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- 238000000034 method Methods 0.000 title claims abstract description 24
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 16
- WZELXJBMMZFDDU-UHFFFAOYSA-N Imidazol-2-one Chemical class O=C1N=CC=N1 WZELXJBMMZFDDU-UHFFFAOYSA-N 0.000 title claims description 16
- 239000003054 catalyst Substances 0.000 claims abstract description 41
- 239000002808 molecular sieve Substances 0.000 claims abstract description 31
- 238000006243 chemical reaction Methods 0.000 claims abstract description 29
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims abstract description 16
- -1 imidazolone compound Chemical class 0.000 claims abstract description 15
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 claims abstract description 11
- 239000004327 boric acid Substances 0.000 claims abstract description 8
- PPTXVXKCQZKFBN-UHFFFAOYSA-N (S)-(-)-1,1'-Bi-2-naphthol Chemical compound C1=CC=C2C(C3=C4C=CC=CC4=CC=C3O)=C(O)C=CC2=C1 PPTXVXKCQZKFBN-UHFFFAOYSA-N 0.000 claims abstract description 7
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 claims abstract description 7
- 239000002994 raw material Substances 0.000 claims abstract description 6
- 239000003960 organic solvent Substances 0.000 claims abstract description 5
- WKYGPLBOLUEBGZ-UHFFFAOYSA-N 1,2,3,4-tetraphenylcycloocta-1,3,5,7-tetraene Chemical compound C1(=CC=CC=C1)C1=C(C(=C(C=CC=C1)C1=CC=CC=C1)C1=CC=CC=C1)C1=CC=CC=C1 WKYGPLBOLUEBGZ-UHFFFAOYSA-N 0.000 claims abstract description 4
- 229940125904 compound 1 Drugs 0.000 claims abstract 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 64
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 42
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 39
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 25
- 229910052757 nitrogen Inorganic materials 0.000 claims description 23
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 229910052794 bromium Inorganic materials 0.000 claims description 5
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 4
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 4
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 4
- GETTZEONDQJALK-UHFFFAOYSA-N (trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC=C1 GETTZEONDQJALK-UHFFFAOYSA-N 0.000 claims description 4
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 4
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- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 125000002541 furyl group Chemical group 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 4
- 229910052740 iodine Inorganic materials 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 125000001544 thienyl group Chemical group 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- 125000004185 ester group Chemical group 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 125000005504 styryl group Chemical group 0.000 claims description 3
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- KTVKQTNGWVJHFL-UHFFFAOYSA-N 2-ethylchromen-4-one Chemical compound C1=CC=C2OC(CC)=CC(=O)C2=C1 KTVKQTNGWVJHFL-UHFFFAOYSA-N 0.000 claims description 2
- 229910052786 argon Inorganic materials 0.000 claims description 2
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 2
- 229940078552 o-xylene Drugs 0.000 claims description 2
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- KTQYWNARBMKMCX-UHFFFAOYSA-N tetraphenylene Chemical compound C1=CC=C2C3=CC=CC=C3C3=CC=CC=C3C3=CC=CC=C3C2=C1 KTQYWNARBMKMCX-UHFFFAOYSA-N 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims description 2
- 238000007259 addition reaction Methods 0.000 abstract description 4
- 230000003197 catalytic effect Effects 0.000 abstract description 2
- CAAMSDWKXXPUJR-UHFFFAOYSA-N 3,5-dihydro-4H-imidazol-4-one Chemical compound O=C1CNC=N1 CAAMSDWKXXPUJR-UHFFFAOYSA-N 0.000 abstract 1
- 229940126214 compound 3 Drugs 0.000 abstract 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 63
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 54
- 238000004128 high performance liquid chromatography Methods 0.000 description 22
- 239000011777 magnesium Substances 0.000 description 21
- 239000002904 solvent Substances 0.000 description 21
- 239000002253 acid Substances 0.000 description 20
- 101150019148 Slc7a3 gene Proteins 0.000 description 19
- 230000008034 disappearance Effects 0.000 description 18
- 239000003208 petroleum Substances 0.000 description 18
- 238000003756 stirring Methods 0.000 description 17
- 239000007788 liquid Substances 0.000 description 16
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 14
- 239000000741 silica gel Substances 0.000 description 14
- 229910002027 silica gel Inorganic materials 0.000 description 14
- 238000003818 flash chromatography Methods 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- 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 10
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen(.) Chemical compound [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 7
- 238000002390 rotary evaporation Methods 0.000 description 7
- 238000010438 heat treatment Methods 0.000 description 6
- 238000010898 silica gel chromatography Methods 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 5
- 150000002576 ketones Chemical class 0.000 description 4
- 238000010926 purge Methods 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 238000001816 cooling Methods 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 238000010791 quenching Methods 0.000 description 3
- 230000000171 quenching effect Effects 0.000 description 3
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 description 2
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 2
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 238000011049 filling Methods 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 231100000053 low toxicity Toxicity 0.000 description 2
- IVSZLXZYQVIEFR-UHFFFAOYSA-N m-xylene Chemical group CC1=CC=CC(C)=C1 IVSZLXZYQVIEFR-UHFFFAOYSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 238000009738 saturating Methods 0.000 description 2
- 238000000926 separation method Methods 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
- 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
- KJCVRFUGPWSIIH-UHFFFAOYSA-N 1-naphthol Chemical compound C1=CC=C2C(O)=CC=CC2=C1 KJCVRFUGPWSIIH-UHFFFAOYSA-N 0.000 description 1
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 1
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 1
- JLBJTVDPSNHSKJ-UHFFFAOYSA-N 4-Methylstyrene Chemical compound CC1=CC=C(C=C)C=C1 JLBJTVDPSNHSKJ-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
- FEJUGLKDZJDVFY-UHFFFAOYSA-N 9-borabicyclo[3.3.1]nonane Substances C1CCC2CCCC1B2 FEJUGLKDZJDVFY-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
- 101150116295 CAT2 gene Proteins 0.000 description 1
- 101100326920 Caenorhabditis elegans ctl-1 gene Proteins 0.000 description 1
- 101100005280 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) cat-3 gene Proteins 0.000 description 1
- 101100126846 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) katG gene Proteins 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-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
- 239000000654 additive Substances 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 150000001639 boron compounds Chemical class 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 125000003037 imidazol-2-yl group Chemical group [H]N1C([*])=NC([H])=C1[H] 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- PBIMIGNDTBRRPI-UHFFFAOYSA-N trifluoro borate Chemical compound FOB(OF)OF PBIMIGNDTBRRPI-UHFFFAOYSA-N 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/10—Preparation of carboxylic acid amides from compounds not provided for in groups C07C231/02 - C07C231/08
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
- C07C45/673—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by change of size of the carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- 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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/584—Recycling of catalysts
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Catalysts (AREA)
Abstract
本发明公开了不对称共轭加成合成光学活性咪唑酮类化合物的方法，属于有机化学中技术领域。以α,β‑不饱和2‑酰基咪唑化合物1和有机硼酸2为原料，在手性联二萘酚类或四苯并环辛四烯类催化剂、分子筛存在下，有机溶剂中经过不对称共轭加成反应得到光学活性咪唑酮类化合物3。本方法反应原料易得，催化剂结构简单，催化效率高，反应条件温和，后处理简单。
Description
技术领域
本发明属于有机化学中的不对称合成技术领域，具体涉及α,β-不饱和2-酰基咪唑化合物与有机硼酸不对称共轭加成合成光学活性酮类化合物的方法。
背景技术
近年来，有机小分子催化α,β-不饱和酮与有机硼化物不对称共轭加成反应是构筑C-C键的重要合成方法(Molecules 2018,23,2317–2353)，该方法存在很多优点，例如催化剂低毒性、易于制备、稳定性好；所使用的有机硼化物(烃基硼酸、有机硼酸酯和有机硼酸盐)低毒、廉价易得和良好官能团耐受性，反应操作简单和不存在反应后金属残留等优点在现代有机合成中发挥重要作用。
α,β-不饱和2-酰基咪唑化合物是一类重要反应底物，2-酰基咪唑基可以转化为各种羧基官能团。2012年，Ohmiya等报道了铜-N-杂环卡宾配合物催化烷基硼烷(烷基-9-BBN)与α,β-不饱和2-酰基咪唑化合物对映选择性共轭加成生成咪唑-2-基α,β-不饱和酮类衍生物(J.Am.Chem.Soc.2012,134,11896–11899)。2016年，Meggers等开发了在光氧化还原条件下手性铑络合物催化三氟硼酸盐与α,β-不饱和2-酰基咪唑不对称共轭加成反应合成咪唑-2-基α,β-不饱和酮类衍生物(J.Am.Chem.Soc.2016,138,6936–6939)。
到目前为止，用于该反应的手性催化剂种类还比较少。因此，发展一种无过渡金属参与、反应活性好、操作简单的催化体系，实现简单易得、相对稳定的有机硼酸与α,β-不饱和2-酰基咪唑的不对称共轭加成反应，得到系列光学活性酰基咪唑酮衍生物仍非常必要。
发明内容
为了克服上述技术缺陷，本发明提供了不对称共轭加成合成光学活性咪唑酮衍生物的方法。采用有机硼酸与α,β-不饱和2-酰基咪唑作为原料，在手性联萘酚类化合物或四苯并环辛四烯类化合物作为催化剂，分子筛作为添加剂下经过不对称共轭加成反应，以高收率、高对映选择性一步合成光学活性咪唑酮衍生物。
本发明所述不对称共轭加成合成光学活性咪唑酮衍生物的方法，包括如下步骤：以α,β-不饱和2-酰基咪唑1和有机硼酸2为原料，在手性联二萘酚类或手性四苯并环辛四烯类催化剂和分子筛存在下，有机溶剂中反应得到咪唑酮类化合物3。反应方程式如下：
其中：R1选自C1-C6烷基、苄基、酯基；R2选自取代苯基、萘基、呋喃基、噻吩基、C1-C6烷基或取代苯基乙基，所述取代苯基中取代基为氢、C1-C4烷基、C1-C4烷氧基、卤素、三氟甲基、C1-C4烷氧羰基或硝基；R3选自取代苯乙烯基、呋喃基、苯丙呋喃基、噻吩基、苯并噻吩基或C1-C8烷烯基，所述取代苯中取代基为氢、C1-C4烷基、C1-C4烷氧基、卤素、三氟甲基、C1-C4烷氧羰基或硝基。
进一步地，在上述技术方案中，R1为甲基、异丙基、苄基；R2自烷基、苄基、酯基；R2为取代苯基、2-噻吩基、2-呋喃基、1-萘基、2-萘基、甲基或环己基；R3为苯乙烯基、对甲基苯乙烯基、对氯苯乙烯基、对溴苯乙烯基、对三氟甲基苯乙烯基、2-呋喃基、2-苯并呋喃基、2-噻吩基、2-苯并噻吩基或二甲基乙烯基。
进一步地，在上述技术方案中，所述手性联二萘酚类催化剂为
R＝H、F、Cl、Br、I、Ph、3,5-Me2C6H4、3,5-(MeO)2C6H4、3,5-(CF3)2C6H4；优选条件下，手性联二萘酚类催化剂为如下三种：
进一步地，在上述技术方案中，所述手性四苯并环辛四烯酚类催化剂为
R＝H、F、Cl、Br、I、Ph、3,5-Me2C6H4、3,5-(MeO)2C6H4、3,5-(CF3)2C6H4；优选条件下，手性四苯并环辛四烯酚类催化剂为如下两种：
进一步地，在上述技术方案中，所述α,β-不饱和2-酰基咪唑1、有机硼酸2与催化剂摩尔比为1:2-4:0.05-0.20。
进一步地，在上述技术方案中，所述有机溶剂选自甲苯、二氯甲烷、四氢呋喃、三氟甲苯、邻二甲苯、间二甲苯、氯苯、1,2-二氯乙烷、***、甲基叔丁基醚、乙腈或1,4-二氧六环。
进一步地，在上述技术方案中，反应温度为0-80℃，优选40-80℃。
进一步地，在上述技术方案中，反应中加入叔丁醇镁、甲醇、异丙醇或叔丁醇；所述分子筛选自
或
分子筛。
进一步地，在上述技术方案中，整个反应过程在氮气或氩气下进行，优选氮气。
发明有益效果：
本发明反应原料易得，反应条件温和、后处理简单，催化剂可回收再利用，产物收率和对映选择性良好至优秀。
具体实施方式
实施例1
aα,β-不饱和2-酰基咪唑化合物1a(0.1mmol)、反式-2-苯乙烯基硼酸2a(0.2mmol)、催化剂(0.01mmol,10mol％)、Mg(OtBu)2(0.01mmol,10mol％)、
分子筛(100mg)、1.0mL无水溶剂，氮气气氛b分离产率cee通过HPLC手性柱分析d无Mg(OtBu)2 e HOtBu(0.01mmol,10mol％)f无分子筛
分子筛(100mg)
分子筛(100mg)i40℃j25℃kCat 3(0.005mmol,5mol％).
在反应条件筛选过程中，考察了不同手性催化剂对反应影响(标号1-10)，确定了Cat 2和Cat 3为最佳催化剂。接着考察了不同溶剂对反应影响(标号11-18)，最终选用甲苯作溶剂。同时考察了Mg(OtBu)2、温度、分子筛和催化剂用量对反应的影响(标号19-25)，最终选择反应温度为60℃，催化剂用量为10mol％。
反应条件典型操作(以标号1为例)：
在氮气保护下，向Schlenk管(无水无氧处理，下同)中加入100mg
分子筛、催化剂Cat 3(5.4mg，0.01mmol)、Mg(OtBu)2(1.7mg，0.01mmol)、α,β-不饱和2-酰基咪唑化合物1a(21.2mg，0.1mmol)和有机硼酸2a(29.6mg，0.2mmol，2.0eq)，抽换气3次，再加入干燥甲苯(1.0mL)，60℃搅拌48h。TLC显示1a消失，减压除去溶剂后快速硅胶柱层析(乙酸乙酯/石油醚1/5-1/2)分离纯化得到29.6mg黄色液体3aa，收率94％。HPLC(Daicel Chiralcel OD-H,hexane/i-PrOH＝90:10,flow rate 1.0mL/min,λ＝254nm),tR(major)＝8.7min,tR(minor)＝9.6min,97.6:2.4e.r.,95％ee；[α]D 18＝+4.4(c 1.0,CHCl3)；1H NMR(600MHz,CDCl3)δ7.35-7.33(m,2H),7.31-7.28(m,4H),7.26-7.24(m,2H),7.21-7.14(m,3H),6.99(s,1H),6.45-6.37(m,2H),4.27(q,J＝7.2Hz,1H),3.92(s,3H)3.76(dd,J＝7.8,16.2Hz,1H),3.61(dd,J＝7.2,16.2Hz,1H)；13C NMR(100MHz,CDCl3)δ190.9,143.3,137.4,132.9,129.8,129.2,128.7,128.6,127.9,127.3,127.1,126.6,126.4,44.5,44.3,36.3；HRMS(ESI)m/z:[M+Na]+Calcd for C21H20N2ONa 339.1468；Found 339.1464.
实施例2
在氮气保护下，向Schlenk管中加入100mg
分子筛、催化剂Cat 3(5.4mg，0.01mmol)、Mg(OtBu)2(1.7mg，0.01mmol)、α,β-不饱和2-酰基咪唑化合物1b(22.6mg，0.1mmol)和有机硼酸2a(29.6mg，0.2mmol，2.0eq)，抽换气3次，再加入干燥甲苯(1.0mL)，60℃搅拌48h。TLC显示1b消失，减压除去溶剂后快速硅胶柱层析(乙酸乙酯/石油醚1/5-1/2)分离纯化得到32.9mg黄色液体3ba，收率99％。HPLC(Daicel Chiralpak ID,hexane/i-PrOH＝90:10,flow rate 1.0mL/min,λ＝254nm tR(minor)＝12.6min,tR(major)＝13.3min,2.2:97.8e.r.,96％ee；[α]D 18＝+3.2(c 1.0,CHCl3)；1H NMR(600MHz,CDCl3)δ7.29-7.22(m,6H),7.17-7.10(m,4H),6.97(s,1H),6.44-6.35(m,2H),4.24(q,J＝7.2Hz,1H),3.91(s,3H),3.75(dd,J＝7.8,16.2Hz,1H),3.58(dd,J＝7.2,16.2Hz,1H),2.30(s,3H)；13C NMR(150MHz,CDCl3)δ191.0,143.4,143.0,137.5,136.1,133.2,129.6,129.4,129.1,128.5,127.8,127.2,127.1,126.4,44.6,43.9,36.2,21.1；HRMS(ESI)m/z:[M+Na]+Calcd forC22H22N2ONa 353.1624；Found 353.1620.
实施例3
在氮气保护下，向Schlenk管中加入100mg
分子筛、催化剂Cat 3(5.4mg，0.01mmol)、Mg(OtBu)2(1.7mg，0.01mmol)、α,β-不饱和2-酰基咪唑化合物1c(24.2mg，0.1mmol)和有机硼酸2a(29.6mg，0.2mmol，2.0eq)，抽换气3次，再加入干燥甲苯(1.0mL)，60℃搅拌48h。TLC显示1c消失，减压除去溶剂后快速硅胶柱层析(乙酸乙酯/石油醚1/3-1/1)分离纯化得到34.6mg黄色液体3ca，收率99％。
3ca:HPLC(Daicel Chiralcel OD-H,hexane/i-PrOH＝90:10,flow rate1.0mL/min,λ＝254nm)tR(major)＝11.8min,tR(minor)＝13.1min,97.1:2.9e.r.,94％ee；[α]D 18＝+7.6(c 1.0,CHCl3)；1H NMR(400MHz,CDCl3)δ7.30-7.23(m,6H),7.18-7.14(m,2H),6.98(s,1H),6.85-6.82(m,2H),6.44-6.33(m,2H),4.23(q,J＝7.2Hz,1H),3.91(s,3H),3.77(s,3H),3.72(dd,J＝7.6,16.4Hz,1H),3.58(dd,J＝7.2,16.4Hz,1H)；13C NMR(100MHz,CDCl3)δ191.1,158.3,143.4,137.5,135.4,133.3,129.5,129.2,128.9,128.5,127.2,127.1,126.4,114.1,55.4,44.6,43.5,36.3；HRMS(ESI)m/z:[M+Na]+Calcd for C22H22N2O2Na369.1573；Found369.1573.
实施例4
在氮气保护下，向Schlenk管中加入100mg
分子筛、催化剂Cat 3(5.4mg，0.01mmol)、Mg(OtBu)2(1.7mg，0.01mmol)、α,β-不饱和2-酰基咪唑化合物1d(23.0mg，0.1mmol)和有机硼酸2a(29.6mg，0.2mmol，2.0eq)，抽换气3次，再加入干燥甲苯(1.0mL)，60℃搅拌48h。TLC显示1d消失，减压除去溶剂后快速硅胶柱层析(乙酸乙酯/石油醚1/5-1/2)分离纯化得到33.3mg黄色液体3da，收率99％。HPLC(Daicel Chiralcel OD-H,hexane/i-PrOH＝90:10,flow rate 1.0mL/min,λ＝254nm)tR(major)＝8.5min,tR(minor)＝9.7min,97.7:2.3e.r.,95％ee；[α]D 19＝+3.3(c 1.0,CHCl3)；1H NMR(400MHz,CDCl3)δ7.31-7.24(m,6H),7.20-7.14(m,2H),7.00-6.95(m,3H),6.44-6.32(m,2H),4.26(q,J＝7.2Hz,1H),3.92(s,3H),3.71(dd,J＝7.6,16.4Hz,1H),3.60(dd,J＝7.6,16.4Hz,1H)；13C NMR(100MHz,CDCl3)δ190.7,161.7(d,J＝243.0Hz),143.3,139.0(d,J＝3.0Hz),137.3,132.7,129.9,129.4(d,J＝8.0Hz),129.2,128.6,127.4,127.2,126.4,115.4(d,J＝21.0Hz),44.6,43.5,36.3；19F NMR(376MHz,CDCl3)δ-116.6；HRMS(ESI)m/z:[M+Na]+Calcd for C21H19FN2ONa357.1374；Found 357.1374.
实施例5
在氮气保护下，向Schlenk管中加入100mg
分子筛、催化剂Cat 3(5.4mg，0.01mmol)、Mg(OtBu)2(1.7mg，0.01mmol)、α,β-不饱和2-酰基咪唑化合物1e(31.1mg，0.1mmol)和有机硼酸2a(29.6mg，0.2mmol，2.0eq)，抽换气3次，再加入干燥甲苯(1.0mL)，60℃搅拌48h。TLC显示1e消失，减压除去溶剂后快速硅胶柱层析(乙酸乙酯/石油醚1/5-1/2)分离纯化得到32.8mg黄色液体3ea，收率93％。HPLC(FLM Chiral MD,hexane/i-PrOH＝90:10,flow rate 1.0mL/min,λ＝254nm)tR(major)＝7.6min,tR(minor)＝8.8min,97.2:2.8e.r.,94％ee；[α]D 18＝+1.2(c 1.0,CHCl3)；1H NMR(600MHz,CDCl3)δ7.30-7.24(m,8H),7.20-7.17(m,1H),7.14(s,1H),6.99(s,1H),6.44-6.32(m,2H),4.25(q,J＝7.2Hz,1H),3.92(s,3H),3.70(dd,J＝7.2,16.2Hz,1H),3.62(dd,J＝7.2,16.2Hz,1H)；13C NMR(150MHz,CDCl3)δ190.6,143.2,141.8,137.2,132.3,130.2,129.4,129.3,128.8,128.6,127.5,127.3,126.4,44.3,43.6,36.3；HRMS(ESI)m/z:[M+Na]+Calcd for C21H19ClN2ONa373.1078；Found 373.1078.
实施例6
在氮气保护下，向Schlenk管中加入100mg
分子筛、催化剂Cat 3(5.4mg，0.01mmol)、Mg(OtBu)2(1.7mg，0.01mmol)、α,β-不饱和2-酰基咪唑化合物1f(29.1mg，0.1mmol)和有机硼酸2a(29.6mg，0.2mmol，2.0eq)，抽换气3次，再加入干燥甲苯(1.0mL)，60℃搅拌48h。TLC显示1f消失，减压除去溶剂后快速硅胶柱层析(乙酸乙酯/石油醚1/5-1/2)分离纯化得到39.5mg无色液体3fa，收率99％。HPLC(Daicel Chiralcel OD-H,hexane/i-PrOH＝90:10,flow rate 1.0mL/min,λ＝254nm)tR(major)＝9.1min,tR(minor)＝10.7min,97.4:2.6e.r.,95％ee；[α]D 19＝+2.3(c1.0,CHCl3)；1H NMR(400MHz,CDCl3)δ7.43-7.39(m,2H),7.30-7.16(m,7H),7.14-7.13(m,1H),6.99(s,1H),6.44-6.30(m,2H),4.23(q,J＝7.2Hz,1H),3.92(s,3H),3.70(dd,J＝7.2,16.4Hz,1H),3.62(dd,J＝7.6,16.4Hz,1H)；13CNMR(100MHz,CDCl3)δ190.5,143.2,142.3,137.2,132.2,131.8,130.2,129.8,129.3,128.6,127.5,127.3,126.4,120.4,44.3,43.6,36.3；HRMS(ESI)m/z:[M+Na]+Calcd forC21H19BrN2ONa 417.0573；Found 417.0571.
实施例7
在氮气保护下，向Schlenk管中加入100mg
分子筛、催化剂Cat 3(5.4mg，0.01mmol)、Mg(OtBu)2(1.7mg，0.01mmol)、α,β-不饱和2-酰基咪唑化合物1g(26.2mg，0.1mmol)和有机硼酸2a(29.6mg，0.2mmol，2.0eq)，抽换气3次，再加入干燥甲苯(1.0mL)，60℃搅拌48h。TLC显示1g消失，减压除去溶剂后快速硅胶柱层析(乙酸乙酯/石油醚1/5-1/2)分离纯化得到34.9mg黄色固体3ga，收率95％。HPLC(Daicel Chiralcel OD-H,hexane/i-PrOH＝90:10,flow rate 1.0mL/min,λ＝254nm)tR(major)＝10.8min,tR(minor)＝11.9min,95.6:4.4e.r.,91％ee；[α]D 18＝+5.6(c 1.0,CHCl3)；1H NMR(600MHz,CDCl3)δ7.79-7.78(m,4H),7.50-7.48(m,1H),7.46-7.40(m,2H),7.31-7.30(m,2H),7.26-7.24(m,3H),7.18-7.16(m,2H),7.00(s,1H),6.50-6.44(m,2H),4.45(dd,J＝7.2,13.2Hz,1H),3.91(s,1H),3.84(dd,J＝7.8,16.8Hz,1H),3.75(dd,J＝7.2,16.2Hz,1H)；13C NMR(150MHz,CDCl3)δ190.9,143.3,140.8,137.4,133.7,132.8,132.5,130.1,129.2,128.6,128.4,127.9,127.7,127.3,127.2,126.7,126.4,126.2,126.1,125.6,44.4,44.3,36.3；HRMS(ESI)m/z:[M+Na]+Calcd for C25H22N2ONa 389.1624；Found 389.1624.
实施例8
在氮气保护下，向Schlenk管中加入100mg
分子筛、催化剂Cat 3(5.4mg，0.01mmol)、Mg(OtBu)2(1.7mg，0.01mmol)、α,β-不饱和2-酰基咪唑化合物1h(21.8mg，0.1mmol)和有机硼酸2a(29.6mg，0.2mmol，2.0eq)，抽换气3次，再加入干燥甲苯(1.0mL)，60℃搅拌48h。TLC显示1h消失，减压除去溶剂后快速硅胶柱层析(乙酸乙酯/石油醚1/5-1/2)分离纯化得到28.8mg黄色液体3ha，收率89％。HPLC(Chiralcel OD-H,hexane/i-PrOH＝90:10,flow rate 1.0mL/min,λ＝254nm)tR(major)＝8.4min,tR(minor)＝9.0min,95.0:5.0e.r.,90％ee；[α]D 20＝+16.4(c 0.5,CHCl3)；1H NMR(600MHz,CDCl3)δ7.32-7.30(m,1H),7.28-7.25(m,4H),7.20-7.15(m,2H),7.10-7.01(m,3H),6.45-6.33(m,2H),4.38(q,J＝7.2Hz,1H),3.95(s,3H),3.69(dd,J＝7.8,16.2Hz,1H),3.62(dd,J＝7.2,16.8Hz,1H)；13CNMR(100MHz,CDCl3)δ190.9,144.0,143.3,137.4,132.4,130.1,129.2,128.6,127.6,127.4,127.2,126.4,125.8,120.6,44.5,40.4,36.3；HRMS(ESI)m/z:[M+Na]+Calcd forC19H18N2SO Na 345.1032；Found 345.1032.
实施例9
在氮气保护下，向Schlenk管中加入100mg
分子筛、催化剂Cat 3(5.4mg，0.01mmol)、Mg(OtBu)2(1.7mg，0.01mmol)、α,β-不饱和2-酰基咪唑化合物1i(16.4mg，0.1mmol)和有机硼酸2a(29.6mg，0.2mmol，2.0eq)，抽换气3次，再加入干燥甲苯(1.0mL)，60℃搅拌48h。TLC显示1i消失，减压除去溶剂后快速硅胶柱层析(乙酸乙酯/石油醚1/5-1/2)分离纯化得到25.4mg黄色液体3ia，收率99％。HPLC(Daicel Chiralpak IA,hexane/i-PrOH＝90:10,flow rate 1.0mL/min,λ＝254nm)tR(minor)＝6.6min,tR(major)＝6.9min,5.2:94.8e.r.,90％ee；[α]D 18＝+46.8(c 1.0,CHCl3)；1H NMR(600MHz,CDCl3)δ7.31-7.30(m,2H),7.27-7.25(m,2H),7.18-7.16(m,1H),7.13(s,1H),7.00(s,1H),6.39(d,J＝15.6Hz,1H),6.21(dd,J＝7.2,15.6Hz,1H),3.30(dd,J＝7.2,15.6Hz,1H),3.15(dd,J＝7.2,15.6Hz,1H),3.08-3.06(m,1H),1.18(d,J＝6.6Hz,3H)；13C NMR(150MHz,CDCl3)δ192.1,143.4,137.7,135.2,129.1,128.6,128.5,127.1,126.2,45.9,36.3,33.6,20.7；HRMS(ESI)m/z:[M+Na]+Calcd for C16H18N2ONa 277.1311；Found 277.1300.
实施例10
在氮气保护下，向Schlenk管中加入100mg
分子筛、催化剂Cat 3(5.4mg，0.01mmol)、Mg(OtBu)2(1.7mg，0.01mmol)、α,β-不饱和2-酰基咪唑化合物1j(28.8mg，0.1mmol)和有机硼酸2a(29.6mg，0.2mmol，2.0eq)，抽换气3次，再加入干燥甲苯(1.0mL)，60℃搅拌48h。TLC显示1j消失，减压除去溶剂后快速硅胶柱层析(乙酸乙酯/石油醚1/5-1/2)分离纯化得到39.2mg黄色液体3ja，收率99％。HPLC(FLM Chiral MD,hexane/i-PrOH＝90:10,flow rate 1.0mL/min,λ＝254nm)tR(major)＝10.4min,tR(minor)＝11.4min,97.3:2.7e.r.,94％ee；[α]D 18＝+12.3(c 1.0,CHCl3)；1H NMR(400MHz,CDCl3)δ7.34-7.15(m,14H),7.05-7.01(m,3H),6.44-6.34(m,2H),5.60-5.51(m,2H),4.29-4.24(m,1H),3.79(dd,J＝8.0,16.0Hz,1H)3.59(dd,J＝7.2,16.0Hz,1H)；13C NMR(150MHz,CDCl3)δ191.2,143.2,142.9,137.4,136.4,132.8,129.9,129.6,128.9,128.7,128.5,128.1,127.9,127.6,127.3,126.6,126.4,126.1,51.8,44.8,44.6；HRMS(ESI)m/z:[M+Na]+Calcd forC27H24N2ONa415.1781；Found 415.1782.
实施例11
在氮气保护下，向Schlenk管中加入100mg
分子筛、催化剂Cat3(5.4mg，0.01mmol)、Mg(OtBu)2(1.7mg，0.01mmol)、α,β-不饱和2-酰基咪唑化合物1k(19.4mg，0.1mmol)和有机硼酸2a(29.6mg，0.2mmol，2.0eq)，抽换气3次，再加入干燥甲苯(1.0mL)，60℃搅拌48h。TLC显示1k消失，减压除去溶剂后快速硅胶柱层析(乙酸乙酯/石油醚1/5-1/3)分离纯化得到31.1mg黄色液体3ka，收率99％。HPLC(Daicel Chiralpak IA,hexane/i-PrOH＝90:10,flow rate 1.0mL/min,λ＝254nm)tR(minor)＝21.2min,tR(major)＝23.9min,4.7:95.3e.r.,91％ee；[α]D 18＝+31.6(c 1.0,CHCl3)；1H NMR(400MHz,CDCl3)δ7.36-7.22(m,5H),7.15(s,1H),7.02(s,1H),6.59(d,J＝15.6Hz,1H),6.28(dd,J＝7.6,16.0Hz,1H),4.19(q,J＝7.2Hz,2H),3.98(s,3H),3.84-3.76(m,2H),3.55-3.47(m,1H),1.26(t,J＝7.2Hz,3H)；13C NMR(100MHz,CDCl3)δ190.0,173.1,142.7,136.7,132.6,129.2,128.5,127.7,127.0,126.4,126.1,61.0,44.1,41.0,36.1,14.2；HRMS(ESI)m/z:[M+Na]+Calcdfor C18H20N2O3Na 335.1366；Found335.1366.
实施例12
根据实施例10反应条件，采用α,β-不饱和2-酰基咪唑化合物1a与不同有机硼酸类化合物2，反应结果如下：
实施例13
在氮气保护下，向Schlenk管中加入100mg
分子筛、催化剂Cat 3(5.4mg，0.01mmol)、Mg(OtBu)2(1.7mg，0.01mmol)、α,β-不饱和2-酰基咪唑化合物1a(21.2mg，0.1mmol)和有机硼酸2b(32.4mg，0.2mmol，2.0eq)，抽换气3次，再加入干燥甲苯(1.0mL)，60℃搅拌48h。TLC显示1a消失，减压除去溶剂后快速硅胶柱层析(乙酸乙酯/石油醚1/5-1/2)分离纯化得到33.0mg无色液体3ab，收率99％。HPLC(Daicel Chiralpak IA,hexane/i-PrOH＝90:10,flow rate 1.0mL/min,λ＝254nm)tR(major)＝11.6min,tR(minor)＝12.4min,96.6:3.4e.r.,93％ee；[α]D 18＝-3.5(c 1.0,CHCl3)；1H NMR(400MHz,CDCl3)δ7.35-7.25(m,4H),7.20-7.13(m,4H),7.06-7.04(m,2H),6.97(s,1H),6.41(d,J＝16.0,Hz,1H),6.32(dd,J＝7.2,16.0Hz,1H),4.25(q,J＝7.2,Hz,1H),3.90(s,1H),3.75(dd,J＝7.6,16.4Hz,1H),3.59(dd,J＝7.2,16.4Hz,1H),2.29(s,3H)；13C NMR(100MHz,CDCl3)δ191.0,143.5,143.3,137.0,134.6,131.9,129.7,129.23,129.15,128.7,127.9,127.1,126.6,126.3,44.6,44.3,36.2,21.3；HRMS(ESI)m/z:[M+Na]+Calcd for C22H22N2ONa 353.1624；Found353.1620.
实施例14
在氮气保护下，向Schlenk管中加入100mg
分子筛、催化剂Cat 3(5.4mg，0.01mmol)、Mg(OtBu)2(1.7mg，0.01mmol)、α,β-不饱和2-酰基咪唑化合物1a(21.2mg，0.1mmol)和有机硼酸2c(33.2mg，0.2mmol，2.0eq)，抽换气3次，再加入干燥甲苯(1.0mL)，60℃搅拌48h。TLC显示1a消失，减压除去溶剂后快速硅胶柱层析(乙酸乙酯/石油醚1/5-1/2)分离纯化得到33.4mg无色液体3ac，收率99％。HPLC(Daicel Chiralcel OD-H,hexane/i-PrOH＝90:10,flow rate 1.0mL/min,λ＝254nm)tR(major)＝8.7min,tR(minor)＝9.4min,98.0:2.0e.r.,96％ee；[α]D 18＝-4.0(c 1.0,CHCl3)；1H NMR(600MHz,CDCl3)δ7.34-7.29(m,4H),7.22-7.18(m,2H),7.14(s,1H),7.05-7.04(m,1H),6.99-6.98(m,2H),6.87-6.84(m,1H),6.403-6.397(m,2H),4.29-4.25(m,1H),3.92(s,3H),3.76(dd,J＝8.4,16.8Hz,1H),3.60(dd,J＝6.6,16.2Hz,1H)；13CNMR(150MHz,CDCl3)δ190.8,163.2(d,J＝243.0Hz),143.3,143.0,139.8(d,J＝7.5Hz),134.4,129.9(d,J＝9.0Hz),129.2,128.8(d,J＝3.0Hz),128.77,127.9,127.2,126.8,122.2(d,J＝3.0Hz),114.0(d,J＝21.0Hz),112.8(d,J＝21.0Hz),44.4,44.2,36.3；19F NMR(564MHz,CDCl3)δ-113.8；HRMS(ESI)m/z:[M+Na]+Calcd for C21H19FN2ONa357.1374；Found 357.1374.
实施例15
在氮气保护下，向Schlenk管中加入100mg
分子筛、催化剂Cat 3(5.4mg，0.01mmol)、Mg(OtBu)2(1.7mg，0.01mmol)、α,β-不饱和2-酰基咪唑化合物1a(21.2mg，0.1mmol)和有机硼酸2e(36.5mg，0.2mmol，2.0eq)，抽换气3次，再加入干燥甲苯(1.0mL)，60℃搅拌48h。TLC显示1a消失，减压除去溶剂后快速硅胶柱层析(乙酸乙酯/石油醚1/5-1/2)分离纯化得到32.7mg无色液体3ae，收率93％。HPLC(Daicel Chiralpak IC,hexane/i-PrOH＝90:10,flow rate 1.0mL/min,λ＝254nm)tR(minor)＝11.6min,tR(major)＝12.0min,3.6:96.4e.r.,93％ee；[α]D 18＝+2.0(c 1.0,CHCl3)；1H NMR(600MHz,CDCl3)δ7.33-7.30(m,4H),7.21-7.20(m,5H),7.14(s,1H),6.99(s,1H),6.40-6.34(m,2H),4.27-4.24(m,1H),3.92(s,3H),3.76(dd,J＝7.8,16.2Hz,1H),3.60(dd,J＝7.2,16.2Hz,1H)；13C NMR(150MHz,CDCl3)δ190.8,143.3,143.1,135.9,133.7,132.9,129.2,128.8,128.67,128.65,127.9,127.6,127.2,126.8,44.5,44.3,36.3；HRMS(ESI)m/z:[M+Na]+Calcd for C21H19ClN2ONa373.1078；Found 373.1076.
实施例16
在氮气保护下，向Schlenk管中加入100mg
分子筛、催化剂Cat 3(5.4mg，0.01mmol)、Mg(OtBu)2(1.7mg，0.01mmol)、α,β-不饱和2-酰基咪唑化合物1a(21.2mg，0.1mmol)和有机硼酸2f(45.4mg，0.2mmol，2.0eq)，抽换气3次，再加入干燥甲苯(1.0mL)，60℃搅拌48h。TLC显示1a消失，减压除去溶剂后快速硅胶柱层析(乙酸乙酯/石油醚1/5-1/2)分离纯化得到39.5mg无色液体3af，收率99％。HPLC(FLM Chiral MD,hexane/i-PrOH＝90:10,flow rate 1.0mL/min,λ＝254nm)tR(major)＝8.3min,tR(minor)＝8.8min,97.8:2.2e.r.,96％ee；[α]D 18＝+3.6(c 1.0,CHCl3)；1H NMR(600MHz,CDCl3)δ7.37-7.35(m,2H),7.33-7.29(m,4H),7.21-7.20(m,1H),7.15-7.14(m,3H),7.00(s,1H),6.41-6.34(m,2H),4.27-4.23(m,1H),3.92(s,3H),3.76(dd,J＝7.8,16.2Hz,1H),3.59(dd,J＝7.2,16.2Hz,1H)；13C NMR(150MHz,CDCl3)δ190.8,143.3,143.0,136.4,133.8,131.6,129.2,128.8,128.7,127.9,127.2,126.8,121.0,44.4,44.3,36.3；HRMS(ESI)m/z:[M+Na]+Calcd forC21H19BrN2ONa417.0573；Found417.0564.
实施例17
在氮气保护下，向Schlenk管中加入100mg
分子筛、催化剂Cat 3(5.4mg，0.01mmol)、Mg(OtBu)2(1.7mg，0.01mmol)、α,β-不饱和2-酰基咪唑化合物1a(21.2mg，0.1mmol)和有机硼酸2j(25.5mg，0.2mmol，2.0eq)，抽换气3次，再加入干燥甲苯(1.0mL)，60℃搅拌48h。TLC显示1a消失，减压除去溶剂后快速硅胶柱层析(乙酸乙酯/石油醚1/5-1/2)分离纯化得到29.6mg无色液体3aj，收率99％。HPLC(Daicel Chiralpak IE,hexane/i-PrOH＝90:10,flow rate 1.0mL/min,λ＝254nm)tR(major)＝13.8min,tR(minor)＝14.6min,95.0:5.0e.r.,90％ee；[α]D 18＝-24.0(c 1.0,CHCl3)；1H NMR(400MHz,CDCl3)δ7.36-7.34(m,2H),7.29-7.26(m,2H),7.20-7.16(m,1H),7.14(d,J＝0.8Hz,1H),7.11-7.10(m,1H),6.99(s,1H),6.89-6.86(m,2H),5.01(t,J＝7.6Hz,1H),4.00(dd,J＝7.2,16.8Hz,1H),3.91(s,3H),3.89(dd,J＝7.2,17.2Hz,1H)；13C NMR(100MHz,CDCl3)δ190.1,148.5,143.9,143.1,129.3,128.7,127.9,127.2,126.8,126.7,124.1,123.9,46.2,41.7,36.2；HRMS(ESI)m/z:[M+Na]+Calcd for C17H16N2OSNa 319.0876；Found 319.0878.
实施例18
在氮气保护下，向Schlenk管中加入100mg
分子筛、催化剂Cat 3(5.4mg，0.01mmol)、Mg(OtBu)2(1.7mg，0.01mmol)、α,β-不饱和2-酰基咪唑化合物1a(21.2mg，0.1mmol)和有机硼酸2j(35.6mg，0.2mmol，2.0eq)，抽换气3次，再加入干燥甲苯(1.0mL)，60℃搅拌48h。TLC显示1a消失，减压除去溶剂后快速硅胶柱层析(乙酸乙酯/石油醚1/5-1/2)分离纯化得到33.2mg无色液体3aj，收率96％。HPLC(Daicel Chiralpak IA,hexane/i-PrOH＝90:10,flow rate 1.0mL/min,λ＝254nm)tR(major)＝16.7min,tR(minor)＝19.2min,92.8:7.2e.r.,86％ee；[α]D 18＝-16.6(c 1.0,CHCl3)；1H NMR(400MHz,CDCl3)δ7.69-7.62(m,2H),7.41-7.38(m,2H),7.31-7.18(m,5H),7.14(s,2H),6.98(s,1H),5.06(t,J＝7.2Hz,1H),4.13(dd,J＝8.0,17.2Hz,1H),3.94-3.88(m,4H)；13C NMR(150MHz,CDCl3)δ189.9,149.3,143.2,143.0,139.9,139.7,129.3,128.8,128.0,127.3,127.1,124.2,123.8,123.3,122.4,120.7,45.6,42.3,36.3；HRMS(ESI)m/z:[M+Na]+Calcd for C21H18N2OSNa369.1032；Found 369.1030.
实施例19
在氮气保护下，向Schlenk管中加入100mg
分子筛、催化剂Cat 3(5.4mg，0.01mmol)、Mg(OtBu)2(1.7mg，0.01mmol)、α,β-不饱和2-酰基咪唑化合物1a(21.2mg，0.1mmol)和有机硼酸2l(22.8mg，0.2mmol，2.0eq)，抽换气3次，再加入干燥甲苯(1.0mL)，60℃搅拌48h。TLC显示1a消失，减压除去溶剂后快速硅胶柱层析(乙酸乙酯/石油醚1/3-1/2)分离纯化得到26.8mg无色液体3al，收率99％。HPLC(Daicel Chiralpak IC,hexane/i-PrOH＝90:10,flow rate 1.0mL/min,λ＝254nm)tR(minor)＝9.4min,tR(major)＝11.0min,6.7:93.3e.r.,87％ee；[α]D 18＝+34.8(c 1.0,CHCl3)；1H NMR(400MHz,CDCl3)δ7.30-7.24(m,4H),7.17-7.12(m,2H),6.98(s,1H),5.34-5.31(m,1H),4.32-4.25(m,1H),3.92(s,3H),3.55-3.43(m,2H),1.66-1.65(m,6H)；13C NMR(100MHz,CDCl3)δ191.5,145.1,143.4,132.2,129.1,128.6,127.7,127.5,126.9,126.1,46.1,40.2,36.2,26.0,18.2；HRMS(ESI)m/z:[M+Na]+Calcd for C17H20N2ONa 291.1468；Found 291.1464.
实施例20
真空条件下高温加热，凉至室温后，抽换气，充氮气条件下加入3ja(0.1mmol,1.0eq)、NaBH4(0.25mmol,2.5eq)和1mL超干MeOH溶液，室温下搅拌2小时，用水淬灭，EA萃取，旋蒸除去溶剂后，加入MeI(1.0mmol,10.0eq)和1mL EA，50℃条件下加热12h，室温条件下旋蒸除去MeI,在反应瓶中加入10％K2CO3水溶液(0.5mmol,5.0eq)，1mL甲苯，60℃条件下搅拌24h，EA萃取，无水Na2SO4干燥，旋蒸除去溶液，样品快速通过硅胶柱进行纯化得到产物4。HPLC(FLM Chiral MD,hexane/i-PrOH＝90:10,flow rate 1.0mL/min,λ＝254nm)tR(major)＝9.6min,tR(minor)＝11.1min,97.2:2.8e.r.,94％ee；[α]D 22＝-2.30(c 0.5,CHCl3)；1H NMR(400MHz,CDCl3)δ9.77(t,J＝4.0Hz,1H),7.36-7.19(m,11H),6.45-6.31(m,2H),4.13(q,J＝8.0Hz,1H),2.96-2.93(m,2H)；13C NMR(100MHz,CDCl3)δ201.3,142.5,137.0,131.9,130.6,129.0,128.7,127.7,127.6,127.1,126.4,49.2,43.0；HRMS(ESI)m/z:[M+Na]+Calcd for C17H16ONa 259.1093；Found 259.1093.
实施例21
真空条件下高温加热，凉至室温后，抽换气，充满氮气条件下加入3ja(0.1mmol,1.0eq)、MeI(1.0mmol,10.0eq)和1mL超干MeCN溶液，60℃条件下加热24h，旋蒸除去MeI和MeCN，在反应瓶中加入DBU(0.5mmol,5.0eq)、DCM(1.0mmol,10.0eq)和甲醇(1.0mmol,10.0eq)，室温搅拌24h后，饱和NH4Cl水溶液淬灭，EA萃取，无水Na2SO4干燥，旋蒸除去溶液，快速硅胶柱进行纯化得到产物5。HPLC(FLM Chiral MD,hexane/i-PrOH＝90:10,flow rate1.0mL/min,λ＝220nm)tR(major)＝5.5min,tR(minor)＝7.8min,97.1:2.9e.r.,94％ee；[α]D 18＝-11.1(c 0.25,CHCl3)；1H NMR(600MHz,CDCl3)δ7.34-7.31(m,4H),7.29-7.26(m,4H),7.24-7.20(m,2H),6.43(d,J＝15.6Hz,1H),6.34(dd,J＝7.2,15.6Hz,1H),4.04(q,J＝7.2Hz,1H),3.62(s,3H),2.88-2.79(m,2H)；13C NMR(150MHz,CDCl3)δ172.4,142.7,137.2,132.1,130.3,128.8,128.6,127.7,127.5,126.9,126.4,51.8,45.1,40.7；HRMS(ESI)m/z:[M+Na]+Calcd for C18H18O2Na 289.1192；Found 289.1199.
实施例22
真空条件下高温加热，凉至室温后，抽换气，充满氮气条件下加入3ja(0.1mmol,1.0eq)、MeI(1.0mmol,10.0eq)、和1mL超干DMF溶液，60℃条件下加热24h，旋蒸除去MeI和MeCN，在反应瓶中加入DBU(0.5mmol,5.0eq)和异丙胺(1.0mmol,10.0eq)、室温搅拌24h后，饱和NH4Cl水溶液淬灭，EA萃取，无水Na2SO4干燥，旋蒸除去溶液，快速硅胶柱进行纯化得到产物6。HPLC(FLM Chiral MD,hexane/i-PrOH＝90:10,flow rate 1.0mL/min,λ＝220nm)tR(major)＝10.0min,tR(minor)＝11.5min,97.0:3.0e.r.,94％ee；[α]D 18＝-10.8(c0.5,CHCl3)；1H NMR(600MHz,CDCl3)δ7.34-7.31(m,4H),7.29-7.26(m,4H),7.24-7.19(m,2H),6.43(d,J＝16.2Hz,1H),6.36(dd,J＝6.6,15.6Hz,1H),5.07-5.05(m,1H),4.05-4.02(m,1H),3.99-3.96(m,1H),2.64(dd,J＝7.8,13.8Hz,1H),2.56(dd,J＝7.8,13.8Hz,1H),1.01(d,J＝6.6Hz,3H),0.92(d,J＝6.6Hz,3H)；13C NMR(150MHz,CDCl3)δ170.2,143.0,137.3,132.3,130.4,128.9,128.6,127.8,127.5,126.9,126.4,45.8,44.0,41.4,22.9,22.7；HRMS(ESI)m/z:[M+Na]+Calcd for C20H23NONa 316.1672；Found 316.1672.
以上实施例描述了本发明的基本原理、主要特征及优点。本行业的技术人员应该了解，本发明不受上述实施例的限制，上述实施例和说明书中描述的只是说明本发明的原理，在不脱离本发明原理的范围下，本发明还会有各种变化和改进，这些变化和改进均落入本发明保护的范围内。
Claims (10)
1.不对称共轭加成合成光学活性咪唑酮类化合物的方法，其特征在于，包括如下步骤：以α,β-不饱和2-酰基咪唑化合物1和有机硼酸2为原料，在手性联二萘酚类或手性四苯并环辛四烯类催化剂和分子筛存在下，有机溶剂中反应得到咪唑酮衍生物3；反应方程式表示为：
其中：R1选自C1-C6烷基、苄基、酯基；R2选自取代苯基、萘基、呋喃基、噻吩基、C1-C6烷基或取代苯基乙基，所述取代苯基中取代基为氢、C1-C4烷基、C1-C4烷氧基、卤素、三氟甲基、C1-C4烷氧羰基或硝基；R3选自取代苯乙烯基、呋喃基、苯丙呋喃基、噻吩基、苯并噻吩基或C1-C8烷烯基，所述取代苯中取代基为氢、C1-C4烷基、C1-C4烷氧基、卤素、三氟甲基、C1-C4烷氧羰基或硝基。
2.根据权利要求1所述不对称共轭加成合成光学活性咪唑酮衍生物的方法，其特征在于：手性联二萘酚类催化剂和手性四苯并环辛四烯酚类催化剂分别为
其中，R选自H、F、Cl、Br、I、Ph、3,5-Me2C6H4、3,5-(MeO)2C6H4或3,5-(CF3)2C6H4。
3.根据权利要求2所述不对称共轭加成合成光学活性咪唑酮衍生物的方法，其特征在于：手性联二萘酚类催化剂中，R选自Cl、Br、I或3,5-(CF3)2C6H4。
4.根据权利要求2所述不对称共轭加成合成光学活性咪唑酮酮衍生物的方法，其特征在于：手性四苯并环辛四烯酚类催化剂中，R选自Cl或Br。
5.根据权利要求1所述不对称共轭加成合成光学活性咪唑酮衍生物的方法，其特征在于：所述α,β-不饱和2-酰基咪唑化合物1、有机硼酸2与催化剂摩尔比为1:2-4:0.05-0.20。
6.根据权利要求1所述不对称共轭加成合成光学活性咪唑酮衍生物的方法，其特征在于：所述有机溶剂选自甲苯、二氯甲烷、四氢呋喃、三氟甲苯、邻二甲苯、1,2-二氯乙烷、***、甲基叔丁基醚、乙腈或1,4-二氧六环。
7.根据权利要求1所述不对称共轭加成合成光学活性咪唑酮衍生物的方法，其特征在于：反应温度为0-80℃。
8.根据权利要求1所述不对称共轭加成合成光学活性咪唑酮衍生物的方法，其特征在于：反应中加入叔丁醇镁、甲醇、异丙醇或叔丁醇。
9.根据权利要求1所述不对称共轭加成合成光学活性咪唑酮衍生物的方法，其特征在于：分子筛选自
或
分子筛。
10.根据权利要求1-9任意一项所述不对称共轭加成合成光学活性咪唑酮衍生物的方法，其特征在于：整个反应过程在氮气或氩气下进行。
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