CN109956944A - 一种多取代吡咯里西啶化合物及其制备方法 - Google Patents
一种多取代吡咯里西啶化合物及其制备方法 Download PDFInfo
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- CN109956944A CN109956944A CN201711360275.6A CN201711360275A CN109956944A CN 109956944 A CN109956944 A CN 109956944A CN 201711360275 A CN201711360275 A CN 201711360275A CN 109956944 A CN109956944 A CN 109956944A
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- room temperature
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- benzaldehyde
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- -1 acridine compound Chemical class 0.000 title claims abstract description 36
- 150000003233 pyrroles Chemical class 0.000 title claims abstract description 16
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- DZBUGLKDJFMEHC-UHFFFAOYSA-N benzoquinolinylidene Natural products C1=CC=CC2=CC3=CC=CC=C3N=C21 DZBUGLKDJFMEHC-UHFFFAOYSA-N 0.000 title claims abstract description 11
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 12
- 239000001257 hydrogen Substances 0.000 claims abstract description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 6
- 125000001424 substituent group Chemical group 0.000 claims abstract description 6
- 239000000126 substance Substances 0.000 claims abstract description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 117
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 84
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 84
- 238000006243 chemical reaction Methods 0.000 claims description 82
- 229910052943 magnesium sulfate Inorganic materials 0.000 claims description 42
- 235000019341 magnesium sulphate Nutrition 0.000 claims description 42
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 claims description 41
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 35
- 150000001875 compounds Chemical class 0.000 claims description 33
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzenecarboxaldehyde Natural products O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 claims description 19
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 claims description 10
- WMPDAIZRQDCGFH-UHFFFAOYSA-N 3-methoxybenzaldehyde Chemical compound COC1=CC=CC(C=O)=C1 WMPDAIZRQDCGFH-UHFFFAOYSA-N 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 8
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 7
- ISDBWOPVZKNQDW-UHFFFAOYSA-N 4-phenylbenzaldehyde Chemical compound C1=CC(C=O)=CC=C1C1=CC=CC=C1 ISDBWOPVZKNQDW-UHFFFAOYSA-N 0.000 claims description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- 239000000654 additive Substances 0.000 claims description 6
- 230000000996 additive effect Effects 0.000 claims description 6
- HYBBIBNJHNGZAN-UHFFFAOYSA-N furfural Chemical compound O=CC1=CC=CO1 HYBBIBNJHNGZAN-UHFFFAOYSA-N 0.000 claims description 6
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 claims description 6
- 150000003934 aromatic aldehydes Chemical class 0.000 claims description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N dichloromethane Natural products ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 5
- ZWDVQMVZZYIAHO-UHFFFAOYSA-N 2-fluorobenzaldehyde Chemical compound FC1=CC=CC=C1C=O ZWDVQMVZZYIAHO-UHFFFAOYSA-N 0.000 claims description 4
- PJKVFARRVXDXAD-UHFFFAOYSA-N 2-naphthaldehyde Chemical compound C1=CC=CC2=CC(C=O)=CC=C21 PJKVFARRVXDXAD-UHFFFAOYSA-N 0.000 claims description 4
- SRWILAKSARHZPR-UHFFFAOYSA-N 3-chlorobenzaldehyde Chemical compound ClC1=CC=CC(C=O)=C1 SRWILAKSARHZPR-UHFFFAOYSA-N 0.000 claims description 4
- PIKNVEVCWAAOMJ-UHFFFAOYSA-N 3-fluorobenzaldehyde Chemical compound FC1=CC=CC(C=O)=C1 PIKNVEVCWAAOMJ-UHFFFAOYSA-N 0.000 claims description 4
- ZRYZBQLXDKPBDU-UHFFFAOYSA-N 4-bromobenzaldehyde Chemical compound BrC1=CC=C(C=O)C=C1 ZRYZBQLXDKPBDU-UHFFFAOYSA-N 0.000 claims description 4
- AVPYQKSLYISFPO-UHFFFAOYSA-N 4-chlorobenzaldehyde Chemical compound ClC1=CC=C(C=O)C=C1 AVPYQKSLYISFPO-UHFFFAOYSA-N 0.000 claims description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- FLJPGEWQYJVDPF-UHFFFAOYSA-L caesium sulfate Chemical compound [Cs+].[Cs+].[O-]S([O-])(=O)=O FLJPGEWQYJVDPF-UHFFFAOYSA-L 0.000 claims description 4
- CNUDBTRUORMMPA-UHFFFAOYSA-N formylthiophene Chemical compound O=CC1=CC=CS1 CNUDBTRUORMMPA-UHFFFAOYSA-N 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 235000002906 tartaric acid Nutrition 0.000 claims description 4
- 239000011975 tartaric acid Substances 0.000 claims description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical group CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 4
- SQAINHDHICKHLX-UHFFFAOYSA-N 1-naphthaldehyde Chemical compound C1=CC=C2C(C=O)=CC=CC2=C1 SQAINHDHICKHLX-UHFFFAOYSA-N 0.000 claims description 3
- NDOPHXWIAZIXPR-UHFFFAOYSA-N 2-bromobenzaldehyde Chemical compound BrC1=CC=CC=C1C=O NDOPHXWIAZIXPR-UHFFFAOYSA-N 0.000 claims description 3
- FPYUJUBAXZAQNL-UHFFFAOYSA-N 2-chlorobenzaldehyde Chemical compound ClC1=CC=CC=C1C=O FPYUJUBAXZAQNL-UHFFFAOYSA-N 0.000 claims description 3
- UOQXIWFBQSVDPP-UHFFFAOYSA-N 4-fluorobenzaldehyde Chemical compound FC1=CC=C(C=O)C=C1 UOQXIWFBQSVDPP-UHFFFAOYSA-N 0.000 claims description 3
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 3
- 125000003118 aryl group Chemical group 0.000 claims description 3
- OVWYEQOVUDKZNU-UHFFFAOYSA-N m-tolualdehyde Chemical compound CC1=CC=CC(C=O)=C1 OVWYEQOVUDKZNU-UHFFFAOYSA-N 0.000 claims description 3
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 claims description 2
- 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
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 claims description 2
- 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=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
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 claims description 2
- KQJQICVXLJTWQD-UHFFFAOYSA-N N-Methylthiourea Chemical compound CNC(N)=S KQJQICVXLJTWQD-UHFFFAOYSA-N 0.000 claims description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- HTKFORQRBXIQHD-UHFFFAOYSA-N allylthiourea Chemical compound NC(=S)NCC=C HTKFORQRBXIQHD-UHFFFAOYSA-N 0.000 claims description 2
- 229960001748 allylthiourea Drugs 0.000 claims description 2
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 claims description 2
- 229910052921 ammonium sulfate Inorganic materials 0.000 claims description 2
- 235000011130 ammonium sulphate Nutrition 0.000 claims description 2
- 239000007864 aqueous solution Substances 0.000 claims description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 2
- OKGXJRGLYVRVNE-UHFFFAOYSA-N diaminomethylidenethiourea Chemical compound NC(N)=NC(N)=S OKGXJRGLYVRVNE-UHFFFAOYSA-N 0.000 claims description 2
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 2
- 235000019441 ethanol Nutrition 0.000 claims description 2
- SDDKIZNHOCEXTF-UHFFFAOYSA-N methyl carbamimidothioate Chemical compound CSC(N)=N SDDKIZNHOCEXTF-UHFFFAOYSA-N 0.000 claims description 2
- 229910000403 monosodium phosphate Inorganic materials 0.000 claims description 2
- 235000019799 monosodium phosphate Nutrition 0.000 claims description 2
- 150000002894 organic compounds Chemical class 0.000 claims description 2
- CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 claims description 2
- 229910000343 potassium bisulfate Inorganic materials 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- GAPYKZAARZMMGP-UHFFFAOYSA-N pyridin-1-ium;acetate Chemical compound CC(O)=O.C1=CC=NC=C1 GAPYKZAARZMMGP-UHFFFAOYSA-N 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 150000003583 thiosemicarbazides Chemical class 0.000 claims description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims 2
- ZVTWZSXLLMNMQC-DETAZLGJSA-N 4-phenylmethoxybenzaldehyde Chemical compound C1=CC([13CH]=O)=CC=C1OCC1=CC=CC=C1 ZVTWZSXLLMNMQC-DETAZLGJSA-N 0.000 claims 1
- WRLRISOTNFYPMU-UHFFFAOYSA-N [S].CC1=CC=CC=C1 Chemical compound [S].CC1=CC=CC=C1 WRLRISOTNFYPMU-UHFFFAOYSA-N 0.000 claims 1
- 150000001299 aldehydes Chemical class 0.000 claims 1
- HUMNYLRZRPPJDN-KWCOIAHCSA-N benzaldehyde Chemical group O=[11CH]C1=CC=CC=C1 HUMNYLRZRPPJDN-KWCOIAHCSA-N 0.000 claims 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims 1
- 229910052794 bromium Inorganic materials 0.000 claims 1
- 150000001879 copper Chemical class 0.000 claims 1
- 238000003825 pressing Methods 0.000 claims 1
- ZDYVRSLAEXCVBX-UHFFFAOYSA-N pyridinium p-toluenesulfonate Chemical group C1=CC=[NH+]C=C1.CC1=CC=C(S([O-])(=O)=O)C=C1 ZDYVRSLAEXCVBX-UHFFFAOYSA-N 0.000 claims 1
- 229910052938 sodium sulfate Inorganic materials 0.000 claims 1
- 235000011152 sodium sulphate Nutrition 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 abstract description 8
- 230000015572 biosynthetic process Effects 0.000 abstract description 4
- 230000001766 physiological effect Effects 0.000 abstract description 3
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 2
- 239000003795 chemical substances by application Substances 0.000 abstract description 2
- 238000005516 engineering process Methods 0.000 abstract description 2
- 229930014626 natural product Natural products 0.000 abstract description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 70
- 239000000243 solution Substances 0.000 description 46
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 39
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 39
- 239000002024 ethyl acetate extract Substances 0.000 description 39
- 239000012074 organic phase Substances 0.000 description 39
- 239000000741 silica gel Substances 0.000 description 39
- 229910002027 silica gel Inorganic materials 0.000 description 39
- 229960001866 silicon dioxide Drugs 0.000 description 39
- 238000005406 washing Methods 0.000 description 38
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 38
- 238000010791 quenching Methods 0.000 description 37
- 230000000171 quenching effect Effects 0.000 description 37
- 238000005160 1H NMR spectroscopy Methods 0.000 description 35
- 238000000746 purification Methods 0.000 description 34
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 6
- FDPIMTJIUBPUKL-UHFFFAOYSA-N dimethylacetone Natural products CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 description 6
- 150000002431 hydrogen Chemical class 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- 229910052708 sodium Inorganic materials 0.000 description 6
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- YLEIFZAVNWDOBM-ZTNXSLBXSA-N ac1l9hc7 Chemical compound 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 4
- 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 4
- ADRDEXBBJTUCND-UHFFFAOYSA-N pyrrolizidine Chemical class C1CCN2CCCC21 ADRDEXBBJTUCND-UHFFFAOYSA-N 0.000 description 4
- SUISZCALMBHJQX-UHFFFAOYSA-N 3-bromobenzaldehyde Chemical compound BrC1=CC=CC(C=O)=C1 SUISZCALMBHJQX-UHFFFAOYSA-N 0.000 description 3
- QWLHJVDRPZNVBS-UHFFFAOYSA-N 4-phenoxybenzaldehyde Chemical compound C1=CC(C=O)=CC=C1OC1=CC=CC=C1 QWLHJVDRPZNVBS-UHFFFAOYSA-N 0.000 description 3
- 239000002547 new drug Substances 0.000 description 3
- 229930002356 pyrrolizidine alkaloid Natural products 0.000 description 3
- 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 2
- 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 2
- QKLXBIHSGMPUQS-FGZHOGPDSA-M (3r,5r)-7-[4-(4-fluorophenyl)-2,5-dimethyl-1-phenylpyrrol-3-yl]-3,5-dihydroxyheptanoate Chemical compound CC1=C(CC[C@@H](O)C[C@@H](O)CC([O-])=O)C(C=2C=CC(F)=CC=2)=C(C)N1C1=CC=CC=C1 QKLXBIHSGMPUQS-FGZHOGPDSA-M 0.000 description 2
- 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 compound 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 2
- QRDAPCMJAOQZSU-KQQUZDAGSA-N (e)-3-[4-[(e)-3-(3-fluorophenyl)-3-oxoprop-1-enyl]-1-methylpyrrol-2-yl]-n-hydroxyprop-2-enamide Chemical compound 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 2
- 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 2
- 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 2
- HZYLVYNCWLAIGF-UHFFFAOYSA-N 4-[[[2-(cyclohexylamino)-2-oxoethyl]-(4-propan-2-ylbenzoyl)amino]methyl]-N-hydroxybenzamide Chemical compound CC(C)c1ccc(cc1)C(=O)N(CC(=O)NC1CCCCC1)Cc1ccc(cc1)C(=O)NO HZYLVYNCWLAIGF-UHFFFAOYSA-N 0.000 description 2
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- 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 2
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- 235000002639 sodium chloride Nutrition 0.000 description 2
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- 125000006275 3-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C([H])C(*)=C1[H] 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
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- 238000010276 construction Methods 0.000 description 1
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- 238000012216 screening Methods 0.000 description 1
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- 238000010189 synthetic method Methods 0.000 description 1
Classifications
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
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- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
- C07F7/1872—Preparation; Treatments not provided for in C07F7/20
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Abstract
本发明属于化学合成领域,涉及一种具有下式化学结构的多取代吡咯里西啶化合物及其制备方法。所述制备多取代吡咯里西啶类化合物的技术路线,操作简单,路线简洁,收率较高,所用的试剂均为常用试剂,而且,可适合大规模制备,所得目标产物可用于多个具有重要生理活性天然产物的多样性合成研究。其中,取代基R1代表芳香基,R2代表氢或叔丁基二甲基硅氧基。
Description
技术领域
本发明属于化学合成领域,涉及一种多取代吡咯里西啶化合物及其制备方法。
背景技术
现有技术公开了吡咯里西啶生物碱广泛存在于自然界中,其中绝大多数具有广泛的生理活性。近年来,随着分离技术的逐步发展和新药研究的需求,更多的吡咯里西啶类生物碱被发现,虽然吡咯里西啶生物碱广泛存在于自然界中,但其含量很低,无法满足进一步药理学等研究。目前,已有部分吡咯里西啶类生物碱可以通过化学合成得到,但实现大量制备仍有一定的困难。实践显示,化学合成与从生物体分离的方法相比,其优势是可以得到自然界不存在或目前还没有被发现的新颖骨架结构;这些的骨架结构为新药的筛选提供了更多的可能。
基于现有技术的现状,本申请的发明人拟采用新的合成方法实现新颖化合物骨架的多样性大量合成,尤其涉及一种多取代吡咯里西啶化合物及其制备方法,本发明可为有关新药研究提供物质基础。
发明内容
本发明的目的在于提供一种多取代吡咯里西啶类化合物及其制备方法。本发明的制备方法的特点是:合成反应条件简单,选择性高,可以进行多取代吡咯里西啶类化合物的大量制备。
本发明所述的多取代吡咯里西啶化合物具有下式的化学结构:
其中,取代基R1代表芳香基,R2代表氢或叔丁基二甲基硅氧基。
优选的,所述取代基R1代表苯基,2-甲基苯基,3-甲基苯基,4-甲基苯基,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-氟苯基,3-氟苯基,4-氟苯基,3-三氟甲基苯基,4-三氟甲基苯基,2-甲氧基苯基,3-甲氧基苯基,4-苯基苯基,4-苯氧基苯基,α-萘基,β-萘基,α-呋喃基,α-噻吩基,β-噻吩基。
更优选的,本发明的吡咯里西啶类化合物的具体编号依次为1a、1b、1c、1d、1e、1f、1g、1h、1i、1j、1k、1l、1m、1n、1o、1p、1q、1r、1s、1t、1u、1v、1w、1x、2a、2b、2c、2d、2e、2f、2g、2h、2i、2j、2k、2l、2m;具备下述化学结构:
为了详实的描述所述化合物的结构,本发明定义上下文中的术语。
术语“芳香基”又可以称为“芳基”,应包括碳环芳环基团,碳原子数为C6-C10芳环基团,比如苯基(C6)、萘基(C10)和C8芳环基团。
为了合成所述的结构的吡咯里西啶类化合物,本发明的具体技术路线如下,在下文的陈述实施例中,中间体通式是根据结构式中的编号,用阿拉伯数字表示。
上述合成路线包括以下合成步骤:
步骤1:室温下将一种芳香醛,丙酮,脯氨酸和一种添加剂溶解于一种有机溶剂中,保持室温反应12-72小时后加入饱和碳酸氢钠水溶液,用乙酸乙酯萃取,浓缩,纯化得到目标化合物1a-1x和2a-2m;
其中芳香醛指羰基上的两个单键,一个与芳烃基连接,一个与氢连接的化合物;特别是指苯甲醛,2-甲基苯甲醛,3-甲基苯甲醛,4-甲基苯甲醛,2-氯苯甲醛,3-氯苯甲醛,4-氯苯甲醛,2-溴苯甲醛,3-溴苯甲醛,4-溴苯甲醛,2-氟苯甲醛,3-氟苯甲醛,4-氟苯甲醛,3-三氟甲基苯甲醛,4-三氟甲基苯甲醛,2-甲氧基苯甲醛,3-甲氧基苯甲醛,4-苯基苯甲醛,4-苯氧基苯甲醛,α-萘甲醛,β-萘甲醛,α-呋喃甲醛,α-噻吩甲醛,β-噻吩甲醛;
所述的添加剂是指对甲基苯磺酸,樟脑磺酸,酒石酸,等具有酸性的有机化合物;对甲基苯磺酸吡啶盐,乙酸吡啶盐等有机盐;甲基硫脲,脒基硫脲,氨基硫脲,烯丙基硫脲等硫脲类化合物;碳酸钠,碳酸钾,磷酸二氢钠,磷酸氢二钠,硫酸铵,硫酸氢钾,硫酸镁,硫酸钠,硫酸铯,硫酸铜等无机盐;特别是指酒石酸,对甲基苯磺酸吡啶盐,S-甲基硫脲,硫酸镁。
所述的一种有机溶剂指的是甲醇,乙醇,二氯甲烷,四氢呋喃,二甲基亚砜,乙腈,甲苯,N,N-二甲基甲酰胺等,特别是指二甲基亚砜。
本发明提供了一种新结构的多取代吡咯里西啶类化合物及其制备方法;所述制备多取代吡咯里西啶类化合物的技术路线,操作简单,路线简洁,收率较高,所用的试剂均为常用试剂,而且,可适合大规模制备,所得目标产物可用于多个具有重要生理活性天然产物的多样性合成研究。
具体实施方式
实施例1 合成化合物1a
室温下将苯甲醛(531mg,5mmol),脯氨酸(288mg,2.5mmol)和硫酸镁(60mg,0.5mmol)溶解于20mL二甲基亚砜中,加入丙酮(3.7mL)后保持室温反应48小时,加入饱和碳酸氢钠溶液淬灭反应,乙酸乙酯萃取三次,有机相用饱和食盐水洗涤,干燥,浓缩后经硅胶柱纯化得黄色油状化合物1a(1.17g,68%)。1H NMR(400MHz,CDCl3)δ7.41-7.37(m,2H),7.36-7.30(m,6H),7.30-7.27(m,1H),7.25-7.20(m,1H),6.51(d,J=16.2Hz,1H),6.23(d,J=16.2Hz,1H),3.73-3.69(m,1H),3.67-3.59(m,1H),3.55(d,J=11.6Hz,1H),3.03-2.95(m,1H),2.75-2.66(m,1H),1.98(s,3H),1.97-1.88(m,1H),1.82-1.76(m,1H),1.73(s,3H),1.61-1.55(m,1H)ppm.
合成化合物1b
室温下将α-呋喃甲醛(480mg,5mmol),脯氨酸(288mg,2.5mmol)和硫酸镁(60mg)溶解于20mL二甲基亚砜中,加入丙酮(3.7mL)后保持室温反应48小时,加入饱和碳酸氢钠溶液淬灭反应,乙酸乙酯萃取三次,有机相用饱和食盐水洗涤,干燥,浓缩后经硅胶柱纯化得黄色油状化合物1b(1.09g,67%)。1H NMR(400MHz,CDCl3)δ7.36--7.30(m,2H),6.38-6.36(m,1H),6.3-6.27(m,2H),6.25-6.23(m,1H),6.13(d,J=16.2Hz,1H),6.10-6.07(m,1H),3.83-3.76(m,1H),3.75-3.69(m,1H),3.55(d,J=11.2Hz,1H),2.97-2.90(m,1H),2.74-2.66(m,1H),2.08(s,3H),2.04-1.96(m,1H),1.85-1.76(m,2H),1.73-1.66(m,1H),1.64(s,3H)ppm.
合成化合物1c
室温下将α-噻吩甲醛(561mg,5mmol),脯氨酸(288mg,2.5mmol)和硫酸镁(60mg)溶解于20mL二甲基亚砜中,加入丙酮(3.7mL)后保持室温反应48小时,加入饱和碳酸氢钠溶液淬灭反应,乙酸乙酯萃取三次,有机相用饱和食盐水洗涤,干燥,浓缩后经硅胶柱纯化得黄色油状化合物1c(0.95g,53%)。1H NMR(400MHz,CDCl3)δ7.20-7.13(m,2H),6.98-6.95(m,2H),6.94-6.88(m,2H),6.61(d,J=16.2Hz,1H),6.03(d,J=16.2Hz,1H),3.92-3.85(m,1H),3.80-3.73(m,1H),3.45(d,J=11.2Hz,1H),3.01-2.93(m,1H),2.73-2.65(m,1H),2.06(s,3H),2.04-1.97(m,1H),1.84-1.77(m,2H),1.71-1.68(m,1H),1.67(s,3H)ppm.
合成化合物1d
室温下将β-噻吩甲醛(561mg,5mmol),脯氨酸(288mg,2.5mmol)和硫酸镁(60mg)溶解于20mL二甲基亚砜中,加入丙酮(3.7mL)后保持室温反应48小时,加入饱和碳酸氢钠溶液淬灭反应,乙酸乙酯萃取三次,有机相用饱和食盐水洗涤,干燥,浓缩后经硅胶柱纯化得黄色油状化合物1d(0.93g,52%)。1H NMR(400MHz,CDCl3)δ7.30-7.27(m,2H),7.23-7.21(m,1H),7.17-7.15(m,1H),7.09-7.07(m,1H),7.06-7.03(m,1H),6.50(d,J=16.0Hz,1H),6.05(d,J=16.0Hz,1H),3.78-3.69(m,2H),3.47(d,J=10.4Hz,1H),3.00-2.93(m,1H),2.73-2.66(m,1H),2.01(s,3H),1.98-1.94(m,1H),1.82-1.76(m,2H),1.67(s,3H),1.61-1.56(m,1H)ppm.
合成化合物1e
室温下将2-氯苯甲醛(700mg,5mmol),脯氨酸(288mg,2.5mmol)和硫酸镁(60mg)溶解于20mL二甲基亚砜中,加入丙酮(3.7mL)后保持室温反应48小时,加入饱和碳酸氢钠溶液淬灭反应,乙酸乙酯萃取三次,有机相用饱和食盐水洗涤,干燥,浓缩后经硅胶柱纯化得黄色油状化合物1e(0.85g,41%)。1H NMR(400MHz,CDCl3)δ7.51-7.47(m,1H),7.41-7.33(m,3H),7.29-7.26(m,1H),7.25-7.20(m,2H),7.18-7.12(m,1H),6.89(d,J=16.2Hz,1H),6.20(d,J=16.2Hz,1H),4.29-4.22(m,1H),3.72(d,J=11.6Hz,1H),3.65(dd,J=14.8,6.8Hz,1H),3.07-2.98(m,1H),2.78-2.70(m,1H),2.02(s,3H),1.95-1.89(m,1H),1.85-1.79(m,2H),1.77(s,3H),1.74-1.70(m,1H)ppm.
合成化合物1f
室温下将3-氯苯甲醛(700mg,5mmol),脯氨酸(288mg,2.5mmol)和硫酸镁(60mg)溶解于20mL二甲基亚砜中,加入丙酮(3.7mL)后保持室温反应48小时,加入饱和碳酸氢钠溶液淬灭反应,乙酸乙酯萃取三次,有机相用饱和食盐水洗涤,干燥,浓缩后经硅胶柱纯化得黄色油状化合物1f(1.18g,57%)。1H NMR(400MHz,CDCl3)δ7.36-7.32(m,2H),7.26-7.13(m,6H),6.44(d,J=16.2Hz,1H),6.18(d,J=16.2Hz,1H),3.69(dd,J=14.8,7.2Hz,1H),3.64-3.57(m,1H),3.53(d,J=11.2Hz,1H),2.97-2.90(m,1H),2.74-2.67(m,1H),2.00(s,3H),1.97-1.90(m,1H),1.83-1.75(m,2H),1.72(s,3H),1.60-1.53(m,1H)ppm.
合成化合物1g
室温下将2-氟苯甲醛(621mg,5mmol),脯氨酸(288mg,2.5mmol)和硫酸镁(60mg)溶解于20mL二甲基亚砜中,加入丙酮(3.7mL)后保持室温反应48小时,加入饱和碳酸氢钠溶液淬灭反应,乙酸乙酯萃取三次,有机相用饱和食盐水洗涤,干燥,浓缩后经硅胶柱纯化得黄色油状化合物1g(0.76g,40%)。1H NMR(400MHz,CDCl3)δ7.49-7.43(m,1H),7.35-7.29(m,1H),7.25-7.16(m,2H),7.15-7.09(m,2H),7.08-7.00(m,2H),6.68(d,J=16.2Hz,1H),6.31(d,J=16.2Hz,1H),3.92-3.85(m,1H),3.77-3.70(m,2H),3.04-2.95(m,1H),2.76-2.69(m,1H),2.02(s,3H),1.98-1.90(m,1H),1.84-1.78(m,.2H),1.75(s,3H),1.67-1.64(m,1H)ppm.
合成化合物1h
室温下将3-氟苯甲醛(621mg,5mmol),脯氨酸(288mg,2.5mmol)和硫酸镁(60mg)溶解于20mL二甲基亚砜中,加入丙酮(3.7mL)后保持室温反应48小时,加入饱和碳酸氢钠溶液淬灭反应,乙酸乙酯萃取三次,有机相用饱和食盐水洗涤,干燥,浓缩后经硅胶柱纯化得黄色油状化合物1h(1.04g,53%)。1H NMR(400MHz,CDCl3)δ7.64-7.54(m,4H),7.49-7.42(m,4H),6.54(d,J=16.2Hz,1H),6.28(d,J=16.2Hz,1H),3.77-3.66(m,2H),3.58(d,J=10.4Hz,1H),2.97-2.91(m,1H),2.76-2.69(m,1H),2.00(s,3H),1.97-1.89(m,1H),1.83-1.77(m,2H),1.75(s,3H),1.59-1.53(m,1H)ppm.
合成化合物1i
室温下将4-氯苯甲醛(700mg,5mmol),脯氨酸(288mg,2.5mmol)和硫酸镁(60mg)溶解于20mL二甲基亚砜中,加入丙酮(3.7mL)后保持室温反应48小时,加入饱和碳酸氢钠溶液淬灭反应,乙酸乙酯萃取三次,有机相用饱和食盐水洗涤,干燥,浓缩后经硅胶柱纯化得黄色油状化合物1i(1.57g.76%),6.15(d,J=16.2Hz,1H),3.71(dd,J=14.4,7.2Hz,1H),3.63-3.56(m,1H),3.53(d,J=11.6Hz,1H),2.98-2.90(m,1H),2.75-2.67(m,1H),1.98(s,3H),1.95-1.90(m,1H),1.82-1.75(m,2H),1.72(s,3H),1.58-1.51(m,1H)ppm.
合成化合物1j
室温下将4-氟苯甲醛(621mg,5mmol),脯氨酸(288mg,2.5mmol)和硫酸镁(60mg)溶解于20mL二甲基亚砜中,加入丙酮(3.7mL)后保持室温反应48小时,加入饱和碳酸氢钠溶液淬灭反应,乙酸乙酯萃取三次,有机相用饱和食盐水洗涤,干燥,浓缩后经硅胶柱纯化得黄色油状化合物1j(1.14g,60%)。1H NMR(400MHz,CDCl3)δ7.37-7.26(m,4H),7.05-6.95(m,4H),6.46(d,J=16.2Hz,1H),6.10(d,J=16.2Hz,1H),3.72-3.65(m,1H),3.62-3.56(m,1H),3.50(d,J=11.6Hz,1H),2.98-2.93(m,1H),2.74-2.66(m,1H),1.98(s,3H),1.95-1.89(m,1H),1.82-1.75(m,2H),1.71(s,3H),1.59-1.51(m,1H)ppm.
合成化合物1k
室温下将2-溴苯甲醛(920mg,5mmol),脯氨酸(288mg,2.5mmol)和硫酸镁(60mg)溶解于20mL二甲基亚砜中,加入丙酮(3.7mL)后保持室温反应48小时,加入饱和碳酸氢钠溶液淬灭反应,乙酸乙酯萃取三次,有机相用饱和食盐水洗涤,干燥,浓缩后经硅胶柱纯化得黄色油状化合物1k(1.18g,47%)。1H NMR(400MHz,CDCl3)δ7.59-7.53(m,2H),7.48-7.45(m,1H),7.40-7.36(m,1H),7.34-7.28(m,2H),7.16-7.05(m,2H),6.84(d,J=16.2Hz,1H),6.15(d,J=16.2Hz,1H),4.27(dd,J=11.6,9.2Hz,1H),3.68(d,J=11.6Hz,1H),3.65-3.59(m,1H),3.08-3.00(m,1H),2.78-2.70(m,1H),2.02(s,3H),1.94-1.89(m,1H),1.85-1.80(m,2H),1.78(s,3H),1.76-1.71(m,1H)ppm.
合成化合物1l
室温下将3-溴苯甲醛(920mg,5mmol),脯氨酸(288mg,2.5mmol)和硫酸镁(60mg)溶解于20mL二甲基亚砜中,加入丙酮(3.7mL)后保持室温反应48小时,加入饱和碳酸氢钠溶液淬灭反应,乙酸乙酯萃取三次,有机相用饱和食盐水洗涤,干燥,浓缩后经硅胶柱纯化得黄色油状化合物1l(1.43g,57%)。1H NMR(400MHz,CDCl3)δ7.52-7.48(m,2H),7.40-7.33(m,2H),7.31-7.26(m,2H),7.22-7.15(m,2H),6.43(d,J=16.2Hz,1H),6.17(d,J=16.2Hz,1H),3.62-3.56(m,1H),3.59(dd,J=11.6,10.8Hz,1H),3.53(d,J=11.2Hz,1H),2.97-2.89(m,1H),2.75-2.67(m,1H),2.00(s,3H),1.97-1.93(m,1H),1.82-1.75(m,2H),1.72(s,3H),1.59-1.53(m,1H)ppm.
合成化合物1m
室温下将4-溴苯甲醛(920mg,5mmol),脯氨酸(288mg,2.5mmol)和硫酸镁(60mg)溶解于20mL二甲基亚砜中,加入丙酮(3.7mL)后保持室温反应48小时,加入饱和碳酸氢钠溶液淬灭反应,乙酸乙酯萃取三次,有机相用饱和食盐水洗涤,干燥,浓缩后经硅胶柱纯化得黄色油状化合物1m(1.95g,78%)。1H NMR(400MHz,CDCl3)δ7.47-7.41(m,4H),7.25-7.18(m,4H),6.43(d,J=16.2Hz,1H),6.16(d,J=16.2Hz,1H),3.67(dd,J=14.8,7.6Hz,1H),3.61-3.54(m,1H),3.49(d,J=11.6Hz,1H),2.97-2.90(m,1H),2.73-2.66(m,1H),1.98(s,3H),1.95-1.88(m,1H),1.81-1.73(m,2H),1.71(s,3H),1.56-1.51(m,1H)ppm.
合成化合物1n
室温下将4-苯基苯甲醛(910mg,5mmol),脯氨酸(288mg,2.5mmol)和硫酸镁(60mg)溶解于20mL二甲基亚砜中,加入丙酮(3.7mL)后保持室温反应48小时,加入饱和碳酸氢钠溶液淬灭反应,乙酸乙酯萃取三次,有机相用饱和食盐水洗涤,干燥,浓缩后经硅胶柱纯化得黄色油状化合物1n(1.39g,56%)。1H NMR(400MHz,CDCl3)δ7.61-7.53(m,8H),7.49-7.40(m,8H),7.38-7.30(m,2H),6.56(d,J=16.2Hz,1H),6.29(d,J=16.2Hz,1H),3.83-3.75(m,1H),3.74-3.67(m,1H),3.65-3.57(m,1H),3.06-2.97(m,1H),2.78-2.70(m,1H),2.03(s,3H),1.99-1.94(m,1H),1.86-1.79(m,2H),1.77(s,3H),1.68-1.60(m,1H)ppm.
合成化合物1o
室温下将4-三氟甲基苯甲醛(870mg,5mmol),脯氨酸(288mg,2.5mmol)和硫酸镁(60mg)溶解于20mL二甲基亚砜中,加入丙酮(3.7mL)后保持室温反应48小时,加入饱和碳酸氢钠溶液淬灭反应,乙酸乙酯萃取三次,有机相用饱和食盐水洗涤,干燥,浓缩后经硅胶柱纯化得黄色油状化合物1o(1.66g,69%)。1HNMR(400MHz,CDCl3)δ7.61-7.56(m,4H),7.50-7.45(m,4H),6.56(d,J=16.2Hz,1H),6.29(d,J=16.2Hz,1H),3.81-3.74(m,1H),3.74-3.67(m,1H),3.62(d,J=11.2Hz,1H),2.99-2.92(m,1H),2.80-2.72(m,1H),2.00(s,3H),1.97-1.93(m,1H),1.86-1.78(m,2H),1.77(s,3H),1.62-1.55(m,1H)ppm.
合成化合物1p
室温下将3-三氟甲基苯甲醛(870mg,5mmol),脯氨酸(288mg,2.5mmol)和硫酸镁(60mg)溶解于20mL二甲基亚砜中,加入丙酮(3.7mL)后保持室温反应48小时,加入饱和碳酸氢钠溶液淬灭反应,乙酸乙酯萃取三次,有机相用饱和食盐水洗涤,干燥,浓缩后经硅胶柱纯化得黄色油状化合物1p(1.18g,49%)。1H NMR(400MHz,CDCl3)δ7.61-7.42(m,8H),6.55(d,J=16.2Hz,1H),6.25(d,J=16.2Hz,1H),3.77-3.68(m,2H),3.60(d,J=10.4Hz,1H),2.99-2.92(m,1H),2.78-2.71(m,1H),2.01(s,3H),1.98-1.92(m,1H),1.84-1.79(m,2H),1.76(s,3H),1.62-1.54(m,1H)ppm.
合成化合物1q
室温下将2-甲氧基苯甲醛(680mg,5mmol),脯氨酸(288mg,2.5mmol)和硫酸镁(60mg)溶解于20mL二甲基亚砜中,加入丙酮(3.7mL)后保持室温反应48小时,加入饱和碳酸氢钠溶液淬灭反应,乙酸乙酯萃取三次,有机相用饱和食盐水洗涤,干燥,浓缩后经硅胶柱纯化得黄色油状化合物1q(0.93g,46%)。1H NMR(400MHz,CDCl3)δ7.46-7.42(m,1H),7.24-7.16(m,2H),6.98-6.85(m,6H),6.30(d,J=16.2Hz,1H),4.02-3.95(m,1H),3.88(s,3H),3.85(s,3H),3.80-3.77(m,1H),3.76-3.74(m,1H),3.08-3.00(m,1H),2.75-2.66(m,1H),1.99(s,3H),1.92-1.87(m,1H),1.83-1.76(m,2H),1.73(s,3H),1.69-1.64(m,1H)ppm.
合成化合物1r
室温下将4-苯氧基苯甲醛(990mg,5mmol),脯氨酸(288mg,2.5mmol)和硫酸镁(60mg)溶解于20mL二甲基亚砜中,加入丙酮(3.7mL)后保持室温反应48小时,加入饱和碳酸氢钠溶液淬灭反应,乙酸乙酯萃取三次,有机相用饱和食盐水洗涤,干燥,浓缩后经硅胶柱纯化得黄色油状化合物1r(1.61g,61%)。1HNMR(400MHz,CDCl3)δ7.39-7.29(m,8H),7.15-7.09(m,2H),7.04-6.92(m,8H),6.51(d,J=16.2Hz,1H),6.13(d,J=16.2Hz,1H),3.91-3.80(m,1H),3.68-3.58(m,2H),3.06-2.98(m,1H),2.87-2.78(m,1H),2.01(s,3H),1.99-1.95(m,1H),1.89-1.83(m,2H),1.79(s,3H),1.67-1.60(m,1H)ppm.
合成化合物1s
室温下将3-甲氧基苯甲醛(680mg,5mmol),脯氨酸(288mg,2.5mmol)和硫酸镁(60mg)溶解于20mL二甲基亚砜中,加入丙酮(3.7mL)后保持室温反应48小时,加入饱和碳酸氢钠溶液淬灭反应,乙酸乙酯萃取三次,有机相用饱和食盐水洗涤,干燥,浓缩后经硅胶柱纯化得黄色油状化合物1s(1.26g,62%)。1H NMR(400MHz,CDCl3)δ7.28-7.20(m,2H),7.01-6.98(m,1H),6.94-6.87(m,3H),6.83-6.75(m,2H),6.47(d,J=16.2Hz,1H),6.22(d,J=16.2Hz,1H),3.84(s,3H),3.81(s,3H),3.77-3.71(m,1H),3.63-3.54(m,2H),3.01-2.94(m,1H),2.75-2.68(m,1H),1.99(s,3H),1.96-1.90(m,1H),1.83-1.76(m,2H),1.72(s,3H),1.63-1.56(m,1H)ppm.
合成化合物1t
室温下将2-甲基苯甲醛(601mg,5mmol),脯氨酸(288mg,2.5mmol)和硫酸镁(60mg)溶解于20mL二甲基亚砜中,加入丙酮(3.7mL)后保持室温反应48小时,加入饱和碳酸氢钠溶液淬灭反应,乙酸乙酯萃取三次,有机相用饱和食盐水洗涤,干燥,浓缩后经硅胶柱纯化得黄色油状化合物1t(1.10g,59%)。1HNMR(400MHz,CDCl3)δ7.39-7.34(m,2H),7.21-7.08(m,6H),6.71(d,J=16.0Hz,1H),6.07(d,J=16.0Hz,1H),4.02-3.94(m,1H),3.69-3.62(m,2H),3.08-3.00(m,1H),2.78-2.71(m,1H),2.51(s,3H),2.34(s,3H),1.99(s,3H),1.95-1.88(m,1H),1.86-1.79(m,2H),1.77(s,3H),1.58-1.50(m,1H)ppm.
合成化合物1u
室温下将α-萘甲醛(780mg,5mmol),脯氨酸(288mg,2.5mmol)和硫酸镁(60mg)溶解于20mL二甲基亚砜中,加入丙酮(3.7mL)后保持室温反应48小时,加入饱和碳酸氢钠溶液淬灭反应,乙酸乙酯萃取三次,有机相用饱和食盐水洗涤,干燥,浓缩后经硅胶柱纯化得黄色油状化合物1u(1.20g,54%)。1H NMR(400MHz,CDCl3)δ8.48-8.42(m,1H),8.10-8.04(m,1H),7.90-7.78(m,3H),7.76-7.71(m,1H),7.62-7.54(m,4H),7.53-7.45(m,4H),7.29(d,J=15.6Hz,1H),6.38(d,J=15.6Hz,1H),4.58(dd,J=10.8,10.0Hz,1H),3.96(d,J=10.8Hz,1H),3.91-3.82(m,1H),3.23-3.14(m,1H),2.90-2.81(m,1H),2.00(s,3H),1.93(s,3H),1.93-1.86(m,2H),1.85-1.76(m,1H),1.67-1.63(m,1H)ppm.
合成化合物1v
室温下将β-萘甲醛(780mg,5mmol),脯氨酸(288mg,2.5mmol)和硫酸镁(60mg)溶解于20mL二甲基亚砜中,加入丙酮(3.7mL)后保持室温反应48小时,加入饱和碳酸氢钠溶液淬灭反应,乙酸乙酯萃取三次,有机相用饱和食盐水洗涤,干燥,浓缩后经硅胶柱纯化得黄色油状化合物1v(1.51g,68%)。1H NMR(400MHz,CDCl3)δ7.85-7.76(m,8H),7.65-7.60(m,1H),7.54-7.49(m,1H),7.48-7.42(m,4H),6.70(d,J=16.0Hz,1H),6.40(d,J=16.0Hz,1H),3.89-3.83(m,2H),3.73-3.68(m,1H),3.10-3.03(m,1H),2.80-2.73(m,1H),2.00(s,3H),1.98-1.92(m,1H),1.88-1.83(m,2H),1.82(s,3H),1.72-1.64(m,1H)ppm.
合成化合物1w
室温下将3-甲基苯甲醛(601mg,5mmol),脯氨酸(288mg,2.5mmol)和硫酸镁(60mg)溶解于20mL二甲基亚砜中,加入丙酮(3.7mL)后保持室温反应48小时,加入饱和碳酸氢钠溶液淬灭反应,乙酸乙酯萃取三次,有机相用饱和食盐水洗涤,干燥,浓缩后经硅胶柱纯化得黄色油状化合物1w(1.19g,64%)(d,J=16.4Hz,1H),6.20(d,J=16.4Hz,1H),3.80-3.70(m,1H),3.64-3.55(m,2H),3.03-2.95(m,1H),2.78-2.68(m,1H),2.37(s,3H),2.34(s,3H),1.98(s,3H),1.96-1.89(m,1H),1.83-1.77(m,2H),1.74(s,3H),1.64-1.56(m,1H)ppm.
合成化合物1x
室温下将4-甲基苯甲醛(601mg,5mmol),脯氨酸(288mg,2.5mmol)和硫酸镁(60mg)溶解于20mL二甲基亚砜中,加入丙酮(3.7mL)后保持室温反应48小时,加入饱和碳酸氢钠溶液淬灭反应,乙酸乙酯萃取三次,有机相用饱和食盐水洗涤,干燥,浓缩后经硅胶柱纯化得黄色油状化合物1x(1.21g,65%)。1H NMR(400MHz,CDCl3)δ7.30-7.26(m,2H),7.24-7.20(m,2H),7.16-7.10(m,4H),6.47(d,J=16.4Hz,1H),6.17(d,J=16.4Hz,1H),3.73-3.66(m,1H),3.61-3.49(m,2H),3.02-2.94(m,1H),2.73-2.66(m,1H),2.34(s,3H),2.31(s,3H),1.97(s,3H),1.94-1.87(m,1H),1.79-1.74(m,2H),1.71(s,3H),1.62-1.55(m,1H)ppm.
合成化合物2a
室温下将苯甲醛(531mg,5mmol),4-叔丁基二甲基硅氧基脯氨酸(613mg,2.5mmol)和硫酸镁(60mg,0.5mmol)溶解于20mL二甲基亚砜中,加入丙酮(3.7mL)后保持室温反应48小时,加入饱和碳酸氢钠溶液淬灭反应,乙酸乙酯萃取三次,有机相用饱和食盐水洗涤,干燥,浓缩后经硅胶柱纯化得黄色油状化合物2a(1.09g,46%)。1H NMR(400MHz,CDCl3)δ7.39-7.30(m,8H),7.26-7.22(m,2H),6.50(d,J=16.4Hz,1H),6.11(d,J=16.4Hz,1H),4.37-4.32(m,1H),4.04-3.95(m,1H),3.69-3.57(m,2H),3.12(dd,J=11.6,5.6Hz,1H),2.66(dd,J=12.0,4.4Hz,1H),1.98(s,3H),1.94-1.89(m,1H),1.79-1.73(m,1H),1.71(s,3H),0.79(s,9H),-0.06(s,3H),-0.08(s,3H)ppm.
合成化合物2b
室温下将2-甲氧基苯甲醛(680mg,5mmol),4-叔丁基二甲基硅氧基脯氨酸(613mg,2.5mmol)和硫酸镁(60mg)溶解于20mL二甲基亚砜中,加入丙酮(3.7mL)后保持室温反应48小时,加入饱和碳酸氢钠溶液淬灭反应,乙酸乙酯萃取三次,有机相用饱和食盐水洗涤,干燥,浓缩后经硅胶柱纯化得黄色油状化合物2b(1.23g,46%)。1H NMR(400MHz,CDCl3)δ7.45-7.42(m,1H),7.24-7.18(m,2H),6.95-6.82(m,5H),6.81(d,J=16.2Hz,1H),6.17(d,J=16.2Hz,1H),4.37-4.30(m,1H),4.01(dd,J=11.8,8.4Hz,1H),3.86(s,3H),3.85(s,3H),3.83-3.79(m,1H),3.73(d,J=12.0Hz,1H),3.16(dd,J=12.0,6.0Hz,1H),2.59(dd,J=12.0,4.8Hz,1H),2.00(s,3H),1.89-1.85(m,2H),1.68(s,3H),0.80(s,9H),-0.04(s,3H),-0,07(s,3H)ppm.
合成化合物2c
室温下将α-噻吩甲醛(561mg,5mmol),4-叔丁基二甲基硅氧基脯氨酸(613mg,2.5mmol)和硫酸镁(60mg)溶解于20mL二甲基亚砜中,加入丙酮(3.7mL)后保持室温反应48小时,加入饱和碳酸氢钠溶液淬灭反应,乙酸乙酯萃取三次,有机相用饱和食盐水洗涤,干燥,浓缩后经硅胶柱纯化得黄色油状化合物2c(1.10g,45%)。1H NMR(400MHz,CDCl3)δ7.19-7.12(m,2H),6.99-6.90(m,4H),6.58(d,J=16.0Hz,1H),5.89(d,J=16.0Hz,1H),4.37-4.28(m,1H),3.96-3.83(m,2H),3.48(d,J=11.2Hz,1H),3.08(dd,J=12.0,5.6Hz,1H),2.59(dd,J=12.0,4.8Hz,1H),2.06(s,3H),1.99-1.91(m,1H),1.82-1.75(m,1H),1.62(s,3H),0.82(s,9H),-0.03(s,6H)ppm
合成化合物2d
室温下将3-氟苯甲醛(621mg,5mmol),4-叔丁基二甲基硅氧基脯氨酸(613mg,2.5mmol)和硫酸镁(60mg)溶解于20mL二甲基亚砜中,加入丙酮(3.7mL)后保持室温反应48小时,加入饱和碳酸氢钠溶液淬灭反应,乙酸乙酯萃取三次,有机相用饱和食盐水洗涤,干燥,浓缩后经硅胶柱纯化得黄色油状化合物2d(1.15g,45%)。1H NMR(400MHz,CDCl3)δ7.32-7.26(m,2H),7.15-7.10(m,2H),7.14-7.02(m,2H),6.97-6.90(m,2H),6.43(d,J=16.2Hz,1H),6.07(d,J=16.2Hz,1H),4.35-4.28(m,1H),3.88(d,J=14.8,7.2Hz,1H),3.63(dd,J=11.6,10.8Hz,1H),3.52(d,J=11.2Hz,1H),3.07(dd,J=12.0,5.6Hz,1H),2.61(dd,J=12.0,4.4Hz,1H),2.01(s,3H),1.93-1.86(m,1H),1.75-1.70(m,1H),1.67(s,3H),0.80(s,9H),-0.05(s,3H),-0.07(s,3H)ppm.
合成化合物2e
室温下将4-氯苯甲醛(700mg,5mmol),4-叔丁基二甲基硅氧基脯氨酸(613mg,2.5mmol)和硫酸镁(60mg)溶解于20mL二甲基亚砜中,加入丙酮(3.7mL)后保持室温反应48小时,加入饱和碳酸氢钠溶液淬灭反应,乙酸乙酯萃取三次,有机相用饱和食盐水洗涤,干燥,浓缩后经硅胶柱纯化得黄色油状化合物2e(1.30g,48%)。1H NMR(400MHz,CDCl3)δ7.31-7.23(m,8H),6.42(d,J=16.2Hz,1H),6.03(d,J=16.2Hz,1H),4.33-4.26(m,1H),3.90-3.81(m,1H),3.62-3.55(m,1H),3.51-3.46(m,1H),3.09-3.02(m,1H),2.63-2.57(m,1H),1.99(s,3H),1.91-1.83(m,1H),1.72-1.66(m,1H),1.62(s,3H),0.80(s,9H),-0.05(s,3H),-0.07(s,3H)ppm.
合成化合物2f
室温下将3-氯苯甲醛(700mg,5mmol),4-叔丁基二甲基硅氧基脯氨酸(613mg,2.5mmol)和硫酸镁(60mg)溶解于20mL二甲基亚砜中,加入丙酮(3.7mL)后保持室温反应4小时8,加入饱和碳酸氢钠溶液淬灭反应,乙酸乙酯萃取三次,有机相用饱和食盐水洗涤,干燥,浓缩后经硅胶柱纯化得黄色油状化合物2f(1.14g,42%)。1H NMR(400MHz,CDCl3)δ7.25-7.10(m,8H),6.37(d,J=16.2Hz,1H),6.01(d,J=16.2Hz,1H),4.29-4.22(m,1H),3.83(dd,J=14.8,7.2Hz,1H),3.59-3.53(m,1H),3.47(d,J=11.6Hz,1H),3.01(dd,J=11.6,5.6Hz,1H),2.57(dd,J=12.0,4.4Hz,1H),1.96(s,3H),1.87-1.80(m,1H),1.69-1.62(m,1H),1.62(s,3H),0.76(s,9H),-0.09(s,3H),-0.10(s,3H)ppm.
合成化合物2g
室温下将2-氟苯甲醛(621mg,5mmol),4-叔丁基二甲基硅氧基脯氨酸(613mg,2.5mmol)和硫酸镁(60mg)溶解于20mL二甲基亚砜中,加入丙酮(3.7mL)后保持室温反应48小时,加入饱和碳酸氢钠溶液淬灭反应,乙酸乙酯萃取三次,有机相用饱和食盐水洗涤,干燥,浓缩后经硅胶柱纯化得黄色油状化合物2g(1.10g,43%)。1H NMR(400MHz,CDCl3)δ7.47-7.42(m,1H),7.36-7.31(m,1H),7.25-7.17(m,2H),7.14-7.08(m,2H),7.06-7.00(m,2H),6.65(d,J=16.2Hz,1H),6.19(d,J=16.2Hz,1H),4.37-4.31(m,1H),3.95-3.84(m,2H),3.71(d,J=10.8Hz,1H),3.12(dd,J=11.6,5.2Hz,1H),2.63(dd,J=11.6,3.6Hz,1H),2.03(s,3H),1.94-1.86(m,1H),1.82-1.77(m,1H),1.70(s,3H),0.80(s,9H),-0.04(s,3H),-0.06(s,3H)ppm.
合成化合物2h
室温下将3-溴苯甲醛(920mg,5mmol),4-叔丁基二甲基硅氧基脯氨酸(613mg,2.5mmol)和硫酸镁(60mg)溶解于20mL二甲基亚砜中,加入丙酮(3.7mL)后保持室温反应48小时,加入饱和碳酸氢钠溶液淬灭反应,乙酸乙酯萃取三次,有机相用饱和食盐水洗涤,干燥,浓缩后经硅胶柱纯化得黄色油状化合物2h(1.48g,47%)。1H NMR(400MHz,CDCl3)δ7.51-7.48(m,2H),7.40-7.34(m,3H),7.23-7.15(m,3H),6.40(d,J=16.4Hz,1H),6.04(d,J=16.4Hz),4.35-4.28(m,1H),3.87(dd,J=15.2,7.6Hz,1H),3.59(dd,J=11.2,8.0Hz,1H),3.50(d,J=10.8Hz,1H),3.05(dd,J=116,5.6Hz,1H),2.60(dd,J=11.6,4.4Hz,1H),200(s,3H),1.93-1.86(m,1H),1.74-1.66(m,1H),1.66(s,3H),0.81(s,9H),-0.04(s,3H),-0.06(s,3H)ppm.
合成化合物2i
室温下将4-溴苯甲醛(920mg,5mmol),4-叔丁基二甲基硅氧基脯氨酸(613mg,2.5mmol)和硫酸镁(60mg)溶解于20mL二甲基亚砜中,加入丙酮(3.7mL)后保持室温反应48小时,加入饱和碳酸氢钠溶液淬灭反应,乙酸乙酯萃取三次,有机相用饱和食盐水洗涤,干燥,浓缩后经硅胶柱纯化得黄色油状化合物2i(1.64g,52%)。1H NMR(600MHz,1H,CDCl3)δ7.45-7.42(m,4H),7.24-7.20(m,4H),6.41(d,J=16.2Hz,1H),6.04(d,J=16.2Hz,1H),4.34-4.29(m,1H),3.93-3.85(m,1H),3.62-3.57(m,1H),3.53-3.49(m,1H),3.06(dd,J=11.4,5.4Hz,1H),2.65-2.61(m,1H),1.98(s,3H),1.90-1.85(m,1H),1.70-1.68(m,1H),1.66(s,3H),0.80(s,9H),-0.06(s,3H),-0.07(s,3H)ppm.
合成化合物2j
室温下将4-苯氧基苯甲醛(990mg,5mmol),4-叔丁基二甲基硅氧基脯氨酸(613mg,2.5mmol)和硫酸镁(60mg)溶解于20mL二甲基亚砜中,加入丙酮(3.7mL)后保持室温反应48小时,加入饱和碳酸氢钠溶液淬灭反应,乙酸乙酯萃取三次,有机相用饱和食盐水洗涤,干燥,浓缩后经硅胶柱纯化得黄色油状化合物2j(1.38g,42%)。1H NMR(400MHz,CDCl3)δ7.37-7.26(m,8H),7.13-7.06(m,2H),7.02-6.91(m,8H),6.44(d,J=16.2Hz,1H),6.00(d,J=16.2Hz,1H),4.32(dd,J=3.6,2.8Hz,1H),3.89(dd,J=14.8,7.6Hz,1H),3.65-3.56(mn,1H),3.50(d,J=11.6Hz,1H),3.10(dd,J=12.0,5.2Hz,1H),2.61(dd,J=12.4,4.0Hz,1H),2.01(s,3H),1.93-1.85(m,1H),1.76-1.71(m,1H),1.67(s,3H),0.80(s,9H),-0.04(s,3H),-0.06(s,3H)ppm.
合成化合物2k
室温下将4-三氟甲基苯甲醛(870mg,5mmol),4-叔丁基二甲基硅氧基脯氨酸(613mg,2.5mmol)和硫酸镁(60mg)溶解于20mL二甲基亚砜中,加入丙酮(3.7mL)后保持室温反应48小时,加入饱和碳酸氢钠溶液淬灭反应,乙酸乙酯萃取三次,有机相用饱和食盐水洗涤,干燥,浓缩后经硅胶柱纯化得黄色油状化合物2k(1.37g,45%)。1H NMR(400MHz,CDCl3)δ7.61-7.56(m,4H),7.47-7.44(m,4H),6.51(d,J=16.2Hz,1H),6.16(d,J=16.2Hz,1H),4.36-4.31(m,1H),3.93(dd,J=15.2,7.6Hz,1H),3.75-3.69(m,1H),3.57(d,J=11.2Hz,1H),3.07(dd,J=12.0,12.0),2.64(dd,J=11.6,3.6Hz,1H),2.00(s,3H),1.93-1.86(m,1H),1.70(s,1H),1.68-1.65(m,1H),0.80(s,9H),-0.05(s,3H),-0.07(s,3H)ppm.
合成化合物2l
室温下将3-甲氧基苯甲醛(680mg,5mmol),4-叔丁基二甲基硅氧基脯氨酸(613mg,2.5mmol)和硫酸镁(60mg)溶解于20mL二甲基亚砜中,加入丙酮(3.7mL)后保持室温反应48小时,加入饱和碳酸氢钠溶液淬灭反应,乙酸乙酯萃取三次,有机相用饱和食盐水洗涤,干燥,浓缩后经硅胶柱纯化得黄色油状化合物2l(1.23g,46%)。1H NMR(400MHz,CDCl3)δ7.25-7.20(m,2H),7.00-6.98(m,1H),6.95-6.92(m,1H),6.92-6.87(m,2H),6.82-6.75(m,2H),6.43(d,J=16.4Hz,1H),6.08(d,J=16.4Hz),4.37-4.31(m,1H),3.91(dd,J=14.8,7.2Hz,1H),3.84(s,3H),3.81(s,3H),3.64-3.57(m,1H),3.53(d,J=11.6Hz,1H),3.11(dd,J=12.0,5.6Hz,1H),2.61(dd,J=12.0,4.0Hz,1H),1.99(s,3H),1.94-1.87(m,1H),1.76-1.70(m,1H),1.66(s,3H),0.80(s,9H),-0.05(s,3H),-0.07(s,3H)ppm.
合成化合物2m
室温下将β-萘甲醛(780mg,5mmol),4-叔丁基二甲基硅氧基脯氨酸(613mg,2.5mmol)和硫酸镁(60mg)溶解于20mL二甲基亚砜中,加入丙酮(3.7mL)后保持室温反应48小时,加入饱和碳酸氢钠溶液淬灭反应,乙酸乙酯萃取三次,有机相用饱和食盐水洗涤,干燥,浓缩后经硅胶柱纯化得黄色油状化合物2m(1.38g,48%)。1H NMR(400MHz,CDCl3)δ7.85-7.80(m,7H),7.76-7.74(m,1H),7.63-7.59(m,1H),7.55-7.51(m,1H),7.50-7.41(m,4H),6.67(d,J=16.2Hz,1H),6.28(d,J=16.2Hz,1H),4.42-4.35(m,1H),4.06(dd,J=14.8,7.2Hz,1H),3.88(dd,J=11.6,8.8Hz,1H),3.71(d,J=11.6Hz,1H),3.19(dd,J=11.6,5.6Hz,1H),2.67(dd,J=11.6,4.0Hz,1H),2.00(s,3H),1.97-1.89(m,1H),1.84-1.80(m,1H),1.77(s,3H),0.77(s,9H),-0.07(s,3H),-0.09(s,3H)ppm.
实施例2
合成化合物1a
室温下将苯甲醛(531mg,5mmol),脯氨酸(288mg,2.5mmol)和硫脲(38mg,0.5mmol)溶解于20mL二甲基亚砜中,加入丙酮(3.7mL)后保持室温反应48小时,加入饱和碳酸氢钠溶液淬灭反应,乙酸乙酯萃取三次,有机相用饱和食盐水洗涤,干燥,浓缩后经硅胶柱纯化得黄色油状化合物1a(1.03g,68%)。
化合物1b-x,2a-2m的制备与实施例1相同。
实施例3
合成化合物2a
室温下将苯甲醛(531mg,5mmol),4-叔丁基二甲基硅氧基脯氨酸(613mg,2.5mmol)和硫酸镁(38mg,0.5mmol)溶解于20mL二甲基亚砜中,加入丙酮(3.7mL)后保持室温反应48小时,加入饱和碳酸氢钠溶液淬灭反应,乙酸乙酯萃取三次,有机相用饱和食盐水洗涤,干燥,浓缩后经硅胶柱纯化得黄色油状化合物2a(0.95g,40%)。
化合物1a-x,2b-2m的制备与实施例1相同。
Claims (10)
1.一种多取代吡咯里西啶化合物,其特征在于,具有下式的化学结构:
其中,取代基R1代表芳香基,R2代表氢或叔丁基二甲基硅氧基。
2.根据权利要求1所述的多取代吡咯里西啶化合物,其特征在于,所述取代基R1代表苯基,2-甲基苯基,3-甲基苯基,4-甲基苯基,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-氟苯基,3-氟苯基,4-氟苯基,3-三氟甲基苯基,4-三氟甲基苯基,2-甲氧基苯基,3-甲氧基苯基,4-苯基苯基,4-苯氧基苯基,α-萘基,β-萘基,α-呋喃基,α-噻吩基,β-噻吩基。
3.根据权利要求1所述的多取代吡咯里西啶化合物,其特征在于,所述的多取代吡咯里西啶化合物具有下述结构:
4.权利要求1所述的多取代吡咯里西啶化合物的制备方法,其特征在于,采用下述反应路线制备:
其中,取代基R1代表芳香基,R2代表氢或叔丁基二甲基硅氧基;
其中,室温下将一种芳香醛,丙酮,脯氨酸和一种添加剂溶解于一种有机溶剂中,保持室温反应12-72小时后加入饱和碳酸氢钠水溶液,用乙酸乙酯萃取,浓缩,纯化制得目标化合物1a-1x和2a-l。
5.按权利要求4所述的方法,其特征在于,所述的一种芳香醛指羰基上的两个单键,一个与芳烃基连接,一个与氢连接的化合物。
6.按权利要求4或5所述的方法,其特征在于,所述的一种芳香醛是苯甲醛,2-甲基苯甲醛,3-甲基苯甲醛,4-甲基苯甲醛,2-氯苯甲醛,3-氯苯甲醛,4-氯苯甲醛,2-溴苯甲醛,3-溴苯甲醛,4-溴苯甲醛,2-氟苯甲醛,3-氟苯甲醛,4-氟苯甲醛,3-三氟甲基苯甲醛,4-三氟甲基苯甲醛,2-甲氧基苯甲醛,3-甲氧基苯甲醛,4-苯基苯甲醛,4-苯基氧苯甲醛,α-萘甲醛,β-萘甲醛,α-呋喃甲醛,α-噻吩甲醛或β-噻吩甲醛。
7.按权利要求4所述的方法,其特征在于,所述的一种添加剂是指具有酸性的有机化合物,选自对甲基苯磺酸,樟脑磺酸或酒石酸。
8.按权利要求4或7所述的方法,其特征在于,所述的一种添加剂是对甲基苯磺酸吡啶盐,乙酸吡啶盐有机盐;甲基硫脲,脒基硫脲,氨基硫脲,烯丙基硫脲硫脲类化合物;碳酸钠,碳酸钾,磷酸二氢钠,磷酸氢二钠,硫酸铵,硫酸氢钾,硫酸镁,硫酸钠,硫酸铯或硫酸铜无机盐。
9.按权利要求4或7所述的方法,其特征在于,所述的一种添加剂是酒石酸,对甲基苯磺酸吡啶盐,S-甲基硫脲或硫酸镁。
10.按权利要求4所述的方法,其特征在于,所述的一种有机溶剂是甲醇,乙醇,二氯甲烷,四氢呋喃,二甲基亚砜,乙腈,甲苯或N,N-二甲基甲酰胺。
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