CN114736107A - Preparation method of alkynylamide mediated ketone compound - Google Patents
Preparation method of alkynylamide mediated ketone compound Download PDFInfo
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- CN114736107A CN114736107A CN202210503934.1A CN202210503934A CN114736107A CN 114736107 A CN114736107 A CN 114736107A CN 202210503934 A CN202210503934 A CN 202210503934A CN 114736107 A CN114736107 A CN 114736107A
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- -1 ketone compound Chemical class 0.000 title claims abstract description 74
- 230000001404 mediated effect Effects 0.000 title claims abstract description 11
- 238000002360 preparation method Methods 0.000 title abstract description 7
- 238000006243 chemical reaction Methods 0.000 claims abstract description 73
- 238000000034 method Methods 0.000 claims abstract description 25
- 150000001875 compounds Chemical class 0.000 claims abstract description 17
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 8
- 229910052751 metal Inorganic materials 0.000 claims abstract description 6
- 239000002184 metal Substances 0.000 claims abstract description 6
- 239000002994 raw material Substances 0.000 claims abstract description 6
- 230000003213 activating effect Effects 0.000 claims abstract description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 147
- 239000012074 organic phase Substances 0.000 claims description 30
- 239000002904 solvent Substances 0.000 claims description 29
- 125000003118 aryl group Chemical group 0.000 claims description 24
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 20
- 125000000217 alkyl group Chemical group 0.000 claims description 19
- 229910052757 nitrogen Inorganic materials 0.000 claims description 15
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 14
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 14
- 238000004440 column chromatography Methods 0.000 claims description 14
- 238000010791 quenching Methods 0.000 claims description 14
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 14
- 125000001424 substituent group Chemical group 0.000 claims description 14
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 12
- 125000006575 electron-withdrawing group Chemical group 0.000 claims description 11
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 125000000304 alkynyl group Chemical group 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 8
- 125000003107 substituted aryl group Chemical group 0.000 claims description 8
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 7
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 7
- 238000004821 distillation Methods 0.000 claims description 7
- 150000002902 organometallic compounds Chemical class 0.000 claims description 7
- 238000003756 stirring Methods 0.000 claims description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- 125000005842 heteroatom Chemical group 0.000 claims description 6
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 6
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 6
- 125000003342 alkenyl group Chemical group 0.000 claims description 5
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
- 239000002585 base Substances 0.000 claims description 5
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 5
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 150000002367 halogens Chemical class 0.000 claims description 5
- 239000000203 mixture Substances 0.000 claims description 5
- UOCLXMDMGBRAIB-UHFFFAOYSA-N 1,1,1-trichloroethane Chemical compound CC(Cl)(Cl)Cl UOCLXMDMGBRAIB-UHFFFAOYSA-N 0.000 claims description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 4
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-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
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 4
- 150000002825 nitriles Chemical class 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- 239000003208 petroleum Substances 0.000 claims description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 claims description 3
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 3
- 125000006125 ethylsulfonyl group Chemical group 0.000 claims description 3
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims description 3
- 229910052760 oxygen Inorganic materials 0.000 claims description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 claims description 3
- 229910052717 sulfur Inorganic materials 0.000 claims description 3
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 3
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical group [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical group [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical group [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 2
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 2
- 125000003435 aroyl group Chemical group 0.000 claims description 2
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 125000001589 carboacyl group Chemical group 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 238000001816 cooling Methods 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- 229910052744 lithium Inorganic materials 0.000 claims description 2
- 229910052749 magnesium Inorganic materials 0.000 claims description 2
- 239000011777 magnesium Substances 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 125000001624 naphthyl group Chemical group 0.000 claims description 2
- 239000012299 nitrogen atmosphere Substances 0.000 claims description 2
- 239000012071 phase Substances 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 2
- 229910052725 zinc Chemical group 0.000 claims description 2
- 239000011701 zinc Chemical group 0.000 claims description 2
- 125000003275 alpha amino acid group Chemical group 0.000 claims 1
- 150000001408 amides Chemical class 0.000 claims 1
- 238000004809 thin layer chromatography Methods 0.000 claims 1
- 210000004899 c-terminal region Anatomy 0.000 abstract description 3
- 238000001308 synthesis method Methods 0.000 abstract description 3
- 230000002194 synthesizing effect Effects 0.000 abstract description 3
- 150000001413 amino acids Chemical class 0.000 abstract description 2
- 238000011191 terminal modification Methods 0.000 abstract description 2
- 150000001735 carboxylic acids Chemical class 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 48
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 24
- 239000012043 crude product Substances 0.000 description 24
- 239000000047 product Substances 0.000 description 24
- 238000003786 synthesis reaction Methods 0.000 description 22
- 230000015572 biosynthetic process Effects 0.000 description 19
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 12
- 238000005160 1H NMR spectroscopy Methods 0.000 description 12
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 12
- 239000008346 aqueous phase Substances 0.000 description 12
- VRNLIJIYOKNEOP-UHFFFAOYSA-N n-ethynyl-n,4-dimethylbenzenesulfonamide Chemical compound C#CN(C)S(=O)(=O)C1=CC=C(C)C=C1 VRNLIJIYOKNEOP-UHFFFAOYSA-N 0.000 description 12
- 239000012312 sodium hydride Substances 0.000 description 12
- 239000007787 solid Substances 0.000 description 10
- ANRQGKOBLBYXFM-UHFFFAOYSA-M phenylmagnesium bromide Chemical compound Br[Mg]C1=CC=CC=C1 ANRQGKOBLBYXFM-UHFFFAOYSA-M 0.000 description 9
- 238000000746 purification Methods 0.000 description 7
- 238000000926 separation method Methods 0.000 description 7
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- LPNBBFKOUUSUDB-UHFFFAOYSA-N p-toluic acid Chemical compound CC1=CC=C(C(O)=O)C=C1 LPNBBFKOUUSUDB-UHFFFAOYSA-N 0.000 description 6
- 238000010276 construction Methods 0.000 description 5
- LFKDJXLFVYVEFG-UHFFFAOYSA-N tert-butyl carbamate Chemical compound CC(C)(C)OC(N)=O LFKDJXLFVYVEFG-UHFFFAOYSA-N 0.000 description 5
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 4
- NZNMSOFKMUBTKW-UHFFFAOYSA-N cyclohexanecarboxylic acid Chemical compound OC(=O)C1CCCCC1 NZNMSOFKMUBTKW-UHFFFAOYSA-N 0.000 description 4
- 239000000758 substrate Substances 0.000 description 4
- AMHOPTNGSNYSBL-UHFFFAOYSA-N 1-cyclohexylpropan-1-one Chemical compound CCC(=O)C1CCCCC1 AMHOPTNGSNYSBL-UHFFFAOYSA-N 0.000 description 3
- GNKZMNRKLCTJAY-UHFFFAOYSA-N 4'-Methylacetophenone Chemical compound CC(=O)C1=CC=C(C)C=C1 GNKZMNRKLCTJAY-UHFFFAOYSA-N 0.000 description 3
- 238000005580 one pot reaction Methods 0.000 description 3
- OHTYZZYAMUVKQS-UHFFFAOYSA-N phenyl-[4-(trifluoromethyl)phenyl]methanone Chemical compound C1=CC(C(F)(F)F)=CC=C1C(=O)C1=CC=CC=C1 OHTYZZYAMUVKQS-UHFFFAOYSA-N 0.000 description 3
- XKGLSKVNOSHTAD-UHFFFAOYSA-N valerophenone Chemical compound CCCCC(=O)C1=CC=CC=C1 XKGLSKVNOSHTAD-UHFFFAOYSA-N 0.000 description 3
- LRFZIPCTFBPFLX-SSDOTTSWSA-N (2s)-3,3-dimethyl-2-[(2-methylpropan-2-yl)oxycarbonylamino]butanoic acid Chemical compound CC(C)(C)OC(=O)N[C@H](C(O)=O)C(C)(C)C LRFZIPCTFBPFLX-SSDOTTSWSA-N 0.000 description 2
- CIXAYNMKFFQEFU-UHFFFAOYSA-N (4-Methylphenyl)acetaldehyde Chemical compound CC1=CC=C(CC=O)C=C1 CIXAYNMKFFQEFU-UHFFFAOYSA-N 0.000 description 2
- WXPWZZHELZEVPO-UHFFFAOYSA-N (4-methylphenyl)-phenylmethanone Chemical compound C1=CC(C)=CC=C1C(=O)C1=CC=CC=C1 WXPWZZHELZEVPO-UHFFFAOYSA-N 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- VZFUCHSFHOYXIS-UHFFFAOYSA-N cycloheptane carboxylic acid Natural products OC(=O)C1CCCCCC1 VZFUCHSFHOYXIS-UHFFFAOYSA-N 0.000 description 2
- BMFYCFSWWDXEPB-UHFFFAOYSA-N cyclohexyl(phenyl)methanone Chemical compound C=1C=CC=CC=1C(=O)C1CCCCC1 BMFYCFSWWDXEPB-UHFFFAOYSA-N 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- DWYFUJJWTRPARQ-UHFFFAOYSA-N phenyl(thiophen-2-yl)methanone Chemical compound C=1C=CC=CC=1C(=O)C1=CC=CS1 DWYFUJJWTRPARQ-UHFFFAOYSA-N 0.000 description 2
- 229920001184 polypeptide Polymers 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 230000036632 reaction speed Effects 0.000 description 2
- 229910052723 transition metal Inorganic materials 0.000 description 2
- 150000003624 transition metals Chemical class 0.000 description 2
- 238000005292 vacuum distillation Methods 0.000 description 2
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 1
- SZXBQTSZISFIAO-ZETCQYMHSA-N (2s)-3-methyl-2-[(2-methylpropan-2-yl)oxycarbonylamino]butanoic acid Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)OC(C)(C)C SZXBQTSZISFIAO-ZETCQYMHSA-N 0.000 description 1
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 1
- TZKBVRDEOITLRB-UHFFFAOYSA-N 4-methyl-n-[4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]-3-[2-(1h-pyrazolo[3,4-b]pyridin-5-yl)ethynyl]benzamide Chemical compound C1CN(C)CCN1CC(C(=C1)C(F)(F)F)=CC=C1NC(=O)C1=CC=C(C)C(C#CC=2C=C3C=NNC3=NC=2)=C1 TZKBVRDEOITLRB-UHFFFAOYSA-N 0.000 description 1
- SWKPKONEIZGROQ-UHFFFAOYSA-N 4-trifluoromethylbenzoic acid Chemical compound OC(=O)C1=CC=C(C(F)(F)F)C=C1 SWKPKONEIZGROQ-UHFFFAOYSA-N 0.000 description 1
- MITGKKFYIJJQGL-UHFFFAOYSA-N 9-(4-chlorobenzoyl)-6-methylsulfonyl-2,3-dihydro-1H-carbazol-4-one Chemical compound ClC1=CC=C(C(=O)N2C3=CC=C(C=C3C=3C(CCCC2=3)=O)S(=O)(=O)C)C=C1 MITGKKFYIJJQGL-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- HPKJGHVHQWJOOT-ZJOUEHCJSA-N N-[(2S)-3-cyclohexyl-1-oxo-1-({(2S)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}amino)propan-2-yl]-1H-indole-2-carboxamide Chemical compound C1C(CCCC1)C[C@H](NC(=O)C=1NC2=CC=CC=C2C=1)C(=O)N[C@@H](C[C@H]1C(=O)NCC1)C=O HPKJGHVHQWJOOT-ZJOUEHCJSA-N 0.000 description 1
- 150000007514 bases Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 239000012965 benzophenone Substances 0.000 description 1
- LUEHNHVFDCZTGL-UHFFFAOYSA-N but-2-ynoic acid Chemical compound CC#CC(O)=O LUEHNHVFDCZTGL-UHFFFAOYSA-N 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 229940125797 compound 12 Drugs 0.000 description 1
- 238000006880 cross-coupling reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- RXKJFZQQPQGTFL-UHFFFAOYSA-N dihydroxyacetone Chemical class OCC(=O)CO RXKJFZQQPQGTFL-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000012039 electrophile Substances 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 description 1
- QGEFGPVWRJCFQP-UHFFFAOYSA-M magnesium;methanidylbenzene;bromide Chemical compound [Mg+2].[Br-].[CH2-]C1=CC=CC=C1 QGEFGPVWRJCFQP-UHFFFAOYSA-M 0.000 description 1
- LVKCSZQWLOVUGB-UHFFFAOYSA-M magnesium;propane;bromide Chemical compound [Mg+2].[Br-].C[CH-]C LVKCSZQWLOVUGB-UHFFFAOYSA-M 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 239000012038 nucleophile Substances 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- QERYCTSHXKAMIS-UHFFFAOYSA-N thiophene-2-carboxylic acid Chemical compound OC(=O)C1=CC=CS1 QERYCTSHXKAMIS-UHFFFAOYSA-N 0.000 description 1
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- 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
- C07C45/45—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation
- C07C45/455—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation with carboxylic acids or their derivatives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/36—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids
- C07C303/40—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids by reactions not involving the formation of sulfonamide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/22—Radicals substituted by doubly bound hetero atoms, or by two hetero atoms other than halogen singly bound to the same carbon atom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
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Abstract
The invention discloses a preparation method of an alkynylamide-mediated ketone compound, which takes carboxylic acid as a raw material, an alkynylamide compound as an activating reagent for reaction to obtain an alpha-acyloxy alkenyl amide compound, and then the alpha-acyloxy alkenyl amide compound is coupled with a metal organic reagent to obtain a target ketone compound. The synthesis method of the ketone compound provided by the invention has the advantages of wide application range, simple operation and high reaction rate. It is worth noting that the reaction can also be used for C-terminal modification of amino acid, and an efficient new method is provided for synthesizing ketone compounds.
Description
Technical Field
The invention relates to preparation of ketone compounds, in particular to a preparation method of alkyne amide mediated ketone compounds, belonging to the technical field of organic synthesis.
Background
The ketone compound is one of the basic compounds in organic chemistry and plays an important role in organic synthesis. Ketone compounds are not only widely found in natural products and drugs, but also are raw materials and substrates for many chemical reactions. Therefore, the synthesis of the ketone compound has very important significance.
The construction of ketones via carbon-carbon bonds has always been one of the hot spots in organic chemistry. With the development of organic synthetic chemistry in recent years, electrophiles and nucleophiles which cannot directly react in the traditional mode can efficiently realize the construction of carbon-carbon bonds through transition metal catalyzed cross coupling reaction. Although the construction of the carbon-carbon bond catalyzed by the transition metal is excellent in the synthesis of aromatic ketone compounds, the method is slightly inferior to the synthesis of aliphatic ketone compounds. Mainly because the fatty compounds are susceptible to free radical β -H elimination. In addition, the carbon-carbon bond construction method for synthesizing the aminoketone compound by amino acid carboxyl modification is relatively few. Therefore, the development of a synthesis method of the ketone compound which is mild in condition, good in selectivity and capable of being used for modifying C-terminal by amino acid and polypeptide is of great significance.
Disclosure of Invention
Aiming at the defects of the prior art, the invention discloses a preparation method of an alkynylamide mediated ketone compound. In the method, the synthesis reaction has the advantages of mild conditions, tolerance of a plurality of functional groups, wide substrate application range, simplicity in operation, high reaction speed and the like on the construction of the ketone carbonyl group. The raw materials are simple and easily available carboxylic acid substrates, so that the strategy has wider practicability and economical efficiency. Importantly, the alpha-chiral carboxylic acid keeps the stereochemical integrity in the conversion process, so that a new idea can be provided for polypeptide and protein C-terminal modification.
In order to achieve the above purpose, the technical scheme adopted by the invention is as follows:
according to a first embodiment of the present invention, there is provided a process for preparing an alkynylamide-mediated ketone compound.
A preparation method of an alkynylamide mediated ketone compound is characterized in that the ketone compound with a general structural formula (V) is prepared by taking carboxylic acid with a general structural formula (I) as a raw material, taking alkynylamide with a general structural formula (II) as an activating reagent to react to obtain an intermediate, and then reacting the intermediate with a metal organic reagent. Wherein the carboxylic acid with the general structural formula (I), the alkynylamide with the general structural formula (II) and the ketone compound with the general structural formula (V) are shown as follows:
in the formula (I), the formula (II) and the formula (V), R1Selected from alkyl, cycloalkyl, substituted aromatic ring group, heterocyclic aryl. R2Selected from hydrogen, alkyl, aryl, alkynyl, alkenyl. R3Selected from alkyl, aryl and substituted aromatic ring radical.
Preferably, the method specifically comprises the following steps:
1) firstly, carboxylic acid with a general structural formula (I) and alkynylamide with a general structural formula (II) react in a first solvent to obtain an alpha-acyloxy alkenyl amide compound with a general structural formula (III):
2) reacting an alpha-acyloxyenamide compound having the general structural formula (III) with a metal organic compound having the general structural formula (IV) in a second solvent in the presence of a base to obtain a ketone compound having the general structural formula (V):
in the formula (I) -formula (V), R1And R4Each independently selected from alkyl, cycloalkyl, alkynyl, aryl, substituted aromatic cyclic, heterocyclic aryl. R2Selected from hydrogen, alkyl, aryl, alkynyl, alkenyl. R3Selected from alkyl, aryl and substituted aromatic ring radical. M is a metal. EWG (Electron withdrawing group) is selected from the group consisting of alkylsulfonyl, alkanoyl, arylsulfonyl, aroyl, nitrile, nitro.
Preferably, R1Selected from methyl, butyl, isobutyl, cyclohexyl, adamantyl, n-octyl, propynyl, phenylethynyl, phenyl, substituted aryl, and heterocyclic aryl.
R2Selected from hydrogen, phenyl, methyl, propyl, isobutyl, ethynyl, ethenyl.
R3Selected from methyl, ethyl, phenyl, heterocyclic aryl and halogenated aromatic ring radical.
R4Selected from methyl, ethyl, benzyl, naphthyl, aryl and substituted aryl.
M is selected from magnesium, lithium and zinc. And/or
EWG (Electron withdrawing group) is selected from methylsulfonyl, ethylsulfonyl, phenylsulfonyl, substituted phenylsulfonyl, nitrile, nitro.
Preferably, the substituent of the substituted benzenesulfonyl group is selected from methyl, tert-butyl, methoxy, phenyl, F, Cl, Br, I, benzyloxy, benzyloxycarbonyl and cyano, and the number of the substituents is 1 or 2.
Preferably, the substituent of the substituted aryl is selected from alkyl, alkoxy, halogen, phenyl, benzyl, benzyloxy and cyano, and the number of the substituent is an integer of 1-3.
Preferably, the heteroatom of the heterocyclic aryl group is O, N or S, and the number of heteroatoms is 1 or 2.
Preferably, the substituent of the substituted aromatic ring group is selected from alkyl, alkoxy, halogen, phenyl, benzyl, benzyloxy and cyano, and the number of the substituent is an integer of 1 to 3.
Preferably, the EWG is specifically one of p-methoxybenzenesulfonyl (a), p-methylbenzenesulfonyl (B), p-fluorobenzenesulfonyl (C), p-chlorobenzenesulfonyl (D), m-iodobenzenesulfonyl (E), m-bromobenzenesulfonyl (F), p-cyanobenzenesulfonyl (G), 3, 5-dimethylbenzenesulfonyl (H), p-bromobenzenesulfonyl (I), 2-methylpropanesulfonyl (J), ethanesulfonyl (K) and methanesulfonyl (L):
preferably, in step 1), the first solvent is an organic solvent. Preferably, the first solvent is selected from one or more of Dichloromethane (DCM), trichloroethane, dimethylsulfoxide, methanol, acetonitrile, N-dimethylformamide, tetrahydrofuran, N-pentane, diethyl ether, petroleum ether.
Preferably, in step 2), the second solvent is an organic solvent. Preferably, the second solvent is selected from one or more of Dichloromethane (DCM), trichloroethane, dimethylsulfoxide, methanol, acetonitrile, N-dimethylformamide, tetrahydrofuran, N-pentane, diethyl ether, petroleum ether.
Preferably, in step 2), the alkali is NaH, NaOH or Na2CO3、Et3N, EtONa, respectively.
Preferably, the first solvent and the second solvent are the same solvent. Preferably, the first solvent and the second solvent are both Dichloromethane (DCM).
Preferably, in step 1), the carboxylic acid of the general structural formula (I) and the alkynylamide of the general structural formula (II) are added in a molar ratio of 1:0.5 to 8. Preferably 1:0.8-5, more preferably 1: 1-3.
Preferably, in the step 2), the mole ratio of the alpha-acyloxy alkenyl amide compound with the general structural formula (III), the metal organic compound with the general structural formula (IV) and the base is 1:1-8:1-8, and preferably 1:1.5-5: 1.5-5. More preferably 1:2-3.5: 2-3.5.
Preferably, step 1) is specifically: the method comprises the steps of dissolving carboxylic acid with a structural general formula (I) and alkynylamide with a structural general formula (II) in a first solvent according to a ratio, stirring and mixing at room temperature for reaction, and carrying out reduced pressure distillation after the reaction is finished to obtain the alpha-acyloxy alkenyl amide compound with a structural general formula (III).
Preferably, step 2) is specifically: under the protection of nitrogen atmosphere, firstly dissolving the alpha-acyloxy alkenyl amide compound with the general formula (III) and alkali in a second solvent, then placing the mixture in a low-temperature reaction kettle at the temperature of between 50 ℃ below zero and 90 ℃ below zero (preferably between 60 ℃ below zero and 80 ℃) for cooling for 1 to 30min (preferably 5 to 15min), then slowly adding the metal organic compound with the general formula (IV) for reaction, adopting TLC tracking monitoring, adding saturated ammonium chloride solution after the reaction is completed to quench the reaction, and extracting the water phase for 1 to 3 times by using the second solvent. And (3) combining the organic phases, drying the organic phases by using anhydrous magnesium sulfate, concentrating the organic phases, and separating and purifying by column chromatography to obtain the ketone compound with the structural general formula (V).
According to a second embodiment of the present invention, there is provided a ketone compound having the general structural formula (V).
A ketone compound having the general structural formula (V) prepared by the method according to the first embodiment of the present invention:
in the formula (V), R1Selected from alkyl, cycloalkyl, alkynyl, aryl, substituted aromatic ring, heterocyclic aryl, preferably R1Selected from methyl, butyl, isobutyl, cyclohexyl, adamantyl, n-octyl, propynyl, phenylacetylenePhenyl, substituted aryl, heterocyclic aryl. R2Selected from hydrogen, alkyl, aryl, alkynyl, alkenyl, preferably R2Selected from hydrogen, phenyl, methyl, propyl, isobutyl, ethynyl, ethenyl.
Preferably, the substituent of the substituted aryl or substituted aromatic ring group is selected from alkyl, alkoxy, halogen, phenyl, benzyl, benzyloxy and cyano, and the number of the substituent is an integer of 1 to 3. The heteroatom of the heterocyclic aryl group is O, N or S, and the number of the heteroatoms is 1 or 2.
In the present invention, the ketone compound having the general structural formula (V) according to the present invention can be prepared by a "two-pot two-step" method (i.e. the method according to the first embodiment of the present invention), or by a "one-pot two-step" method, i.e. after a carboxylic acid having the general structural formula (I) and an alkynylamide having the general structural formula (II) are reacted to obtain an α -acyloxyalkenamide compound (intermediate) having the general structural formula (III), the reaction of the alkynylamide-mediated ketone compound having the general structural formula (V) can be achieved by directly adding a base and a metal organic compound having the general structural formula (IV) without separating the intermediate, and the reaction formula is shown as follows:
in the above reaction formula, EWG, R1、R2、R3、R4The definition of (b) is the same as in the first embodiment.
Compared with the prior art, the invention has the following beneficial technical effects:
1. the invention relates to a brand new synthesis method of ketone compounds, which is prepared by taking carboxylic acid compounds as raw materials, taking alkynylamide as an activating reagent to react to obtain an intermediate, and finally reacting with a metal organic reagent; namely, the method mediates the synthesis of the ketone compound by using the alkynylamide compound for the first time, and has the advantages of mild reaction conditions, high reaction speed, high reaction efficiency and the like.
2. The reaction for synthesizing the ketone compound mediated by the alkynylamide can be carried out by a one-pot two-step method, the operation is simple, no other side reaction exists, the application range of the substrate is wide, and the high-efficiency synthesis of the aromatic ketone compound, the aliphatic ketone compound and the alpha-amino ketone compound can be realized.
Drawings
FIG. 1 is a schematic diagram of the synthesis of ketone compounds having the general structural formula (V) according to the present invention.
FIG. 2 is a schematic diagram of the synthesis of ketones having the general structural formula (V) by an alkynylamide-mediated "one-pot two-step" process.
Figure 3 is an HPLC profile of a racemic mixture of compound 10a (L: D ═ 1: 1).
FIG. 4 is an HPLC chromatogram of Compound 10 a.
Figure 5 is an HPLC profile of a racemic mixture of compound 11a (L: D ═ 1: 1).
FIG. 6 is an HPLC chromatogram of Compound 11 a.
Fig. 7 is an HPLC profile of a racemic mixture of compound 12a (L: D ═ 1: 1).
FIG. 8 is an HPLC chromatogram of Compound 12 a.
Detailed Description
The technical solution of the present invention is illustrated below, and the claimed scope of the present invention includes, but is not limited to, the following examples.
Example 1
Synthesis of Compound 4-methylbenzophenone (1a)
Dissolving p-methylbenzoic acid (0.1mmol) and N-methyl-N-ethynyl p-toluenesulfonamide (MYTSA, 0.1mmol) in dichloromethane (DCM,2.0mL) at room temperature, stirring at room temperature, and distilling under reduced pressure after the reaction is completed to obtain a crude product of the alpha-acyloxyenamide. The crude product was dissolved with sodium hydride (0.3mmol) in ultra dry DCM (2.0mL) under nitrogen. It was cooled in a low-temperature reaction vessel at-78 ℃ for ten minutes, and phenylmagnesium bromide (0.3mmol) was slowly added. Follow-up by TLC, add saturated ammonium chloride solution to quench the reaction after the reaction is complete, extract the aqueous phase twice with DCM, combine the organic phases and dry over anhydrous magnesium sulfate. Concentrating the organic phase, and separating and purifying by column chromatography to obtain the target product 1a, white solid with the yield of 96%. The following are the nmr experimental data for the product:
1H NMR(400MHz,CDCl3)δ7.86–7.75(m,2H),7.72(d,J＝8.2Hz,2H),7.57(t,J＝7.4Hz,1H),7.47(t,J＝7.6Hz,2H),7.28(d,J＝7.9Hz,2H),2.44(s,3H)；
13C NMR(100MHz,CDCl3)δ196.50,143.23,137.97,134.90,132.15,130.31,129.93,128.98,128.21,21.67.
example 2
Synthesis of Compound 4-methyl-2-phenylethanone (2a)
At room temperature, p-methylbenzoic acid (0.1mmol) and N-methyl-N-ethynyl p-toluenesulfonamide (MYTSA, 0.1mmol) are dissolved in DCM (2.0mL) solvent, stirred at room temperature, and after the reaction is completed, reduced pressure distillation is carried out to obtain the crude product of alpha-acyloxy alkene amide. The crude product was dissolved with sodium hydride (0.3mmol) in ultra dry DCM (2.0mL) under nitrogen. It was cooled in a low-temperature reaction vessel at-78 ℃ for ten minutes, and benzylmagnesium bromide (0.3mmol) was slowly added. Follow-up by TLC, add saturated ammonium chloride solution to quench the reaction after the reaction is complete, extract the aqueous phase twice with DCM, combine the organic phases and dry over anhydrous magnesium sulfate. Concentrating the organic phase, and performing column chromatography separation and purification to obtain the target product 2a, namely a white solid with the yield of 63%. The following are the nmr experimental data for the product:
1H NMR(400MHz,CDCl3)δ8.02(dd,J＝8.2,1.3Hz,2H),7.49(d,J＝6.2Hz,2H),7.43(t,J＝6.5Hz,2H),7.40–7.36(m,1H),7.27(d,J＝6.5Hz,2H),5.40(s,2H),2.44(s,3H)；
13C NMR(100MHz,CDCl3)δ166.53,143.74,136.24,129.77,129.12,128.60,128.20,128.14,127.44,66.53,21.69.
example 3
Synthesis of Compound 4-methylacetophenone (3a)
P-methylbenzoic acid (0.1mmol) and N-methyl-N-ethynyl p-toluenesulfonamide (MYTSA, 0.1mmol) are dissolved in DCM (2.0mL) at room temperature, stirred at room temperature, and subjected to vacuum distillation after complete reaction to obtain a crude product of alpha-acyloxy enamide. The crude product was dissolved with sodium hydride (0.3mmol) in ultra dry DCM (2.0mL) under nitrogen. It was cooled in a low-temperature reaction vessel at-78 ℃ for ten minutes, and methylmagnesium bromide (0.3mmol) was slowly added thereto. Follow-up by TLC, quench the reaction by adding saturated ammonium chloride solution after the reaction is complete, extract the aqueous phase twice with DCM, combine the organic phases and dry over anhydrous magnesium sulfate. Concentrating the organic phase, and performing column chromatography separation and purification to obtain the target product 3a, namely a white solid with the yield of 67%. The following are the nmr experimental data for the product:
1H NMR(400MHz,CDCl3)δ7.86(d,J＝7.6Hz,2H),7.26(d,J＝7.9Hz,2H),2.58(d,J＝1.4Hz,3H),2.41(s,3H)；
13C NMR(100MHz,CDCl3)δ197.75,143.83,134.72,129.22,128.42,26.48,21.60.
example 4
Synthesis of benzophenone compound (4a)
At room temperature, benzoic acid (0.1mmol) and N-methyl-N-ethynyl p-toluenesulfonamide (MYTSA, 0.1mmol) are dissolved in DCM (2.0mL), stirred at room temperature, and after the reaction is completed, the crude product of the alpha-acyloxy enamide is obtained by reduced pressure distillation. The crude product was dissolved with sodium hydride (0.3mmol) in ultra dry DCM (2.0mL) under nitrogen. It was cooled in a low-temperature reaction vessel at-78 ℃ for ten minutes, and phenylmagnesium bromide (0.3mmol) was slowly added. Follow-up by TLC, add saturated ammonium chloride solution to quench the reaction after the reaction is complete, extract the aqueous phase twice with DCM, combine the organic phases and dry over anhydrous magnesium sulfate. Concentrating the organic phase, and performing column chromatography separation and purification to obtain the target product 4a, namely a white solid with the yield of 75%. The following are the nmr experimental data for the product:
1H NMR(400MHz,CDCl3)δ7.86–7.80(m,4H),7.60(d,J＝7.4Hz,2H),7.50(t,J＝7.6Hz,4H)；
13C NMR(100MHz,CDCl3)δ196.74,137.61,132.43,130.06,128.29.
example 5
Synthesis of Compound 4-trifluoromethylbenzophenone (5a)
At room temperature, p-trifluoromethylbenzoic acid (0.1mmol) and N-methyl-N-ethynyl p-toluenesulfonamide (MYTSA, 0.1mmol) are dissolved in DCM (2.0mL), stirred at room temperature, and after the reaction is completed, reduced pressure distillation is carried out to obtain a crude product of alpha-acyloxy alkene amide. The crude product was dissolved with sodium hydride (0.3mmol) in ultra dry DCM (2.0mL) under nitrogen. It was cooled in a low-temperature reaction vessel at-78 ℃ for ten minutes, and phenylmagnesium bromide (0.3mmol) was slowly added. Follow-up by TLC, quench the reaction by adding saturated ammonium chloride solution after the reaction is complete, extract the aqueous phase twice with DCM, combine the organic phases and dry over anhydrous magnesium sulfate. Concentrating the organic phase, and separating and purifying by column chromatography to obtain the target product 5a as a white solid with the yield of 90%. The following are the nmr experimental data for the product:
1H NMR(400MHz,CDCl3)δ7.92(d,J＝8.1Hz,2H),7.83(d,J＝6.9Hz,2H),7.78(d,J＝8.1Hz,2H),7.68–7.63(m,1H),7.53(t,J＝7.8Hz,2H)；
13C NMR(100MHz,CDCl3)δ195.53,140.73,136.73,133.72(q,J＝32.7Hz),133.09,130.14,130.10,128.53,125.36(q,J＝26.0Hz),123.68(q,J＝272.5Hz).
example 6
Synthesis of Compound 2-benzoylthiophene (6a)
Dissolving 2-thiophenecarboxylic acid (0.1mmol) and N-methyl-N-ethynyl p-toluenesulfonamide (MYTSA, 0.1mmol) in DCM (2.0mL) at room temperature, stirring at room temperature, and distilling under reduced pressure after the reaction is completed to obtain a crude product of alpha-acyloxyenamide. The crude product was dissolved with sodium hydride (0.3mmol) in ultra dry DCM (2.0mL) under nitrogen. It was cooled in a low temperature reaction kettle at-78 ℃ for ten minutes and phenylmagnesium bromide (0.3mmol) was added slowly. Follow-up by TLC, add saturated ammonium chloride solution to quench the reaction after the reaction is complete, extract the aqueous phase twice with DCM, combine the organic phases and dry over anhydrous magnesium sulfate. Concentrating the organic phase, and performing column chromatography separation and purification to obtain the target product 6a, namely a white solid with the yield of 72%. The following are the nmr experimental data for the product:
1H NMR(400MHz,CDCl3)δ7.92–7.87(m,2H),7.75(dd,J＝4.9,1.2Hz,1H),7.68(dd,J＝3.8,1.1Hz,1H),7.65–7.60(m,1H),7.53(dd,J＝8.3,7.0Hz,2H),7.19(dd,J＝5.0,3.8Hz,1H)；
13C NMR(100MHz,CDCl3)δ188.25,143.65,138.16,134.85,134.21,132.27,129.18,128.42,127.95.
example 7
Synthesis of Compound phenylbutylketone (7a)
Dissolving 2-butynoic acid (0.1mmol) and N-methyl-N-ethynyl p-toluenesulfonamide (MYTSA, 0.1mmol) in DCM (2.0mL) at room temperature, stirring at room temperature, and distilling under reduced pressure after the reaction is completed to obtain a crude product of the alpha-acyloxyenamide. The crude product was dissolved with sodium hydride (0.3mmol) in ultra dry DCM (2.0mL) under nitrogen. It was cooled in a low-temperature reaction vessel at-78 ℃ for ten minutes, and phenylmagnesium bromide (0.3mmol) was slowly added. Follow-up by TLC, add saturated ammonium chloride solution to quench the reaction after the reaction is complete, extract the aqueous phase twice with DCM, combine the organic phases and dry over anhydrous magnesium sulfate. Concentrating the organic phase, and separating and purifying by column chromatography to obtain the target product 7a which is colorless oily liquid with the yield of 79 percent. The following are the nmr experimental data for the product:
1H NMR(400MHz,CDCl3)δ8.14(d,J＝7.0Hz,2H),7.62–7.57(m,1H),7.51–7.43(m,2H),2.15(s,3H)；
13C NMR(100MHz,CDCl3)δ178.20,136.79,133.94,129.55,128.49,92.55,78.99,4.31.
example 8
Synthesis of Compound Cyclohexylphenyl methanone (8a)
At room temperature, cyclohexane carboxylic acid (0.1mmol) and N-methyl-N-ethynyl p-toluenesulfonamide (MYTSA, 0.1mmol) are dissolved in DCM (2.0mL), stirred at room temperature, and after the reaction is completed, the crude product of the alpha-acyloxy alkene amide is obtained by reduced pressure distillation. The crude product was dissolved with sodium hydride (0.3mmol) in ultra dry DCM (2.0mL) under nitrogen. It was cooled in a low-temperature reaction vessel at-78 ℃ for ten minutes, and phenylmagnesium bromide (0.3mmol) was slowly added. Follow-up by TLC, add saturated ammonium chloride solution to quench the reaction after the reaction is complete, extract the aqueous phase twice with DCM, combine the organic phases and dry over anhydrous magnesium sulfate. Concentrating the organic phase, and performing column chromatography separation and purification to obtain the target product 8a, namely a white solid with the yield of 87%. The following are the nmr experimental data for the product:
1H NMR(400MHz,CDCl3)δ7.97–7.92(d,2H),7.57–7.52(m,1H),7.46(dd,J＝8.2,6.7Hz,2H),3.26(t,1H),1.88(m,J＝21.7,11.8,5.3,2.8Hz,4H),1.58–1.20(m,6H)；
13C NMR(100MHz,CDCl3)δ203.86,136.39,132.70,128.57,128.25,45.65,29.43,25.98,25.87.
example 9
Synthesis of Compound Cyclohexylethyl ketone (9a)
At room temperature, cyclohexane carboxylic acid (0.1mmol) and N-methyl-N-ethynyl p-toluenesulfonamide (MYTSA, 0.1mmol) are dissolved in DCM (2.0mL), stirred at room temperature, and after the reaction is completed, the crude product of the alpha-acyloxy alkene amide is obtained by reduced pressure distillation. The crude product was dissolved with sodium hydride (0.3mmol) in ultra dry DCM (2.0mL) under nitrogen. It was cooled in a low temperature reaction kettle at-78 ℃ for ten minutes and phenylmagnesium bromide (0.3mmol) was added slowly. Follow-up by TLC, add saturated ammonium chloride solution to quench the reaction after the reaction is complete, extract the aqueous phase twice with DCM, combine the organic phases and dry over anhydrous magnesium sulfate. Concentrating the organic phase, and separating and purifying by column chromatography to obtain the target product 9a which is colorless oily liquid with the yield of 83 percent. The following are the nmr experimental data for the product:
1H NMR(400MHz,CDCl3)δ2.46(q,J＝7.3Hz,2H),2.35(t,J＝10.4Hz,1H),1.80(dd,J＝19.5,10.8Hz,4H),1.67(d,J＝10.4Hz,4H),1.28(dt,J＝19.2,10.6Hz,2H),1.03(t,J＝7.3Hz,3H)；
13C NMR(100MHz,CDCl3)δ214.64,50.54,33.61,28.58,25.85,25.68,7.73.
example 10
Synthesis of Compound S- (1-benzoyl-1-tert-butyl) carbamic acid tert-butyl ester (10a)
And (3) dissolving Boc-tert-leucine (0.1mmol) and N-methyl-N-ethynyl-p-toluenesulfonamide (MYTSA, 0.1mmol) in DCM (2.0mL) at room temperature, stirring at room temperature, and distilling under reduced pressure after the reaction is completed to obtain a crude product of the alpha-acyloxy enamide. The crude product was dissolved with sodium hydride (0.3mmol) in ultra dry DCM (2.0mL) under nitrogen. It was cooled in a low temperature reaction kettle at-78 ℃ for ten minutes and phenylmagnesium bromide (0.3mmol) was added slowly. Follow-up by TLC, quench the reaction by adding saturated ammonium chloride solution after the reaction is complete, extract the aqueous phase twice with DCM, combine the organic phases and dry over anhydrous magnesium sulfate. Concentrating the organic phase, and carrying out column chromatography separation and purification to obtain the target product 10a which is a white solid with the yield of 78%. The following are the nmr experimental data for the product:
1HNMR(400MHz,CDCl3)δ8.01(s,2H),7.58(s,1H),7.49(d,J＝5.6Hz,2H),5.45(s,1H),1.45(s,9H),0.94(s,9H)；
13C NMR(100MHz,CDCl3)δ201.61,155.71,137.98,133.38,128.71,128.57,79.62,60.41,35.51,28.36,26.96.
example 11
Synthesis of Compound S- (1-benzoyl-1-isopropyl) carbamic acid tert-butyl ester (11a)
Boc-valine (0.1mmol) and N-methyl-N-ethynyl p-toluenesulfonamide (MYTSA, 0.1mmol) are dissolved in DCM (2.0mL) at room temperature, stirred at room temperature, and subjected to vacuum distillation after the reaction is completed to obtain an alpha-acyloxy enamide crude product. The crude product was dissolved with sodium hydride (0.3mmol) in ultra dry DCM (2.0mL) under nitrogen. It was cooled in a low-temperature reaction vessel at-78 ℃ for ten minutes, and phenylmagnesium bromide (0.3mmol) was slowly added. Follow-up by TLC, add saturated ammonium chloride solution to quench the reaction after the reaction is complete, extract the aqueous phase twice with DCM, combine the organic phases and dry over anhydrous magnesium sulfate. Concentrating the organic phase, and carrying out column chromatography separation and purification to obtain the target product 11a, namely a white solid with the yield of 78%. The following are the nmr experimental data for the product:
1H NMR(400MHz,CDCl3)δ7.97(d,J＝7.5Hz,2H),7.59(t,J＝7.4Hz,1H),7.49(t,J＝7.7Hz,2H),5.50–5.34(m,1H),5.31–5.15(m,1H),1.45(s,9H),1.04(d,J＝6.8Hz,3H),0.76(d,J＝6.8Hz,3H)；
13C NMR(100MHz,CDCl3)δ199.87,133.57,128.81,128.58,59.59,31.63,28.35,20.03,16.43.
example 12
Synthesis of Compound S- (1-acryloyl-1-tert-butyl) carbamic acid tert-butyl ester (12a)
And (3) dissolving Boc-tert-leucine (0.1mmol) and N-methyl-N-ethynyl-p-toluenesulfonamide (MYTSA, 0.1mmol) in DCM (2.0mL) at room temperature, stirring at room temperature, and distilling under reduced pressure after the reaction is completed to obtain a crude product of the alpha-acyloxy enamide. The crude product was dissolved with sodium hydride (0.3mmol) in ultra dry DCM (2.0mL) under nitrogen. It was cooled in a low-temperature reaction vessel at-78 ℃ for ten minutes, and isopropyl magnesium bromide (0.3mmol) was slowly added thereto. Follow-up by TLC, add saturated ammonium chloride solution to quench the reaction after the reaction is complete, extract the aqueous phase twice with DCM, combine the organic phases and dry over anhydrous magnesium sulfate. Concentrating the organic phase, and separating and purifying by column chromatography to obtain the target product 12a, which is a white solid with the yield of 70%. The following are the nmr experimental data for the product:
1H NMR(400MHz,CDCl3)δ5.97(s,1H),5.80(s,1H),4.16(d,J＝13.7Hz,1H),1.87(s,3H),1.42(s,9H),0.94(s,9H)；
13C NMR(100MHz,CDCl3)δ197.61,155.91,144.98,79.94,79.62,35.51,28.36,26.96,17.71。
Claims (10)
1. a method for preparing alkynylamide mediated ketone compounds is characterized in that: the ketone compound with the general structural formula (V) is prepared by taking carboxylic acid with the general structural formula (I) as a raw material, taking alkynylamide with the general structural formula (II) as an activating reagent for reaction to obtain an intermediate, and then reacting the intermediate with a metal organic reagent; wherein the carboxylic acid with the general structural formula (I), the alkynylamide with the general structural formula (II) and the ketone compound with the general structural formula (V) are shown as follows:
in the formula (I), formula (II) and formula (V), R1Selected from the group consisting of alkyl, cycloalkyl, substituted aromatic ring, heterocyclic aryl, alpha-amino acid residue; r2Selected from hydrogen, alkyl, aryl, alkynyl, alkenyl; r3Selected from alkyl, aryl and substituted aromatic ring.
2. The method of claim 1, wherein: the method specifically comprises the following steps:
1) firstly, carboxylic acid with a general structural formula (I) and alkynylamide with a general structural formula (II) are reacted in a first solvent to obtain an alpha-acyloxy alkenyl amide compound with a general structural formula (III):
2) reacting an alpha-acyloxyenamide compound having the general structural formula (III) with a metal organic compound having the general structural formula (IV) in a second solvent in the presence of a base to obtain a ketone compound having the general structural formula (V):
in the formula (I) -formula (V), R1And R4Each independently selected from alkyl, cycloalkyl, alkynyl, aryl, substituted aromatic ring, heterocyclic aryl; r is2Selected from hydrogen, alkyl, aryl, alkynyl, alkenyl; r3Selected from alkyl, aryl, substituted aromatic ring radical; m is a metal(ii) a EWG (Electron withdrawing group) is selected from the group consisting of alkylsulfonyl, alkanoyl, arylsulfonyl, aroyl, nitrile, nitro.
3. The method of claim 2, wherein: r1Selected from methyl, butyl, isobutyl, cyclohexyl, adamantyl, n-octyl, propynyl, phenylethynyl, phenyl, substituted aryl, heterocyclic aryl; and/or
R2Selected from hydrogen, phenyl, methyl, propyl, isobutyl, ethynyl, ethenyl; and/or
R3Selected from methyl, ethyl, phenyl, heterocyclic aryl, halogenated aromatic ring radical; and/or
R4Selected from methyl, ethyl, benzyl, naphthyl, aryl and substituted aryl; and/or
M is selected from magnesium, lithium and zinc; and/or
EWG (Electron withdrawing group) is selected from methylsulfonyl, ethylsulfonyl, phenylsulfonyl, substituted phenylsulfonyl, nitrile, nitro.
4. The method of claim 3, wherein: the substituent of the substituted benzenesulfonyl is selected from methyl, tert-butyl, methoxy, phenyl, F, Cl, Br, I, benzyloxy, benzyloxycarbonyl and cyano, and the number of the substituents is 1 or 2; and/or
The substituent of the substituted aryl is selected from alkyl, alkoxy, halogen, phenyl, benzyl, benzyloxy and cyano, and the number of the substituents is an integer of 1-3.
5. The method according to any one of claims 2-4, wherein: the heteroatom of the heterocyclic aryl is O, N or S, and the number of the heteroatoms is 1 or 2; and/or
The substituent of the substituted aromatic ring group is selected from alkyl, alkoxy, halogen, phenyl, benzyl, benzyloxy and cyano, and the number of the substituent is an integer of 1-3.
6. The method according to any one of claims 2-5, wherein: the EWG is specifically one of p-methoxybenzenesulfonyl (A), p-methylbenzenesulfonyl (B), p-fluorobenzenesulfonyl (C), p-chlorobenzenesulfonyl (D), m-iodobenzenesulfonyl (E), m-bromobenzenesulfonyl (F), p-cyanobenzenesulfonyl (G), 3, 5-dimethylbenzenesulfonyl (H), p-bromobenzenesulfonyl (I), 2-methylpropanesulfonyl (J), ethylsulfonyl (K) and methylsulfonyl (L):
7. the method according to any one of claims 2-6, wherein: in step 1), the first solvent is an organic solvent; preferably, the first solvent is selected from one or more of Dichloromethane (DCM), trichloroethane, dimethyl sulfoxide, methanol, acetonitrile, N-dimethylformamide, tetrahydrofuran, N-pentane, diethyl ether, petroleum ether; and/or
In step 2), the second solvent is an organic solvent; preferably, the second solvent is selected from one or more of Dichloromethane (DCM), trichloroethane, dimethyl sulfoxide, methanol, acetonitrile, N-dimethylformamide, tetrahydrofuran, N-pentane, diethyl ether, petroleum ether; and/or
In the step 2), the alkali is NaH, NaOH or Na2CO3、Et3N, EtONa;
preferably, the first solvent and the second solvent are the same solvent; preferably, the first solvent and the second solvent are both Dichloromethane (DCM).
8. The method according to any one of claims 2-7, wherein: in step 1), the molar ratio of the carboxylic acid having the general structural formula (I) to the acetylenic amide having the general structural formula (II) is 1: 0.5-8; preferably 1:0.8-5, more preferably 1: 1-3; and/or
In the step 2), the mole ratio of the alpha-acyloxy alkenyl amide compound with the structural general formula (III), the metal organic compound with the structural general formula (IV) and the base is 1:1-8:1-8, preferably 1:1.5-5: 1.5-5; more preferably 1:2-3.5: 2-3.5.
9. The method of claim 8, wherein: the step 1) is specifically as follows: the method comprises the steps of dissolving carboxylic acid with a structural general formula (I) and alkynylamide with a structural general formula (II) in a first solvent according to a ratio, stirring and mixing at room temperature for reaction, and carrying out reduced pressure distillation after the reaction is finished to obtain the alpha-acyloxy alkenyl amide compound with a structural general formula (III).
10. The method of claim 8, wherein: the step 2) is specifically as follows: under the protection of nitrogen atmosphere, firstly dissolving an alpha-acyloxy alkenyl amide compound with a general formula (III) and alkali in a second solvent, then placing the mixture in a low-temperature reaction kettle with the temperature of-90 to 50 ℃ (preferably 0 to 80 ℃) for cooling for 1 to 30min (preferably 5 to 15min), then slowly adding a metal organic compound with a general formula (IV) for reaction, adopting TLC (thin layer chromatography) to track and monitor, adding saturated ammonium chloride solution after the reaction is completed to quench the reaction, and extracting the water phase of the reaction for 1 to 3 times by using the second solvent; and (3) combining the organic phases, drying the organic phases by using anhydrous magnesium sulfate, concentrating the organic phases, and separating and purifying by column chromatography to obtain the ketone compound with the structural general formula (V).
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