CN114560888A - 一种α,β-不饱和膦酰胺类化合物的制备方法 - Google Patents
一种α,β-不饱和膦酰胺类化合物的制备方法 Download PDFInfo
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- CN114560888A CN114560888A CN202210227182.0A CN202210227182A CN114560888A CN 114560888 A CN114560888 A CN 114560888A CN 202210227182 A CN202210227182 A CN 202210227182A CN 114560888 A CN114560888 A CN 114560888A
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- China
- Prior art keywords
- group
- unsaturated
- phosphonamide
- beta
- preparation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
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- -1 beta-unsaturated phosphonamide compound Chemical class 0.000 title claims abstract description 62
- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- 238000006243 chemical reaction Methods 0.000 claims abstract description 14
- 150000002466 imines Chemical class 0.000 claims abstract description 13
- 239000003513 alkali Substances 0.000 claims abstract description 4
- 150000001412 amines Chemical class 0.000 claims abstract description 4
- 238000011065 in-situ storage Methods 0.000 claims abstract description 3
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims abstract 2
- 125000005541 phosphonamide group Chemical group 0.000 claims description 17
- 125000004432 carbon atom Chemical group C* 0.000 claims description 16
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 13
- 238000000034 method Methods 0.000 claims description 12
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-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
- 125000003118 aryl group Chemical group 0.000 claims description 6
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 6
- 238000010438 heat treatment Methods 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 239000000203 mixture Substances 0.000 claims description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 5
- 125000001424 substituent group Chemical group 0.000 claims description 5
- FYGHSUNMUKGBRK-UHFFFAOYSA-N 1,2,3-trimethylbenzene Chemical compound CC1=CC=CC(C)=C1C FYGHSUNMUKGBRK-UHFFFAOYSA-N 0.000 claims description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 125000003342 alkenyl group Chemical group 0.000 claims description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 4
- RWGFKTVRMDUZSP-UHFFFAOYSA-N cumene Chemical compound CC(C)C1=CC=CC=C1 RWGFKTVRMDUZSP-UHFFFAOYSA-N 0.000 claims description 4
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 4
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 claims description 4
- UPRXAOPZPSAYHF-UHFFFAOYSA-N lithium;cyclohexyl(propan-2-yl)azanide Chemical compound CC(C)N([Li])C1CCCCC1 UPRXAOPZPSAYHF-UHFFFAOYSA-N 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
- 239000001301 oxygen Substances 0.000 claims description 4
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 claims description 4
- ZMJJCODMIXQWCQ-UHFFFAOYSA-N potassium;di(propan-2-yl)azanide Chemical compound [K+].CC(C)[N-]C(C)C ZMJJCODMIXQWCQ-UHFFFAOYSA-N 0.000 claims description 4
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 claims description 4
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 4
- YHOBGCSGTGDMLF-UHFFFAOYSA-N sodium;di(propan-2-yl)azanide Chemical compound [Na+].CC(C)[N-]C(C)C YHOBGCSGTGDMLF-UHFFFAOYSA-N 0.000 claims description 4
- 239000002585 base Substances 0.000 claims description 3
- RELMFMZEBKVZJC-UHFFFAOYSA-N 1,2,3-trichlorobenzene Chemical compound ClC1=CC=CC(Cl)=C1Cl RELMFMZEBKVZJC-UHFFFAOYSA-N 0.000 claims description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- OCJBOOLMMGQPQU-UHFFFAOYSA-N 1,4-dichlorobenzene Chemical compound ClC1=CC=C(Cl)C=C1 OCJBOOLMMGQPQU-UHFFFAOYSA-N 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 2
- CYTYCFOTNPOANT-UHFFFAOYSA-N Perchloroethylene Chemical group ClC(Cl)=C(Cl)Cl CYTYCFOTNPOANT-UHFFFAOYSA-N 0.000 claims description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 2
- 125000005018 aryl alkenyl group Chemical group 0.000 claims description 2
- RBHJBMIOOPYDBQ-UHFFFAOYSA-N carbon dioxide;propan-2-one Chemical compound O=C=O.CC(C)=O RBHJBMIOOPYDBQ-UHFFFAOYSA-N 0.000 claims description 2
- 229940117389 dichlorobenzene Drugs 0.000 claims description 2
- 238000005485 electric heating Methods 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 239000005457 ice water Substances 0.000 claims description 2
- 229910000103 lithium hydride Inorganic materials 0.000 claims description 2
- LZWQNOHZMQIFBX-UHFFFAOYSA-N lithium;2-methylpropan-2-olate Chemical compound [Li+].CC(C)(C)[O-] LZWQNOHZMQIFBX-UHFFFAOYSA-N 0.000 claims description 2
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 claims description 2
- 229910000105 potassium hydride Inorganic materials 0.000 claims description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 2
- WTUKAJUKZAMQFE-UHFFFAOYSA-N potassium;cyclohexyl(propan-2-yl)azanide Chemical compound [K+].CC(C)[N-]C1CCCCC1 WTUKAJUKZAMQFE-UHFFFAOYSA-N 0.000 claims description 2
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 2
- 239000012312 sodium hydride Substances 0.000 claims description 2
- KWUYGGSQGOQHKD-UHFFFAOYSA-N sodium;cyclohexyl(propan-2-yl)azanide Chemical compound [Na+].CC(C)[N-]C1CCCCC1 KWUYGGSQGOQHKD-UHFFFAOYSA-N 0.000 claims description 2
- 229950011008 tetrachloroethylene Drugs 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- OJWYYSVOSNWCCE-UHFFFAOYSA-N 2-methoxyethyl hypofluorite Chemical compound COCCOF OJWYYSVOSNWCCE-UHFFFAOYSA-N 0.000 claims 1
- 125000001246 bromo group Chemical group Br* 0.000 claims 1
- 125000001309 chloro group Chemical group Cl* 0.000 claims 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims 1
- 125000001153 fluoro group Chemical group F* 0.000 claims 1
- SIAPCJWMELPYOE-UHFFFAOYSA-N lithium hydride Chemical compound [LiH] SIAPCJWMELPYOE-UHFFFAOYSA-N 0.000 claims 1
- HAUKUGBTJXWQMF-UHFFFAOYSA-N lithium;propan-2-olate Chemical compound [Li+].CC(C)[O-] HAUKUGBTJXWQMF-UHFFFAOYSA-N 0.000 claims 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims 1
- 239000012299 nitrogen atmosphere Substances 0.000 claims 1
- WQKGAJDYBZOFSR-UHFFFAOYSA-N potassium;propan-2-olate Chemical compound [K+].CC(C)[O-] WQKGAJDYBZOFSR-UHFFFAOYSA-N 0.000 claims 1
- WBQTXTBONIWRGK-UHFFFAOYSA-N sodium;propan-2-olate Chemical compound [Na+].CC(C)[O-] WBQTXTBONIWRGK-UHFFFAOYSA-N 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 11
- 239000003814 drug Substances 0.000 abstract description 8
- 150000001875 compounds Chemical class 0.000 abstract description 7
- 239000000575 pesticide Substances 0.000 abstract description 7
- 239000000543 intermediate Substances 0.000 abstract description 5
- 239000011368 organic material Substances 0.000 abstract description 5
- 229940079593 drug Drugs 0.000 abstract description 4
- 230000002194 synthesizing effect Effects 0.000 abstract description 3
- NJLHHACGWKAWKL-UHFFFAOYSA-N ClP(Cl)=O Chemical compound ClP(Cl)=O NJLHHACGWKAWKL-UHFFFAOYSA-N 0.000 abstract description 2
- 239000003112 inhibitor Substances 0.000 abstract description 2
- 239000000463 material Substances 0.000 abstract description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 54
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 9
- 238000005160 1H NMR spectroscopy Methods 0.000 description 9
- 238000004679 31P NMR spectroscopy Methods 0.000 description 9
- HDVQVZVDVQOEJU-UHFFFAOYSA-N C1(=CC=CC=C1)C=CP(OCC)=O Chemical compound C1(=CC=CC=C1)C=CP(OCC)=O HDVQVZVDVQOEJU-UHFFFAOYSA-N 0.000 description 7
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 5
- UZVGSSNIUNSOFA-UHFFFAOYSA-N dibenzofuran-1-carboxylic acid Chemical compound O1C2=CC=CC=C2C2=C1C=CC=C2C(=O)O UZVGSSNIUNSOFA-UHFFFAOYSA-N 0.000 description 5
- 239000003921 oil Substances 0.000 description 5
- 239000012230 colorless oil Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- ZGEGCLOFRBLKSE-UHFFFAOYSA-N 1-Heptene Chemical group CCCCCC=C ZGEGCLOFRBLKSE-UHFFFAOYSA-N 0.000 description 3
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 3
- 239000011737 fluorine Substances 0.000 description 3
- 229910052731 fluorine Inorganic materials 0.000 description 3
- ATYBXHSAIOKLMG-UHFFFAOYSA-N oxepin Chemical compound O1C=CC=CC=C1 ATYBXHSAIOKLMG-UHFFFAOYSA-N 0.000 description 3
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- JJLCHGHEDNCYSU-UHFFFAOYSA-N C1(=CC=CC=C1)CCC=CP(OCC)=O Chemical compound C1(=CC=CC=C1)CCC=CP(OCC)=O JJLCHGHEDNCYSU-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- YNQLUTRBYVCPMQ-UHFFFAOYSA-N Ethylbenzene Chemical compound CCC1=CC=CC=C1 YNQLUTRBYVCPMQ-UHFFFAOYSA-N 0.000 description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 239000002532 enzyme inhibitor Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- ODLMAHJVESYWTB-UHFFFAOYSA-N propylbenzene Chemical compound CCCC1=CC=CC=C1 ODLMAHJVESYWTB-UHFFFAOYSA-N 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 125000005504 styryl group Chemical group 0.000 description 2
- NYERMPLPURRVGM-UHFFFAOYSA-N thiazepine Chemical compound S1C=CC=CC=N1 NYERMPLPURRVGM-UHFFFAOYSA-N 0.000 description 2
- KJPRLNWUNMBNBZ-QPJJXVBHSA-N (E)-cinnamaldehyde Chemical compound O=C\C=C\C1=CC=CC=C1 KJPRLNWUNMBNBZ-QPJJXVBHSA-N 0.000 description 1
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 1
- UFBMNJNYTSWUFV-UHFFFAOYSA-N 2-[chloro(ethoxy)phosphoryl]oxyethylbenzene Chemical compound CCOP(Cl)(=O)OCCC1=CC=CC=C1 UFBMNJNYTSWUFV-UHFFFAOYSA-N 0.000 description 1
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 description 1
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 description 1
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 description 1
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 description 1
- KRZCOLNOCZKSDF-UHFFFAOYSA-N 4-fluoroaniline Chemical compound NC1=CC=C(F)C=C1 KRZCOLNOCZKSDF-UHFFFAOYSA-N 0.000 description 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 1
- 125000006181 4-methyl benzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])C([H])([H])* 0.000 description 1
- 229930091051 Arenine Natural products 0.000 description 1
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- 208000005176 Hepatitis C Diseases 0.000 description 1
- 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 1
- RFFFKMOABOFIDF-UHFFFAOYSA-N Pentanenitrile Chemical compound CCCCC#N RFFFKMOABOFIDF-UHFFFAOYSA-N 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 101800001554 RNA-directed RNA polymerase Proteins 0.000 description 1
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- 150000001299 aldehydes Chemical class 0.000 description 1
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- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- KJPRLNWUNMBNBZ-UHFFFAOYSA-N cinnamic aldehyde Natural products O=CC=CC1=CC=CC=C1 KJPRLNWUNMBNBZ-UHFFFAOYSA-N 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 229940125532 enzyme inhibitor Drugs 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L magnesium sulphate Substances [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 125000006431 methyl cyclopropyl group Chemical group 0.000 description 1
- HHVIBTZHLRERCL-UHFFFAOYSA-N methylsulphonylmethane Natural products CS(C)(=O)=O HHVIBTZHLRERCL-UHFFFAOYSA-N 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 239000012434 nucleophilic reagent Substances 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 150000003833 nucleoside derivatives Chemical class 0.000 description 1
- 125000001209 o-nitrophenyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])[N+]([O-])=O 0.000 description 1
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- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 150000008039 phosphoramides Chemical class 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- NAQDBCITRPZPBZ-UHFFFAOYSA-N potassium;bis(trimethylsilyl)azanide;toluene Chemical compound [K+].CC1=CC=CC=C1.C[Si](C)(C)[N-][Si](C)(C)C NAQDBCITRPZPBZ-UHFFFAOYSA-N 0.000 description 1
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
Classifications
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids RP(=O)(OH)2; Thiophosphonic acids, i.e. RP(=X)(XH)2 (X = S, Se)
- C07F9/44—Amides thereof
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids RP(=O)(OH)2; Thiophosphonic acids, i.e. RP(=X)(XH)2 (X = S, Se)
- C07F9/44—Amides thereof
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- C07F9/4415—Amides of cycloaliphatic acids
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- C07F9/02—Phosphorus compounds
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- C07F9/44—Amides thereof
- C07F9/4461—Amides thereof the amide moiety containing a substituent or a structure which is considered as characteristic
- C07F9/4476—Amides thereof the amide moiety containing a substituent or a structure which is considered as characteristic of aromatic amines (N-C aromatic linkage)
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids RP(=O)(OH)2; Thiophosphonic acids, i.e. RP(=X)(XH)2 (X = S, Se)
- C07F9/44—Amides thereof
- C07F9/4461—Amides thereof the amide moiety containing a substituent or a structure which is considered as characteristic
- C07F9/448—Amides thereof the amide moiety containing a substituent or a structure which is considered as characteristic of aralkylamines
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6527—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having nitrogen and oxygen atoms as the only ring hetero atoms
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6536—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having nitrogen and sulfur atoms with or without oxygen atoms, as the only ring hetero atoms
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- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
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Abstract
本发明提供了一种α,β‑不饱和膦酰胺类化合物的制备方法。膦酰氯类化合物与亚胺类化合物反应,在碱存在下反应得到反式构型的α,β‑不饱和膦酰胺类化合物。亚胺可以通过醛和胺原位反应制备,该制备方法原料简单易得,操作方便。所得到的化合物可应用于重要的有机材料和抑制剂类药物以及农药,还可以用于有机材料和药物合成中间体,用于多种材料和药物制备。
Description
技术领域
本发明属于有机合成技术领域,具体涉及α,β-不饱和膦酰胺类化合物的制备方法。
背景技术
α,β-不饱和膦酰胺类化合物是α,β-不饱和酰胺类化合物的重要含磷类似物,可以作为抗病毒药物(中国发明专利申请说明书11021816.0)和酶抑制剂,如丙型肝炎NS5B毒株的非核苷类抑制剂(C.P.Rouviere,A.Amador,E.Badaroux,T.Convard,D.Da Costa,D.Dukhan,L.Griffe,J.-F.Griffon,M.La Colla,F.Leroy,M.Liuzzi,A.Giulia Loi,J.McCarville,V.Mascia,J.Milhau,L.Onidi,J.-L.Paparin,R.Rahali,E.Sais,M.Seifer,D.Surleraux,D.Standring,C.Dousson,Bioorg.Med.Chem.Lett.2016,26,4536–4541.),还可以用做荧光探针(A.Simeonov,A.Jadhav,C.J.Thomas,Y.Wang,R.Huang,N.T.Southall,P.Shinn,J.Smith,C.P.Austin,D.S.Auld,J.Inglese,J.Med.Chem.2008,51,2363–2371.)。此外,α,β-不饱和膦酰胺类化合物还是重要的有机合成中间体,在药物化学、农药和合成化学领域都有广泛应用。
由于α,β-不饱和膦酰胺类化合物具有重要的药用价值和在有机合成中广泛应用,人们为其开发了几种制备方法。通过α,β-不饱和膦酰氯与胺反应来制备α,β-不饱和膦酰胺(A.M.G.S.D.Fazylov,A.B.Karimova,S.Z.Kudaibergenova,Russ.J.Gen.Chem.2000,74,1133–1134),通过烯丙基膦酰胺的加热重排制备α,β-不饱和膦酰胺(R.Zhu,C.Q.Pan,Z.H.Gu,Org.Lett.2015,17,5862–5865.D.A.Evans,J.M.Takacs,K.M.Hurst,J.Am.Chem.Soc.1979,101,371–378),通过P-氨基-1,2-氧磷杂环丁烯衍生物的加热电开环来制备α,β-不饱和膦酰胺(O.Illa,H.Gornitzka,V.Branchadell,Eur.J.Org.Chem.2003,2003,3147–3152.O.I.Kolodyazhnii A.O.Kolodyazhnaya,Russ.J.Gen.Chem.2015,85,359–365),以及亲核试剂对乙炔基膦酰胺的亲核加成来合成α,β-不饱和膦酰胺(M.A.Kasper,M.Glanz,A.Stengl,M.Penkert,S.Klenk,T.Sauer,D.Schumacher,J.Helma,E.M.Krause,C.Cardoso,H.Leonhardt,C.P.R.Hackenbergerl,Angew.Chem.Int.Ed.2019,58,11625–11630)。这些制备方法往往底物适用范围有限或者立体选择性差,难以合成结构多样性的和高立体选择性的α,β-不饱和膦酰胺类化合物。
本发明通过膦酰氯类化合物和亚胺类化合物在碱存在下反应得到α,β-不饱和膦酰胺类化合物。反应原料简单易得,过程容易操作。所得到的化合物可应用于重要的有机合成中间体、有机材料、药物以及农药等多个领域。
发明内容
本发明的目的是提供一种α,β-不饱和膦酰胺类化合物的制备方法。该类化合物可作为重要的有机材料、药物以及农药,还可用作有机材料、药物及农药合成的中间体,用于多种材料、药物和农药的制备。本发明化合物的制备方法采用膦酰氯类化合物和亚胺为原料,原料简单易得,且不需要繁琐的操作,是一种适合于大量制备的简便方法。
本发明的技术方案如下:
α,β-不饱和膦酰胺类化合物(式1),其是通过膦酰氯类化合物(式2)与亚胺类化合物(式3)在碱存在下发生反应得到的。
上述反应式中:
R2、R3、R4、R6和R7可以为氢;R1、R2、R3、R4、R5、R6和R7表示具有1~6个碳原子的烷基、具有3~6个碳原子的环烷基、具有6~12个碳原子的芳基,R4和R6还表示具有2~6个碳原子的烯基、具有8~12个碳原子的芳基烯基,芳基可以含有烷基、氟、氯、溴、氰基、硝基、二甲氨基作为取代基;R1、R2、R3、R4、R5、R6和R7可以相同,也可以不同;R3和R4可以成环,形成环烷基;R5和R7可以成环,形成的环可以含有氧或者硫杂原子,形成的环还可以有1~2个并合的苯环,并合的苯环上还可以带有甲基、乙基、氟、氯、溴、氰基、硝基作为取代基。
其中所述的烷基是指具有1~6个碳原子的直链或支链烷基,例如:甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、仲丁基、戊基、异戊基、仲戊基、新戊基、己基、异己基,特别优选具有1~3个碳原子的直链或支链烷基,最优选为甲基和乙基。
所述的环烷基是指具有3~6个碳原子的环烷基,例如:环丙基、环丁基、环戊基、环己基、甲基环丙基、甲基环戊基、二甲基环丙基。
所述的芳基是指具有6~12个碳原子的芳基。优选为苯基、邻甲基苯基、间甲基苯基、对甲基苯基、邻乙基苯基、间乙基苯基、对乙基苯基、2,3-二甲基苯基、2,4-二甲基苯基、2,5-二甲基苯基、2,6-二甲基苯基、3,4-二甲基苯基、3,5-二甲基苯基、邻甲氧基苯基、间甲氧基苯基、对甲氧基苯基、邻乙氧基苯基、间乙氧基苯基、对乙氧基苯基、2,3-亚甲氧基苯基、3,4-亚甲氧基苯基、邻氟苯基、间氟苯基、对氟苯基、邻氯苯基、间氯苯基、对氯苯基、邻硝基苯基、间硝基苯基、对硝基苯基、邻氰基苯基、间氰基苯基、对氰基苯基、萘-1-基、萘-2-基、联苯基等。
所述的烯基是指具有2~6个碳原子的直链或支链烯基,例如:乙烯基、烯丙基、(E)和(Z)-丙-1-烯基、(E)和(Z)-丁-1-烯基、2-甲基丙-1-烯基、(E)和(Z)-3-甲基-丁-1-烯基、(E)和(Z)-戊-1-烯基、(E)和(Z)-戊-2-烯基、(E)和(Z)-戊-3-烯基、(E)和(Z)-戊-4-烯基、(E)和(Z)-2-甲基戊-1-烯基、(E)和(Z)-3-甲基戊-1-烯基、(E)和(Z)-4-甲基戊-1-烯基、(E)和(Z)-己-1-烯基、(E)和(Z)-己-2-烯基、(E)和(Z)-己-3-烯基、(E)和(Z)-己-4-烯基、(E)和(Z)-己-5-烯基。
所述的芳烯基是指具有8~12个碳原子的直链或支链芳烯基,例如:苯乙烯基、(E)和(Z)-3-苯基烯丙基、(E)和(Z)-3-苯基丙-1-烯基、(E)和(Z)-4-苯基丁-1-烯基、邻间対位取代的苯乙烯基,取代基可以是烷基、氟、氯、溴、氰基、硝基、二甲氨基。
R3和R4成环时,R3,R4为亚乙基、亚丙基、亚丁基、亚戊基、亚己基和亚庚基。
R5和R7成环时,R5,R7为亚丙基、亚丁基、亚戊基、亚己基和亚庚基;含有氧或硫杂原子的亚丙基、亚丁基、亚戊基、亚己基和亚庚基;以及含有一个或两个并合苯环的含有氧或硫杂原子的亚丙基、亚丁基、亚戊基、亚己基和亚庚基。
所制备的α,β-不饱和膦酰胺类化合物,例如下述1a~1i九种化合物:
1a:R1=Et,R2=R3=R6=H,R4=Ph,R5=4-MeC6H4CH2,R7=4-MeC6H4;
1b:R1=Et,R2=R3=R6=H,R4=Ph,R5=4-FC6H4,R7=(E)-PhCH=CH;
1c:R1=Et,R2=R3=R6=H,R4=Ph,R5=CH2=CHCH2,R7=(E)-PhCH=CH;
1d:R1=Et,R2=R3=R6=H,R4=cyclohex,R5=4-ClC6H4,R7=(E)-PhCH=CH;
1e:R1=Et,R2=R3=R7=H,R4=Ph,
1f:R1=Et,R2=R3=R7=H,R4=Ph,
1g:R1=Et,R2=R3=R7=H,R4=PhCH2CH2,
1h:R1=Et,R2=R3=R7=H,R4=Ph,
1i:R1=Et,R2=R3=R7=H,R4=Ph,
上述的制备方法,通常是通过膦酰氯类化合物与亚胺类化合物在碱存在下在溶剂中反应得到反式构型α,β-不饱和膦酰胺类化合物。
上述的制备方法,所述膦酰氯类化合物和亚胺类化合物原料可直接按照文献方法制备;亚胺还可以由醛和胺原位制备。
上述的制备方法,所用的碱为双(三甲基硅烷基)氨基钾(KHMDS)、双(三甲基硅烷基)氨基钠(NaHMDS)、双(三甲基硅烷基)氨基锂(LiHMDS)、二异丙基氨基锂(LDA)、二异丙基氨基钠(SDA)、二异丙基氨基钾(PDA)、异丙基环己基氨基锂(LIHA)、异丙基环己基氨基钠(SIHA)、异丙基环己基氨基钾(PIHA)、叔丁醇钾、叔丁醇钠、叔丁醇锂、异丙醇钾、异丙醇钠、异丙醇锂、氢化钠、氢化钾、氢化锂等。
上述的制备方法,通常所用的溶剂为二甲基亚砜、环丁亚砜、二甲基砜、环丁砜、乙腈、丙腈、丁腈、戊腈、氯仿、1,2-二氯乙烷、四氯乙烯、四氢呋喃、1,4-二氧六环、乙二醇二甲醚、苯、甲苯、二甲苯、三甲苯、乙苯、丙苯、异丙苯、氯苯、二氯苯、三氯苯或它们的混和物。
上述的制备方法,所用的反应温度为-50–150℃,反应可以采用冰水浴、低温浴槽、丙酮干冰浴或者丙酮加液氮冷却,加热可以采用传统的蒸汽加热、电加热、微波加热进行。
上述的制备方法,所用的反应条件为在氮气保护下,在无水溶剂中进行。
本发明的优点和积极效果:
本发明制备的α,β-不饱和膦酰胺类化合物是一类非常重要的有机中间体,在药物、农药化学和合成化学领域有着广泛用途,其本身也表现出抗病毒和酶抑制剂等多种生物活性,还可以用做荧光探针。
本发明提供的化合物及其制备方法,以简单易得的膦酰氯类化合物与亚胺类化合物为原料,其可以按已知方法来制备。该方法操作简单,合成路线短,可以用于合成含有结构多样性的反式α,β-不饱和膦酰胺类化合物,适合于大规模制备,对于此类化合物的制备及应用具有十分重要的意义。
具体实施方式
下面通过实施例的方式进一步说明本发明,并不因此将本发明限制在所述实施例的范围之中。
实施例一
N,N-双(4-甲基苯基)-P-苯乙烯基膦酰胺乙酯1a
将O-乙基-2-苯乙基膦酰氯(104.7mg,0.45mmol)和(E)-N-(4-甲基苄基)-1-(4-甲基苯基)甲亚胺(22.3mg,0.1mmol)加入干燥的反应管中,加入0.5mL甲苯,在0℃搅拌反应1分钟,加入0.5mol/L的KHMDS甲苯溶液(0.45mmol,0.9mL)。然后,将反应混合物立即在60℃搅拌反应24小时。加入饱和氯化铵水溶液淬灭反应,用二氯甲烷萃取(4mL×3),合并有机相,用饱和食盐水洗涤(5mL×3),用无水硫酸钠干燥,蒸除溶剂,残余物硅胶柱色谱分离,石油醚和乙酸乙酯(2/1到1/1,v/v)洗脱得到无色液体,13mg,31%产率.1HNMR(400MHz,CDCl3)7.37–7.33(2H,m),7.40–7.34(4H,m),7.22–7.13(2H,m),7.10(4H,d,J=8.0Hz),7.05(4H,d,J=7.9Hz),6.25(1H,dd,J=17.9,18.2Hz),4.12–4.05(1H,m),4.03(2H,s),4.01(2H,s),3.99–3.90(1H,m),2.27(6H,s),1.27(3H,t,J=7.0Hz).13CNMR(101MHz,CDCl3)146.5(d,J=5.4Hz),137.1,135.6(d,J=21.9Hz),134.6(d,J=2.5Hz),129.9,129.3,128.9,128.8,127.7,126.6,117.2(d,J=177.4Hz),60.7(d,J=5.5Hz),47.4(d,J=4.9Hz),21.3,16.6(d,J=6.9Hz).31P NMR(162MHz,CDCl3)23.24.
实施例二
N-(4-氟苯基)-N-肉桂基-P-((E)-2-苯基乙烯基)膦酰胺乙酯1b
按实施例一中描述的方法,用O-乙基-2-苯基乙基膦酰氯和(1E,2E)-N-(4-氟苯基)-3-苯基丙-2-烯-1-亚胺为原料,得到N-(4-氟苯基)-N-肉桂基-P-((E)-苯乙烯基)膦酰胺乙酯,无色油状物,28mg,67%产率.1H NMR(400MHz,CDCl3)7.50–7.38(3H,m),7.38–7.32(3H,m),7.31–7.27(4H,m),7.25–7.17(3H,m),7.00–6.95(2H,m),6.41(1H,d,J=15.9Hz),6.29(1H,dd,J=18.9,17.6Hz),6.20(1H,dt,J=15.8,6.5Hz),4.38–4.30(1H,m),4.30–4.23(1H,m),4.23–4.14(1H,m),4.14–4.04(1H,m),1.33(3H,t,J=7.0Hz).13C NMR(101MHz,CDCl3)161.8,159.4,147.4(d,J=5.7Hz),138.3,136.7,135.3(d,J=22.3Hz),133.0,129.0(d,J=2.8Hz),128.9,128.7,127.8,127.7,126.5,126.3,116.3(d,J=178.2Hz),116.1,115.9,61.0(d,J=5.6Hz),52.2(d,J=4.9Hz),16.5(d,J=6.8Hz).31P NMR(162MHz,CDCl3)20.20。
实施例三
N-烯丙基-N-肉桂基-P-((E)-苯乙烯基)膦酰胺乙酯1c
按实施例一中描述的方法,用O-乙基-2-苯基乙基膦酰氯和(1E,2E)-N-(4-烯丙基)-3-苯基丙-2-烯-1-亚胺为原料,得到N-烯丙基-N-肉桂基-P-((E)-苯乙烯基)膦酰胺乙酯,无色油状物,11mg,30%产率.1H NMR(400MHz,CDCl3)7.51–7.47(2H,m),7.44–7.28(10H,m),6.52(1H,d,J=15.8Hz),6.37(1H,dd,J=20.6,15.3Hz),6.15(dt,J=15.7,6.6Hz,1H),5.86–5.74(m,1H),4.23–4.13(1H,m),4.12–4.01(1H,m),3.88–3.84(2H,m),3.73(2H,dd,J=9.0,7.2Hz),1.39(3H,t,J=7.1Hz).13C NMR(101MHz,CDCl3)152.0(d,J=2.7Hz),146.2(d,J=5.2Hz),142.3,136.6,133.4,129.8,128.8,128.6,127.7,127.6,126.4,125.8(d,J=2.6Hz),116.8(d,J=178.5Hz),110.3,108.7,60.2(d,J=5.6Hz),47.0(d,J=4.9Hz),41.1(d,J=5.3Hz),16.4(d,J=6.9Hz).31P NMR(162MHz,CDCl3)23.01。
实施例四
N-(4-氯苯基)-N-肉桂基-P-((E)-2-环己基乙烯基)膦酰胺乙酯1d
按实施例一中描述的方法,用O-乙基-2-环己基乙基膦酰氯和(1E,2E)-N-(4-氯苯基)-3-苯基丙-2-烯-1-亚胺为原料,得到N-(4-氯苯基)-N-肉桂基-P-((E)-2-环己基乙烯基)膦酰胺乙酯,黄色油状物,22mg,49%产率.1H NMR(400MHz,CDCl3)7.22–7.21(4H,m),7.18–7.08(5H,m),6.64–6.49(1H,m),6.36(1H,d,J=15.9Hz),6.10(1H,dt,J=15.9,6.3Hz),5.56(1H,dd,J=22.7,17.2),4.26–4.21(2H,m),4.11–4.01(1H,m),4.00–3.89(1H,m),1.37–1.18(12H,m),0.81(3H,t,J=6.7Hz).13C NMR(101MHz,CDCl3)157.7(d,J=2.2Hz),141.4(d,J=4.4Hz),136.7,132.7,130.2,129.1,128.7,127.8,126.8(d,J=3.2Hz),126.5,126.3,116.1(d,J=175.3Hz),60.8(d,J=5.9Hz),51.1(d,J=4.8Hz),42.1(d,J=19.7Hz),31.6,26.8,26.5(d,J=6.4Hz).,26.0,25.7,16.4(d,J=7.1Hz).31P NMR(162MHz,CDCl3)20.44。
实施例五
(E)-二苯并[b,f][1,4]噁卓-10(11H)-基(苯乙烯基)次膦酸乙酯1e
按实施例一中描述的方法,用O-乙基-2-苯基乙基膦酰氯和二苯并[b,f][1,4]噁卓为原料,得到(E)-二苯并[b,f][1,4]噁卓-10(11H)-基(苯乙烯基)次膦酸乙酯,黄色油状物,37mg,96%产率.1H NMR(400MHz,CDCl3)7.37(1H,d,J=7.9Hz),7.32–7.30(5H,m),7.28(1H,dd,J=22.0,17.4Hz),7.22–6.96(7H,m),6.17(1H,dd,J=19.3,17.6Hz),4.78(1H,dd,J=16.3,10.6Hz),4.71(1H,dd,J=16.3,10.5Hz),4.22–4.09(1H,m),4.09–3.97(1H,m),1.27(3H,t,J=7.1Hz).13C NMR(101MHz,CDCl3):154.7,153.9(d,JP-C=4.2Hz),147.1(d,JP-C=5.8Hz),135.3(d,JP-C=22.5Hz),134.1(d,JP-C=4.4Hz),129.9,128.9,128.8,128.7(d,JP-C=1.4Hz),128.6,127.9,127.5(d,JP-C=0.6Hz),127.4,124.20(d,JP-C=0.7Hz),123.1,121.9,120.7,116.4(,d,JP-C=178.6Hz),60.9(d,JP-C=5.8Hz),51.0(d,JP-C=5.3Hz),16.3(d,JP-C=6.9Hz).31P NMR(162MHz,CDCl3)20.0。
实施例六
(E)-(3,7-二氯二苯并[b,f][1,4]噁卓-10(11H)-基)(苯乙烯基)次膦酸乙酯1f
按实施例一中描述的方法,用O-乙基-2-苯基乙基膦酰氯和3,7-二氯二苯并[b,f][1,4]噁卓为原料,得到(E)-(3,7-二氯二苯并[b,f][1,4]噁卓-10(11H)-基)(苯乙烯基)次膦酸乙酯,黄色油状物,28mg,60%产率.1H NMR(400MHz,CDCl3)7.29–7.20(6H,m),7.16(1H,d,J=3.9Hz),7.12(1H,d,J=2.2Hz),7.04(1H,d,J=1.8Hz),7.01–6.91(3H,m),6.02(1H,dd,J=18.4,16.4Hz),4.65(1H,dd,J=15.5,9.4Hz),4.55(1H,dd,J=15.3,10.1Hz),4.12–4.02(1H,m),4.00–3.90(1H,m),1.23(3H,t,J=6.8Hz).13C NMR(101MHz,CDCl3)153.7,152.3(d,J=4.3Hz),146.8(d,J=5.8Hz),134.0(d,J=22.6Hz),132.9,131.5(d,J=4.5Hz),131.4(d,J=1.3Hz),129.2,128.9,128.6,127.9,126.7,125.1,123.5,122.6,121.1,119.9,114.7(d,J=178.0Hz),60.2(d,J=5.8Hz),49.6(d,J=5.2Hz),15.4(d,J=6.9Hz).31P NMR(162MHz,CDCl3)19.76。
实施例七
(E)-二苯并[b,f][1,4]噁卓-10(11H)-基(4-苯丁-1-烯基)次膦酸乙酯1g
按实施例一中描述的方法,用O-乙基-4-苯基丁基膦酰氯和二苯并[b,f][1,4]噁卓为原料,得到(E)-二苯并[b,f][1,4]噁卓-10(11H)-基(4-苯基丁-1-烯基)次膦酸乙酯,黄色油状物,20mg,49%产率.1H NMR(400MHz,CDCl3)7.19–7.16(2H,m),,7.15–7.05(6H,m),7.04–6.90(6H,m),5.54(1H,dd,J=21.8,17.1Hz),4.62(1H,dd,J=16.1,10.1Hz),4.54(1H,dd,J=16.2,10.6Hz),4.03–3.92(1H,m),3.91–3.80(1H,m),2.52(2H,t,J=8.0Hz),2.30(2H,dd,J=14.5,7.1Hz),1.14(3H,t,J=7.0Hz).13C NMR(101MHz,CDCl3)153.5,149.8(d,J=3.9Hz),133.3(d,J=22.6Hz),127.8,127.5(d,J=1.3Hz),127.4,127.4,127.3,127.3,126.3(d,J=1.2Hz),126.2,125.1,123.0,121.9,120.7,119.4,118.5(d,J=175.2Hz),59.5(d,J=6.0Hz),49.6(d,J=5.3Hz),34.5,33.0(d,J=1.3Hz),15.1(d,J=6.9Hz).31P NMR(162MHz,CDCl3)19.05。
实施例八
(E)-(二苯并[b,f][1,4]噁卓-10(11H)-基)(苯乙烯基)次膦酸乙酯1h
按实施例一中描述的方法,用O-乙基-2-苯基乙基膦酰氯和二苯并[b,f][1,4]噻卓为原料,得到(E)-(二苯并[b,f][1,4]噁卓-10(11H)-基)(苯乙烯基)次膦酸乙酯,无色油状物,30mg 74%产率.1H NMR(400MHz,CDCl3)7.46(2H,d,J=8.0Hz),7.40–7.30(6H,m),7.30–7.09(6H,m),6.20(1H,dd,J=19.1,17.6Hz),4.80(1H,dd,J=16.4,10.5Hz),4.68(1H,dd,J=16.4,10.4Hz),4.21–4.12(1H,m),4.12–4.01(1H,m),1.27(3H,t,J=7.0Hz).13CNMR(101MHz,CDCl3)147.3(d,J=5.5Hz),144.8(d,J=5.3Hz),137.0,135.4(d,J=22.5Hz),133.4(d,J=4.9Hz),132.9,130.2,129.9,129.7,128.8(d,J=7.4Hz),128.4,128.2,128.0,127.7,126.8,126.1,116.7(d,J=177.4Hz),61.1(d,J=5.5Hz),53.2(d,J=5.7Hz),16.4(d,J=6.9Hz).31PNMR(162MHz,CDCl3)19.90。
实施例九
(E)-(3,7-二甲基二苯并[b,f][1,4]噻卓-10(11H)-基)(苯乙烯基)次膦酸乙酯1i
按实施例一中描述的方法,用O-乙基-2-苯基乙基膦酰氯和3,7-二甲基二苯并[b,f][1,4]噻卓为原料,得到(E)-(3,7-二甲基二苯并[b,f][1,4]噁卓-10(11H)-基)(苯乙烯基)次膦酸乙酯,黄色油状物,12mg,25%产率.1H NMR(400MHz,CDCl3)7.37–7.30(5H,m),7.28–7.19(2H,m),7.02–6.98(2H,m),6.93(1H,s),6.87(1H,dd,J=8.0,1.4Hz),6.81(1H,d,J=7.7Hz),6.16(1H,dd,J=19.2,17.5Hz),4.73(1H,dd,J=16.1,10.6Hz),4.66(1H,dd,J=16.1,10.5Hz),4.18(1H,dq,J=10.0,7.1Hz),4.06(1H,dq,J=10.1,7.1Hz),2.33(3H,s),2.28(3H,s),1.30(3H,t,J=7.1Hz).13C NMR(101MHz,CDCl3)154.4,153.6 146.7,138.6,137.7,135.6(d,J=20.8Hz),131.2,129.7,128.7,128.5,127.6,124.8,124.3,123.7,122.1,121.0,116.6(d,J=177.0Hz),60.8(d,J=8.7Hz),51.1(d,J=19.5Hz),21.0,20.9,16.4(d,J=8.8Hz).31P NMR(162MHz,CDCl3)20.06。
实施例十
N-(4-氟苯基)-N-肉桂基-P-((E)-2-苯基乙烯基)膦酰胺乙酯1b
先将对氟苯胺(11.1mg,0.1mmol)和肉桂醛(13.2mg,0.1mmol)溶解到1mL无水甲苯中,加入无水硫酸镁(24mg,0.2mmol),室温下搅拌12小时,然后,过滤,得到亚胺的甲苯溶液。然后将O-乙基-2-苯基乙基膦酰氯加入制备的亚胺溶液中,按实施例一中描述的方法,得到N-(4-氟苯基)-N-肉桂基-P-((E)-苯乙烯基)膦酰胺乙酯,无色油状物,26mg,63%产率。
Claims (7)
1.一种如式1所示的α,β-不饱和膦酰胺类化合物的制备方法,将式2所示的膦酰氯类化合物和式3所示的亚胺类化合物与碱反应得到式1所示的α,β-不饱和膦酰胺类化合物;
其中:R2、R3、R4、R6和R7可以为氢;R1、R2、R3、R4、R5、R6和R7表示具有1~6个碳原子的烷基、具有3~6个碳原子的环烷基、具有6~12个碳原子的芳基,R4和R6还表示具有2~6个碳原子的烯基、具有8~12个碳原子的芳基烯基,芳基可以含有甲基、乙基、甲氧基、乙氧基、氟、氯、溴、氰基、硝基、二甲氨基作为取代基;R1、R2、R3、R4、R5、R6和R7可以相同,也可以不同;R3和R4可以成环,形成环烷基;R5和R7可以成环,形成的环可以含有氧或者硫杂原子,形成的环还可以有1~2个并合的苯环,并合的苯环上还可以带有甲基、乙基、甲氧基、乙氧基、氟、氯、溴、氰基、硝基、二甲氨基作为取代基。
2.如权利要求1所述的α,β-不饱和膦酰胺类化合物的制备方法,其特征在于所制备的α,β-不饱和膦酰胺类化合物为反式构型。
3.如权利要求1所述的α,β-不饱和膦酰胺类化合物的制备方法,其特征在于所用的亚胺由醛和胺原位反应生成,直接使用。
4.如权利要求1和3所述的α,β-不饱和膦酰胺类化合物的制备方法,其特征在于所用的碱为双(三甲基硅烷基)氨基钾(KHMDS)、双(三甲基硅烷基)氨基钠(NaHMDS)、双(三甲基硅烷基)氨基锂(LiHMDS)、二异丙基氨基锂(LDA)、二异丙基氨基钠(SDA)、二异丙基氨基钾(PDA)、异丙基环己基氨基锂(LIHA)、异丙基环己基氨基钠(SIHA)、异丙基环己基氨基钾(PIHA)、叔丁醇钾、叔丁醇钠、叔丁醇锂、异丙醇钾、异丙醇钠、异丙醇锂、氢化钠、氢化钾、氢化锂或它们的混和物。
5.如权利要求1和3所述的α,β-不饱和膦酰胺类化合物的制备方法,其特征在于所用的溶剂为二甲基亚砜、环丁亚砜、1,2-二氯乙烷、四氯乙烯、四氢呋喃、1,4-二氧六环、乙二醇二甲醚、苯、甲苯、二甲苯、三甲苯、异丙苯、氯苯、二氯苯、三氯苯或它们的混和物。
6.如权利要求1和3所述的α,β-不饱和膦酰胺类化合物的制备方法,其特征在于所用的反应温度为-50-150℃,反应可以采用冰水浴、低温浴槽、丙酮干冰浴或者丙酮加液氮冷却,加热可以采用传统的蒸汽加热、电加热、微波加热进行。
7.如权利要求1和3所述的α,β-不饱和膦酰胺类化合物的制备方法,其特征在于所用的反应条件为在氮气保护下,在无水溶剂中进行。
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