CN106187825A - 一种n,n‑二酰胺基取代腙衍生物及合成方法 - Google Patents
一种n,n‑二酰胺基取代腙衍生物及合成方法 Download PDFInfo
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- CN106187825A CN106187825A CN201610560893.4A CN201610560893A CN106187825A CN 106187825 A CN106187825 A CN 106187825A CN 201610560893 A CN201610560893 A CN 201610560893A CN 106187825 A CN106187825 A CN 106187825A
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- Prior art keywords
- diamides
- base
- palladium
- synthetic method
- hydazone derivative
- Prior art date
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- Granted
Links
- 229910052757 nitrogen Inorganic materials 0.000 title claims abstract description 27
- 238000010189 synthetic method Methods 0.000 title claims abstract description 15
- 150000001470 diamides Chemical class 0.000 title claims abstract description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 135
- 238000006243 chemical reaction Methods 0.000 claims abstract description 66
- 238000003756 stirring Methods 0.000 claims abstract description 43
- -1 p-toluenesulfonyl hydrazone Chemical class 0.000 claims abstract description 33
- 239000002585 base Substances 0.000 claims abstract description 28
- 239000002904 solvent Substances 0.000 claims abstract description 27
- 238000004440 column chromatography Methods 0.000 claims abstract description 26
- 239000012295 chemical reaction liquid Substances 0.000 claims abstract description 23
- 239000003054 catalyst Substances 0.000 claims abstract description 10
- 150000002940 palladium Chemical class 0.000 claims abstract description 9
- 239000003513 alkali Substances 0.000 claims abstract description 7
- 238000000034 method Methods 0.000 claims abstract description 7
- 239000012043 crude product Substances 0.000 claims abstract description 3
- 238000011017 operating method Methods 0.000 claims abstract description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 61
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 44
- 239000003480 eluent Substances 0.000 claims description 22
- 239000012046 mixed solvent Substances 0.000 claims description 22
- PBDBXAQKXCXZCJ-UHFFFAOYSA-L palladium(2+);2,2,2-trifluoroacetate Chemical compound [Pd+2].[O-]C(=O)C(F)(F)F.[O-]C(=O)C(F)(F)F PBDBXAQKXCXZCJ-UHFFFAOYSA-L 0.000 claims description 20
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 18
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 18
- 239000003208 petroleum Substances 0.000 claims description 17
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- 150000007857 hydrazones Chemical class 0.000 claims description 6
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 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
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- 125000001207 fluorophenyl group Chemical group 0.000 claims description 5
- 229910052763 palladium Inorganic materials 0.000 claims description 5
- XHLHPRDBBAGVEG-UHFFFAOYSA-N 1-tetralone Chemical compound C1=CC=C2C(=O)CCCC2=C1 XHLHPRDBBAGVEG-UHFFFAOYSA-N 0.000 claims description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-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
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- TZIHFWKZFHZASV-UHFFFAOYSA-N methyl formate Chemical compound COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 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
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical class ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 3
- KWHUHTFXMNQHAA-UHFFFAOYSA-N 6,7,8,9-tetrahydrobenzo[7]annulen-5-one Chemical compound O=C1CCCCC2=CC=CC=C12 KWHUHTFXMNQHAA-UHFFFAOYSA-N 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 3
- NHOWDZOIZKMVAI-UHFFFAOYSA-N (2-chlorophenyl)(4-chlorophenyl)pyrimidin-5-ylmethanol Chemical group C=1N=CN=CC=1C(C=1C(=CC=CC=1)Cl)(O)C1=CC=C(Cl)C=C1 NHOWDZOIZKMVAI-UHFFFAOYSA-N 0.000 claims description 2
- RFFLAFLAYFXFSW-UHFFFAOYSA-N 1,2-dichlorobenzene Chemical compound ClC1=CC=CC=C1Cl RFFLAFLAYFXFSW-UHFFFAOYSA-N 0.000 claims description 2
- VYXHVRARDIDEHS-UHFFFAOYSA-N 1,5-cyclooctadiene Chemical compound C1CC=CCCC=C1 VYXHVRARDIDEHS-UHFFFAOYSA-N 0.000 claims description 2
- 239000004912 1,5-cyclooctadiene Substances 0.000 claims description 2
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims description 2
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000003762 3,4-dimethoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 claims description 2
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 claims description 2
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 2
- 125000004799 bromophenyl group Chemical group 0.000 claims description 2
- 125000004802 cyanophenyl group Chemical group 0.000 claims description 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 2
- WMKGGPCROCCUDY-PHEQNACWSA-N dibenzylideneacetone Chemical compound C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 WMKGGPCROCCUDY-PHEQNACWSA-N 0.000 claims description 2
- 125000003963 dichloro group Chemical group Cl* 0.000 claims description 2
- 125000006303 iodophenyl group Chemical group 0.000 claims description 2
- INIOZDBICVTGEO-UHFFFAOYSA-L palladium(ii) bromide Chemical compound Br[Pd]Br INIOZDBICVTGEO-UHFFFAOYSA-L 0.000 claims description 2
- UQPUONNXJVWHRM-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 UQPUONNXJVWHRM-UHFFFAOYSA-N 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 239000001632 sodium acetate Substances 0.000 claims description 2
- 235000017281 sodium acetate Nutrition 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 2
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 claims 2
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims 2
- 238000004458 analytical method Methods 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 claims 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 claims 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 1
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 claims 1
- PYLWMHQQBFSUBP-UHFFFAOYSA-N monofluorobenzene Chemical compound FC1=CC=CC=C1 PYLWMHQQBFSUBP-UHFFFAOYSA-N 0.000 claims 1
- FGIUAXJPYTZDNR-UHFFFAOYSA-N potassium nitrate Chemical compound [K+].[O-][N+]([O-])=O FGIUAXJPYTZDNR-UHFFFAOYSA-N 0.000 claims 1
- 239000000047 product Substances 0.000 abstract description 72
- 230000015572 biosynthetic process Effects 0.000 abstract description 5
- 238000003786 synthesis reaction Methods 0.000 abstract description 5
- 239000002994 raw material Substances 0.000 abstract description 4
- 239000003814 drug Substances 0.000 abstract description 3
- 231100000252 nontoxic Toxicity 0.000 abstract description 3
- 230000003000 nontoxic effect Effects 0.000 abstract description 3
- 239000000758 substrate Substances 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 2
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 2
- 125000000524 functional group Chemical group 0.000 abstract 1
- 238000004519 manufacturing process Methods 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- 239000000575 pesticide Substances 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 52
- ZMXDDKWLCZADIW-UHFFFAOYSA-N Vilsmeier-Haack reagent Natural products CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 36
- 238000007445 Chromatographic isolation Methods 0.000 description 20
- 238000011097 chromatography purification Methods 0.000 description 20
- 238000010438 heat treatment Methods 0.000 description 20
- 238000010992 reflux Methods 0.000 description 20
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 13
- 238000005160 1H NMR spectroscopy Methods 0.000 description 13
- 238000012512 characterization method Methods 0.000 description 13
- 230000006837 decompression Effects 0.000 description 10
- FZFLTDNAHASQQC-RVDMUPIBSA-N n-[(e)-benzylideneamino]-4-methylbenzenesulfonamide Chemical compound C1=CC(C)=CC=C1S(=O)(=O)N\N=C\C1=CC=CC=C1 FZFLTDNAHASQQC-RVDMUPIBSA-N 0.000 description 7
- VIKNJXKGJWUCNN-XGXHKTLJSA-N norethisterone Chemical compound O=C1CC[C@@H]2[C@H]3CC[C@](C)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 VIKNJXKGJWUCNN-XGXHKTLJSA-N 0.000 description 7
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 239000011734 sodium Substances 0.000 description 4
- 239000004575 stone Substances 0.000 description 4
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- ZRSNZINYAWTAHE-UHFFFAOYSA-N p-methoxybenzaldehyde Chemical compound COC1=CC=C(C=O)C=C1 ZRSNZINYAWTAHE-UHFFFAOYSA-N 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- FTJGECIARDVRJC-UHFFFAOYSA-N 1-(4-methylsulfanylphenyl)propan-1-one Chemical compound CCC(=O)C1=CC=C(SC)C=C1 FTJGECIARDVRJC-UHFFFAOYSA-N 0.000 description 1
- HIKRJHFHGKZKRI-UHFFFAOYSA-N 2,4,6-trimethylbenzaldehyde Chemical class CC1=CC(C)=C(C=O)C(C)=C1 HIKRJHFHGKZKRI-UHFFFAOYSA-N 0.000 description 1
- NLPHXWGWBKZSJC-UHFFFAOYSA-N 4-acetylbenzonitrile Chemical compound CC(=O)C1=CC=C(C#N)C=C1 NLPHXWGWBKZSJC-UHFFFAOYSA-N 0.000 description 1
- GUEMDXLIHCONOI-UHFFFAOYSA-N 4-methyl-n-(pentan-3-ylideneamino)benzenesulfonamide Chemical compound CCC(CC)=NNS(=O)(=O)C1=CC=C(C)C=C1 GUEMDXLIHCONOI-UHFFFAOYSA-N 0.000 description 1
- YQYGPGKTNQNXMH-UHFFFAOYSA-N 4-nitroacetophenone Chemical compound CC(=O)C1=CC=C([N+]([O-])=O)C=C1 YQYGPGKTNQNXMH-UHFFFAOYSA-N 0.000 description 1
- 239000004156 Azodicarbonamide Substances 0.000 description 1
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 1
- XOZUGNYVDXMRKW-AATRIKPKSA-N azodicarbonamide Chemical compound NC(=O)\N=N\C(N)=O XOZUGNYVDXMRKW-AATRIKPKSA-N 0.000 description 1
- 235000019399 azodicarbonamide Nutrition 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- FZFLTDNAHASQQC-UHFFFAOYSA-N n-(benzylideneamino)-4-methylbenzenesulfonamide Chemical class C1=CC(C)=CC=C1S(=O)(=O)NN=CC1=CC=CC=C1 FZFLTDNAHASQQC-UHFFFAOYSA-N 0.000 description 1
- JHDVKJFLEBHSQD-UHFFFAOYSA-N n-(hexan-2-ylideneamino)-4-methylbenzenesulfonamide Chemical compound CCCCC(C)=NNS(=O)(=O)C1=CC=C(C)C=C1 JHDVKJFLEBHSQD-UHFFFAOYSA-N 0.000 description 1
- BPJBUIWCUYKVNL-MHWRWJLKSA-N n-[(e)-(4-bromophenyl)methylideneamino]-4-methylbenzenesulfonamide Chemical compound C1=CC(C)=CC=C1S(=O)(=O)N\N=C\C1=CC=C(Br)C=C1 BPJBUIWCUYKVNL-MHWRWJLKSA-N 0.000 description 1
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical group [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 1
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
- 150000003053 piperidines Chemical class 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- SYXYWTXQFUUWLP-UHFFFAOYSA-N sodium;butan-1-olate Chemical compound [Na+].CCCC[O-] SYXYWTXQFUUWLP-UHFFFAOYSA-N 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C281/00—Derivatives of carbonic acid containing functional groups covered by groups C07C269/00 - C07C279/00 in which at least one nitrogen atom of these functional groups is further bound to another nitrogen atom not being part of a nitro or nitroso group
- C07C281/06—Compounds containing any of the groups, e.g. semicarbazides
- C07C281/08—Compounds containing any of the groups, e.g. semicarbazides the other nitrogen atom being further doubly-bound to a carbon atom, e.g. semicarbazones
- C07C281/14—Compounds containing any of the groups, e.g. semicarbazides the other nitrogen atom being further doubly-bound to a carbon atom, e.g. semicarbazones the carbon atom being further bound to a carbon atom of a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C281/00—Derivatives of carbonic acid containing functional groups covered by groups C07C269/00 - C07C279/00 in which at least one nitrogen atom of these functional groups is further bound to another nitrogen atom not being part of a nitro or nitroso group
- C07C281/06—Compounds containing any of the groups, e.g. semicarbazides
- C07C281/08—Compounds containing any of the groups, e.g. semicarbazides the other nitrogen atom being further doubly-bound to a carbon atom, e.g. semicarbazones
- C07C281/12—Compounds containing any of the groups, e.g. semicarbazides the other nitrogen atom being further doubly-bound to a carbon atom, e.g. semicarbazones the carbon atom being part of a ring other than a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
- C07D295/215—Radicals derived from nitrogen analogues of carbonic acid
-
- 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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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明属于医药化工合成技术领域,公开了一种N,N‑二酰胺基取代腙衍生物及合成方法。所述合成方法包括以下操作步骤:在反应器中,加入N‑对甲苯磺酰基腙、偶氮二烷基二酰胺、碱、钯盐催化剂和溶剂,在70~90℃下搅拌反应12~24小时,反应结束后冷却至室温,乙酸乙酯萃取反应液,减压蒸除溶剂得粗产物,经柱层析提纯得到N,N‑二酰胺基取代腙衍生物。本发明方法使用较为廉价易得的钯盐为催化剂,所用原料无毒、廉价易得;反应对官能团适应性好,对底物适应性广,产物收率高,可以放大至克级规模生产合成,有利于工业生产,所得产物在农药、医药及材料领域中具有广泛用途。
Description
技术领域
本发明属于医药化工合成技术领域,具体涉及一种N,N-二酰胺基取代腙衍生物及合成方法。
背景技术
N,N-二取代腙衍生物是一类非常重要的合成中间体、配体、催化剂(Job,A.Janeck,C.F.;Bettray,W.;Peters,R.;Enders,D.Tetrahedron 2002,58,2253.Sugiura,M.;Kobayashi,D.Angew.Chem.Int.Ed.2005,44,5176.Friestad,G.K.Eur.J.Org.Chem.2005,3157.Lazny,R.;Nodzewska,A.Chem.Rev.2010,110,1386)。近年来,随着过渡金属催化的快速发展及其所催化反应种类的不断增加,N,N-二取代腙衍生物参与的合成转化反应受到了科学家们越来越多的关注,呈现出蓬勃发展的趋势(Pair,E.;Monteiro,N.;Bouyssi,D.;Baudoin,O.Angew.Chem.Int.Ed.2013,52,5346.Prieto,A.;Melot,R.;Bouyssi,D.;Monteiro,N.Angew.Chem.Int.Ed.2016,55,1885.Prieto,A.;Melot,R.;Bouyssi,D.;Monteiro,N.ACS Catal.2016,6,1093.Xie,J.;Zhang,T.;Chen,F.;Mehrkens,N.;Rominger,F.;Rudolph,M.;Hashmi,A.S.K.Angew.Chem.Int.Ed.2016,55,2934.Xu,P.;Wang,G.;Zhu,Y.;Li,W.;Cheng,Y.;Li,S.;Zhu,C.Angew.Chem.Int.Ed.2016,55,2939.)。但是上述反应和方法的底物只涉及到N,N-二烷基取代腙衍生物,而对于其它类型的N,N-二取代腙衍生物,如N,N-二酰胺取代腙衍生物则没有进行相关研究,这可能是由于缺少高效合成N,N-二酰胺取代腙衍生物的方法。
商品化的N-对甲苯磺酰基腙具有种类丰富、价格便宜、无毒、易储存等特点,用其合成结构复杂且功能多样性的分子已引起了大家的极大兴趣(J.R.Fulton,V.K.Aggarwal,J.de Vicente,Eur.J.Org.Chem.2005,1479–1492;J.Barluenga,C.Angew.Chem.Int.Ed.2011,50,7486–7500;Z.Shao,H.Zhang,Chem.Soc.Rev.2012,41,560–572;H.Jiang,W.Fu,H.Chen,Chem.Eur.J.2012,18,11884–11888;Q.Xiao,Y.Zhang,J.Wang,Acc.Chem.Res.2013,46,236–247;Y.Xia,Y.Zhang,J.Wang,ACS Catal.2013,3,2586–2598;C.Zhu,J.Li,P.Chen,W.Wu,Y.Ren,H.Jiang,Org.Lett.2016,18,1470–1473)。但目前尚未有利用N-对甲苯磺酰基腙为原料直接高效合成N,N-二酰胺基取代腙衍生物的报道。
发明内容
为了解决以上现有技术的缺点和不足之处,本发明的首要目的在于提供一种N,N-二酰胺基取代腙衍生物的合成方法。
本发明的另一目的在于提供一种由上述方法合成得到的N,N-二酰胺基取代腙衍生物。
本发明目的通过以下技术方案实现:
一种N,N-二酰胺基取代腙衍生物的合成方法,包括以下操作步骤:
在反应器中,加入N-对甲苯磺酰基腙、偶氮二烷基二酰胺、碱、钯盐催化剂和溶剂,在70~90℃下搅拌反应12~24小时,反应结束后冷却至室温,乙酸乙酯萃取反应液,减压蒸除溶剂得粗产物,经柱层析提纯得到N,N-二酰胺基取代腙衍生物。
所述的N-对甲苯磺酰基腙为1-茚酮对甲苯磺酰腙、1-四氢萘酮对甲苯磺酰腙或1-苯并环庚酮对甲苯磺酰腙;其中,Ts表示对甲苯磺酰基,R1为苯基、对氟苯基、间氟苯基、邻氟苯基、对氯苯基、间氯苯基、对溴苯基、间溴苯基、对碘苯基、对甲苯基、对甲氧基苯基、对甲硫基苯基、对氰基苯基、对甲砜基苯基、对甲酸甲酯基苯基、对三氟甲基苯基、对硝基苯基、3,4-二氯苯基、3,4-二甲氧基苯基、2-萘基、2-噻吩基、3-吡啶基、2-苯基乙基或联萘;R2为氢、甲基、乙基、丙基、异丙基、环丙基、环丁基或叔丁基。
所述的偶氮二烷基二酰胺为其中,R为甲基,乙基,异丙基,环己基或叔丁基。
所述N-对甲苯磺酰基腙与偶氮二烷基二酰胺的摩尔比优选为(0.33~2):1。
所述碱优选为碳酸钠、碳酸钾、碳酸铯、氢氧化钠、甲醇钠、乙酸钠、叔丁醇钾和叔丁醇钠中的一种或两种以上;碱的加入量与N-对甲苯磺酰基腙的摩尔比为(1~1.5):1。
所述钯盐催化剂优选为醋酸钯、氯化钯、溴化钯、三氟乙酸钯、二氯二三苯基膦钯、四三苯基磷钯、三(二亚苄基丙酮)二钯、双(乙腈)二氯钯(II)、(1,5-环辛二烯)二氯化钯(II)中的一种或两种以上;钯盐催化剂的加入量与偶氮二烷基二酰胺的摩尔比优选为0.1:1。
所述的溶剂优选为甲苯、苯、二甲苯、1,2-二氯乙烷、四氢呋喃和乙腈中的一种或两种以上的混合。
所述的柱层析提纯是指以体积比为(0.5~2):1的石油醚:乙酸乙酯的混合溶剂为洗脱液的柱层析提纯。
一种N,N-二酰胺基取代腙衍生物,通过以上方法制备得到。
本发明方法所涉及的反应方程式如下式所示:
本发明的制备方法及所得到的产物具有如下优点及有益效果:
(1)本发明的合成方法以N-对甲苯磺酰基腙为原料直接高效合成N,N-二酰胺基取代腙衍生物,并使用较为廉价易得的钯盐为催化剂,所用原料无毒、廉价易得;反应对官能团适应性好,对底物适应性广,产物收率高。
(2)本发明的合成方法可以放大至克级规模生产,且操作简单、安全,反应条件温和,对水和空气不敏感,具有良好的工业应用前景。
附图说明
图1是实施例1-8所得产物的氢谱图;
图2是实施例1-8所得产物的碳谱图。
具体实施方式
下面结合实施例及附图对本发明作进一步详细的描述,但本发明的实施方式不限于此。
实施例1
在装有回流冷凝管25毫升反应瓶中,加入0.2毫摩尔苯甲醛对甲苯磺酰腙,0.2毫摩尔碳酸铯,0.01毫摩尔三氟乙酸钯,0.1毫摩尔偶氮二甲基甲酰胺,2毫升甲苯,反应体系在90℃搅拌反应12小时,停止加热及搅拌,冷却至室温。乙酸乙酯萃取反应液,减压旋蒸去除溶剂,再通过柱层析分离纯化,得到目标产物,所用的柱层析洗脱液为体积比为2:1的石油醚:乙酸乙酯混合溶剂,得产物为油状液体,产率为91%。
实施例2
在装有回流冷凝管25毫升反应瓶中,加入0.2毫摩尔苯甲醛对甲苯磺酰腙,0.3毫摩尔碳酸钾,0.01毫摩尔三氟乙酸钯,0.1毫摩尔偶氮二甲基甲酰胺,2毫升甲苯,反应体系在90℃搅拌反应12小时,停止加热及搅拌,冷却至室温。乙酸乙酯萃取反应液,减压旋蒸去除溶剂,再通过柱层析分离纯化,得到目标产物,所用的柱层析洗脱液为体积比为2:1的石油醚:乙酸乙酯混合溶剂,得产物为油状液体,产率为83%。
实施例3
在装有回流冷凝管25毫升反应瓶中,加入0.2毫摩尔苯甲醛对甲苯磺酰腙,0.2毫摩尔叔丁醇钾,0.01毫摩尔三氟乙酸钯,0.1毫摩尔偶氮二甲基甲酰胺,2毫升甲苯,反应体系在90℃搅拌反应12小时,停止加热及搅拌,冷却至室温。乙酸乙酯萃取反应液,减压旋蒸去除溶剂,再通过柱层析分离纯化,得到目标产物,所用的柱层析洗脱液为体积比为2:1的石油醚:乙酸乙酯混合溶剂,得产物为油状液体,产率为86%。
实施例4
在装有回流冷凝管25毫升反应瓶中,加入0.2毫摩尔苯甲醛对甲苯磺酰腙、0.2毫摩尔碳酸铯、0.01毫摩尔三氟乙酸钯,0.1毫摩尔偶氮二甲基甲酰胺,2毫升乙腈,反应体系在90℃搅拌反应12小时,停止加热及搅拌,冷却至室温。乙酸乙酯萃取反应液,减压旋蒸去除溶剂,再通过柱层析分离纯化,得到目标产物,所用的柱层析洗脱液为体积比为2:1的石油醚:乙酸乙酯混合溶剂,得产物为油状液体,产率为37%。
实施例5
装有回流冷凝管25毫升反应瓶中,加入0.2毫摩尔苯甲醛对甲苯磺酰腙,0.2毫摩尔碳酸铯,0.01毫摩尔三氟乙酸钯,0.1毫摩尔偶氮二甲基甲酰胺,2毫升1,2-二氯乙烷,反应体系在90℃搅拌反应12小时,停止加热及搅拌,冷却至室温。乙酸乙酯萃取反应液,减压旋蒸去除溶剂,再通过柱层析分离纯化,得到目标产物,所用的柱层析洗脱液为体积比为2:1的石油醚:乙酸乙酯混合溶剂,得产物为油状液体,产率为62%。
实施例6
在装有回流冷凝管25毫升反应瓶中,加入0.2毫摩尔苯甲醛对甲苯磺酰腙,0.3毫摩尔叔丁醇锂,0.01毫摩尔醋酸钯,0.1毫摩尔偶氮二甲基甲酰胺,2毫升甲苯,反应体系在90℃搅拌反应12小时,停止加热及搅拌,冷却至室温。乙酸乙酯萃取反应液,减压旋蒸去除溶剂,再通过柱层析分离纯化,得到目标产物,所用的柱层析洗脱液为体积比为2:1的石油醚:乙酸乙酯混合溶剂,得产物为油状液体,产率为45%。
实施例7
在装有回流冷凝管25毫升反应瓶中,加入0.2毫摩尔苯甲醛对甲苯磺酰腙,0.2毫摩尔叔丁醇锂,0.01毫摩尔四三苯基膦钯,0.1毫摩尔偶氮二甲基甲酰胺,2毫升甲苯,反应体系在90℃搅拌反应12小时,停止加热及搅拌,冷却至室温。乙酸乙酯萃取反应液,减压旋蒸去除溶剂,再通过柱层析分离纯化,得到目标产物,所用的柱层析洗脱液为体积比为2:1的石油醚:乙酸乙酯混合溶剂,得产物主要非对映异构体,产率为39%。
实施例8
在装有回流冷凝管的250毫升反应瓶中,加入7.5毫摩尔苯甲醛对甲苯磺酰腙,7.5毫摩尔碳酸铯,0.5毫摩尔三氟乙酸钯,5毫摩尔偶氮二甲基甲酰胺,100毫升甲苯,反应体系在90℃搅拌反应12小时,停止加热及搅拌,冷却至室温。乙酸乙酯萃取反应液,减压旋蒸去除溶剂,再通过柱层析分离纯化,得到目标产物,所用的柱层析洗脱液为体积比为2:1的石油醚:乙酸乙酯混合溶剂,得产物主要非对映异构体,产率为87%。
实施例1~8所得产物的氢谱图和碳谱图分别如图1和图2所示;其结构表征数据如下所示:
1H NMR(400MHz,CDCl3):δ=7.80(s,1H),7.63-7.66(m,2H),7.36-7.38(m,3H),3.06(s,12H);
13C NMR(100MHz,CDCl3):δ=156.2,145.7,134.5,129.9,128.6,127.1,37.6;
IR(KBr):2930,1688,1487,1380,1261,1160,1061(cm-1);
HRMS-ESI(m/z):[M+H]+Calcd.for C13H18N4O2+H,263.1503;found,263.1501。
根据以上数据推断实施例1~8所得产物的结构如下式所示:
实施例9
在装有回流冷凝管25毫升反应瓶中,加入0.2毫摩尔4-甲基苯甲醛对甲苯磺酰腙,0.2毫摩尔碳酸铯,0.01毫摩尔三氟乙酸钯,0.1毫摩尔偶氮二甲基甲酰胺,2毫升甲苯,反应体系在90℃搅拌反应12小时,停止加热及搅拌,冷却至室温。乙酸乙酯萃取反应液,减压旋蒸去除溶剂,再通过柱层析分离纯化,得到目标产物,所用的柱层析洗脱液为体积比为2:1的石油醚:乙酸乙酯混合溶剂,得产物主要非对映异构体,产率为91%。
本实施例所得产物的结构表征数据如下所示:
1H NMR(400MHz,CDCl3):δ=7.77(s,1H),7.53(s,2H),7.18(s,2H),3.05-3.05(m,12H),2.36(s,3H);
13C NMR(100MHz,CDCl3):δ=156.3,146.1,140.2,131.8,129.4,127.1,37.6,21.4;
IR(KBr):2927,1688,1488,1374,1261,1159,1059(cm-1);
HRMS-ESI(m/z):[M+H]+Calcd.for C14H20N4O2+H,277.1659;found,277.1656。
根据以上数据推断本实施例所得产物的结构如下式所示:
实施例10
在装有回流冷凝管25毫升反应瓶中,加入0.2毫摩尔4-溴苯甲醛对甲苯磺酰腙,0.2毫摩尔碳酸铯,0.01毫摩尔三氟乙酸钯,0.1毫摩尔偶氮二甲基甲酰胺,2毫升甲苯,反应体系在90℃搅拌反应12小时,停止加热及搅拌,冷却至室温。乙酸乙酯萃取反应液,减压旋蒸去除溶剂,再通过柱层析分离纯化,得到目标产物,所用的柱层析洗脱液为体积比为2:1的石油醚:乙酸乙酯混合溶剂,得产物主要非对映异构体,产率为91%。
本实施例所得产物的结构表征数据如下所示:
1H NMR(400MHz,CDCl3):δ=7.77(s,1H),7.44-7.58(m,4H),3.06(s,12H);
13C NMR(100MHz,CDCl3):δ=156.0,144.6,133.5,131.8,128.5,124.0,37.6;
IR(KBr):2929,1688,1486,1378,1261,1159,1063(cm-1);
HRMS-ESI(m/z):[M+Na]+Calcd.for C13H17BrN4O2+Na,363.0427;found,363.0423。
根据以上数据推断本实施例所得产物的结构如下式所示:
实施例11
在装有回流冷凝管25毫升反应瓶中,加入0.2毫摩尔4-甲氧基苯甲醛对甲苯磺酰腙,0.2毫摩尔碳酸铯,0.01毫摩尔三氟乙酸钯,0.1毫摩尔偶氮二甲基甲酰胺,2毫升甲苯,反应体系在90℃搅拌反应12小时,停止加热及搅拌,冷却至室温。乙酸乙酯萃取反应液,减压旋蒸去除溶剂,再通过柱层析分离纯化,得到目标产物,所用的柱层析洗脱液为体积比为2:1的石油醚:乙酸乙酯混合溶剂,得产物主要非对映异构体,产率为91%。
本实施例所得产物的结构表征数据如下所示:
1H NMR(400MHz,CDCl3):δ=7.76(s,1H),7.59(d,J=8.8Hz,2H),6.90(d,J=8.4Hz,2H),3.83(s,3H),3.06(s,12H);
13C NMR(100MHz,CDCl3):δ=161.1,156.5,146.2,128.7,127.3,114.1,55.3,37.6;
IR(KBr):2925,2854,1682,1606,1497,1377,1252,1161,1029(cm-1);
HRMS ESI(m/z):[M+H]+Calcd.for C14H20N4O3+H,293.1608;found,293.1608。
根据以上数据推断本实施例所得产物的结构如下式所示:
实施例12
在装有回流冷凝管25毫升反应瓶中,加入0.2毫摩尔2,4,6-三甲基苯甲醛对甲苯磺酰腙,0.2毫摩尔碳酸铯,0.01毫摩尔三氟乙酸钯,0.1毫摩尔偶氮二甲基甲酰胺,2毫升甲苯,反应体系在90℃搅拌反应12小时,停止加热及搅拌,冷却至室温。乙酸乙酯萃取反应液,减压旋蒸去除溶剂,再通过柱层析分离纯化,得到目标产物,所用的柱层析洗脱液为体积比为2:1的石油醚:乙酸乙酯混合溶剂,得产物主要非对映异构体,产率为74%。
本实施例所得产物的结构表征数据如下所示:
1H NMR(400MHz,CDCl3):δ=8.13(s,1H),6.88(s,2H),3.05(s,12H),2.41(s,6H),2.29(s,3H);
13C NMR(100MHz,CDCl3):δ=156.8,148.4,138.8,137.5,129.4,128.7,37.6,21.0;
IR(KBr):2928,1679,1486,1378,1262,1156,1059(cm-1);
HRMS ESI(m/z):[M+H]+Calcd.for C16H24N4O2+H,305.1972;found,305.1974。
根据以上数据推断本实施例所得产物的结构如下式所示:
实施例13
在装有回流冷凝管25毫升反应瓶中,加入0.2毫摩尔4-甲硫基苯乙酮对甲苯磺酰腙,0.2毫摩尔碳酸铯,0.01毫摩尔三氟乙酸钯,0.1毫摩尔偶氮二甲基甲酰胺,2毫升甲苯,反应体系在90℃搅拌反应12小时,停止加热及搅拌,冷却至室温。乙酸乙酯萃取反应液,减压旋蒸去除溶剂,再通过柱层析分离纯化,得到目标产物,所用的柱层析洗脱液为体积比为2:1的石油醚:乙酸乙酯混合溶剂,得产物主要非对映异构体,产率为80%。
本实施例所得产物的结构表征数据如下所示:
1H NMR(400MHz,CDCl3):δ=7.75(d,J=8.4Hz,2H),7.22(d,J=8.4Hz,2H),3.00(s,12H),2.49(s,3H),2.12(s,3H);
13C NMR(100MHz,CDCl3):δ=162.8,157.8,141.2,134.1,127.1,125.6,37.3,16.6,15.3;
IR(KBr):2927,1681,1488,1378,1264,1177,1067(cm-1);
HRMS ESI(m/z):[M+H]+Calcd.for C15H22N4O2S+H,323.1536;found,323.1232。
根据以上数据推断本实施例所得产物的结构如下式所示:
实施例14
在装有回流冷凝管25毫升反应瓶中,加入0.2毫摩尔4-氰基苯乙酮对甲苯磺酰腙,0.2毫摩尔碳酸铯,0.01毫摩尔三氟乙酸钯,0.1毫摩尔偶氮二甲基甲酰胺,2毫升甲苯,反应体系在90℃搅拌反应12小时,停止加热及搅拌,冷却至室温。乙酸乙酯萃取反应液,减压旋蒸去除溶剂,再通过柱层析分离纯化,得到目标产物,所用的柱层析洗脱液为体积比为2:1的石油醚:乙酸乙酯混合溶剂,得产物主要非对映异构体,产率为81%。
本实施例所得产物的结构表征数据如下所示:
1H NMR(400MHz,CDCl3):δ=7.92(d,J=7.6Hz,2H),7.66(d,J=8.0Hz,2H),3.01(s,12H),2.15(s,3H);
13C NMR(100MHz,CDCl3):δ=160.4,157.3,141.7,132.1,127.2,118.6,113.2,37.3,18.6;
IR(KBr):2928,1681,1489,1379,1264,1174,1073(cm-1);
HRMS ESI(m/z):[M+H]+Calcd.for C15H19N5O2+H,302.1612;found,302.1609。
根据以上数据推断本实施例所得产物的结构如下式所示:
实施例15
在装有回流冷凝管25毫升反应瓶中,加入0.2毫摩尔4-硝基苯乙酮对甲苯磺酰腙,0.2毫摩尔碳酸铯,0.01毫摩尔三氟乙酸钯,0.1毫摩尔偶氮二甲基甲酰胺,2毫升甲苯,反应体系在70℃搅拌反应12小时,停止加热及搅拌,冷却至室温。乙酸乙酯萃取反应液,减压旋蒸去除溶剂,再通过柱层析分离纯化,得到目标产物,所用的柱层析洗脱液为体积比为1:1的石油醚:乙酸乙酯混合溶剂,得产物主要非对映异构体,产率为61%。
本实施例所得产物主要非对映异构体的结构表征数据如下所示:
1H NMR(400MHz,CDCl3):δ=8.21(d,J=7.2Hz,2H),7.99(d,J=7.2Hz,2H),3.03(s,12H),2.19(s,3H);
13C NMR(100MHz,CDCl3):δ=160.0,157.3,148.5,143.5,127.5,123.5,37.3,17.0;
IR(KBr):2933,1670,1503,1384,1264,1172,1070(cm-1);
HRMS ESI(m/z):[M+H]+Calcd.for C14H19N5O4+H,322.1510;found,322.1511。
根据以上数据推断本实施例所得产物的结构如下式所示:
实施例16
在装有回流冷凝管25毫升反应瓶中,加入0.2毫摩尔1-苯并环己酮对甲苯磺酰腙,0.2毫摩尔碳酸铯,0.01毫摩尔三氟乙酸钯,0.1毫摩尔偶氮二甲基甲酰胺,2毫升甲苯,反应体系在90℃搅拌反应12小时,停止加热及搅拌,冷却至室温。乙酸乙酯萃取反应液,减压旋蒸去除溶剂,再通过柱层析分离纯化,得到目标产物,所用的柱层析洗脱液为体积比为1:1的石油醚:乙酸乙酯混合溶剂,得产物主要非对映异构体,产率为74%。
本实施例所得产物主要非对映异构体的结构表征数据如下所示:
1H NMR(400MHz,CDCl3):δ=8.25(d,J=8.0Hz,1H),7.29(t,J=8.0Hz,1H),7.20(t,J=7.6Hz,1H),7.13(d,J=7.6Hz,1H),2.99(s,12H),2.83(t,J=6.0Hz,2H),2.25(t,J=6.4Hz,2H),1.90(quint,J=6.0Hz,2H);
13C NMR(100MHz,CDCl3):δ=62.6,157.9,140.3,131.9,130.1,128.6,126.3,125.9,37.4,29.6,28.4,22.3;
IR(KBr):2934,1680,1488,1377,1264,1180,1061(cm-1);
HRMS ESI(m/z):[M+H]+Calcd.for C16H22N4O2+H,303.1816;found,303.1814。
根据以上数据推断本实施例所得产物的结构如下式所示:
实施例17
在装有回流冷凝管25毫升反应瓶中,加入0.2毫摩尔1-苯并环庚酮对甲苯磺酰腙,0.2毫摩尔碳酸铯,0.01毫摩尔三氟乙酸钯,0.1毫摩尔偶氮二甲基甲酰胺,2毫升甲苯,反应体系在70℃搅拌反应12小时,停止加热及搅拌,冷却至室温。乙酸乙酯萃取反应液,减压旋蒸去除溶剂,再通过柱层析分离纯化,得到目标产物,所用的柱层析洗脱液为体积比为2:1的石油醚:乙酸乙酯混合溶剂,得产物主要非对映异构体,产率为51%。
本实施例所得产物的结构表征数据如下所示:
1H NMR(400MHz,CDCl3):δ=7.62(d,J=7.6Hz,1H),7.31(t,J=7.2Hz,1H),7.24(t,J=7.6Hz,1H),7.11(d,J=7.6Hz,1H),2.99(s,12H),2.76(t,J=6.4Hz,2H),2.45(t,J=5.6Hz,2H),1.74-1.79(m,2H),1.61(quint,J=6.0Hz,2H);
13C NMR(100MHz,CDCl3):δ=172.5,157.9,139.1,137.6,129.8,128.6,127.8,126.5,37.3,30.2,25.9,21.3;
IR(KBr):2930,2861,1677,1486,1376,1264,1172,1062(cm-1);
HRMS ESI(m/z):M+H]+Calcd.for C17H24N4O2+H,317.1971;found,317.1971。
根据以上数据推断本实施例所得产物的结构如下式所示:
实施例18
在装有回流冷凝管25毫升反应瓶中,加入0.2毫摩尔2-噻吩乙酮对甲苯磺酰腙,0.2毫摩尔碳酸铯,0.01毫摩尔三氟乙酸钯,0.1毫摩尔偶氮二甲基甲酰胺,2毫升甲苯,反应体系在90℃搅拌反应12小时,停止加热及搅拌,冷却至室温。乙酸乙酯萃取反应液,减压旋蒸去除溶剂,再通过柱层析分离纯化,得到目标产物,所用的柱层析洗脱液为体积比为2:1的石油醚:乙酸乙酯混合溶剂,得产物主要非对映异构体,产率为53%。
本实施例所得产物主要非对映异构体的结构表征数据如下所示:
1H NMR(400MHz,CDCl3):δ=7.34-7.36(m,2H),7.03(t,J=4.4Hz,1H),3.00(s,12H),1.61(s,3H);
13C NMR(100MHz,CDCl3):δ=158.1,157.5,142.7,128.7,127.7,127.1,37.4,16.7;
IR(KBr):2925,1681,1488,1373,1264,1172,1062(cm-1);
HRMS ESI(m/z):[M+H]+Calcd.for C12H18N4O2S+H,283.1223;found,283.1226。
根据以上数据推断本实施例所得产物的结构如下式所示:
实施例19
在装有回流冷凝管25毫升反应瓶中,加入0.1毫摩尔2,2’-联萘甲醛对甲苯磺酰腙,0.2毫摩尔碳酸铯,0.01毫摩尔三氟乙酸钯,0.3毫摩尔偶氮二甲基甲酰胺,2毫升甲苯,反应体系在90℃搅拌反应12小时,停止加热及搅拌,冷却至室温。乙酸乙酯萃取反应液,减压旋蒸去除溶剂,再通过柱层析分离纯化,得到目标产物,所用的柱层析洗脱液为体积比为1:2的石油醚:乙酸乙酯混合溶剂,得产物主要非对映异构体,产率为65%。
本实施例所得产物的结构表征数据如下所示:
1H NMR(400MHz,CDCl3):δ=8.21(d,J=8.8Hz,2H),7.99(d,J=8.8Hz,2H),7.94(d,J=8.4Hz,2H),7.51(t,J=7.6Hz,2H),7.27-7.31(m,2H),7.13(d,J=8.4Hz,2H),6.94(s,2H),2.72(s,24H);
13C NMR(100MHz,CDCl3):δ=155.1,140.2,134.9,133.9,133.2,131.7,128.9,128.3,127.3,126.6,122.1,37.4;
IR(KBr):2931,2861,1693,1483,1452,1374,1262,1155,1057(cm-1);
HRMS ESI(m/z):[M+Na]+Calcd.for C34H38N8O4+Na,645.2908;found,645.2913.。
根据以上数据推断本实施例所得产物的结构如下式所示:
实施例20
在装有回流冷凝管25毫升反应瓶中,加入0.2毫摩尔苯乙酮对甲苯磺酰腙,0.2毫摩尔碳酸铯,0.01毫摩尔三氟乙酸钯,0.1毫摩尔偶氮二甲酰胺二哌啶,2毫升甲苯,反应体系在90℃搅拌反应24小时,停止加热及搅拌,冷却至室温。乙酸乙酯萃取反应液,减压旋蒸去除溶剂,再通过柱层析分离纯化,得到目标产物,所用的柱层析洗脱液为体积比为2:1的石油醚:乙酸乙酯混合溶剂,得产物主要非对映异构体,产率为89%。
本实施例所得产物的结构表征数据如下所示:
1H NMR(400MHz,CDCl3):δ=7.81-7.84(m,2H),7.37-7.33(m,3H),3.47(brs,9H),2.18(s,3H),1.61(brs,13H);
13C NMR(100MHz,CDCl3):δ=162.3,156.9,137.8,129.8,128.2,126.7,46.1,25.8,24.5,16.8;
IR(KBr):2934,2856,1679,1425,1225,1145,1022(cm-1);
HRMS ESI(m/z):[M+H]+Calcd.for C20H28N4O2+H,357.2285;found,357.2283。
根据以上数据推断本实施例所得产物主要非对映异构体的结构如下式所示:
上述实施例为本发明较佳的实施方式,但本发明的实施方式并不受上述实施例的限制,其它的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化,均应为等效的置换方式,都包含在本发明的保护范围之内。
Claims (7)
1.一种N,N-二酰胺基取代腙衍生物的合成方法,其特征在于包括以下操作步骤:
在反应器中,加入N-对甲苯磺酰基腙、偶氮二烷基二酰胺、碱、钯盐催化剂和溶剂,在70~90℃下搅拌反应12~24小时,反应结束后冷却至室温,乙酸乙酯萃取反应液,减压蒸除溶剂得粗产物,经柱层析提纯得到N,N-二酰胺基腙衍生物;
所述的N-对甲苯磺酰基腙为1-茚酮对甲苯磺酰腙、1-四氢萘酮对甲苯磺酰腙或1-苯并环庚酮对甲苯磺酰腙;其中,Ts表示对甲苯磺酰基,R1为苯基、对氟苯基、间氟苯基、邻氟苯基、对氯苯基、间氯苯基、对溴苯基、间溴苯基、对碘苯基、对甲苯基、对甲氧基苯基、对甲硫基苯基、对氰基苯基、对甲砜基苯基、对甲酸甲酯基苯基、对三氟甲基苯基、对硝基苯基、3,4-二氯苯基、3,4-二甲氧基苯基、2-萘基、2-噻吩基、3-吡啶基或2-苯基乙基;R2为氢、甲基、乙基、丙基、异丙基、环丙基、环丁基或叔丁基;
所述的偶氮二烷基二酰胺为其中,R为甲基,乙基,异丙基,环己基或叔丁基。
2.根据权利要求1所述的一种N,N-二酰胺基取代腙衍生物的合成方法,其特征在于:所述N-对甲苯磺酰基腙与偶氮二烷基二酰胺的摩尔比为(1~2):1。
3.根据权利要求1所述的一种N,N-二酰胺基取代腙衍生物的合成方法,其特征在于:所述的碱是指碳酸钠、碳酸钾、碳酸铯、氢氧化钠、甲醇钠、乙酸钠、叔丁醇钾和叔丁醇钠中的一种或两种以上;碱的加入量与N-对甲苯磺酰基腙的摩尔比为(1~1.5):1。
4.根据权利要求1所述的一种N,N-二酰胺基取代腙衍生物的合成方法,其特征在于:所述钯盐催化剂为醋酸钯、氯化钯、溴化钯、三氟乙酸钯、二氯二三苯基膦钯、四三苯基磷钯、三(二亚苄基丙酮)二钯、双(乙腈)二氯钯(II)、(1,5-环辛二烯)二氯化钯(II)中的一种或两种以上;钯盐催化剂的加入量与偶氮二烷基二酰胺的摩尔比为0.1:1。
5.根据权利要求1所述的一种N,N-二酰胺基取代腙衍生物的合成方法,其特征在于:所述的溶剂是指甲苯、苯、二甲苯、1,2-二氯乙烷、四氢呋喃和乙腈中的一种或两种以上的混合。
6.根据权利要求1所述的一种N,N-二酰胺基取代腙衍生物的合成方法,其特征在于:所述的柱层析提纯是指以体积比为(1~2):1的石油醚:乙酸乙酯的混合溶剂为洗脱液的柱层析提纯。
7.一种N,N-二酰胺基取代腙衍生物,其特征在于:通过权利要求1~6任一项所述的方法制备得到。
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