CN114920616B - 一种脒类化合物的合成工艺 - Google Patents
一种脒类化合物的合成工艺 Download PDFInfo
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- CN114920616B CN114920616B CN202210706106.8A CN202210706106A CN114920616B CN 114920616 B CN114920616 B CN 114920616B CN 202210706106 A CN202210706106 A CN 202210706106A CN 114920616 B CN114920616 B CN 114920616B
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- reaction
- sulfonamide
- compound
- triphenylphosphine
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- -1 amidine compound Chemical class 0.000 title claims abstract description 85
- 238000000034 method Methods 0.000 title claims abstract description 35
- 238000003786 synthesis reaction Methods 0.000 title claims abstract description 31
- 230000015572 biosynthetic process Effects 0.000 title claims abstract description 30
- 238000006243 chemical reaction Methods 0.000 claims abstract description 78
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims abstract description 58
- 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 abstract description 58
- 229940124530 sulfonamide Drugs 0.000 claims abstract description 21
- ZHNUHDYFZUAESO-UHFFFAOYSA-N formamide Substances NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000002994 raw material Substances 0.000 claims abstract description 5
- 238000011065 in-situ storage Methods 0.000 claims abstract description 4
- 150000004714 phosphonium salts Chemical class 0.000 claims abstract description 4
- 239000012190 activator Substances 0.000 claims abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 133
- 229910052757 nitrogen Inorganic materials 0.000 claims description 39
- 238000001308 synthesis method Methods 0.000 claims description 8
- 230000002194 synthesizing effect Effects 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- 125000005842 heteroatom Chemical group 0.000 claims description 7
- 229910052717 sulfur Inorganic materials 0.000 claims description 7
- 125000001424 substituent group Chemical group 0.000 claims description 5
- 125000003118 aryl group Chemical group 0.000 claims description 4
- 239000007810 chemical reaction solvent Substances 0.000 claims description 4
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 4
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims 2
- 125000006737 (C6-C20) arylalkyl group Chemical group 0.000 claims 1
- 239000000758 substrate Substances 0.000 abstract description 5
- 125000004421 aryl sulphonamide group Chemical group 0.000 abstract description 4
- ABOYDMHGKWRPFD-UHFFFAOYSA-N phenylmethanesulfonamide Chemical compound NS(=O)(=O)CC1=CC=CC=C1 ABOYDMHGKWRPFD-UHFFFAOYSA-N 0.000 abstract description 4
- 230000003213 activating effect Effects 0.000 abstract description 3
- 239000003795 chemical substances by application Substances 0.000 abstract description 3
- 238000006482 condensation reaction Methods 0.000 abstract description 3
- 150000001408 amides Chemical class 0.000 abstract description 2
- 125000000524 functional group Chemical group 0.000 abstract description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 abstract 1
- 150000003948 formamides Chemical class 0.000 abstract 1
- 125000000623 heterocyclic group Chemical group 0.000 abstract 1
- 239000012299 nitrogen atmosphere Substances 0.000 abstract 1
- 239000002243 precursor Substances 0.000 abstract 1
- 238000005481 NMR spectroscopy Methods 0.000 description 45
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 42
- 239000000047 product Substances 0.000 description 41
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 32
- 238000004440 column chromatography Methods 0.000 description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 21
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 20
- 239000012043 crude product Substances 0.000 description 20
- 239000012044 organic layer Substances 0.000 description 20
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 20
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 18
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 9
- LMYRWZFENFIFIT-UHFFFAOYSA-N toluene-4-sulfonamide Chemical compound CC1=CC=C(S(N)(=O)=O)C=C1 LMYRWZFENFIFIT-UHFFFAOYSA-N 0.000 description 7
- KHBQMWCZKVMBLN-UHFFFAOYSA-N Benzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CC=C1 KHBQMWCZKVMBLN-UHFFFAOYSA-N 0.000 description 6
- 239000003054 catalyst Substances 0.000 description 6
- AWICAOQZHLERQF-UHFFFAOYSA-N n,n-dimethyl-n'-(4-methylphenyl)sulfonylmethanimidamide Chemical compound CN(C)C=NS(=O)(=O)C1=CC=C(C)C=C1 AWICAOQZHLERQF-UHFFFAOYSA-N 0.000 description 5
- KGPBEOXRCQCABU-UHFFFAOYSA-N N'-(4-methoxyphenyl)sulfonyl-N,N-dimethylmethanimidamide Chemical compound COc1ccc(cc1)S(=O)(=O)N=CN(C)C KGPBEOXRCQCABU-UHFFFAOYSA-N 0.000 description 4
- SXVAHNFISJOTHN-UHFFFAOYSA-N N'-benzylsulfonyl-N,N-dimethylmethanimidamide Chemical compound CN(C)C=NS(=O)(=O)Cc1ccccc1 SXVAHNFISJOTHN-UHFFFAOYSA-N 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 239000012467 final product Substances 0.000 description 4
- 238000009776 industrial production Methods 0.000 description 4
- LCEDQNDDFOCWGG-UHFFFAOYSA-N morpholine-4-carbaldehyde Chemical compound O=CN1CCOCC1 LCEDQNDDFOCWGG-UHFFFAOYSA-N 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 3
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical group C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 3
- 125000004422 alkyl sulphonamide group Chemical group 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 230000007547 defect Effects 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000007800 oxidant agent Substances 0.000 description 3
- CIHOLLKRGTVIJN-UHFFFAOYSA-N tert‐butyl hydroperoxide Chemical compound CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 description 3
- FEWLNYSYJNLUOO-UHFFFAOYSA-N 1-Piperidinecarboxaldehyde Chemical compound O=CN1CCCCC1 FEWLNYSYJNLUOO-UHFFFAOYSA-N 0.000 description 2
- AGRIQBHIKABLPJ-UHFFFAOYSA-N 1-Pyrrolidinecarboxaldehyde Chemical compound O=CN1CCCC1 AGRIQBHIKABLPJ-UHFFFAOYSA-N 0.000 description 2
- KTFDYVNEGTXQCV-UHFFFAOYSA-N 2-Thiophenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CS1 KTFDYVNEGTXQCV-UHFFFAOYSA-N 0.000 description 2
- RGOJCHYYBKMRLL-UHFFFAOYSA-N 4-(trifluoromethoxy)benzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=C(OC(F)(F)F)C=C1 RGOJCHYYBKMRLL-UHFFFAOYSA-N 0.000 description 2
- STYQHICBPYRHQK-UHFFFAOYSA-N 4-bromobenzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=C(Br)C=C1 STYQHICBPYRHQK-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- UEXCJVNBTNXOEH-UHFFFAOYSA-N Ethynylbenzene Chemical group C#CC1=CC=CC=C1 UEXCJVNBTNXOEH-UHFFFAOYSA-N 0.000 description 2
- PNKUSGQVOMIXLU-UHFFFAOYSA-N Formamidine Chemical compound NC=N PNKUSGQVOMIXLU-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- NQOZOCJHTQZUFB-UHFFFAOYSA-N N,N-diethyl-N'-(4-methylphenyl)sulfonylmethanimidamide Chemical compound CCN(CC)C=NS(=O)(=O)C1=CC=C(C)C=C1 NQOZOCJHTQZUFB-UHFFFAOYSA-N 0.000 description 2
- FVWOKBZMZNLHRZ-UHFFFAOYSA-N N,N-dimethyl-N'-(4-nitrophenyl)sulfonylmethanimidamide Chemical compound CN(C)C=NS(=O)(=O)C1=CC=C(C=C1)[N+](=O)[O-] FVWOKBZMZNLHRZ-UHFFFAOYSA-N 0.000 description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 150000001409 amidines Chemical class 0.000 description 2
- 150000003857 carboxamides Chemical class 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 125000004185 ester group Chemical group 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- SQXPQOHYLPTCHJ-UHFFFAOYSA-N n'-(5-bromothiophen-2-yl)sulfonyl-n,n-dimethylmethanimidamide Chemical compound CN(C)C=NS(=O)(=O)C1=CC=C(Br)S1 SQXPQOHYLPTCHJ-UHFFFAOYSA-N 0.000 description 2
- QXJFYAWCKNBRJO-UHFFFAOYSA-N n-methyl-n'-(4-methylphenyl)sulfonyl-n-phenylmethanimidamide Chemical compound C=1C=CC=CC=1N(C)C=NS(=O)(=O)C1=CC=C(C)C=C1 QXJFYAWCKNBRJO-UHFFFAOYSA-N 0.000 description 2
- 125000001736 nosyl group Chemical group S(=O)(=O)(C1=CC=C([N+](=O)[O-])C=C1)* 0.000 description 2
- 238000005457 optimization Methods 0.000 description 2
- 230000001590 oxidative effect Effects 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- SJHPCNCNNSSLPL-CSKARUKUSA-N (4e)-4-(ethoxymethylidene)-2-phenyl-1,3-oxazol-5-one Chemical compound O1C(=O)C(=C/OCC)\N=C1C1=CC=CC=C1 SJHPCNCNNSSLPL-CSKARUKUSA-N 0.000 description 1
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 1
- UIYMPDRCTPYBLI-UHFFFAOYSA-N 2-(2-methoxyethoxy)benzenesulfonamide Chemical compound COCCOC1=CC=CC=C1S(N)(=O)=O UIYMPDRCTPYBLI-UHFFFAOYSA-N 0.000 description 1
- TUCRZHGAIRVWTI-UHFFFAOYSA-N 2-bromothiophene Chemical group BrC1=CC=CS1 TUCRZHGAIRVWTI-UHFFFAOYSA-N 0.000 description 1
- MQQJFLHZXQRKKJ-UHFFFAOYSA-N 2-methoxy-5-(2-oxopropyl)benzenesulfonamide Chemical compound COC1=CC=C(CC(C)=O)C=C1S(N)(=O)=O MQQJFLHZXQRKKJ-UHFFFAOYSA-N 0.000 description 1
- APHNQOGPYLTSFX-UHFFFAOYSA-N 3-tert-butyl-1,2-oxazol-5-amine Chemical compound CC(C)(C)C=1C=C(N)ON=1 APHNQOGPYLTSFX-UHFFFAOYSA-N 0.000 description 1
- YGJKWZMVXNZAOT-UHFFFAOYSA-N 3-thiophen-3-yl-1,2-oxazol-5-amine Chemical compound O1C(N)=CC(C2=CSC=C2)=N1 YGJKWZMVXNZAOT-UHFFFAOYSA-N 0.000 description 1
- MSFQEZBRFPAFEX-UHFFFAOYSA-N 4-methoxybenzenesulfonamide Chemical compound COC1=CC=C(S(N)(=O)=O)C=C1 MSFQEZBRFPAFEX-UHFFFAOYSA-N 0.000 description 1
- QWKKYJLAUWFPDB-UHFFFAOYSA-N 4-nitrobenzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=C([N+]([O-])=O)C=C1 QWKKYJLAUWFPDB-UHFFFAOYSA-N 0.000 description 1
- WXJQQLDICAOBJB-UHFFFAOYSA-N 5-bromothiophene-2-sulfonamide Chemical compound NS(=O)(=O)C1=CC=C(Br)S1 WXJQQLDICAOBJB-UHFFFAOYSA-N 0.000 description 1
- JUKYGWLXURRKNE-UHFFFAOYSA-N C1(=CC=CC=C1)S(=O)(=O)N.C(OC)(O)O Chemical compound C1(=CC=CC=C1)S(=O)(=O)N.C(OC)(O)O JUKYGWLXURRKNE-UHFFFAOYSA-N 0.000 description 1
- 125000003358 C2-C20 alkenyl group Chemical group 0.000 description 1
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 1
- 101100391174 Dictyostelium discoideum forC gene Proteins 0.000 description 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- SUAKHGWARZSWIH-UHFFFAOYSA-N N,N‐diethylformamide Chemical compound CCN(CC)C=O SUAKHGWARZSWIH-UHFFFAOYSA-N 0.000 description 1
- 241000935974 Paralichthys dentatus Species 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 230000000895 acaricidal effect Effects 0.000 description 1
- 239000000642 acaricide Substances 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940124599 anti-inflammatory drug Drugs 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 150000001502 aryl halides Chemical class 0.000 description 1
- JPYQFYIEOUVJDU-UHFFFAOYSA-N beclamide Chemical compound ClCCC(=O)NCC1=CC=CC=C1 JPYQFYIEOUVJDU-UHFFFAOYSA-N 0.000 description 1
- 150000003937 benzamidines Chemical class 0.000 description 1
- 125000003865 brosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Br)S(*)(=O)=O 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 description 1
- 239000012954 diazonium Substances 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-O diazynium Chemical compound [NH+]#N IJGRMHOSHXDMSA-UHFFFAOYSA-O 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 238000002848 electrochemical method Methods 0.000 description 1
- 239000007772 electrode material Substances 0.000 description 1
- 125000006575 electron-withdrawing group Chemical group 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000004880 explosion Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 150000002463 imidates Chemical class 0.000 description 1
- 150000002466 imines Chemical class 0.000 description 1
- 239000000077 insect repellent Substances 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 description 1
- YBERTMQAGHYOFM-UHFFFAOYSA-N methyl 2-(dimethylaminomethylideneamino)sulfonylbenzoate Chemical compound COC(=O)C1=CC=CC=C1S(=O)(=O)N=CN(C)C YBERTMQAGHYOFM-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- ALORMAUGCHGNLU-UHFFFAOYSA-N n'-(4-bromophenyl)sulfonyl-n,n-dimethylmethanimidamide Chemical compound CN(C)C=NS(=O)(=O)C1=CC=C(Br)C=C1 ALORMAUGCHGNLU-UHFFFAOYSA-N 0.000 description 1
- OTHBCWKTCXJYAW-UHFFFAOYSA-N n,n-dibenzylformamide Chemical compound C=1C=CC=CC=1CN(C=O)CC1=CC=CC=C1 OTHBCWKTCXJYAW-UHFFFAOYSA-N 0.000 description 1
- JIKUXBYRTXDNIY-UHFFFAOYSA-N n-methyl-n-phenylformamide Chemical compound O=CN(C)C1=CC=CC=C1 JIKUXBYRTXDNIY-UHFFFAOYSA-N 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- HSVFKFNNMLUVEY-UHFFFAOYSA-N sulfuryl diazide Chemical compound [N-]=[N+]=NS(=O)(=O)N=[N+]=[N-] HSVFKFNNMLUVEY-UHFFFAOYSA-N 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- NDLIRBZKZSDGSO-UHFFFAOYSA-N tosyl azide Chemical compound CC1=CC=C(S(=O)(=O)[N-][N+]#N)C=C1 NDLIRBZKZSDGSO-UHFFFAOYSA-N 0.000 description 1
- 238000006257 total synthesis reaction Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B43/00—Formation or introduction of functional groups containing nitrogen
-
- 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
- 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
- C07D295/04—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/12—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
- C07D295/125—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
-
- 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
- C07D333/26—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D333/30—Hetero atoms other than halogen
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Abstract
本发明公开了一种脒类化合物的合成工艺;在氮气氛围下,以三苯基膦和四氯化碳原位生成的鏻盐为活化剂,磺酰胺类化合物与甲酰胺类化合物在40℃下发生缩合反应,生成N‑磺酰基脒化合物;其中三苯基膦与四氯化碳为活化剂前体;磺酰胺类化合物包括芳基磺酰胺、苄基磺酰胺、杂环磺酰胺;同时,该方法将底物范围进行了拓展,异噁唑胺也可以完成此反应;甲酰胺类化合物包括芳基甲酰胺、杂环甲酰胺,以及N上连有苄基的酰胺。该方法所需原料简单易得,反应条件温和、操作简单,反应收率高,底物官能团兼容性优异。
Description
技术领域
本发明涉及有机中间体合成技术领域,尤其涉及一种脒类化合物的合成工艺。
背景技术
脒是一类重要的含氮有机化合物,应用广泛。首先,脒类化合物因其独特的结构(R1-N=C-N-R2),成为有机合成中的重要砌块,常用于各种含氮杂环化合物的制备,如通过脒类化合物合成嘧啶、噻唑、苯并咪唑等。其次,脒类化合物因其独特的生理活性,成为重要的医药、农药中间体,广泛存在于抗生素、消炎药、驱虫剂和广谱杀螨剂中,如脒盐可以治疗吸虫病,长链烷氧基取代的苯甲脒盐具有表面活性剂的作用。因此,脒类化合物的合成具有重要的理论意义和工业实用价值。
目前,合成脒类化合物的方法有:
方法一:使用锌作催化剂,回流12小时,酰胺和磺酰胺直接缩合,生成了脒化合物。
该方法的局限在于:使用过渡金属作催化剂和重氮酸酯原料,对环境的危害大,且试剂价格昂贵,成本高,具有爆炸危险,不利于工业化生产。
方法二:使用氯化钯作催化剂,芳基卤化物、异氰化物和酚在高温下反应,得到亚胺中间体,该中间体再通过酰亚胺酯一锅法得到脒化合物。
该方法的弊端在于:使用贵金属氯化钯作催化剂,价格昂贵,成本高。除此之外,反应需在加热条件下进行,存在一定的安全风险。
方法三:使用叔丁基过氧化氢作氧化剂,1,2-二氯乙烷作溶剂,对甲苯磺酰叠氮与胺在80℃下反应,得到了脒化合物。
该方法的弊端在于:使用叔丁基过氧化氢作氧化剂,该品为一级有机氧化剂,高温时易爆炸,存在较大的危险性。除此之外,该合成方法仅限于脂肪族胺,底物受限大。
方法四:醋酸铜于膦配体中作催化体系,氯仿作溶剂,噁唑酮、端基苯乙炔与二异丙基胺反应得到脒化合物。
该方法的局限在于:底物受限,伯胺等小位阻的胺都无法由此策略得到相应的酰基脒,只有使用较大位阻的仲胺反应才有较好的选择性。
方法五:使用电化学的方法,以磺酰叠氮化物和脂肪胺为原料合成磺酰脒。
该方法的弊端在于:电化学电极材料成本高,技术普及面不够广泛,工业化生产实现困难。
综上所述,尽管目前脒类化合物的合成方法多种多样,但是合成策略仍面临着反应条件苛刻、需金属参与、成本高、普适性不高等问题。
发明内容
针对上述存在的问题,本发明目的在于提供一种操作简便、所需试剂和操作都比较安全,且官能团耐受性好,易于在工业生产推广,反应产率高的脒类化合物的合成工艺。
为了达到上述目的,本发明采用的技术方案如下:一种脒类化合物的合成工艺,所述工艺的合成方法如下:
其中,活化剂为三苯基膦和四氯化碳原位生成的鏻盐;
R1、R2、R3均为取代基,三者可以相同或不同;取代基选自:C1-C20烷基、C2-C20烯基、C1-C20的烃基氧基、C6-C20芳基、包含1-5个O、N、S杂原子的5-10元杂芳基、C2-C30的酯基、碳原子数在2-20包含1-5个O、N、S杂原子的环烷基、三氟甲基或卤素。
本发明的合成方法中取代基R1、R2、R3优选为:C1-C10烷基、C6-C20芳基、包含1-5个O、N、S杂原子的5-10元杂芳基、C2-C20的酯基、碳原子数在2-10包含1-5个O、N、S杂原子的烷基和环烷基、三氟甲基或卤素;当取代基R1、R2、R3为上述优选方案时,工艺最终产品的收率较高。
本发明所述的甲酰胺类化合物与磺酰胺类化合物的摩尔比为1~3:1;优选的摩尔比为3:1;当甲酰胺类化合物与磺酰胺类化合物摩尔比为3:1时,最终产品的收率达到最高。
本发明所述的四氯化碳与磺酰胺类化合物摩尔比为1~1.5:1,优选的摩尔比为1.2:1;当四氯化碳与磺酰胺类化合物摩尔比为1.2:1时,最终产品的收率达到最高。
本发明所述的三苯基膦与磺酰胺类化合物摩尔比为1~2:1,优选的摩尔比为2:1;当三苯基膦与磺酰胺类化合物摩尔比2:1时,最终产品收率高。
本发明所述的合成方法中反应溶剂为二氯甲烷或N,N-二甲基甲酰胺,本发明以单一有机溶剂为反应体系,如有其他需要,体系中可以存在其他有机溶剂,但从反应效率和操作的简洁性角度考虑,优选为不加其他有机溶剂,即以单一有机溶剂作为反应体系;原料磺酰胺类化合物在反应溶剂中的摩尔浓度为0.1mmol/mL。
本发明所述的合成方法中反应温度20~50℃,优选40℃;反应时间为8~18h,优选12h;本发明的反应温度和反应时间可以由技术人员按照不同的甲酰胺而定,根据实际需要自行确定。
一种脒类化合物的精制方法,所述的精制方法如下:反应完成后,用水洗涤反应液,二氯甲烷萃取三次,经柱层析分离,得到精制后的脒类化合物。
本发明的优点在于:本发明是一种适用范围广的合成脒类化合物的方法,本方法适用于合成多种脒类化合物。对于磺酰胺类化合物,无论是芳基磺酰胺、烷基磺酰胺,还是杂环磺酰胺,都有良好的耐受性,芳基磺酰胺包含苯环上连有吸电子基团、供电子基团的化合物,烷基磺酰胺主要为苄基磺酰胺,杂环磺酰胺包括噻吩环、吡啶环、双氮杂环、溴代噻吩环,同时异噁唑胺类化合物也可以兼容。对于甲酰胺类化合物,大多数的甲酰胺都能兼容,如吗啉、芳基甲酰胺、环状甲酰胺,以及N上连有苄基的酰胺。
本发明以简单易得的磺酰胺类化合物作为反应底物,与甲酰胺类化合物进行缩合反应,用商业可购买的四氯化碳与三苯基膦作为活化剂,反应温度为40℃,在氮气条件下简单高效地合成了脒类化合物。与其他合成脒类化合物的方法相比,本发明所述策略条件温和、原料易得,不需金属催化剂,成本低,对环境友好,可推广至工业生产。
本发明可以广泛应用于工业和学术界的药物合成、天然产物的全合成中,具有较高的应用价值。
附图说明
图1为实施例1所述N,N-二甲基-N'-对甲苯磺酰基甲脒的核磁氢谱图;
图2为实施例1所述N,N-二甲基-N'-对甲苯磺酰基甲脒的核磁碳谱图;
图3为实施例3所述N,N-二甲基-N'-((4-甲氧基苯基)磺酰基)甲脒的核磁氢谱图;
图4为实施例3所述N,N-二甲基-N'-((4-甲氧基苯基)磺酰基)甲脒的核磁碳谱图;
图5为实施例5所述N,N-二甲基-N'-((4-硝基苯基)磺酰基)甲脒的核磁氢谱图;
图6为实施例5所述N,N-二甲基-N'-((4-硝基苯基)磺酰基)甲脒的核磁碳谱图;
图7为实施例8所述N,N-二甲基-N'-((4-氟苯基)磺酰基)甲脒的核磁氢谱图;
图8为实施例8所述N,N-二甲基-N'-((4-氟苯基)磺酰基)甲脒的核磁碳谱图;
图9为实施例10所述N,N-二甲基-N'-(苄基磺酰基)甲脒的核磁氢谱图;
图10为实施例10所述N,N-二甲基-N'-(苄基磺酰基)甲脒的核磁碳谱图。
具体实施方式
下面结合附图说明和具体实施方式对本发明作进一步详细的描述。
以下具体实施例中所用的原料均商业可购买,各试剂必要时采用本领域公知的手段进行纯化后使用。
在本发明中,“磺酰胺类化合物”具有本领域技术人员所通常理解的含义,即含有与磺酰基直接相连的胺类化合物,例如对甲苯磺酰胺、对甲氧基苯磺酰胺、对溴苯磺酰胺、对三氟甲氧基苯磺酰胺、苄基磺酰胺、噻吩磺酰胺及其各种衍生物。
在本发明中,“甲酰胺类化合物”具有本领域技术人员所通常理解的含义,即含有与甲醛中碳原子连接的胺类化合物,例如N,N-二甲基甲酰胺、N-甲酰基吗啉、N-甲酰吡咯烷、N,N-二苄基甲酰胺、N,N-二乙基甲酰胺及其各种衍生物。
以下具体实施例中所用的原料均商业可购买,各试剂必要时采用本领域公知的手段进行纯化后使用。
1H NMR和13C NMR均采用Bruker Avance 400 spectrometer仪器进行测定。测试温度为室温,溶剂为氘代氯仿(CDCl3)与氘代二甲基亚砜(DMSO-d6),选取参考:1H NMR:CDCl3为7.26ppm;DMSO-d6为2.50ppm;13C NMR:CHCl3为77.0ppm;DMSO-d6为33.5ppm。
实施例1:N,N-二甲基-N'-对甲苯磺酰基甲脒的合成
室温下,在干燥、氮气反复置换3次的25mL史莱克反应管中依次加入对甲苯磺酰胺(51.0mg,0.30mmol)、三苯基膦(157.4mg,0.60mmol)、二氯甲烷(3mL)以及四氯化碳(35μL,0.36mmol)和N,N-二甲基甲酰胺(70μL,0.90mmol),40℃下反应12小时。在反应体系中加入水(10mL)淬灭反应,二氯甲烷萃取三次,每次10mL,有机层用饱和食盐水洗涤,无水硫酸钠干燥,过滤旋蒸后得到粗品,并进一步使用柱层析分离纯化,得到产物52.9mg,产率为78%。
产物N,N-二甲基-N'-对甲苯磺酰基甲脒:1H NMR(400MHz,CDCl3)δ8.11(s,1H),7.75–7.73(m,2H),7.24–7.22(m,2H),3.10(s,3H),2.98(s,3H),2.37(s,3H)ppm.13C NMR(101MHz,CDCl3)δ159.0,142.3,139.4,129.2,126.4,41.4,35.4,21.4ppm.
实施例2:N,N-二甲基-N'-((2-(2-甲氧基乙氧基)苯基)磺酰基)甲脒的合成
室温下,在干燥、氮气反复置换3次的25mL史莱克反应管中依次加入2-(2-甲氧基乙氧基)苯磺酰胺(69.4mg,0.30mmol)、三苯基膦(157.4mg,0.60mmol)、二氯甲烷(3mL)以及四氯化碳(35μL,0.36mmol)和N,N-二甲基甲酰胺(70μL,0.90mmol),40℃下反应12小时。在反应体系中加入水(10mL)淬灭反应,二氯甲烷萃取三次,每次10mL,有机层用饱和食盐水洗涤,无水硫酸钠干燥,过滤旋蒸后得到粗品,并进一步使用柱层析分离纯化,得到产物49.8mg,产率为58%。
产物N,N-二甲基-N'-((2-(2-甲氧基乙氧基)苯基)磺酰基)甲脒:1H NMR(400MHz,CDCl3)δ8.11(s,1H),7.77–7.69(m,2H),7.61–7.52(m,2H),3.12(s,3H),3.00(s,3H)ppm.13CNMR(101MHz,CDCl3)δ159.1,141.4,131.8,128.0,126.5,41.5,35.5ppm.HRMS(ESI)forC12H18氮气O4S[M+H]+:calcd.287.1060;found 287.1051.
实施例3:N,N-二甲基-N'-((4-甲氧基苯基)磺酰基)甲脒的合成
室温下,在干燥、氮气反复置换3次的25mL史莱克反应管中依次加入对甲氧基苯磺酰胺(56.2mg,0.30mmol)、三苯基膦(157.4mg,0.60mmol)、二氯甲烷(3mL)以及四氯化碳(35μL,0.36mmol)和N,N-二甲基甲酰胺(70μL,0.90mmol),40℃下反应12小时。在反应体系中加入水(10mL)淬灭反应,二氯甲烷萃取三次,每次10mL,有机层用饱和食盐水洗涤,无水硫酸钠干燥,过滤旋蒸后得到粗品,并进一步使用柱层析分离纯化,得到产物46.5mg,产率为64%。
产物N,N-二甲基-N'-((4-甲氧基苯基)磺酰基)甲脒:1H NMR(400MHz,CDCl3)δ8.09(s,1H),7.84–7.72(m,2H),6.96–6.85(m,2H),3.81(s,3H),3.08(s,3H),2.97(s,3H)ppm.13CNMR(101MHz,CDCl3)δ162.1,158.8,134.2,128.3,113.7,55.4,41.3,35.3ppm.
实施例4:N,N-二甲基-N'-((4-溴苯基)磺酰基)甲脒的合成
室温下,在干燥、氮气反复置换3次的25mL史莱克反应管中依次加入对溴苯磺酰胺(70.8mg,0.30mmol)、三苯基膦(157.4mg,0.60mmol)、二氯甲烷(3mL)以及四氯化碳(35μL,0.36mmol)和N,N-二甲基甲酰胺(70μL,0.9mmol),40℃下反应12小时。在反应体系中加入水(10mL)淬灭反应,二氯甲烷萃取三次,每次10mL,有机层用饱和食盐水洗涤,无水硫酸钠干燥,过滤旋蒸后得到粗品,并进一步使用柱层析分离纯化,得到产物63.5mg,产率为73%。
产物N,N-二甲基-N'-((4-溴苯基)磺酰基)甲脒:1H NMR(400MHz,CDCl3)δ8.11(s,1H),7.77–7.69(m,2H),7.61–7.52(m,2H),3.12(s,3H),3.00(s,3H)ppm.13C NMR(101MHz,CDCl3)δ159.1,141.4,131.8,128.0,126.5,41.5,35.5ppm.
实施例5:N,N-二甲基-N'-((4-硝基苯基)磺酰基)甲脒的合成
室温下,在干燥、氮气反复置换3次的25mL史莱克反应管中依次加入对硝基苯磺酰胺(60.7mg,0.30mmol)、三苯基膦(157.4mg,0.60mmol)、二氯甲烷(3mL)以及四氯化碳(35μL,0.36mmol)和N,N-二甲基甲酰胺(70μL,0.90mmol),40℃下反应12小时。在反应体系中加入水(10mL)淬灭反应,二氯甲烷萃取三次,每次10mL,有机层用饱和食盐水洗涤,无水硫酸钠干燥,过滤旋蒸后得到粗品,并进一步使用柱层析分离纯化,得到产物41.6mg,产率为54%。
产物N,N-二甲基-N'-((4-硝基苯基)磺酰基)甲脒:1H NMR(400MHz,DMSO)δ8.38–8.31(m,2H),8.28(s,1H),8.10–7.98(m,2H),3.17(s,3H),2.93(s,3H)ppm.13C NMR(101MHz,DMSO)δ160.2,149.1,148.5,127.5,127.2,124.4,41.1,35.2ppm.
实施例6:2-(N-((二甲基氨基)亚甲基)氨磺酰基)苯甲酸甲酯的合成
室温下,在干燥、氮气反复置换3次的25mL史莱克反应管中依次加入邻甲酸甲酯苯磺酰胺(64.6mg,0.30mmol)、三苯基膦(157.4mg,0.60mmol)、二氯甲烷(3mL)以及四氯化碳(35μL,0.36mmol)和N,N-二甲基甲酰胺(70μL,0.90mmol),40℃下反应12小时。在反应体系中加入水(10mL)淬灭反应,二氯甲烷萃取三次,每次10mL,有机层用饱和食盐水洗涤,无水硫酸钠干燥,过滤旋蒸后得到粗品,并进一步使用柱层析分离纯化,得到产物34mg,产率为42%。
产物2-(N-((二甲基氨基)亚甲基)氨磺酰基)苯甲酸甲酯:1H NMR(400MHz,CDCl3)δ8.25–7.96(m,2H),7.66–7.42(m,3H),3.92(s,3H),3.14(s,3H),3.00(s,3H)ppm.13C NMR(101MHz,CDCl3)δ168.4,160.6,140.1,131.6,131.5,130.5,128.9,128.4,52.9,41.5,35.5ppm.
实施例7:N,N-二甲基-N'-((4-(三氟甲氧基)苯基)磺酰基)甲脒的合成
室温下,在干燥、氮气反复置换3次的25mL史莱克反应管中依次加入对三氟甲氧基苯磺酰胺(72.4mg,0.30mmol)、三苯基膦(157.4mg,0.60mmol)、二氯甲烷(3mL)以及四氯化碳(35μL,0.36mmol)和N,N-二甲基甲酰胺(70μL,0.90mmol),40℃下反应12小时。在反应体系中加入水(10mL)淬灭反应,二氯甲烷萃取三次,每次10mL,有机层用饱和食盐水洗涤,无水硫酸钠干燥,过滤旋蒸后得到粗品,并进一步使用柱层析分离纯化,得到产物63.1mg,产率为71%。
产物N,N-二甲基-N'-((4-(三氟甲氧基)苯基)磺酰基)甲脒:1H NMR(400MHz,CDCl3)δ8.12(s,1H),7.95–7.87(m,2H),7.30–7.21(m,2H),3.13(s,3H),3.00(s,3H)ppm.13CNMR(101MHz,CDCl3)δ159.2,151.4(q,JC-F=1.7Hz),140.9,128.5,120.7,120.1(q,JC-F=259.7Hz),41.5,35.5ppm.HRMS(ESI)for C10H11F3氮气O3S[M+H]+:calcd.297.0515;found297.0507.
实施例8:N,N-二甲基-N'-((4-氟苯基)磺酰基)甲脒的合成
室温下,在干燥、氮气反复置换3次的25mL史莱克反应管中依次加入对氟苯磺酰胺(53.0mg,0.30mmol)、三苯基膦(157.4mg,0.60mmol)、二氯甲烷(3mL)以及四氯化碳(35μL,0.36mmol)和N,N-二甲基甲酰胺(70μL,0.90mmol),40℃下反应12小时。在反应体系中加入水(10mL)淬灭反应,二氯甲烷萃取三次,每次10mL,有机层用饱和食盐水洗涤,无水硫酸钠干燥,过滤旋蒸后得到粗品,并进一步使用柱层析分离纯化,得到产物51.8mg,产率为75%。
产物N,N-二甲基-N'-((4-氟苯基)磺酰基)甲脒:1H NMR(400MHz,CDCl3)δ8.10(s,1H),7.97–7.78(m,2H),7.17–6.99(m,2H),3.11(s,3H),2.98(s,3H)ppm.13C NMR(101MHz,CDCl3)δ164.4(d,JC-F=126.9Hz),159.04,138.5(d,JC-F=1.6Hz),128.9(d,JC-F=4.6Hz),115.7(d,JC-F=11.3Hz),41.4,35.4ppm.
实施例9:N,N-二甲基-N'-((2-甲氧基-5-(2-酮-1-丙基)苯基)磺酰基)甲脒的合成
室温下,在干燥、氮气反复置换3次的25mL史莱克反应管中依次加入5-丙酮基-2-甲氧基苯磺酰胺(72.9mg,0.30mmol)、三苯基膦(157.4mg,0.60mmol)、二氯甲烷(3mL)以及四氯化碳(35μL,0.36mmol)和N,N-二甲基甲酰胺(70μL,0.90mmol),40℃下反应12小时。在反应体系中加入水(10mL)淬灭反应,二氯甲烷萃取三次,每次10mL,有机层用饱和食盐水洗涤,无水硫酸钠干燥,过滤旋蒸后得到粗品,并进一步使用柱层析分离纯化,得到产物40.2mg,产率为45%。
产物N,N-二甲基-N'-((2-甲氧基-5-(2-酮-1-丙基)苯基)磺酰基)甲脒:1H NMR(400MHz,CDCl3)δ8.20(s,1H),7.82(d,J=2.0Hz,1H),7.30–7.27(m,1H),6.90(d,J=8.4Hz,1H),3.85(s,3H),3.66(s,2H),3.15(s,3H),2.98(s,3H),2.14(s,3H)ppm.13C NMR(101MHz,CDCl3)δ205.8,161.4,155.3,134.7,130.4,129.3,126.2,112.4,56.0,49.3,41.4,35.4,29.4ppm.
实施例10:N,N-二甲基-N'-(苄基磺酰基)甲脒的合成
室温下,在干燥、氮气反复置换3次的25mL史莱克反应管中依次加入苄基磺酰胺(51.3mg,0.30mmol)、三苯基膦(157.4mg,0.60mmol)、二氯甲烷(3mL)以及四氯化碳(35μL,0.36mmol)和N,N-二甲基甲酰胺(70μL,0.90mmol),40℃下反应12小时。在反应体系中加入水(10mL)淬灭反应,二氯甲烷萃取三次,每次10mL,有机层用饱和食盐水洗涤,无水硫酸钠干燥,过滤旋蒸后得到粗品,并进一步使用柱层析分离纯化,得到产物33.2mg,产率为49%。
产物N,N-二甲基-N'-(苄基磺酰基)甲脒:1H NMR(400MHz,CDCl3)δ7.48(s,1H),7.36–7.28(m,5H),4.23(s,2H),2.97(s,3H),2.91(s,3H)ppm.13C NMR(101MHz,CDCl3)δ160.2,130.8,130.1,128.3,128.2,59.6,41.0,35.2ppm.
实施例11:N,N-二甲基-N'-(2-噻吩磺酰基)甲脒的合成
室温下,在干燥、氮气反复置换3次的25mL史莱克反应管中依次加入噻吩磺酰胺(48.9mg,0.30mmol)、三苯基膦(157.4mg,0.60mmol)、二氯甲烷(3mL)以及四氯化碳(35μL,0.36mmol)和N,N-二甲基甲酰胺(70μL,0.90mmol),40℃下反应12小时。在反应体系中加入水(10mL)淬灭反应,二氯甲烷萃取三次,每次10mL,有机层用饱和食盐水洗涤,无水硫酸钠干燥,过滤旋蒸后得到粗品,并进一步使用柱层析分离纯化,得到产物47.1mg,产率为72%。
产物N,N-二甲基-N'-(2-噻吩磺酰基)甲脒:1H NMR(400MHz,CDCl3)δ8.11(s,1H),7.56–7.55(m,1H),7.51–7.46(m,1H),7.03–6.97(m,1H),3.12(s,3H),3.02(s,3H)ppm.13CNMR(101MHz,CDCl3)δ159.2,143.8,130.6,130.5,126.9,41.6,35.6ppm.HRMS(ESI)forC7H10氮气O2S2[M+H]+:calcd.219.0256;found 219.0251.
实施例12:N,N-二甲基-N'-(5-溴-2-噻吩磺酰基)甲脒的合成
室温下,在干燥、氮气反复置换3次的25mL史莱克反应管中依次加入5-溴噻吩磺酰胺(72.3mg,0.30mmol)、三苯基膦(157.4mg,0.60mmol)、二氯甲烷(3mL)以及四氯化碳(35μL,0.36mmol)和N,N-二甲基甲酰胺(70μL,0.90mmol),40℃下反应12小时。在反应体系中加入水(10mL)淬灭反应,二氯甲烷萃取三次,每次10mL,有机层用饱和食盐水洗涤,无水硫酸钠干燥,过滤旋蒸后得到粗品,并进一步使用柱层析分离纯化,得到产物53.6mg,产率为60%。
产物N,N-二甲基-N'-(5-溴-2-噻吩磺酰基)甲脒:1H NMR(400MHz,CDCl3)δ8.08(s,1H),7.30(d,J=4.0Hz,1H),6.97(d,J=4.0Hz,1H),3.14(s,3H),3.03(s,3H)ppm.13C NMR(101MHz,CDCl3)δ159.2,144.7,130.4,129.8,118.4,41.6,35.6ppm.
实施例13:N,N-二甲基-N'-(3-叔丁基-5-异恶唑基)甲脒的合成
室温下,在干燥、氮气反复置换3次的25mL史莱克反应管中依次加入3-叔丁基异噁唑-5-胺(42.0mg,0.30mmol)、三苯基膦(157.4mg,0.60mmol)、二氯甲烷(3mL)以及四氯化碳(35μL,0.36mmol)和N,N-二甲基甲酰胺(70μL,0.90mmol),40℃下反应12小时。在反应体系中加入水(10mL)淬灭反应,二氯甲烷萃取三次,每次10mL,有机层用饱和食盐水洗涤,无水硫酸钠干燥,过滤旋蒸后得到粗品,并进一步使用柱层析分离纯化,得到产物48mg,产率为82%。
产物N,N-二甲基-N'-(3-叔丁基-5-异恶唑基)甲脒:1H NMR(400MHz,CDCl3)δ7.94(s,1H),5.38(s,1H),3.04(s,3H),2.99(s,3H),1.24(s,9H)ppm.13C NMR(101MHz,CDCl3)δ173.6,172.1,155.1,85.2,40.6,34.3,32.1,29.3ppm.HRMS(ESI)for C10H17N3O[M+H]+:calcd.196.1444;found 196.1440.
实施例14:N,N-二甲基-N'-(3-(2-噻吩)-5-异恶唑基)甲脒的合成
室温下,在干燥、氮气反复置换3次的25mL史莱克反应管中依次加入3-噻吩基异噁唑-5-胺(49.8mg,0.30mmol)、三苯基膦(157.4mg,0.60mmol)、二氯甲烷(3mL)以及四氯化碳(35μL,0.36mmol)和N,N-二甲基甲酰胺(70μL,0.90mmol),40℃下反应12小时。在反应体系中加入水(10mL)淬灭反应,二氯甲烷萃取三次,每次10mL,有机层用饱和食盐水洗涤,无水硫酸钠干燥,过滤旋蒸后得到粗品,并进一步使用柱层析分离纯化,得到产物27.9mg,产率为42%。
产物N,N-二甲基-N'-(3-(2-噻吩)-5-异恶唑基)甲脒:1H NMR(400MHz,CDCl3)δ8.04(s,1H),7.43–7.32(m,2H),7.08–7.06(m,1H),5.76(s,1H),3.10(s,3H),3.06(s,3H)ppm.13C NMR(101MHz,CDCl3)δ173.1,158.8,155.4,132.2,127.3,126.7,126.6,85.3,40.8,34.5ppm.HRMS(ESI)for C10H11N3OS[M+H]+:calcd.222.0696;found 222.0689.
实施例15:4-甲基-N-(吗啉亚甲基)苯磺酰胺的合成
室温下,在干燥、氮气反复置换3次的25mL史莱克反应管中依次加入对甲苯磺酰胺(51.0mg,0.30mmol)、三苯基膦(157.4mg,0.60mmol)、二氯甲烷(3mL)以及四氯化碳(35μL,0.36mmol)和N-甲酰基吗啉(90μL,0.90mmol),40℃下反应12小时。在反应体系中加入水(10mL)淬灭反应,二氯甲烷萃取三次,每次10mL,有机层用饱和食盐水洗涤,无水硫酸钠干燥,过滤旋蒸后得到粗品,并进一步使用柱层析分离纯化,得到产物42.6mg,产率为53%。
产物4-甲基-N-(吗啉亚甲基)苯磺酰胺:1H NMR(400MHz,CDCl3)δ8.19(s,1H),7.75(d,J=8.0Hz,2H),7.25(d,J=8.4Hz,2H),3.76–3.69(m,2H),3.65(s,4H),3.52–3.44(m,2H),2.38(s,3H)ppm.13C NMR(101MHz,CDCl3)δ157.6,142.6,139.1,129.3,126.5,66.7,65.8,50.2,44.1,21.4.ppm
实施例16:N-甲基-N-苯基-N'-对甲苯磺酰基甲脒的合成
室温下,在干燥、氮气反复置换3次的25mL史莱克反应管中依次加入对甲苯磺酰胺(51.0mg,0.30mmol)、三苯基膦(157.4mg,0.60mmol)、二氯甲烷(3mL)以及四氯化碳(35μL,0.36mmol)和N-甲基甲酰苯胺(111μL,0.90mmol),40℃下反应12小时。在反应体系中加入水(10mL)淬灭反应,二氯甲烷萃取三次,每次10mL,有机层用饱和食盐水洗涤,无水硫酸钠干燥,过滤旋蒸后得到粗品,并进一步使用柱层析分离纯化,得到产物35.4mg,产率为41%。
产物N-甲基-N-苯基-N'-对甲苯磺酰基甲脒:1H NMR(400MHz,CDCl3)δ8.56(s,1H),7.82(d,J=8.1Hz,1H),7.44–7.41(m,2H),7.34–7.24(m,3H),7.19(d,J=7.9Hz,2H),3.44(s,3H),2.41(s,3H)ppm.13C NMR(101MHz,CDCl3)δ158.3,143.1,142.8,138.8,129.8,129.4,127.3,126.7,122.0,36.0,21.5ppm.
实施例17:4-甲基-N-(1-吡咯烷亚甲基)苯磺酰胺的合成
室温下,在干燥、氮气反复置换3次的25mL史莱克反应管中依次加入对甲苯磺酰胺(51.0mg,0.30mmol)、三苯基膦(157.4mg,0.60mmol)、二氯甲烷(3mL)以及四氯化碳(35μL,0.36mmol)和N-甲酰吡咯烷(86μL,0.90mmol),40℃下反应12小时。在反应体系中加入水(10mL)淬灭反应,二氯甲烷萃取三次,每次10mL,有机层用饱和食盐水洗涤,无水硫酸钠干燥,过滤旋蒸后得到粗品,并进一步使用柱层析分离纯化,得到产物31.0mg,产率为41%。
产物4-甲基-N-(1-吡咯烷亚甲基)苯磺酰胺:1H NMR(400MHz,CDCl3)δ8.31(s,1H),7.77(d,J=8.4Hz,2H),7.24(d,J=8.0Hz,2H),3.59–3.55(m,2H),3.47–3.44(m,2H),2.38(s,3H),1.98–1.89(m,4H)ppm.13C NMR(101MHz,CDCl3)δ155.7,142.3,139.6,129.2,126.5,49.9,46.4,25.0,24.3,21.4ppm.
实施例18:4-甲基-N-(1-哌啶亚甲基)苯磺酰胺的合成
室温下,在干燥、氮气反复置换3次的25mL史莱克反应管中依次加入对甲苯磺酰胺(51.0mg,0.30mmol)、三苯基膦(157.4mg,0.60mmol)、二氯甲烷(3mL)以及四氯化碳(35μL,0.36mmol)和N-甲酰基哌啶(100μL,0.90mmol),40℃下反应12小时。在反应体系中加入水(10mL)淬灭反应,二氯甲烷萃取三次,每次10mL,有机层用饱和食盐水洗涤,无水硫酸钠干燥,过滤旋蒸后得到粗品,并进一步使用柱层析分离纯化,得到产物50.3mg,产率为63%。
产物4-甲基-N-(1-哌啶亚甲基)苯磺酰胺:1H NMR(400MHz,CDCl3)δ8.10(s,1H),7.75(d,J=8.2Hz,2H),7.24(d,J=8.1Hz,1H),3.66–3.52(m,2H),3.39(t,J=5.1Hz,2H),2.38(s,3H),1.74–1.62(m,4H),1.59–1.54(m,2H)ppm.13C NMR(101MHz,CDCl3)δ157.2,142.3,139.6,129.2,126.4,51.8,44.6,26.4,24.8,23.9,21.4ppm.
实施例19:N,N-二苄基-N'-对甲苯磺酰基甲脒的合成
室温下,在干燥、氮气反复置换3次的25mL史莱克反应管中依次加入对甲苯磺酰胺(51.0mg,0.30mmol)、三苯基膦(157.4mg,0.60mmol)、二氯甲烷(3mL)以及四氯化碳(35μL,0.36mmol)和N,N-二苄基甲酰胺(203.0mg,0.90mmol),40℃下反应12小时。在反应体系中加入水(10mL)淬灭反应,二氯甲烷萃取三次,每次10mL,有机层用饱和食盐水洗涤,无水硫酸钠干燥,过滤旋蒸后得到粗品,并进一步使用柱层析分离纯化,得到产物53.3mg,产率为47%。
产物N,N-二苄基-N'-对甲苯磺酰基甲脒:1H NMR(400MHz,CDCl3)δ8.50(s,1H),7.80(d,J=8.4Hz,2H),7.42–7.34(m,3H),7.30–7.25(m,5H),7.16–7.11(m,4H),4.53(s,2H),4.36(s,2H),2.43(s,3H)ppm.13C NMR(101MHz,CDCl3)δ159.4,142.5,139.4,134.5,134.0,129.3,129.2,128.8,128.7,128.6,128.1,127.9,126.5,55.0,48.5,21.5ppm.
实施例20:N,N-二乙基-N'-甲苯磺酰基甲脒的合成
室温下,在干燥、氮气反复置换3次的25mL史莱克反应管中依次加入对甲苯磺酰胺(51.0mg,0.30mmol)、三苯基膦(157.4mg,0.60mmol)、二氯甲烷(3mL)以及四氯化碳(35μL,0.36mmol)和N,N-二乙基甲酰胺(101μL,0.90mmol),40℃下反应12小时。在反应体系中加入水(10mL)淬灭反应,二氯甲烷萃取三次,每次10mL,有机层用饱和食盐水洗涤,无水硫酸钠干燥,过滤旋蒸后得到粗品,并进一步使用柱层析分离纯化,得到产物44.2mg,产率为58%。
产物N,N-二乙基-N'-甲苯磺酰基甲脒:1H NMR(400MHz,CDCl3)δ8.12(s,1H),7.74(d,J=8.0Hz,2H),7.23(d,J=8.0Hz,2H),3.45(q,J=7.2Hz,2H),3.35(q,J=7.2Hz,2H),2.37(s,3H),1.23(t,J=7.2Hz,3H),1.11(t,J=7.2Hz,3H)ppm.13C NMR(101MHz,CDCl3)δ158.0,142.2,139.7,129.2,126.3,47.0,40.8,21.4,14.4,12.0ppm.
实施案例
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从实施例1-20可知,本发明的方法由各类廉价易得的磺酰胺类化合物出发,以商业可购买的三苯基膦和四氯化碳原位生成的鏻盐为活化剂,与甲酰胺类化合物发生缩合反应,在氮气条件下于40℃反应得到脒类化合物。该方法对芳基磺酰胺类化合物、烷基磺酰胺类化合物、芳基甲酰胺类化合物、烷基甲酰胺类化合物均具有良好的耐受性,是一种条件温和、操作简单的N-磺酰基脒化合物的通用合成方法。
实施例21:N,N-二甲基-N'-对甲苯磺酰基甲脒的合成条件优化试验
反应体系的优化
标准条件:1 0.3mmol(1.0当量);溶剂:3.0mL;产率为分离产率;
DMF=N,N-二甲基甲酰胺,
DCM=二氯甲烷,
THF=四氢呋喃,
DCE=1,2-二氯乙烷;
eq:当量;rt:室温。
需要说明的是,上述仅仅是本发明的较佳实施例,并非用来限定本发明的保护范围,在上述实施例的基础上所做出的任意组合或等同变换均属于本发明的保护范围。
Claims (8)
1.一种脒类化合物的合成工艺,其特征在于,所述工艺的合成方法如下:
;
其中,活化剂为三苯基膦和四氯化碳原位生成的鏻盐;R1、R2、R3均为取代基;
R1选自C6-C20芳基、包含1-5个O、N、S杂原子的5-10元杂芳基;
R2选自C1-C20烷基、C6-C20芳基,碳原子数在2-10 包含1-5 个O、N、S 杂原子的环烷基;
R3选自C1-C20烷基、C6-C20芳基,碳原子数在2-10 包含1-5 个O、N、S 杂原子的环烷基。
2.如权利要求1所述的脒类化合物的合成工艺,其特征在于,所述的合成方法中R2选自:C1-C10烷基;R3选自:C1-C10烷基。
3.如权利要求1或2所述的脒类化合物的合成工艺,其特征在于,所述的甲酰胺类化合物与磺酰胺类化合物的摩尔比为1~3:1。
4.如权利要求1或2所述的脒类化合物的合成工艺,其特征在于,所述的四氯化碳与磺酰胺类化合物摩尔比为1~1.5:1。
5.如权利要求1或2所述的脒类化合物的合成工艺,其特征在于,所述的三苯基膦与磺酰胺类化合物摩尔比为1~2:1。
6.如权利要求1或2所述的脒类化合物的合成工艺,其特征在于,所述的合成方法中反应溶剂为二氯甲烷或N,N-二甲基甲酰胺,原料磺酰胺类化合物在反应溶剂中的摩尔浓度为0.1 mmol/mL。
7.如权利要求1或2所述的脒类化合物的合成工艺,其特征在于,所述的合成方法中反应温度20~50℃。
8.如权利要求1或2所述的脒类化合物的合成工艺,其特征在于,所述的合成方法中反应时间为8~18 h。
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