CN1604891A - 邻位烷基化的改进方法 - Google Patents
邻位烷基化的改进方法 Download PDFInfo
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- CN1604891A CN1604891A CNA028066359A CN02806635A CN1604891A CN 1604891 A CN1604891 A CN 1604891A CN A028066359 A CNA028066359 A CN A028066359A CN 02806635 A CN02806635 A CN 02806635A CN 1604891 A CN1604891 A CN 1604891A
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- 238000000034 method Methods 0.000 title claims abstract description 78
- 230000029936 alkylation Effects 0.000 title description 3
- 238000005804 alkylation reaction Methods 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 71
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims abstract description 70
- 229910052763 palladium Inorganic materials 0.000 claims abstract description 31
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 30
- 239000003054 catalyst Substances 0.000 claims abstract description 18
- 125000004122 cyclic group Chemical group 0.000 claims abstract description 15
- 125000002252 acyl group Chemical group 0.000 claims abstract description 11
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 11
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 11
- 229910052799 carbon Inorganic materials 0.000 claims description 55
- 229910052739 hydrogen Inorganic materials 0.000 claims description 54
- AKEJUJNQAAGONA-UHFFFAOYSA-N sulfur trioxide Chemical compound O=S(=O)=O AKEJUJNQAAGONA-UHFFFAOYSA-N 0.000 claims description 49
- 239000002904 solvent Substances 0.000 claims description 36
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 32
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 30
- 229910052736 halogen Inorganic materials 0.000 claims description 30
- 239000003513 alkali Substances 0.000 claims description 26
- 238000002360 preparation method Methods 0.000 claims description 25
- -1 methyl 2-[(methylsulfinyl)]-4-(trifluoromethyl) aniline Chemical compound 0.000 claims description 23
- 238000005984 hydrogenation reaction Methods 0.000 claims description 16
- 150000001721 carbon Chemical group 0.000 claims description 15
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 14
- 150000002367 halogens Chemical class 0.000 claims description 14
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 claims description 12
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 11
- 238000005406 washing Methods 0.000 claims description 11
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 10
- 239000012442 inert solvent Substances 0.000 claims description 9
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 claims description 9
- 239000012190 activator Substances 0.000 claims description 7
- 239000000010 aprotic solvent Substances 0.000 claims description 7
- 230000008707 rearrangement Effects 0.000 claims description 7
- 125000003545 alkoxy group Chemical group 0.000 claims description 6
- 239000007795 chemical reaction product Substances 0.000 claims description 6
- 230000008569 process Effects 0.000 claims description 6
- GLBQVJGBPFPMMV-UHFFFAOYSA-N sulfilimine Chemical compound S=N GLBQVJGBPFPMMV-UHFFFAOYSA-N 0.000 claims description 5
- 230000003647 oxidation Effects 0.000 claims description 4
- 238000007254 oxidation reaction Methods 0.000 claims description 4
- 229910052700 potassium Inorganic materials 0.000 claims description 4
- 230000015572 biosynthetic process Effects 0.000 claims description 3
- 229910052717 sulfur Inorganic materials 0.000 claims description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 2
- 229910002091 carbon monoxide Inorganic materials 0.000 claims description 2
- 150000003016 phosphoric acids Chemical class 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 abstract description 13
- 125000000217 alkyl group Chemical group 0.000 abstract description 11
- 125000004432 carbon atom Chemical group C* 0.000 abstract 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 114
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 36
- 238000006243 chemical reaction Methods 0.000 description 34
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 25
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 24
- 239000003795 chemical substances by application Substances 0.000 description 20
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- 239000000203 mixture Substances 0.000 description 18
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 17
- 239000000243 solution Substances 0.000 description 17
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 16
- 235000019439 ethyl acetate Nutrition 0.000 description 15
- 239000000047 product Substances 0.000 description 15
- 230000002829 reductive effect Effects 0.000 description 15
- 150000003839 salts Chemical class 0.000 description 15
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 13
- 150000004982 aromatic amines Chemical class 0.000 description 13
- 239000001257 hydrogen Substances 0.000 description 13
- 150000003462 sulfoxides Chemical class 0.000 description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- FZERHIULMFGESH-UHFFFAOYSA-N N-phenylacetamide Chemical compound CC(=O)NC1=CC=CC=C1 FZERHIULMFGESH-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 239000011541 reaction mixture Substances 0.000 description 12
- 238000006722 reduction reaction Methods 0.000 description 12
- 229910052718 tin Inorganic materials 0.000 description 12
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 11
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 11
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N N-phenyl amine Natural products NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 11
- 238000004817 gas chromatography Methods 0.000 description 11
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- GNTDGMZSJNCJKK-UHFFFAOYSA-N divanadium pentaoxide Chemical compound O=[V](=O)O[V](=O)=O GNTDGMZSJNCJKK-UHFFFAOYSA-N 0.000 description 10
- 230000009467 reduction Effects 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- 150000003606 tin compounds Chemical class 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 8
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 8
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 8
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 8
- 239000000460 chlorine Substances 0.000 description 8
- 239000000543 intermediate Substances 0.000 description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 125000000623 heterocyclic group Chemical group 0.000 description 7
- 239000000463 material Substances 0.000 description 7
- 150000002941 palladium compounds Chemical class 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- 238000005481 NMR spectroscopy Methods 0.000 description 6
- 229960001413 acetanilide Drugs 0.000 description 6
- 150000008065 acid anhydrides Chemical class 0.000 description 6
- 229910052801 chlorine Inorganic materials 0.000 description 6
- 238000006477 desulfuration reaction Methods 0.000 description 6
- 230000023556 desulfurization Effects 0.000 description 6
- 238000005516 engineering process Methods 0.000 description 6
- 238000001704 evaporation Methods 0.000 description 6
- 230000008020 evaporation Effects 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 238000012545 processing Methods 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 5
- 239000007868 Raney catalyst Substances 0.000 description 5
- 229910000564 Raney nickel Inorganic materials 0.000 description 5
- 238000005917 acylation reaction Methods 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 4
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 description 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 4
- 150000001266 acyl halides Chemical class 0.000 description 4
- 230000003197 catalytic effect Effects 0.000 description 4
- 125000000524 functional group Chemical group 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical compound O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 4
- 150000003457 sulfones Chemical class 0.000 description 4
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 4
- 239000012808 vapor phase Substances 0.000 description 4
- CUKDRFZGHLCFHT-UHFFFAOYSA-N 2-methyl-4-(trifluoromethyl)aniline;hydrochloride Chemical compound Cl.CC1=CC(C(F)(F)F)=CC=C1N CUKDRFZGHLCFHT-UHFFFAOYSA-N 0.000 description 3
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 3
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 3
- 229910052783 alkali metal Inorganic materials 0.000 description 3
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 239000011737 fluorine Substances 0.000 description 3
- 229910052731 fluorine Inorganic materials 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 230000006872 improvement Effects 0.000 description 3
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 3
- WPHSFRRYZSEVDM-UHFFFAOYSA-N n-[2-methyl-4-(trifluoromethyl)phenyl]acetamide Chemical compound CC(=O)NC1=CC=C(C(F)(F)F)C=C1C WPHSFRRYZSEVDM-UHFFFAOYSA-N 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 239000002699 waste material Substances 0.000 description 3
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 description 2
- AWUFEMPPABUXSZ-UHFFFAOYSA-N 2-(methylsulfanylmethyl)-6-(trifluoromethyl)aniline Chemical compound CSCC1=CC=CC(C(F)(F)F)=C1N AWUFEMPPABUXSZ-UHFFFAOYSA-N 0.000 description 2
- PAXQXJDYVORMOO-UHFFFAOYSA-N 2-methyl-4-(trifluoromethyl)aniline Chemical compound CC1=CC(C(F)(F)F)=CC=C1N PAXQXJDYVORMOO-UHFFFAOYSA-N 0.000 description 2
- LXPCTHRQJVSSIQ-UHFFFAOYSA-N 2-methyl-6-(trifluoromethyl)aniline Chemical compound CC1=CC=CC(C(F)(F)F)=C1N LXPCTHRQJVSSIQ-UHFFFAOYSA-N 0.000 description 2
- ODGIMMLDVSWADK-UHFFFAOYSA-N 4-trifluoromethylaniline Chemical compound NC1=CC=C(C(F)(F)F)C=C1 ODGIMMLDVSWADK-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 241000294743 Gamochaeta Species 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
- 229910002677 Pd–Sn Inorganic materials 0.000 description 2
- ATTZFSUZZUNHBP-UHFFFAOYSA-N Piperonyl sulfoxide Chemical compound CCCCCCCCS(=O)C(C)CC1=CC=C2OCOC2=C1 ATTZFSUZZUNHBP-UHFFFAOYSA-N 0.000 description 2
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 239000005864 Sulphur Substances 0.000 description 2
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 125000002521 alkyl halide group Chemical group 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 150000008064 anhydrides Chemical class 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000012298 atmosphere Substances 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical group NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 235000011089 carbon dioxide Nutrition 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 238000005660 chlorination reaction Methods 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 238000007599 discharging Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 229910000856 hastalloy Inorganic materials 0.000 description 2
- 150000002431 hydrogen Chemical class 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 238000001465 metallisation Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 231100000572 poisoning Toxicity 0.000 description 2
- 230000000607 poisoning effect Effects 0.000 description 2
- 125000003367 polycyclic group Chemical group 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- XSCHRSMBECNVNS-UHFFFAOYSA-N quinoxaline Chemical compound N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000002002 slurry Substances 0.000 description 2
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- 238000000935 solvent evaporation Methods 0.000 description 2
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- 238000003756 stirring Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 229960002317 succinimide Drugs 0.000 description 2
- IXZDIALLLMRYOU-UHFFFAOYSA-N tert-butyl hypochlorite Chemical compound CC(C)(C)OCl IXZDIALLLMRYOU-UHFFFAOYSA-N 0.000 description 2
- 125000000101 thioether group Chemical class 0.000 description 2
- 150000003568 thioethers Chemical class 0.000 description 2
- ODIGIKRIUKFKHP-UHFFFAOYSA-N (n-propan-2-yloxycarbonylanilino) acetate Chemical compound CC(C)OC(=O)N(OC(C)=O)C1=CC=CC=C1 ODIGIKRIUKFKHP-UHFFFAOYSA-N 0.000 description 1
- CSNIZNHTOVFARY-UHFFFAOYSA-N 1,2-benzothiazole Chemical compound C1=CC=C2C=NSC2=C1 CSNIZNHTOVFARY-UHFFFAOYSA-N 0.000 description 1
- BCMCBBGGLRIHSE-UHFFFAOYSA-N 1,3-benzoxazole Chemical compound C1=CC=C2OC=NC2=C1 BCMCBBGGLRIHSE-UHFFFAOYSA-N 0.000 description 1
- NGCDGPPKVSZGRR-UHFFFAOYSA-J 1,4,6,9-tetraoxa-5-stannaspiro[4.4]nonane-2,3,7,8-tetrone Chemical compound [Sn+4].[O-]C(=O)C([O-])=O.[O-]C(=O)C([O-])=O NGCDGPPKVSZGRR-UHFFFAOYSA-J 0.000 description 1
- IANQTJSKSUMEQM-UHFFFAOYSA-N 1-benzofuran Chemical compound C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 1
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 description 1
- SWBBXKASFTWWHM-UHFFFAOYSA-N 2-(methylsulfinylmethyl)-4-(trifluoromethyl)aniline Chemical compound CS(=O)CC1=CC(C(F)(F)F)=CC=C1N SWBBXKASFTWWHM-UHFFFAOYSA-N 0.000 description 1
- VBLXCTYLWZJBKA-UHFFFAOYSA-N 2-(trifluoromethyl)aniline Chemical compound NC1=CC=CC=C1C(F)(F)F VBLXCTYLWZJBKA-UHFFFAOYSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- VHMICKWLTGFITH-UHFFFAOYSA-N 2H-isoindole Chemical compound C1=CC=CC2=CNC=C21 VHMICKWLTGFITH-UHFFFAOYSA-N 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
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- 238000005863 Friedel-Crafts acylation reaction Methods 0.000 description 1
- 238000003547 Friedel-Crafts alkylation reaction Methods 0.000 description 1
- 238000005727 Friedel-Crafts reaction Methods 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- ZQICGTYUOSVFMN-UHFFFAOYSA-N Iselin Natural products CC1=C(COc2c3ccoc3cc3oc(=O)ccc23)CC(C)(C)CC1 ZQICGTYUOSVFMN-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 235000019502 Orange oil Nutrition 0.000 description 1
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 1
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- 229910021627 Tin(IV) chloride Inorganic materials 0.000 description 1
- VREVKZLUMZQJRI-UHFFFAOYSA-N [SH2]=N Chemical compound [SH2]=N VREVKZLUMZQJRI-UHFFFAOYSA-N 0.000 description 1
- KKKAMDZVMJEEHQ-UHFFFAOYSA-N [Sn].[N+](=O)(O)[O-] Chemical compound [Sn].[N+](=O)(O)[O-] KKKAMDZVMJEEHQ-UHFFFAOYSA-N 0.000 description 1
- IKHGUXGNUITLKF-XPULMUKRSA-N acetaldehyde Chemical compound [14CH]([14CH3])=O IKHGUXGNUITLKF-XPULMUKRSA-N 0.000 description 1
- UNRQTHVKJQUDDF-UHFFFAOYSA-N acetylpyruvic acid Chemical compound CC(=O)CC(=O)C(O)=O UNRQTHVKJQUDDF-UHFFFAOYSA-N 0.000 description 1
- 238000010306 acid treatment Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 125000002877 alkyl aryl group Chemical group 0.000 description 1
- 150000004996 alkyl benzenes Chemical class 0.000 description 1
- 125000006350 alkyl thio alkyl group Chemical group 0.000 description 1
- 125000005012 alkyl thioether group Chemical group 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 239000003849 aromatic solvent Substances 0.000 description 1
- 125000004104 aryloxy group Chemical group 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 229910052728 basic metal Inorganic materials 0.000 description 1
- 150000003818 basic metals Chemical class 0.000 description 1
- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical compound C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 description 1
- 239000012964 benzotriazole Substances 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 230000002902 bimodal effect Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000008364 bulk solution Substances 0.000 description 1
- 238000001354 calcination Methods 0.000 description 1
- 125000002837 carbocyclic group Chemical group 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000012159 carrier gas Substances 0.000 description 1
- 239000012018 catalyst precursor Substances 0.000 description 1
- 238000007385 chemical modification Methods 0.000 description 1
- 238000012993 chemical processing Methods 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- WHDPTDWLEKQKKX-UHFFFAOYSA-N cobalt molybdenum Chemical compound [Co].[Co].[Mo] WHDPTDWLEKQKKX-UHFFFAOYSA-N 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000002485 combustion reaction Methods 0.000 description 1
- 150000003983 crown ethers Chemical class 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 230000020176 deacylation Effects 0.000 description 1
- 238000005947 deacylation reaction Methods 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 230000005595 deprotonation Effects 0.000 description 1
- 238000010537 deprotonation reaction Methods 0.000 description 1
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 1
- 239000004205 dimethyl polysiloxane Substances 0.000 description 1
- 235000013870 dimethyl polysiloxane Nutrition 0.000 description 1
- XXBDWLFCJWSEKW-UHFFFAOYSA-N dimethylbenzylamine Chemical compound CN(C)CC1=CC=CC=C1 XXBDWLFCJWSEKW-UHFFFAOYSA-N 0.000 description 1
- OBISXEJSEGNNKL-UHFFFAOYSA-N dinitrogen-n-sulfide Chemical compound [N-]=[N+]=S OBISXEJSEGNNKL-UHFFFAOYSA-N 0.000 description 1
- 238000007598 dipping method Methods 0.000 description 1
- TVQLLNFANZSCGY-UHFFFAOYSA-N disodium;dioxido(oxo)tin Chemical compound [Na+].[Na+].[O-][Sn]([O-])=O TVQLLNFANZSCGY-UHFFFAOYSA-N 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- TXKMVPPZCYKFAC-UHFFFAOYSA-N disulfur monoxide Inorganic materials O=S=S TXKMVPPZCYKFAC-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000005611 electricity Effects 0.000 description 1
- 238000005868 electrolysis reaction Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- JEIPFZHSYJVQDO-UHFFFAOYSA-N ferric oxide Chemical compound O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 150000002240 furans Chemical class 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 239000001307 helium Substances 0.000 description 1
- 229910052734 helium Inorganic materials 0.000 description 1
- SWQJXJOGLNCZEY-UHFFFAOYSA-N helium atom Chemical compound [He] SWQJXJOGLNCZEY-UHFFFAOYSA-N 0.000 description 1
- 125000005842 heteroatom Chemical group 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
- 125000003707 hexyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 239000012433 hydrogen halide Substances 0.000 description 1
- 229910000039 hydrogen halide Inorganic materials 0.000 description 1
- 150000001261 hydroxy acids Chemical group 0.000 description 1
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 238000007654 immersion Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 150000002475 indoles Chemical class 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 239000000395 magnesium oxide Substances 0.000 description 1
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 1
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 150000005054 naphthyridines Chemical class 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 239000010502 orange oil Substances 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 125000000962 organic group Chemical group 0.000 description 1
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 description 1
- CFHIDWOYWUOIHU-UHFFFAOYSA-N oxomethyl Chemical compound O=[CH] CFHIDWOYWUOIHU-UHFFFAOYSA-N 0.000 description 1
- ZMLDXWLZKKZVSS-UHFFFAOYSA-N palladium tin Chemical compound [Pd].[Sn] ZMLDXWLZKKZVSS-UHFFFAOYSA-N 0.000 description 1
- MUJIDPITZJWBSW-UHFFFAOYSA-N palladium(2+) Chemical compound [Pd+2] MUJIDPITZJWBSW-UHFFFAOYSA-N 0.000 description 1
- INIOZDBICVTGEO-UHFFFAOYSA-L palladium(ii) bromide Chemical compound Br[Pd]Br INIOZDBICVTGEO-UHFFFAOYSA-L 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- XCRBXWCUXJNEFX-UHFFFAOYSA-N peroxybenzoic acid Chemical compound OOC(=O)C1=CC=CC=C1 XCRBXWCUXJNEFX-UHFFFAOYSA-N 0.000 description 1
- 229960003418 phenoxybenzamine Drugs 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 239000004476 plant protection product Substances 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 229920000435 poly(dimethylsiloxane) Polymers 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 150000003233 pyrroles Chemical class 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000005057 refrigeration Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- HLBBKKJFGFRGMU-UHFFFAOYSA-M sodium formate Chemical compound [Na+].[O-]C=O HLBBKKJFGFRGMU-UHFFFAOYSA-M 0.000 description 1
- 229940079864 sodium stannate Drugs 0.000 description 1
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- XTQHKBHJIVJGKJ-UHFFFAOYSA-N sulfur monoxide Chemical compound S=O XTQHKBHJIVJGKJ-UHFFFAOYSA-N 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 150000004867 thiadiazoles Chemical class 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 239000012974 tin catalyst Substances 0.000 description 1
- LMYRWZFENFIFIT-UHFFFAOYSA-N toluene-4-sulfonamide Chemical compound CC1=CC=C(S(N)(=O)=O)C=C1 LMYRWZFENFIFIT-UHFFFAOYSA-N 0.000 description 1
- 230000001131 transforming effect Effects 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 239000002023 wood Substances 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen 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
- C07D213/72—Nitrogen atoms
- C07D213/73—Unsubstituted amino or imino radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/68—Preparation of compounds containing amino groups bound to a carbon skeleton from amines, by reactions not involving amino groups, e.g. reduction of unsaturated amines, aromatisation, or substitution of the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C211/00—Compounds containing amino groups bound to a carbon skeleton
- C07C211/43—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
- C07C211/44—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to only one six-membered aromatic ring
- C07C211/52—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to only one six-membered aromatic ring the carbon skeleton being further substituted by halogen atoms or by nitro or nitroso groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/16—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions not involving the amino or carboxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/14—Preparation of carboxylic acid amides by formation of carboxamide groups together with reactions not involving the carboxamide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
- C07C233/24—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
- C07C233/25—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
- C07C317/26—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
- C07C317/28—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to acyclic carbon atoms of the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
- C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
- C07C323/24—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
- C07C323/29—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton containing six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C381/00—Compounds containing carbon and sulfur and having functional groups not covered by groups C07C301/00 - C07C337/00
- C07C381/10—Compounds containing sulfur atoms doubly-bound to nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/28—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group
- C07C67/297—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C68/00—Preparation of esters of carbonic or haloformic acids
- C07C68/06—Preparation of esters of carbonic or haloformic acids from organic carbonates
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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Abstract
本发明涉及一种式I的化合物的制备方法如右式其中A是O或N-L;每个L独立地是H或酰基;K与两个邻近的相连碳原子一起,是苯环、5-或6-元杂芳环或芳族的8-、9-或10-元稠合的碳双环系或杂双环系,其中每个环或环系被任选取代;R1是H、C1-C4烷基或CO2R3;R2是H或C1-C4烷基;和R3是C1-C4烷基;包括在有含钯的催化剂存在的情况下氢化n是0、1或2的式II的化合物而形成式I的化合物。本发明还涉及用于制备式(I)化合物的式(II)化合物的制备方法。本发明还涉及用于这些方法的化合物。
Description
技术领域
本发明涉及制备邻位烷基化芳香醇和芳香胺的改进方法。
背景技术
邻位烷基苯胺和苯酚是制备植物保护剂、药品和其它精细化学品的重要的结构单元。苯胺和苯酚的经典Friedel-Crafts烷基化通常获得对位以及邻位烷基化,并且还经常导致多烷基化。尽管苯胺和苯酚的Friedel-Crafts酰基化通常仅获得单取代,但是在对位和邻位仍然可以发生取代,并且还原去除酰基羰基部分所需的反应条件可能与分子中的其它官能度不相容。
二十世纪七十年代,Paul Gassman开发了一种提供区域选择性邻位烷基化的替代合成方法(主要文献见P.G.Gassman和G.Gruetzmacher,J.Am.Chem.Soc.1973,95,588-589;P.G.Gassman和G.Gruetzmacher,Org. Syn.,Coll.Vol.VI,581-583;P.G.Gassman和H.R.Drewes,J.Am.Chem.Soc.1978,100,7600-7610;P.G.Gassman和D.R.Amick,J Am.Chem.Soc.1978,100,7611-7619)。该Gassman法包括由苯胺或苯酚和烷基硫醚如二甲基硫醚和氧化剂如次氯酸叔丁酯或氯产生据说具有式i的中间体。
其中A是NH或O,并且(R)p代表任选的取代基。
用碱如三乙胺或甲醇钠处理进行重排获得式ii所示的邻位烷硫基烷基化合物。
其中A是NH或O,并且(R)p代表任选的取代基。
最后,用阮内镍进行脱硫处理将烷硫基烷基分裂成式iii所示的烷基。
其中A是NH或O,并且(R)p代表任选的取代基。
尽管该方法是一种芳族烷基化的Friedel-Crafts方法的有诱惑力的替代方法,但是其条件对工业规模制备不理想。特别不利的是它使用阮内镍将烷硫基烷基分裂成烷基。使用阮内镍作为代替真正催化剂的试剂,因此是昂贵的。而且,它自燃,因此必需用水覆盖。尽管P.G.Gassman,G.Gruetzmacher,Org.Syn.,Coll.Vol.VI,581-583建议将该消耗的材料浆化于水中并冲洗排放,但是该文章这样处理对环境有害。使用该方法的工业生产需要一种更令人满意的阮内镍替代物。
这种方法的另一缺陷是用于制备式i所述的物质的步骤经常依赖于低温,低至-50℃。由于冷藏昂贵,在工业生产化学品中需要保持这样低的温度是不理想的。
A.D.Dawson和D.Swern(J.Org.Chem.1977,42,592-597)报道了通过用N-氯琥珀酰亚胺或N-氯苯并三唑激活的二甲基硫醚处理苯胺而制备和分离式i所述的物质,但仍然是在低温下。该文献未公开式ii所述的化合物的重排。U.S.4,496,765公开了用氢氧化钠水溶液洗涤式i的相应化合物的二氯甲烷溶液制备式iv的内鎓盐,所述式i的相应化合物是由2-(三氟甲基)苯胺、二甲基硫醚和N-氯琥珀酰亚胺形成的。
其中(R)p代表任选的取代基。
U.S.4,496,765还公开了通过任选在有催化性的琥珀酰亚胺的情况下加热式iv的内鎓盐制备式ii的化合物。
P.Claus和W.Vycudilik(Tetrahedron Lett.1968,3607-3610;Monatsch.Chem.1970,101,396-404)报道了在接近室温的温度下用氯仿中的二甲基硫醚、五氧化二磷和三乙胺处理可以将苯胺转化成易分离的式iv的内鎓盐。在该反应中,推测三乙胺碱可以将式i所述的中间体去质子。然后报道在有碱如三乙胺的情况下或者在质子溶剂如醇和水中甚至不加入碱,将式iv所述的中间体内鎓盐重排成式ii所述的邻位烷硫基烷基化合物(也参见P.Claus和W.Rieder,Monatsh.Chem.1972,103,1163-1177)。由于该方法不需要低温,因此工业上更有吸引力,但是五氧化二磷的成本和磷废物的处理将是工业上关注的。这些文献没有公开将式ii脱硫转化为式iii。
由于潜在较低的成本和废物较易处理,因此三氧化硫比五氧化二磷在工业上更有吸引力。美国专利U.S.3,527,810公开了一种用二甲亚砜制备三氧化硫复合物的方法,并且T.E.Varkey、G.F.Whitfield和D.Swern(J.Org.Chem.1974,39,3365-3372)报道了在与芳族胺反应时使用三氧化硫激活二甲亚砜,在用碱处理之后形成式iv所述的内鎓盐。就二甲亚砜的三氧化硫复合物与对甲苯磺酰胺的反应而言,该文献报道了助溶剂如氯仿得到较低的产率。就二甲亚砜的三氧化硫复合物与芳族胺的反应而言,该文献不用助溶剂并教导DMSO∶SO3∶芳族胺之比是4-6∶1∶0.6-0.9,并且推荐DMSO∶SO3之比是2-3∶1。该文献还描述了使用乙酸酐、三氟乙酸酐、三氟甲磺酸酐、环己基甲酰亚胺和五氧化二磷作为二甲亚砜的活化剂。该文献没有报道由芳族胺重排这些内鎓盐。
上面的文献没有一篇公开了在将式ii脱硫转化成式iii时该方法所需的阮内镍替代物。美国专利US 4,404,069和4,806,687公开了这些替代物。
美国专利US 4,404,069使用电解脱硫将2-(甲硫基甲基)-6-(三氟甲基)苯胺或其相应的亚砜或砜还原为2-甲基-6-(三氟甲基)苯胺。该方法需要使用大量的季铵盐电解质和极性溶剂,其中有机物不能高度易溶。美国专利US 4,404,069报道了亚砜和砜比硫化物更易还原。将硫化物氧化成亚砜或砜需要另一步骤。不理想的潜在副反应是卤取代基减少。为了避免三氟甲基还原为二氟甲基,美国专利US 4,404,069推荐在转化超过85-90%之前使反应停止或者从极性反应混合物中连续萃取产物,这也可能需要防止反应物和产物与极性反应介质的相分离。
US 4,806,687使用预先硫化的钴-钼催化剂加氢脱硫将2-(甲硫基甲基)-6-(三氟甲基)苯胺还原为2-甲基6-(三氟甲基)苯胺。该反应的优选温度是150-250℃。而且,优选氢压力大于3400kPa以获得可行的反应速度。
根据这些方法的加工需要和限制,仍然需要进一步改进将式ii脱硫转化为式iii的方法。本发明就公开了这种改进。
发明内容
本发明涉及一种式I化合物的制备方法
其中
A是O或N-L;
每个L独立地是H或酰基;
K与两个邻近的相连碳原子一起,是苯环、5-或6-元杂芳环或芳族的8-、9-或10-元稠合的碳双环系或杂双环系,其中每个环或环系被任选取代;
R1是H、C1-C4烷基或CO2R3;
R2是H或C1-C4烷基;和
R3是C1-C4烷基;
包括在有含钯的催化剂存在的情况下氢化式II的化合物而形成式I的化合物
其中n是0、1或2;R4是CHR1R2;并且A、K、L、R1、R2和R3定义如式I。
本发明还涉及前述方法,其中在式I中A是N-L,并且在氢化步骤之前还包括
(a)在有活化剂的情况下将式III的化合物
其中A是NH并且K定义如式I,
与式IV的化合物接触
R1R2CHS(O)R4 IV
其中R4是CHR1R2并且R1和R2定义如式I,
在接触的同时或在接触之后加入碱形成式V的化合物
其中K、R1和R2定义如式I并且R4是CHR1R2;
(b)将式V的化合物重排形成式II的化合物,其中A是N-L,每个L是H并且n是0;
(c)将式II的化合物任选酰化,其中每个L是H,从而形成式II的化合物,其中至少一个L是酰基;和
(d)将式II的化合物任选氧化,其中n是0,从而形成式II的化合物,其中n是1或2。
具体地说,本发明涉及一种式V的化合物的制备方法
其中
K与两个邻近的相连碳原子一起,是苯环、5-或6-元杂芳环或芳族的8-、9-或10-元稠合的碳双环系或杂双环系,其中每个环或环系被任选取代;
R1是H、C1-C4烷基或CO2R3;
R2是H或C1-C4烷基;
R3是C1-C4烷基;和
R4是CHR1R2;
该方法包括
(a)在惰性溶剂中并在有三氧化硫作为活化剂的情况下将式III的化合物
其中A是NH并且K定义如式V,
与式IV的化合物接触
R1R2CHS(O)R4 IV
其中R4是CHR1R2并且R1和R2定义如式V,
形成一反应产物,并在惰性溶剂中用碱的水溶液洗涤该反应产物,形成式V的化合物。
本发明还涉及一种式II的化合物的制备方法
其中n是0;
A是NH;
L是H;
K与两个邻近的相连碳原子一起,是苯环、5-或6-元杂芳环或芳族的8-、9-或10-元稠合的碳双环系或杂双环系,其中每个环或环系被任选取代;
R1是H、C1-C4烷基或CO2R3;
R2是H或C1-C4烷基;
R3是C1-C4烷基;和
R4是CHR1R2;
包括前面刚刚述及的方法以及接下来在溶剂中将式V的化合物重排得到式II的化合物的步骤。
本发明还涉及在这些方法中所用的式I、II和V的新型化合物,例如S,S-二甲基-N-[4-(三氟甲基)苯基]硫亚胺、2-[(甲硫基)甲基]-4-(三氟甲基)苯胺和2-[(甲基亚磺酰基)甲基]-4-(三氟甲基)苯胺。
具体实施方式
术语“烷基”既可以单独使用,也可以在组合词中使用,如“烷基芳基”,该术语包括直链或支链烷基,如甲基、乙基、丙基、异丙基、或者不同的丁基、戊基或己基异构体。“烷氧基”包括,例如甲氧基、乙氧基、丙氧基、异丙氧基以及不同的丁氧基、戊氧基和己氧基异构体。
术语“卤素”,它可以是单独的或在组合词中如“卤烷基”,包括氟、氯、溴或碘,本发明的方法优选氟和氯。
本文所用的术语“芳基”是指芳环系或由其衍生的自由基。术语“芳环系”是指完全不饱和的碳环和杂环,其中该环系是芳族的(其中芳族是指该环系满足Hückel规则)。术语“芳族碳双环系”包括所有环成员都是碳原子的环系并包括完全芳族的环系,以及其中至少一个环是芳族的(其中芳族是指满足Hückel规则)多环系。术语“杂环”或“杂双环系”是指这样一种环或环系,其中至少一个环原子不是碳并且含有1-4个独立地选自氮、氧和硫的杂原子,条件是每个杂环含有不超过4个氮,不超过2个氧并且不超过2个硫。该杂环可以通过取代任何可得的碳或氮上的氢而与所述碳或氮相连。术语“芳族杂双环系”包括完全芳族的杂环,以及其中至少一个环是芳族的(其中芳族是指满足Hückel规则)多环系杂环。
与两个相邻碳原子相连的K的适宜基团的实例是含有芳族和杂芳族5-和6-元环的基团,例如苯、噻吩、吡啶、哒嗪、吡嗪、嘧啶、三唑、吡咯、咪唑、呋喃、噁唑、异噁唑、噻唑、噻二唑、噁噻唑,和含有单核芳族结构的组合的多环,如萘、苯并[b]噻吩、苯并呋喃、喹啉、异喹啉、喹噁啉、吲哚、异吲哚、萘啶、吲唑、苯并吡咯、苯并三唑、苯并咪唑、苯并噁唑、苯并噻二唑和苯并异噻唑。此外,可以包括双环结构,其中一个环是芳族的,另一个是饱和的。实例包括如下化合物:1,2,3,4-四氢萘、二氢吲哚、二氢异吲哚和二氢苯并吡喃。适用于本发明的大量这些芳环系以及这些芳环系的制备方法在本领域为公知。较深入的综述文章见:Comprehensive Organic Chemistry,D.Barton和W.D.Ollis eds.,Pergamon Press,NY,1979,Volumes 1-6;Comprehensive Heterocyclic Chemistry,A.R.Katritzky和C.W.Reeseds.,Pergamon Press,NY,1984,Volumes 1-8;ComprehensiveHeterocyclic Chemistry II,A.R.Katritzky,C.W.Rees和E.F.V.Scriven eds.,Pergamon Press,NY,1996,Volumes 1A-11;并将这些文献引入本文。
芳基上的适宜取代基是在钯催化的氢化反应条件下不能被还原的那些基团,这是本领域技术人员能理解的。关于有机基团对氢化的敏感性的讨论参见P.N.Rylander,Catalytic Hydrogenation in OrganicSyntheses,Academic Press,NY,1979和M.Freifelder,CatalyticHydrogenation in Organic Synthesis Procedures and Commentary,JohnWiley & Sons,NY,1978。例如,耐这些氢化反应条件的取代基包括例如氟和氯的卤素;直链、支链和环烷基;直链和支链烷氧基;直链和支链的卤烷基;直链和支链的卤烷氧基;芳氧基(它可以含有其它取代基如烷基)如苯氧基;羧酸基团;氰基;芳基和芳基烷基基团(它可以含有其它取代基如烷基),例如4-甲基苄基或4-乙基吡啶基。
优选是:
优选1:本发明的方法和化合物,其中A不是O。
优选2:本发明的方法和化合物,其中R1是H或CO2CH3,R2是H并且R4是CH3或CH2CO2CH3。
优选3:本发明的方法和化合物,其中R1和R2是H。
优选4:本发明的方法和化合物,其中K与两个邻近的碳原子在一起,被一个或多个独立地选自以下的基团任选取代:卤素、C1-C4烷基、C1-C4烷氧基、C1-C4卤烷基和C1-C4卤烷氧基。
优选5:本发明的方法和化合物,其中K与两个邻近的碳原子在一起,是被一个或多个独立地选自以下的基团任选取代的苯环:卤素、C1-C4烷基、C1-C4烷氧基、C1-C4卤烷基、C1-C4卤烷氧基、苯基和苯氧基,每个苯基或苯氧基被一个或多个独立地选自以下的基团任选取代:卤素、C1-C4烷基、C1-C4烷氧基、C1-C4卤烷基和C1-C4卤烷氧基。
优选6:本发明的方法和化合物,其中K与两个邻近的碳原子在一起,是被一个或多个独立地选自以下的基团任选取代的苯环:卤素、C1-C4烷基、C1-C4烷氧基、C1-C4卤烷基和C1-C4卤烷氧基。
优选7:优选6的方法和化合物,其中苯环被与A对位的卤素、C1-C4烷基、C1-C4烷氧基、C1-C4卤烷基或C1-C4卤烷氧基取代。
如方案1所示,式I的邻位烷基化芳族醇和胺、及其酰化衍生物可以由式II的化合物制备。
方案1
其中
n是0、1或2;
A是O或N-L;
每个L独立地是H或酰基;
K与两个邻近的相连碳原子在一起,是苯环、5-或6-元杂芳环或者芳族的8-、9-或10-元稠合的碳双环系或杂双环系,其中每个环或环系被任选取代;
R1是H、C1-C4烷基或CO2R3;
R2是H或C1-C4烷基;
R3是C1-C4烷基;和
R4是CHR1R2。
在式I和II中,L所定义的酰基应理解为通过羰基相连的基团,即C(O)-Ra。Ra是可与氢化条件相容的任何基团,例如H、C1-C4烷基、CF3、C1-C4烷氧基或C1-C4卤烷氧基。每个Ra对每个存在的L经独立地选择。
方案1所示的转化可以通过使用含有钯的催化剂在有氢的情况下实现。优选该催化剂除了含有钯之外,还含有锡,以防止硫中毒。催化剂的活性部分可以含有钯并任选仅有锡,或者它还可以含有其它物质以强化性能。优选催化剂中锡的含量为钯重量的约5%-约20%。(这意思是,例如,如果有1000mg的钯,那么锡的量是约50mg-约200mg。)更优选,锡含量是钯重量的约8%-约12%。
本发明所用的催化剂优选附载在一载体上,最优选具有高比表面积的载体。这些载体包括,例如,活性炭或碳、硅胶、氧化铝或氧化镁。优选载体是多孔微粒固体,其中粒径分布典型地就浆液应用而言是5-100μm,就固定床应用而言是约0.8-4mm,并且BET(Brunauer-Emmett-Teller法)表面积典型地是约300-接近2000m2/g。催化剂载体可以经过加工例如具有潜在的酸性、中性或碱性pH。任选该催化剂载体可以经过处理,然后通过本领域通常已知的一种或多种工艺经金属沉积,例如用碱金属盐浸渍和/或煅烧或酸洗涤。优选该催化剂载体是活性炭或碳载体。优选该活性炭或碳载体的平均粒径等级,就浆液应用而言是20μm,就固定床应用而言是3mm,并且BET表面积是约700-约1600m2/g。
钯催化剂典型地是通过将钯化合物如氯化钯(II)与一还原剂接触制得的。通过使钯化合物中包含锡化合物如氯化锡(II)或氯化锡(IV),还原提供钯和锡的催化混合物。
为了制备载体上的钯催化剂,标准方法是制备可溶性钯化合物如氯化钯(II)的水溶液,优选还含有盐酸,并将该溶液加到载体上。然后将水蒸发,将钯化合物沉积到载体基质中。可以通过本领域通常已知的任何技术将溶液加至载体,例如包括,但不限于,浸泡、喷雾等。然后将该干燥或部分干燥的复合物与还原剂接触足够长的时间以将钯还原。这些步骤被R.Mozingo描述于Organic Syntheses,CollectiveVolume 3,Wiley,New York,1955,pages 685-690。
为了在载体上的钯催化剂中包括锡,可以将上面的方法改进以在涂敷到载体上之前在可溶性钯化合物的溶液中加入可溶性锡化合物,例如氯化锡(II)或氯化锡(IV)。或者,可以制备可溶性钯和可溶性锡化合物的单独溶液,然后涂敷到载体上。
就方案1的方法而言,可以任选将催化剂前体加入到氢化反应器中,其中钯和锡的还原在氢化反应器中就地进行。优选催化剂用还原剂预先还原,然后使用。
附载在载体上的钯催化剂的另一制备方法包括将含有悬浮载体和可溶性钯溶液(任选含有可溶性锡化合物)的混合物与一还原剂接触。附载的钯-锡催化剂的另一制备方法包括将载体上的钯化合物溶液蒸发,然后向载体上施加挥发性锡化合物蒸汽,例如四氯化锡(IV),之后与还原剂接触。而且可以使用各种其它的方法或其它模式将钯和/或锡化合物沉积到载体上,例如通过选择性沉淀等,任选用或不用溶剂洗涤以便选择性地除去不希望的抗衡离子。
作为向载体上施加钯和任选的锡化合物然后还原的替代方法,可以首先用还原剂浸渍载体,然后将钯和任选的锡化合物施加到载体上。然后将残余的还原剂洗涤或者从载体上除去。该方法可以优选将这些金属沉积在载体颗粒的表面附近。
为了制备该催化剂,可以使用为水溶性的任何钯化合物。这例如包括,但不限于,乙酸钯(II)、乙酰丙酮酸钯(II)、溴化钯(II)和氯化钯(II)。通常优选氯化钯(II)。
可用于制备该催化剂的锡化合物包括为水溶性或者足够挥发性以能够蒸汽相沉积到载体上的那些。这些包括氯化锡(II)、氯化锡(IV)、草酸锡(II)、硝酸锡(II)、锡酸钠等。由于氯化锡(II)和氯化锡(IV)容易得到,因此典型地使用它们。
用于化学还原钯和任选锡的还原剂通常可以是与液体相还原或蒸汽相还原一致的任何还原剂或还原环境,例如包括,但不限于,甲醛、甲酸钠、葡萄糖、乙醛、氢硼化钠、氢等。使用氢气还原是一优选的还原方法。使用氢气还原可以使用氢化溶剂如乙酸乙酯、四氢呋喃、甲苯、乙酸或乙酸酐中的固体催化剂前体的悬液进行。当使用氢气使用溶剂时,温度范围通常是室温至200℃(优选50-150℃),压力通常是大气压至20000kPa。优选没有溶剂,使用含气态氢的蒸汽相,有或没有惰性气体如氮气等并在有固体催化剂前体的情况下进行使用氢气的还原;通常这种蒸汽相还原是在室温至500℃(优选100-300℃,最优选150-250℃)的温度下、大气压或高至20000kPa的压力下进行的。
含有锡的钯催化剂是由Engelhard Corporation,Chemical Catalysts,Process Technologies Group,101 Wood Avenue,Iselin,New Jersey08830-0770 U.S.A生产的。
方案1的反应通常是在102-104kPa(14.5-1450psi)的压力下在适宜有机溶剂如,但不限于,乙酸乙酯、四氢呋喃、甲苯、乙酸或乙酸酐中进行的。约1000kPa的氢气压力通常获得适宜的反应压力。通常需要80-200℃的温度实现这种转化。
方案1a显示了方案1转化的描述性子方案,其中K与两个邻近的相连碳原子在一起,是被任选取代的苯环。
方案1a
其中n是0、1或2;A是O或N-L;每个L独立地是H或酰基C(O)-Ra;每个Ra独立地选自例如H、C1-C4烷基、CF3、C1-C4烷氧基和C1-C4卤烷氧基;m是0-4;并且每个R5独立地选自卤素、C1-C4烷基、C1-C4烷氧基、C1-C4卤烷基、C1-C4卤烷氧基、苯基或苯氧基,每个苯基或苯氧基被独立地选自以下的基团任选取代:卤素、C1-C4烷基、C1-C4烷氧基、C1-C4卤烷基和C1-C4卤烷氧基。
正如在方案1和1a的方法中已经提到的,L可以是H或酰基C(O)-Ra,其中Ra可以是氢化稳定的任何基团,例如H、C1-C4烷基、CF3、C1-C4烷氧基和C1-C4卤烷氧基。由于乙酸酐的成本低,因此Ra优选是甲基。由于未酰化的氨基可以潜在使催化剂中毒,因此将它们酰化可以有利于方案1和1a的方法。在与氢和催化剂接触之前,可以将式II和IIa的氨基(即A-L是NH2)或羟基(即A-L是OH)官能团转化成酰化衍生物,或者如下面讨论的,如果氢化溶剂包括乙酸酐可以就地进行酰化。
许多酰化氨基和羟基官能团的方法对本领域技术人员为公知。通常酰化式II或IIa的化合物中的A-L基团的方法,其中A-L是OH或NH2,包括将该化合物与酰化剂接触。典型的酰化剂是相应的酰基卤,特别是氯化物(例如Cl-C(O)-Ra),和酸酐(例如Ra-C(O)OC(O)-Ra)。当Ra是H或碳相连的基团如C1-C4烷基和CF3时,更常用酸酐。当所需的酰基官能团是甲酰基(即Ra是H)时,混合的酸酐H-C(O)OC(O)-CH3作为酰化剂特别有用。当Ra是除H之外的,例如是C1-C4烷基、CF3、C1-C4烷氧基和C1-C4卤烷氧基时,酰基卤作为催化剂最有用。经常该酰化反应是在对酰化剂惰性的溶剂如二氯甲烷、四氢呋喃或甲苯中进行的。然而,特别是用不贵的酸酐酰化剂,例如乙酸酐,可以方便地使用该酰化剂作为溶剂。由于酰化反应产生酸副产物(由酸酐酰化剂产生羧酸,例如HO-C(O)-Ra,由酰基卤酰化剂产生卤化氢,例如HCl),因此该反应经常在有碱的情况下进行,特别是用酰基卤酰化剂时。适宜的碱可以包括叔胺如三乙胺、二异丙基乙基胺等,以及无机碱如碱金属和碱土金属碳酸盐。酰化反应可以在有酰化催化剂如4-(二甲基氨基)吡啶的情况下进行。酰化反应经常在接近室温下进行,但是可以在广泛的范围下进行,例如在0℃至溶剂沸点之间。可以通过常规方法,例如将溶剂蒸发、结晶、色谱等将酰化产物(即式II或IIa,其中至少一个L是酰基)分离和纯化。可用于酰化A-L是OH或NH2的式II或IIa的常规步骤分别参见T.W.Greene,Protective Groupsin Organic Synthesis,Wiley-Interscience,New York,1981的第101-107页和第223-266页,并将该文献引入本文。该文献还描述了化合物脱酰形成游离羟基和氨基的方法。
正如已经提到的,即使式II中的每个L都是H,使用乙酸酐或另一酸酐作为氢化溶剂也可以获得式I的酰化衍生物。例如,在方案1a的反应中,其中式IIa中的每个L是H,使用乙酸酐作为溶剂可以生产A是O时的式VIa的酰化衍生物和A是NH时的式VIb的酰化衍生物以及式VIc的二酰化苯胺衍生物。
其中m是0-4;并且每个R5独立地选自卤素、C1-C4烷基、C1-C4烷氧基、C1-C4卤烷基、C1-C4卤烷氧基、苯基或苯氧基,每个苯基或苯氧基被一个或多个独立地选自以下的基团任选取代:卤素、C1-C4烷基、C1-C4烷氧基、C1-C4卤烷基和C1-C4卤烷氧基。
式VIa、VIb或VIc中的乙酰基可以通过标准化学操作容易地除去以提供式I的化合物。例如,用乙醇中的盐酸处理可以除去乙酰基。就芳族胺而言,例如式VIb和VIc,该脱酰步骤将导致形成式Ia的盐酸盐,它可以被分离或者用碱进一步处理提供式Ia的化合物,为游离碱。式VIa,VIb或VIc的化合物向式Ia的化合物的转化可以通过分离式VIa、VIb和VIc的化合物并在分离步骤中除去这些乙酰基或者将来自氢化步骤的粗反应产物直接处理来完成。
在方案1和1a的方法中,n典型地是0,但是本领域技术人员将想到,可以对该硫醚基团进行许多化学改性并且当有利于该转化时可以使用。这些包括将该硫醚基团氧化成亚砜(n是1)或砜(n是2)的改性。n是1或2的式II化合物可以通过用氧化剂,例如但不限于,3-氯过苯甲酸,于惰性溶剂如二氯甲烷中处理n是0的式II的相应化合物制得。许多公知的步骤可用于氧化硫;例如,参见J.March,Advanced Organic Chemistry;3rd edition,John Wiley:New York,(1985),p 1089。由于这需要附加的反应步骤,因此就方案1和1a的方法而言,优选n是0。
正如方案2中概括的,n是0的式II化合物可以由式I的相应芳族醇或胺通过如下制备:用式VII的适宜硫醚和氯化剂如次氯酸叔丁酯或N-氯琥珀酰亚胺处理,接着用碱如三乙胺或甲醇中的甲醇钠处理,从而按照P.G. Gassman,G.Gruetzmacher,J.Am.Chem.Soc.1973,95,588-589、P.G.Gassman,G Gruetzmacher,Org.Syn.,Coll.Vol.VI,581-583;P.G.Gassman,H.R.Drewes,J.Am.Chem.Soc.1978,100,7600-7610;和P.G.Gassman,D.R.Amick,J.Am.Chem.Soc.1978,100,7611-7619中所述的方法进行重排。
方案2
其中
n是0;
A是O或NH;
L是H;
K与两个邻近的相连碳原子在一起,是苯环、5-或6-元杂芳环或芳族的8-、9-或10-元稠合的碳双环系或杂双环系,其中每个环或环系被任选取代;
R1是H、C1-C4烷基或CO2R3;
R2是H或C1-C4烷基;
R3是C1-C4烷基;和
R4是CHR1R2。
当A是NH时,在式III化合物和式II的硫醚与氯化剂于水不混性溶剂中接触然后用含水碱如氢氧化钠溶液洗涤之后,可以分离中间体内鎓盐;然后可以在没有溶剂、或在质子溶剂如甲醇或水中、或在非质子溶剂中在有适宜碱的情况下,或者在质子溶剂、非质子溶剂和下面所述用于方案3中将式V转化成式II的碱的组合中,将该内鎓盐重排成n是0且L是H的式II化合物。
n是0、L是H且A是NH的式II化合物也可以由式III的相应化合物如方案3中所示制备。
方案3
其中
n是0;
A是NH;
L是H;
K与两个邻近的相连碳原子在一起,是苯环、5-或6-元杂芳环或芳族的8-、9-或10-元稠合的碳双环系或杂双环系,其中每个环或环系被任选取代;
R1是H、C1-C4烷基或CO2R3;
R2是H或C1-C4烷基;
R3是C1-C4烷基;和
R4是CHR1R2。
在方案3的方法中,式V的中间体硫亚胺(或者称之为亚氨基硫烷(iminosulfurane))内鎓盐化合物是由式III(A是NH)的芳族胺通过与式IV的二烷基亚砜反应制得,所述式IV的二烷基亚砜已通过与试剂如乙酸酐、三氟乙酸酐、三氟甲磺酸酐、环己基碳二亚胺、三氧化硫或五氧化二磷按照P.Claus和W.Vycudilik Tetrahedron Lett.1968,3607-3610;Monatsch.Chem.1970,101,396-404;和T.E.Varkey,G.F.Whitfield和D.Swern J.Org.Chem.1974,39,3365-3372的步骤处理被“活化”。该反应是在适宜的有机溶剂如二氯甲烷或二甲亚砜中进行的。反应是在-70至25℃的温度下进行的;最佳温度取决于所用溶剂和试剂。
在方案3的方法中,式V的中间体内鎓盐化合物可以经过分离或者不经分离而用于接下来的重排步骤。重排可以在没有溶剂的情况下进行(参见U.S.4,496,765),可以在质子溶剂如甲醇或水中进行(参见P.Claus和W.Rieder,Monatsh.Chem.1972,103,1163-1177),可以在非质子溶剂中在有适宜碱的情况下进行,或者可以在质子溶剂、非质子溶剂和碱的组合中进行。可以将各种非质子溶剂用于该反应中,包括氯化链烷类如二氯甲烷、醚类如四氢呋喃、酰胺类如N,N-二甲基甲酰胺、芳族溶剂如苯、氯苯、甲苯、二甲苯等。可以使用各种碱,包括叔烷基和苄基胺如三乙胺、N,N-二甲基苄基胺和1,8-二氮双环[5.4.0]十一碳-7-烯、以及碱金属醇盐如甲醇钠、乙醇钠和叔丁醇钾,它们可以使用冠醚等溶解。碱金属醇盐对在含有非质子溶剂的溶剂中进行向式II的重排特别有用,具体地说,已发现将甲醇钠的甲醇溶液加入到作为本体溶液的甲苯中对进行该重排效果非常好。在溶剂中进行该反应的温度经常是约40-110℃,但是在没有溶剂的情况下,所需温度通常更高,即约100-200℃。当反应在没有溶剂的情况下进行时,如U.S.4,496,765中所述包括催化量的有机碱或弱酸如琥珀酰亚胺可以增加重排速度。本领域技术人员将意识到,方案3的方法所包含的可操作变化包括产生式V内鎓盐的盐(例如,盐酸盐、硫酸盐或硫酸氢盐),然后用适宜量的碱处理该盐以产生式V的游离内鎓盐。这可以作为一单独步骤或作为包括在向式II的化合物重排的步骤的整体部分进行。
除了具有成本低和便于废物处理之外,已发现三氧化硫在方案3的方法中作为活化剂有效地提供了高产率的式II化合物,它然后可以使用方案1的方法还原得到式I的化合物。因此这代表了本发明的一个优选方面。而且,已发现,使用式IV的亚砜的三氧化硫复合物的反应可方便地进行,产率高,并且式IV亚砜的用量比T.E.Varkey,G.F.Whitfield和D.Swern,J.Org.Chem.1971,39,3365-3372中通过在惰性溶剂中进行反应教导的要小得多。所用的溶剂对三氧化硫与亚砜IV的复合物的高亲电性必须为惰性。通常该溶剂选自氟化和氯化链烷和环烷溶剂。特别有用的是含有二氯甲烷和1,1,2,2-四氯乙烷中至少一种的溶剂。对该反应而言最优选的是含有二氯甲烷的溶剂,已发现它赋予优异的产率,并且它相对便宜,容易从反应产物中通过蒸发除去。该反应通常可以在溶剂的冰点和沸点之间的温度范围内进行,但是典型地是在约-10至40℃的温度下进行。
通常,已发现每摩尔芳族胺(式III,A是NH)需要约2摩尔的三氧化硫获得完全的转化,因此相对式III的芳族胺的量,三氧化硫的最有用的量通常是约1.8-2.2,更优选是约1.9-2.1当量。(正如本文所用的,就三氧化硫和亚砜IV而言,并且也对于芳族胺III(A是NH)如果它具有单氨基官能团的话,本领域技术人员意识到术语“当量”实际上与术语“摩尔”同义)。每摩尔芳族胺需要至少1摩尔亚砜IV用于完全转化。而且每摩尔三氧化硫典型地使用至少1摩尔的亚砜IV,以使所有的三氧化硫被复合。本发明的溶剂条件避免了大量过量亚砜IV的需要,这样会增加成本以及废物处理费用。因此相对于三氧化硫的量,式IV的亚砜的量通常是约0.5-3,更优选是约1-2,最优选是约1-1.5当量。相对于式III的芳族胺的量,式IV的亚砜的量通常是约1-6,更优选是约1.8-4,最优选是约1.8-3当量。
反应通常需要0.1-10小时,并且可以通过传统技术如色谱和核磁共振光谱监控。在反应结束之后,反应混合物用碱的水溶液洗涤。据信芳族胺、亚砜和三氧化硫之间的反应提供了质子化形式的式V产物。然后用碱释放式V的游离内鎓盐物质,并中和反应混合物中的其它酸性副产物。因此,碱的量优选为至少2当量/摩尔反应中所用的三氧化硫,尽管为了方便起见通常使用过量的碱。适宜的碱包括碱金属碳酸盐、氢氧化物和磷酸盐。例如,氢氧化钠为此目的作用非常好。然后通过传统工艺,例如将溶剂蒸发、结晶等,将式V的内鎓盐分离。
已经认识到,为了制备式I的化合物,上面所述的一些反应试剂和反应条件与在中间体内存在的某些官能度可能不相容,在这些情况下,向该合成引入保护/去保护程序或官能团互变将有助于得到所需的产物。保护基的使用与选择对于在化学合成方面的技术人员是清楚的(参见,例如,T.W.Greene和P.G.M.Wuts,Protective Groups inOrganic Synthesis,2nd ed.;Wiley:New York,1991)。本领域技术人员将认识到,在某些情况下,一个给定试剂引入之后,正如在任意单独的方案中所描述的,还必须去完成没有详细介绍的其它路线的合成步骤,以完成式I化合物的合成。本领域的技术人员也知道,为了制备式I的化合物,必须按顺序,而不是以呈现的特定程序所指示的顺序完成在上面反应式中所述的各步骤的结合。
本领域的技术人员也将认识到,在此描述的式I化合物和中间体,可以经过各种亲电、亲核、自由基、有机金属化、氧化和还原反应而加入取代基或改性现有的取代基。
无需进一步详细说明,可以相信,利用前面的描述,本领域的技术人员就能最大程度地利用本发明。因此,以下实施例仅是解释说明,而不在任何方面限制本发明的公开,除了色谱的溶剂混合物或另有说明之外,百分比是指重量百分数。份数和色谱溶剂混合物的百分比是体积比,除非另有说明。1H NMR谱以来自四甲基硅烷的ppm低磁场来报告;“s”是单峰,“d”是双峰,“t”是三峰,“q”是四峰,“m”是多峰,“dd”是双二重峰,“dt”是双三重峰,“br s”是宽单峰。
实施例1
2′-甲基-6′-苯氧基乙酰苯胺的制备
步骤1:2′-[(甲硫基)甲基]-6′-苯氧基乙酰苯胺的制备
在一配备有机械搅拌器的三颈圆底烧瓶中将2-苯氧基苯胺(37.0g,0.2mol)溶解在二氯甲烷(350mL)中。连接维格娄分馏柱并将部分二氯甲烷(100mL)蒸馏掉。然后使用干冰/丙酮浴将反应溶液冷却到-5℃。
加入二甲基硫醚(18mL,0.25mol),同时将反应溶液的温度保持在-5至0℃之间。然后在10分钟内加入N-氯琥珀酰亚胺(27.0g,0.2mol),同时将反应混合物的温度保持在-5至0℃之间。加入结束之后,用冰/水浴替换干冰/丙酮浴以将温度保持在0℃附近,同时将反应混合物搅拌30分钟。然后加入三乙胺(60mL,0.42mol),并将混合物回流加热2小时。将反应混合物冷却至室温之后,将亚硫酸钠(20g)的水溶液(500mL)加入到该搅拌的反应混合物中。10分钟之后,将反应混合物倾析,有机层用水(500mL)洗涤。一250mL的三颈圆底烧瓶配备有蒸馏头和加料漏斗。将部分有机层(100mL)倒入该该烧瓶,并将剩余的有机层倒入加料漏斗。将该有机层物料以每份50mL加入到烧瓶中,同时通过蒸馏除去溶剂。当所有有机层都加入并且烧瓶温度达到110℃之后,将残余物料冷却至室温并用环己烷(50mL)稀释。然后将该混合物加热到60℃,并在15分钟内加入乙酸酐(20mL)。将反应混合物在60℃下保持1小时之后,将其冷却至室温并接种产物结晶。将混合物搅拌1小时之后,过滤收集产物。收集到的物料用己烷和石油醚重复洗涤并真空干燥得到结晶产物(24.41g,59%产率,通过气相色谱面积为98%纯度)。该产物通过用甲苯重结晶纯化得到产物(13.24g),通过气相色谱和1H NMR未显示杂质峰。
步骤2:2′-甲基-6′-苯氧基乙酰苯胺的制备
压力管(C276 Hastalloy金属,10mL)中装有2′-[(甲硫基)-甲基]-6′-苯氧基乙酰苯胺(即步骤1的产物,硫化物的重量列于表A)、催化剂(特性和重量列于表A)和溶剂(特性和重量列于表A)。在摇荡的同时,在表A所列的压力、温度和时间下将压力管中的内容物氢化。然后过滤除去催化剂,并通过气相色谱分析滤液,测定转化百分比,以峰面积计。
表A 通过钯催化氢化2′-[(甲硫基)甲基]-6′-苯氧基乙酰苯胺制备
2′-甲基-6′-苯氧基乙酰苯胺
流程 | 催化剂* | 催化剂重量(g) | 硫化物重量(g) | 溶剂 | 溶剂重量(g) | 温度(℃) | 压力(kPa) | 时间(h) | %转化 |
1 | Pd | 0.441 | 0.591 | EtOAc | 5.278 | 175 | 2760 | 4 | 98 |
2 | Pd | 0.385 | 0.518 | MeOH | 4.365 | 60 | 3450 | 4 | 10 |
3 | Pd | 0.445 | 0.600 | EtOAc | 5.288 | 175 | 1720 | 4 | 70 |
4 | Pd | 0.0438 | 0.594 | EtOAc | 5.288 | 175 | 2760 | 4 | 20 |
5 | Pd | 0.00934 | 0.583 | EtOAc | 5.273 | 175 | 2760 | 4 | 9 |
6 | Pd | 0.444 | 0.508 | EtOAc | 5.283 | 70 | 3450 | 4 | <5 |
7 | Pd | 0.443 | 0.500 | EtOAc | 5.279 | 70 | 3450 | 4 | <5 |
8 | Pd | 0.444 | 0.605 | 甲苯 | 5.270 | 175 | 2760 | 4 | 66 |
9 | Pd | 0.441 | 0.600 | EtOAc | 5.281 | 175 | 2760 | 4 | 95** |
10 | Pd-Sn | 0.045 | 0.594 | EtOAc | 5.278 | 175 | 2760 | 7 | 40 |
11 | 无 | - | 0.599 | EtOAc | 5.276 | 175 | 2760 | 4 | 12*** |
*所用钯(Pd)催化剂是5%pd/C,得自Engelhard(864A-3-288-1)。所用钯-锡(Pd-Sn)催化剂是5%Pd和1%Sn/C,来自Engelhard(864A-3-290-1)。
**通过气相色谱还看到了未知峰。
***流程11可能暗示氢化容器的Hastalloy金属具有一定的催化性能。
实施例2
2-甲基-4-(三氟甲基)苯胺盐酸盐的制备
使用带有一长5m、直径为530μm的HP-1(二甲基聚硅氧烷,可从Agilent Technologies获得)柱的惠普5890系列II+气相色谱仪并以90℃持续1分钟,然后以20℃/min增加到最后温度250℃,在此温度下保持5分钟的加热程序经气相色谱(GC)分析实施例2。使用氦作为载气,流速为10mL/min。
步骤1:S,S-二甲基-N-[4-(三氟甲基)苯基]硫亚胺的制备
在-5至0℃下将三氧化硫(4.84g,60.5mmol)的二氯甲烷溶液(10mL)加入到二甲亚砜(4.84g,62.0mmol)的二氯甲烷溶液(10mL)中。当加入结束之后滴加4-(三氟甲基)苯胺(5.00g,31.0mmol)。将混合物加热至室温。约1小时之后混合物用二氯甲烷(80mL)稀释并用氢氧化钠(1N,100mL)洗涤,干燥并蒸发,得到标题产物固体(6.58g,96%产率)。
1H NMR(CDCl3)δ 7.35(d,2H),6.84(d,2H),2.66(s,6H)。
步骤2:2-[(甲硫基)甲基]-4-(三氟甲基)苯胺的制备
将甲醇钠的甲醇溶液(1.95g,25%,9.02mmol)加入到步骤1的产物(2g,9.04mmol)的甲苯溶液(15mL)中。将混合物加热到约80℃。1小时之后将混合物冷却并倒入水(100mL)中。混合物用乙酸乙酯(2x100mL)萃取并将混合的萃取物干燥并蒸发,得到标题产物固体(1.8g,90%产率),由己烷再结晶之后在65.5-67.5℃下熔融。
IR(nujol)v 3419,3333,1629,1584,1512,1440,1334,1302,1235,1194,1139,1078,979,904,832cm-1。
1H NMR(CDCl3)δ 7.35(dd,J=8.2,1.5Hz,1H),7.26(s,1H),6.72(d,J=8.4Hz,1H),4.39(br s,2H),3.69(s,2H),1.99(3H,s)。
MS 221(M+)。
步骤3:N-[2-甲基-4-(三氟甲基)苯基]乙酰胺的制备
将一玻璃衬里的振荡管装有步骤2的产物(5.00g,22.6mmol)、催化剂(Engelhard 864A-3-290-1,5%Pd,1%Sn/C,0.630g)和乙酸酐(80mL)。室温下用氢将该管加压至100psi(690kPa),然后加热至150℃并摇荡6小时。在这段时间内通过周期性地再加压将压力保持在140psi(965kPa)。6小时之后,将反应容器冷却至室温并将剩余氢排放以释放该压力。GC分析显示两种产物,N-[2-甲基-4-(三氟甲基)苯基]乙酰胺和N-乙酰基-N-[2-甲基-4-(三氟甲基)苯基]乙酰胺,以及两种酰化原料,N-[2-[(甲硫基)甲基]-4-(三氟甲基)苯基]乙酰胺和N-乙酰基-N-[2-[(甲硫基)甲基]-4-(三氟甲基)苯基]乙酰胺的混合物,其峰面积比分别为6∶55∶6∶33。
反应混合物经Celite_硅藻土助滤器过滤,用乙酸乙酯洗涤,并将滤液真空浓缩至橙色油。为了将这些N,N-二乙酰基衍生物转化成其相应的N-乙酰基类似物,将4-(二甲基氨基)吡啶(DMAP)(0.500g)加入到该油的乙醇(50mL)溶液中,并将该溶液回流加热4小时。GC分析显示53∶8∶38∶1的峰面积比。蒸发之后,残余物经闪蒸塔柱色谱(60∶40己烷-乙酸乙酯)纯化。获得N-[2-甲基-4-(三氟甲基)苯基]乙酰胺白色固体(2.85g,58%产率)。原料以其乙酰化衍生物N-[2-[(甲硫基)甲基]-4-(三氟甲基)苯基]乙酰胺回收,产率为31%(1.84g)。
N-[2-甲基-4-(三氟甲基)苯基]乙酰胺:
1H NMR(CDCl3)δ 8.074(br d,7.3Hz,1H),7.4-7.5(m,2 H),7.080(br s,1H),2.313(s,3H),2.235(s,3H)。LC/MS AP+:218(M++1)和259(M++1+41;乙腈加成物)。m.p.159.5-160.5℃。Rf是0.21(60∶40己烷-乙酸乙酯),GC保持时间:3.52分钟。
N-乙酰基-N-[2-甲基-4-(三氟甲基)苯基]乙酰胺:
1H NMR(CDCl3)δ 7.599(s,1H),7.570(d,J=8.0Hz,1H),7.214(d,J=8.0Hz,1H),2.278(s,6H),2.230(s,3H)。LC/MS AP+:259(M+-42+41;在失去1个乙酰基之后相当于乙腈加成物)。m.p.70-72℃。Rf是0.70(60∶40己烷-乙酸乙酯)。GC保持时间:3.432分钟,峰是所有记录的峰的总面积的97.8%。
步骤4:2-甲基-4-(三氟甲基)苯胺盐酸盐的制备
将N-[2-甲基-4-(三氟甲基)苯基]乙酰胺(5.17g)和含水盐酸(37%,12mL)的乙醇(24mL)溶液加热回流3小时,然后在室温下搅拌48小时。反应混合物的GC分析显示2-甲基-4-(三氟甲基)苯胺与原料的峰面积比是98∶2。通过将反应混合物过滤并用乙酸乙酯洗涤固体获得2-甲基-4-(三氟甲基)苯胺盐酸盐白色固体。通过将滤液蒸发至干,在乙酸乙酯中将残余物磨碎,然后过滤获得2-甲基-4-(三氟甲基)苯胺盐酸盐二次收获物,总量为4.27g(85%产率)。
1H NMR(CD3OD)δ 7.726(s,1H),7.664(d,J=8.5Hz,1H),7.544(d,J=8.4Hz,1H),2.484(s,3H)。LC/MS AP+:176(M+),217(M++41,乙腈加成物)。GC保持时间:就2-甲基-4-(三氟甲基)苯胺而言是1.74分钟,就N-[2-甲基-4-(三氟甲基)苯基]乙酰胺而言是3.53分钟。
通过本文所述的方法,特别是包括实施例1所述的步骤,以及本领域已知的方法,可以制备表1A-3D的以下化合物。在以下表中采用的缩写如下:t是叔,s是仲,n是正,i是异,Me是甲基,Et是乙基,Pr是丙基,i-Pr是异丙基,Bu是丁基,Ph是苯基。“Ex.”代表上面的实施例。
表1A
L是H L是H.
R 1
R 2
(R 5 ) m
A
R 1
R 2
(R 5 ) m
A
H H - NH H H 4-OCH3 NH
H H - O H H 4-OCH3 O
Me H - NH H H 4-OCF2H NH
Me H - O H H 4-OCF2H O
Me Me - NH H H 4-Me NH
Me Me - O H H 4-Me O
Et H - NH H H 4-OCH2CF3 NH
n-Bu n-Bu - NH Me H 4-CF3 NH
CO2Me H - NH H H 3,5-di-Me NH
CO2Me Me - NH Me Me 4-CF3 NH
CO2Me n-Bu - NH Me Me 4-CF3 O
H H 4-F NH Et H 4-CF3 NH
H H 4-F O n-Bu n-Bu 4-CF3 NH
H H 4-Cl NH CO2Me H 4-CF3 NH
H H 4-Cl O CO2Me Me 4-CF3 NH
H H 4-Br NH CO2M n-Bu 4-CF3 NH
H H 4-Br O H H 3,4,5-tri-Me NH
H H 4-I NH H H 3,4,5-tri-OMe NH
H H 4-I O H H 6-CF3 NH
H H 4-CF3 NH(实施例2,步骤4) H H 6-F NH
H H 4-CF3 O i-Pr H 4-CF3 NH
H H 4-Ph NH H H 6-Ph NH
H H 4-OPh NH H H 6-Ph O
H H 6-OPh NH H H 4-O(Ph-4′-Cl) NH
H H 4-O(Ph-2′-Me) NH H H 4-(Ph-4′-Cl) NH
L是C(O)CH3 L是C(O)CH3.
R 1
R 2
(R 5 ) m
A
R 1
R 2
(R 5 ) m
A
H H - NH H H 4-OCH3 NH
H H - O H H 4-OCH3 O
Me H - NH H H 4-OCF2H NH
Me H - O H H 4-OCF2H O
Me Me - NH H H 4-Me NH
Me Me - O H H 4-Me O
Et H - NH H H 4-OCH2CF3 NH
n-Bu n-Bu - NH Me H 4-CF3 NH
CO2Me H - NH H H 3,5-di-Me NH
CO2Me Me - NH Me Me 4-CF3 NH
CO2Me n-Bu - NH Me Me 4-CF3 O
H H 4-F NH Et H 4-CF3 NH
H H 4-F O n-Bu n-Bu 4-CF3 NH
H H 4-Cl NH CO2Me H 4-CF3 NH
H H 4-Cl O CO2Me Me 4-CF3 NH
H H 4-Br NH CO2Me n-Bu 4-CF3 NH
H H 4-Br O H H 3,4,5-tri-Me NH
H H 4-I NH H H 3,4,5-tri-OMe NH
H H 4-I O H H 6-CF3 NH
H H 4-CF3 NH(实施例2,步骤3) H H 6-F NH
H H 4-CF3 O i-Pr H 4-CF3 NH
H H 4-Ph NH H H 6-Ph NH
H H 4-OPh NH H H 6-Ph O
H H 6-OPh NH(实施例1,步骤2) H H 4-O(Ph-4′-Cl) NH
H H 4-O(Ph-2′-Me) NH H H 4-(Ph-4′-Cl) NH
R 1
R 2
(R 5 ) m
A
L
R 1
R 2
(R 5)m
A
L
H H - NH C(O)CH2CH3 H H 4-F NH C(O)O(CH2)2CH3
H H - O C(O)CH2CH3 H H 4-Cl O C(O)CH2CH3
H H - NH C(O)CF3 H H 4-CF3 NH C(O)OC(CH3)3
H H - NH C(O)OCH3 H H 4-Me NH C(O)OCH2CH2Br
H H - O C(O)OC(CH3)3 H H 6-CF3 NH C(O)CF3
H H - NH C(O)OC(CH3)3 H H 6-F NH C(O)OCH3
H H - NH C(O)OCH2CH2Cl H H 4-Ph NH C(O)OC(CH3)3
H H - NH C(O)O(CH2)3CH3 H H 4-OPh NH C(O)(CH2)3CH3
R 1
R 2 (R 5 ) m
A
L
R 1
R 2
(R 5 ) m
A
L
H H - NH C(O)(CH2)3CH3 H H 6-OPh NH C(O)CF3
H H - NH C(O)H H H 6-Ph NH C(O)OCH2CH3
Me H - NH C(O)CF3 H H 4-OCH3 NH C(O)CH2CH3
Me H - NH C(O)OCH3 H H 3,4,5-tri-Me O C(O)C(CH3)3
Me Me - NH C(O)OC(CH3)3 H H 3,4,5-tri-OMe NH C(O)CF3
表1B
L是H. L是H.
R 1
R 2 (R 5 ) m
A
R 1
R 2
(R 5 ) m
A
H H - NH H H 4-OCH3 NH
H H - O H H 4-OCF2H NH
Me H - NH H H 4-Me NH
Me H - O H H 8-CH3 NH
Me Me - NH Me H 4-CF3 NH
Et H - NH H H 3,5-di-Me NH
n-Bu n-Bu - NH Me Me 4-CF3 NH
CO2MeH - NH Me Me 4-CF3 O
CO2MeMe - NH Et H 4-CF3 NH
H H 4-F NH n-Bu n-Bu 4-CF3 NH
H H 4-F O CO2Me H 4-CF3 NH
H H 4-Cl NH H H 6-CF3 NH
H H 4-Br NH H H 6-F NH
H H 4-CF3 NH i-Pr H 4-CF3 NH
L是C(O)CH3. L是C(O)CH3.
R 1
R 2 (R 5 ) m
A
R 1
R 2
(R 5 ) m
A
H H - NH H H 4-OCH3 NH
H H - O H H 4-OCF2H NH
Me H - NH H H 4-Me NH
Me H - O H H 8-CH3 NH
L是C(O)CH3. L是C(O)CH3.
R 1
R 2
(R 5 ) m
A
R 1
R 2
(R 5 ) m
A
Me Me - NH Me H 4-CF3 NH
Et H - NH H H 3,5-di-Me NH
n-Bu n-Bu - NH Me Me 4-CF3 NH
CO2Me H - NH Me Me 4-CF3 O
CO2Me Me - NH Et H 4-CF3 NH
H H 4-F NH n-Bu n-Bu 4-CF3 NH
H H 4-F O CO2Me H 4-CF3 NH
H H 4-Cl NH H H 6-CF3 NH
H H 4-Br NH H H 6-F NH
H H 4-CF3 NH i-Pr H 4-CF3 NH
表1C
L是H. L是H.
R 1
R 2
(R 5 ) m
A
R 1
R 2
(R 5 ) m
A
H H - NH H H 4-CF3 NH
H H - O H H 4-OCH3 NH
Me H - NH H H 4-OCF2H NH
Me H - O H H 4-Me NH
Me Me - NH H H 4-OCH2CF3 NH
Et H - NH Me H 4-CF3 NH
n-Bu n-Bu - NH H H 3,5-di-Me NH
CO2Me H - NH Me Me 4-CF3 NH
CO2Me Me - NH Me Me 4-CF3 O
H H 4-F NH Et H 4-CF3 NH
H H 4-F O n-Bu n-Bu 4-CF3 NH
H H 4-Cl NH CO2Me H 4-CF3 NH
H H 4-Br NH i-Pr H 4-CF3 NH
L是C(O)CH3. L是C(O)CH3.
R 1
R 2
(R 5 ) m
A
R 1
R 2
(R 5 ) m
A
H H - NH H H 4-CF3 NH
H H - O H H 4-OCH3 NH
Me H - NH H H 4-OCF2H NH
Me H - O H H 4-Me NH
Me Me - NH H H 4-OCH2CF3 NH
Et H - NH Me H 4-CF3 NH
n-Bu n-Bu - NH H H 3,5-di-Me NH
CO2Me H - NH Me Me 4-CF3 NH
CO2Me Me - NH Me Me 4-CF3 O
H H 4-F NH Et H 4-CF3 NH
H H 4-F O n-Bu n-Bu 4-CF3 NH
H H 4-Cl NH CO2Me H 4-CF3 NH
H H 4-Br NH i-Pr H 4-CF3 NH
表1D
L是H. L是H.
R 1
R 2
(R 5 ) m
A
R 1
R 2
(R 5 ) m
A
H H - NH H H 6-CF3 NH
H H - O H H 6-OCH3 NH
Me H - NH H H 6-OCF2H NH
Me H - O H H 6-Me NH
Me Me - NH H H 6-OCH2CF3 NH
Et H - NH Me H 6-CF3 NH
n-Bu n-Bu - NH H H 3,5-di-Me NH
CO2Me H - NH Me Me 6-CF3 NH
CO2Me Me - NH Me Me 6-CF3 O
H H 6-F NH Et H 6-CF3 NH
H H 6-F O n-Bu n-Bu 6-CF3 NH
H H 6-Cl NH CO2Me H 6-CF3 NH
H H 6-Br NH i-Pr H 6-CF3 NH
L是C(O)CH3. L是C(O)CH3.
R 1
R 2
(R 5 ) m
A
R 1
R 2
(R 5 ) m
A
H H - NH H H 6-CF3 NH
H H - O H H 6-OCH3 NH
Me H - NH H H 6-OCF2H NH
Me H - O H H 6-Me NH
Me Me - NH H H 6-OCH2CF3 NH
Et H - NH Me H 6-CF3 NH
n-Bu n-Bu - NH H H 3,5-di-Me NH
CO2Me H - NH Me Me 6-CF3 NH
CO2Me Me - NH Me Me 6-CF3 O
H H 6-F NH Et H 6-CF3 NH
H H 6-F O n-Bu n-Bu 6-CF3 NH
H H 6-Cl NH CO2Me H 6-CF3 NH
H H 6-Br NH i-Pr H 6-CF3 NH
表2A
L是H,并且n是0 L是H,并且n是0
R 1
R 2
(R 5 ) m
A
R 1
R 2
(R 5 ) m
A
H H - NH H H 4-OCH3 NH
H H - O H H 4-OCH3 O
Me H - NH H H 4-OCF2H NH
Me H - O H H 4-OCF2H O
Me Me - NH H H 4-Me NH
Me Me - O H H 4-Me O
Et H - NH H H 4-OCH2CF3 NH
n-Bu n-Bu - NH Me H 4-CF3 NH
CO2Me H - NH H H 3,5-di-Me NH
CO2Me Me - NH Me Me 4-CF3 NH
CO2Me n-Bu - NH Me Me 4-CF3 O
H H 4-F NH Et H 4-CF3 NH
H H 4-F O n-Bu n-Bu 4-CF3 NH
L是H,并且n是0 L是H,并且n是0
R 1
R 2 (R 5 ) m
A
R 1
R 2
(R 5 ) m
A
H H 4-Cl NH CO2Me H 4-CF3 NH
H H 4-Cl O CO2Me Me 4-CF3 NH
H H 4-Br NH CO2Me n-Bu 4-CF3 NH
H H 4-Br O H H 3,4,5-tri-Me NH
H H 4-I NH H H 3,4,5-tri-OMe NH
H H 4-I O H H 6-CF3 NH
H H 4-CF3 NH(实施例2,步骤2) H H 6-F NH
H H 4-CF3 O i-Pr H 4-CF3 NH
H H 4-Ph NH H H 6-Ph NH
H H 4-OPh NH H H 6-Ph O
H H 6-OPh NH H H 4-O(Ph-4′-Cl) NH
H H 4-O(Ph-2′-Me) NH H H 4-(Ph-4′-Cl) NH
L是C(O)CH3,并且n是0 L是C(O)CH3,并且n是0
R 1
R 2
(R 5 ) m
A
R 1
R 2
(R 5 ) m
A
H H - NH H H 4-OCH3 NH
H H - O H H 4-OCH3 O
Me H - NH H H 4-OCF2H NH
Me H - O H H 4-OCF2H O
Me Me - NH H H 4-Me NH
Me Me - O H H 4-Me O
Et H - NH H H 4-OCH2CF3 NH
n-Bu n-Bu - NH Me H 4-CF3 NH
CO2Me H - NH H H 3,5-di-Me NH
CO2Me Me - NH Me Me 4-CF3 NH
CO2Me n-Bu - NH Me Me 4-CF3 O
H H 4-F NH Et H 4-CF3 NH
H H 4-F O n-Bu n-Bu 4-CF3 NH
H H 4-Cl NH CO2Me H 4-CF3 NH
H H 4-Cl O CO2Me Me 4-CF3 NH
H H 4-Br NH CO2Me n-Bu 4-CF3 NH
H H 4-Br O H H 3,4,5-tri-Me NH
H H 4-I NH H H 3,4,5-tri-OMe NH
H H 4-I O H H 6-CF3 NH
H H 4-CF3 NH(实施例2,步骤2) H H 6-F NH
H H 4-CF3 O i-Pr H 4-CF3 NH
L是C(O)CH3,并且n是0 L是C(O)CH3,并且n是0
R 1
R 2
(R 5 ) m
A
R 1
R 2
(R 5 ) m
A
H H 4-Ph NH H H 6-Ph NH
H H 4-OPh NH H H 6-Ph O
H H 6-OPh NH(Ex.I,step 1)H H 4-O(Ph-4′-Cl) NH
H H 4-O(Ph-2′-Me) NH H H 4-(Ph-4′-Cl) NH
n是0. n是0.
R 1
R 2
(R 5 ) m
A
L
R 1
R 2
(R 5 ) m
A
L
H H - NH C(O)CH2CH3 H H 4-F NH C(O)O(CH2)2CH3
H H - O C(O)CH2CH3 H H 4-Cl O C(O)CH2CH3
H H - NH C(O)CF3 H H 4-CF3 NH C(O)OC(CH3)3
H H - NH C(O)OCH3 H H 4-Me NH C(O)OCH2CH2Br
H H - O C(O)OC(CH3)3 H H 6-CF3 NH C(O)CF3
H H - NH C(O)OC(CH3)3 H H 6-F NH C(O)OCH3
H H - NH C(O)OCH2CH2Cl H H 4-Ph NH C(O)OC(CH3)3
H H - NH C(O)O(CH2)3CH3 H H 4-OPh NH C(O)(CH2)3CH3
H H - NH C(O)(CH2)3CH3 H H 6-OPh NH C(O)CF3
H H - NH C(O)H H H 6-Ph NH C(O)OCH2CH3
Me H - NH C(O)CF3 H H 4-OCH3 NH C(O)CH2CH3
Me H - NH C(O)OCH3 H H 3,4,5-tri-Me O C(O)C(CH3)3
Me Me - NH C(O)OC(CH3)3 H H 3,4,5-tri-OMe NH C(O)CF3
L是H,并且n是1 L是H,并且n是1
R 1
R 2
(R 5 ) m
A
R 1
R 2
(R 5 ) m
A
H H - NH H H 4-OCH3 NH
H H - O H H 4-OCH3 O
Me H - NH H H 4-OCF2H NH
Me H - O H H 4-OCF2H O
Me Me - NH H H 4-Me NH
Me Me - O H H 4-Me O
Et H - NH H H 4-OCH2CF3 NH
n-Bu n-Bu - NH Me H 4-CF3 NH
CO2Me H - NH H H 3,5-di-Me NH
CO2Me Me - NH Me Me 4-CF3 NH
CO2Me n-Bu - NH Me Me 4-CF3 O
H H 4-F NH Et H 4-CF3 NH
H H 4-F O n-Bu n-Bu 4-CF3 NH
L是H,并且n是1 L是H,并且n是1
R 1
R 2
(R 5 ) m
A
R 1
R 2
(R 5 ) m
A
H H 4-Cl NH CO2Me H 4-CF3 NH
H H 4-Cl O CO2Me Me 4-CF3 NH
H H 4-Br NH CO2Me n-Bu 4-CF3 NH
H H 4-Br O H H 3,4,5-tri-Me NH
H H 4-I NH H H 3,4,5-tri-OMe NH
H H 4-I O H H 6-CF3 NH
H H 4-CF3 NH H H 6-F NH
H H 4-CF3 O i-Pr H 4-CF3 NH
H H 4-Ph NH H H 6-Ph NH
H H 4-OPh NH H H 6-Ph O
H H 6-OPh NH H H 4-O(Ph-4′-Cl) NH
H H 4-O(Ph-2′-Me) NH H H 4-(Ph-4′-Cl) NH
L是C(O)CH3,并且n是1 L是C(O)CH3,并且n是1
R 1
R 2
(R 5 ) m
A
R 1
R 2
(R 5 ) m
A
H H - NH H H 4-OCH3 NH
H H - O H H 4-OCH3 O
Me H - NH H H 4-OCF2H NH
Me H - O H H 4-OCF2H O
Me Me - NH H H 4-Me NH
Me Me - O H H 4-Me O
Et H - NH H H 4-OCH2CF3 NH
n-Bu n-Bu - NH Me H 4-CF3 NH
CO2Me H - NH H H 3,5-di-Me NH
CO2Me Me - NH Me Me 4-CF3 NH
CO2Me n-Bu - NH Me Me 4-CF3 O
H H 4-F NH Et H 4-CF3 NH
H H 4-F O n-Bu n-Bu 4-CF3 NH
H H 4-Cl NH CO2Me H 4-CF3 NH
H H 4-Cl O CO2Me Me 4-CF3 NH
H H 4-Br NH CO2Me n-Bu 4-CF3 NH
H H 4-Br O H H 3,4,5-tri-Me NH
H H 4-I NH H H 3,4,5-tri-OMe NH
H H 4-I O H H 6-CF3 NH
H H 4-CF3 NH H H 6-F NH
H H 4-CF3 O i-Pr H 4-CF3 NH
L是C(O)CH3,并且n是1 L是C(O)CH3,并且n是1
R 1
R 2
(R 5 ) m
A
R 1
R 2
(R 5 ) m
A
H H 4-Ph NH H H 6-Ph NH
H H 4-OPh NH H H 6-Ph O
H H 6-OPh NH H H 4-O(Ph-4′-Cl) NH
H H 4-O(Ph-2′-Me) NH H H 4-(Ph-4′-Cl) NH
L是H,并且n是2 L是H,并且n是2
R 1
R 2
(R 5 ) m
A
R 1
R 2
(R 5 ) m
A
H H - NH H H 4-OCH3 NH
H H - O H H 4-OCH3 O
Me H - NH H H 4-OCF2H NH
Me H - O H H 4-OCF2H O
Me Me - NH H H 4-Me NH
Me Me - O H H 4-Me O
Et H - NH H H 4-OCH2CF3 NH
n-Bu n-Bu - NH Me H 4-CF3 NH
CO2Me H - NH H H 3,5-di-Me NH
CO2Me Me - NH Me Me 4-CF3 NH
CO2Me n-Bu - NH Me Me 4-CF3 O
H H 4-F NH Et H 4-CF3 NH
H H 4-F O n-Bu n-Bu 4-CF3 NH
H H 4-Cl NH CO2Me H 4-CF3 NH
H H 4-Cl O CO2Me Me 4-CF3 NH
H H 4-Br NH CO2Me n-Bu 4-CF3 NH
H H 4-Br O H H 3,4,5-tri-Me NH
H H 4-I NH H H 3,4,5-tri-OMe NH
H H 4-I O H H 6-CF3 NH
H H 4-CF3 NH H H 6-F NH
H H 4-CF3 O i-Pr H 4-CF3 NH
H H 4-Ph NH H H 6-Ph NH
H H 4-OPh NH H H 6-Ph O
H H 6-OPh NH H H 4-O(Ph-4′-Cl) NH
H H 4-O(Ph-2′-Me) NH H H 4-(Ph-4′-Cl) NH
L是C(O)CH3,并且n是2 L是C(O)CH3,并且n是2
R 1
R 2
(R 5 ) m
A
R 1
R 2
(R 5 ) m
A
H H - NH H H 4-OCH3 NH
H H - O H H 4-OCH3 O
Me H - NH H H 4-OCF2H NH
Me H - O H H 4-OCF2H O
Me Me - NH H H 4-Me NH
Me Me - O H H 4-Me O
Et H - NH H H 4-OCH2CF3 NH
n-Bu n-Bu - NH Me H 4-CF3 NH
CO2Me H - NH H H 3,5-di-Me NH
CO2Me Me - NH Me Me 4-CF3 NH
CO2Me n-Bu - NH Me Me 4-CF3 O
H H 4-F NH Et H 4-CF3 NH
H H 4-F O n-Bu n-Bu 4-CF3 NH
H H 4-Cl NH CO2Me H 4-CF3 NH
H H 4-Cl O CO2Me Me 4-CF3 NH
H H 4-Br NH CO2Me n-Bu 4-CF3 NH
H H 4-Br O H H 3,4,5-tri-Me NH
H H 4-I NH H H 3,4,5-tri-OMe NH
H H 4-I O H H 6-CF3 NH
H H 4-CF3 NH H H 6-F NH
H H 4-CF3 O i-Pr H 4-CF3 NH
H H 4-Ph NH H H 6-Ph NH
H H 4-OPh NH H H 6-Ph O
H H 6-OPh NH H H 4-O(Ph-4′-Cl) NH
H H 4-O(Ph-2′-Me) NH H H 4-(Ph-4′-Cl) NH
表2B
L是H,并且n是0 L是H,并且n是0
R 1
R 2
(R 5 ) m
A
R 1
R 2
(R 5 ) m
A
H H - NH H H 4-OCH3 NH
H H - O H H 4-OCF2H NH
Me H - NH H H 4-Me NH
Me H - O H H 8-CH3 NH
Me Me - NH Me H 4-CF3 NH
Et H - NH H H 3,5-di-Me NH
n-Bu n-Bu - NH Me Me 4-CF3 NH
CO2Me H - NH Me Me 4-CF3 O
CO2Me Me - NH Et H 4-CF3 NH
H H 4-F NH n-Bu n-Bu 4-CF3 NH
H H 4-F O CO2Me H 4-CF3 NH
H H 4-Cl NH H H 6-CF3 NH
H H 4-Br NH H H 6-F NH
H H 4-CF3 NH i-Pr H 4-CF3 NH
L是C(O)CH3,并且n是0 L是C(O)CH3,并且n是0
R 1
R 2
(R 5 ) m
A
R 1
R 2
(R 5 ) m
A
H H - NH H H 4-OCH3 NH
H H - O H H 4-OCF2H NH
Me H - NH H H 4-Me NH
Me H - O H H 8-CH3 NH
Me Me - NH Me H 4-CF3 NH
Et H - NH H H 3,5-di-Me NH
n-Bu n-Bu - NH Me Me 4-CF3 NH
CO2Me H - NH Me Me 4-CF3 O
CO2Me Me - NH Et H 4-CF3 NH
H H 4-F NH n-Bu n-Bu 4-CF3 NH
H H 4-F O CO2Me H 4-CF3 NH
H H 4-Cl NH H H 6-CF3 NH
H H 4-Br NH H H 6-F NH
H H 4-CF3 NH i-Pr H 4-CF3 NH
表2C
L是H,并且n是0 L是H,并且n是0
R 1
R 2
(R 5 ) m
A
R 1
R 2
(R 5 ) m
A
H H - NH H H 4-CF3 NH
H H - O H H 4-OCH3 NH
Me H - NH H H 4-OCF2H NH
Me H - O H H 4-Me NH
Me Me - NH H H 4-OCH2CF3 NH
Et H - NH Me H 4-CF3 NH
n-Bu n-Bu - NH H H 3,5-di-Me NH
CO2Me H - NH Me Me 4-CF3 NH
CO2Me Me - NH Me Me 4-CF3 O
H H 4-F NH Et H 4-CF3 NH
H H 4-F O n-Bu n-Bu 4-CF3 NH
H H 4-Cl NH CO2Me H 4-CF3 NH
H H 4-Br NH i-Pr H 4-CF3 NH
L是C(O)CH3,并且n是0 L是C(O)CH3,并且n是0
R 1
R 2
(R 5 ) m
A
R 1
R 2
(R 5 ) m
A
H H - NH H H 4-CF3 NH
H H - O H H 4-OCH3 NH
Me H - NH H H 4-OCF2H NH
Me H - O H H 4-Me NH
Me Me - NH H H 4-OCH2CF3 NH
Et H - NH Me H 4-CF3 NH
n-Bu n-Bu - NH H H 3,5-di-Me NH
CO2Me H - NH Me Me 4-CF3 NH
CO2Me Me - NH Me Me 4-CF3 O
H H 4-F NH Et H 4-CF3 NH
H H 4-F O n-Bu n-Bu 4-CF3 NH
H H 4-Cl NH CO2Me H 4-CF3 NH
H H 4-Br NH i-Pr H 4-CF3 NH
表2D
L是H,并且n是0 L是H,并且n是0
R 1
R 2
(R 5 ) m
A
R 1
R 2
(R 5 ) m
A
H H - NH H H 6-CF3 NH
H H - O H H 6-OCH3 NH
Me H - NH H H 6-OCF2H NH
Me H - O H H 6-Me NH
Me Me - NH H H 6-OCH2CF3 NH
Et H - NH Me H 6-CF3 NH
n-Bu n-Bu - NH H H 3,5-di-Me NH
CO2Me H - NH Me Me 6-CF3 NH
CO2Me Me - NH Me Me 6-CF3 O
H H 6-F NH Et H 6-CF3 NH
H H 6-F O n-Bu n-Bu 6-CF3 NH
H H 6-Cl NH CO2Me H 6-CF3 NH
H H 6-Br NH i-Pr H 6-CF3 NH
L是C(O)CH3,并且n是0 L是C(O)CH3,并且n是0
R 1
R 2
(R 5 ) m
A
R 1
R 2
(R 5 ) m
A
H H - NH H H 6-CF3 NH
H H - O H H 6-OCH3 NH
Me H - NH H H 6-OCF2H NH
Me H - O H H 6-Me NH
Me Me - NH H H 6-OCH2CF3 NH
Et H - NH Me H 6-CF3 NH
n-Bu n-Bu - NH H H 3,5-di-Me NH
CO2Me H - NH Me Me 6-CF3 NH
CO2Me Me - NH Me Me 6-CF3 O
H H 6-F NH Et H 6-CF3 NH
H H 6-F O n-Bu n-Bu 6-CF3 NH
H H 6-Cl NH CO2Me H 6-CF3 NH
H H 6-Br NH i-Pr H 6-CF3 NH
表3A
R 1
R 2
(R 5 ) m
R 1
R 2
(R 5 ) m
H H - H H 4-Me
Me H - H H 4-OCH2CF3
Me Me - Me H 4-CF3
Et H - H H 3,5-di-Me
n-Bu n-Bu - Me Me 4-CF3
CO2Me H - Et H 4-CF3
CO2Me Me - n-Bu n-Bu 4-CF3
CO2Me n-Bu - CO2Me H 4-CF3
H H 4-F CO2Me Me 4-CF3
H H 4-Cl CO2Me n-Bu 4-CF3
H H 4-Br H H 3,4,5-tri-Me
H H 4-I H H 3,4,5-tri-OMe
H H 4-CF3(实施例2,步骤1) H H 6-CF3
H H 4-OCH3 H H 6-F
H H 4-OCF2H i-Pr H 4-CF3
H H 4-Ph H H 6-Ph
H H 4-OPh H H 4-O(Ph-4′-Cl)
H H 6-OPh H H 4-(Ph-4′-Cl)
H H 4-O(Ph-2′-Me)
表3B
R 1
R 2
(R 5 ) m
R 1
R 2
(R 5 ) m
R 1
R 2
(R 5 ) m
H H - H H 4-Cl H H 3,5-di-Me
Me H - H H 4-Br Me Me 4-CF3
Me Me - H H 4-CF3 Et H 4-CF3
Et H - H H 4-OCH3 n-Bu n-Bu 4-CF3
R 1
R 2
(R 5 ) m
R 1
R 2
(R 5 ) m
R 1
R 2
(R 5 ) m
n-Bu n-Bu - H H 4-OCF2H CO2Me H 4-CF3
CO2Me H - H H 4-Me H H 6-CF3
CO2Me Me - H H 8-CH3 H H 6-F
H H 4-F Me H 4-CF3 i-Pr H 4-CF3
表3C
R 1
R 2
(R 5 ) m
R 1
R 2
(R 5 ) m
R 1
R 2
(R 5 ) m
H H - H H 4-Cl H H 3,5-di-Me
Me H - H H 4-Br Me Me 4-CF3
Me Me - H H 4-CF3 Et H 4-CF3
Et H - H H 4-OCH3 n-Bu n-Bu 4-CF3
n-Bu n-Bu - H H 4-OCF2H CO2Me H 4-CF3
CO2Me H - H H 4-Me i-Pr H 4-CF3
CO2Me Me - H H 4-OCH2CF3
H H 4-F Me H 4-CF3
表3D
R 1
R 2
(R 5 ) m
R 1
R 2
(R 5 ) m
R 1
R 2
(R 5 ) m
H H - H H 6-Cl H H 3,5-di-Me
Me H - H H 6-Br Me Me 6-CF3
Me Me - H H 6-CF3 Et H 6-CF3
Et H - H H 6-OCH3 n-Bu n-Bu 6-CF3
n-Bu n-Bu - H H 6-OCF2H CO2Me H 6-CF3
CO2Me H - H H 6-Me i-Pr H 6-CF3
CO2Me Me - H H 6-OCH2CF3
H H 6-F Me H 6-CF3
Claims (22)
2、权利要求1的方法,其中n是0。
3、权利要求1的方法,其中在式I中A是N-L,并且在氢化步骤之前还包括
(a)在有活化剂的情况下将式III的化合物
其中A是NH并且K定义如式I,与式IV的化合物接触
R1R2CHS(O)R4 IV
其中R4是CHR1R2并且R1和R2定义如式I,在接触的同时或在接触之后加入碱形成式V的化合物
其中K、R1和R2定义如式I并且R4是CHR1R2;
(b)将式V的化合物重排形成式II的化合物,其中A是N-L,每个L是H并且n是0;
(c)将式II的化合物任选酰化,其中每个L是H,从而形成式II的化合物,其中至少一个L是酰基;和
(d)将式II的化合物任选氧化,其中n是0,从而形成式II的化合物,其中n是1或2。
4、权利要求3的方法,其中步骤(a)中的活化剂是三氧化硫。
5、权利要求3的方法,其中步骤(b)是在甲苯中在有甲醇钠的情况下进行的。
6、权利要求1-5任意一项的方法,其中相对钯重量,所述钯催化剂还含有约5%-约20%的锡。
7、权利要求6的方法,其中锡的量是约8%-约12%的钯重量。
8、一种式V的化合物的制备方法
其中
K与两个邻近的相连碳原子一起,是苯环、5-或6-元杂芳环或芳族的8-、9-或10-元稠合的碳双环系或杂双环系,其中每个环或环系被任选取代;
R1是H、C1-C4烷基或CO2R3;
R2是H或C1-C4烷基;
R3是C1-C4烷基;和
R4是CHR1R2;
该方法包括
(a)在惰性溶剂中并在有三氧化硫作为活化剂的情况下将式III的化合物
其中A是NH并且K定义如式V,
与式IV的化合物接触
R1R2CHS(O)R4 IV
其中R4是CHR1R2并且R1和R2定义如式V,
形成一反应产物,并在惰性溶剂中用碱的水溶液洗涤该反应产物,形成式V的化合物。
9、权利要求8的方法,其中惰性溶剂包括二氯甲烷和1,1,2,2-四氯乙烷中的至少一种。
10、权利要求9的方法,其中惰性溶剂包括二氯甲烷。
11、权利要求8的方法,其中所述的碱选自碱金属碳酸盐、氢氧化物或磷酸盐。
12、权利要求8的方法,其中相对式III的化合物的量,三氧化硫的量是约1.8-2.2当量。
13、权利要求12的方法,其中相对式III的化合物的量,三氧化硫的量是约1.9-2.1当量。
14、权利要求8的方法,其中相对三氧化硫的量,式IV的化合物的量是约0.5-3当量。
15、权利要求14的方法,其中相对三氧化硫的量,式IV的化合物的量是约1-2当量。
16、一种式II的化合物的制备方法
其中n是0;
A是NH;
L是H;
K与两个邻近的相连碳原子一起,是苯环、5-或6-元杂芳环或芳族的8-、9-或10-元稠合的碳双环系或杂双环系,其中每个环或环系被任选取代;
R1是H、C1-C4烷基或CO2R3;
R2是H或C1-C4烷基;
R3是C1-C4烷基;和
R4是CHR1R2;
包括权利要求8的方法以及接下来在溶剂中将式V的化合物重排得到式II的化合物的步骤。
17、权利要求16的方法,其中重排溶剂包括非质子溶剂。
18、权利要求17的方法,其中重排溶剂包括甲苯并且重排碱包括甲醇钠。
19、权利要求1-18任意一项的方法,其中R1是H或CO2CH3,R2是H,并且R4是CH3或CH2CO2CH3。
20、权利要求19的方法,其中R1是H,R2是H并且R4是CH3。
21、权利要求1-20任意一项的方法,其中K与两个邻近的碳原子在一起,是被一个或多个独立地选自以下的基团任选取代的苯环:卤素、C1-C4烷基、C1-C4烷氧基、C1-C4卤烷基、C1-C4卤烷氧基、苯基和苯氧基,每个苯基或苯氧基被一个或多个独立地选自以下的基团任选取代:卤素、C1-C4烷基、C1-C4烷氧基、C1-C4卤烷基和C1-C4卤烷氧基。
22、一种化合物,选自
(a)S,S-二甲基-N-[4-(三氟甲基)苯基]硫亚胺、
(b)2-[(甲硫基)甲基]-4-(三氟甲基)苯胺、和
(c)2-[(甲基亚磺酰基)甲基]-4-(三氟甲基)苯胺。
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US7449481B2 (en) * | 2004-04-13 | 2008-11-11 | Cephalon, Inc. | Thio-substituted biaryl-methanesulfinyl derivatives |
JP5238172B2 (ja) * | 2007-03-22 | 2013-07-17 | 公益財団法人相模中央化学研究所 | パーフルオロアルキル基を有する含窒素六員環化合物およびその製造方法 |
KR101612179B1 (ko) * | 2013-04-19 | 2016-04-12 | 영남대학교 산학협력단 | 아미도피리딘올 유도체 또는 이의 약제학적 허용가능한 염을 유효성분으로 함유하는 암질환 예방 또는 치료용 약학조성물 |
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US3527810A (en) | 1968-06-06 | 1970-09-08 | Kelco Co | Process for preparing a dimethyl sulfoxide-sulfur trioxide complex |
US4006183A (en) * | 1975-07-08 | 1977-02-01 | Sandoz, Inc. | Substituted α-methylsulfinyl-o-toluidines |
US4404069A (en) | 1982-03-17 | 1983-09-13 | Monsanto Company | Electrolytic desulfurization of anilino sulfur compounds |
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US4496765A (en) | 1983-09-07 | 1985-01-29 | Monsanto Company | Preparation of 2-(methylthiomethyl)-6-(trifluoromethyl)aniline from ortho-aminobenzotrifluoride |
US4806687A (en) | 1986-04-02 | 1989-02-21 | Monsanto Company | Catalytic hydrodesulfurization of ortho-aminobenzylsulfides |
DE4308101C1 (de) | 1993-03-15 | 1994-07-28 | Degussa | Verfahren zur Herstellung platingruppenmetallhaltiger Hydrierkatalysatoren auf Aktivkohle |
US5728887A (en) | 1996-04-10 | 1998-03-17 | E. I. Du Pont De Nemours And Company | Catalytic hydrogenolysis of organic thiocyanates and disulfides to thiols |
US6008384A (en) | 1998-03-03 | 1999-12-28 | E. I. Du Pont De Nemours And Company | Method and Ru,Re,Sn/carbon catalyst for hydrogenation in aqueous solution |
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CN110128422B (zh) * | 2019-01-04 | 2022-03-18 | 金凯(辽宁)生命科技股份有限公司 | 5-甲氧基-7-氮杂吲哚的合成方法 |
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CA2437755A1 (en) | 2002-09-19 |
HUP0303515A2 (hu) | 2004-03-01 |
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