CN1174961C - 制备三唑啉酮所用的中间体及其制备方法 - Google Patents
制备三唑啉酮所用的中间体及其制备方法 Download PDFInfo
- Publication number
- CN1174961C CN1174961C CNB001089285A CN00108928A CN1174961C CN 1174961 C CN1174961 C CN 1174961C CN B001089285 A CNB001089285 A CN B001089285A CN 00108928 A CN00108928 A CN 00108928A CN 1174961 C CN1174961 C CN 1174961C
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- China
- Prior art keywords
- formula
- hydrazinecarboxylate
- general formula
- iii
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 238000000034 method Methods 0.000 title claims abstract description 32
- 229960005437 etoperidone Drugs 0.000 title description 3
- IZBNNCFOBMGTQX-UHFFFAOYSA-N etoperidone Chemical compound O=C1N(CC)C(CC)=NN1CCCN1CCN(C=2C=C(Cl)C=CC=2)CC1 IZBNNCFOBMGTQX-UHFFFAOYSA-N 0.000 title 1
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 12
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 5
- 150000001875 compounds Chemical class 0.000 claims description 35
- OWIUPIRUAQMTTK-UHFFFAOYSA-M n-aminocarbamate Chemical compound NNC([O-])=O OWIUPIRUAQMTTK-UHFFFAOYSA-M 0.000 claims description 23
- 238000006243 chemical reaction Methods 0.000 claims description 19
- 238000002360 preparation method Methods 0.000 claims description 17
- 239000000460 chlorine Substances 0.000 claims description 13
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 10
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 10
- 229910052801 chlorine Inorganic materials 0.000 claims description 10
- 239000011737 fluorine Substances 0.000 claims description 10
- 229910052731 fluorine Inorganic materials 0.000 claims description 10
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000003368 amide group Chemical group 0.000 claims description 3
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 3
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract description 6
- 125000003342 alkenyl group Chemical group 0.000 abstract description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract description 4
- 125000003282 alkyl amino group Chemical group 0.000 abstract description 3
- 239000001257 hydrogen Substances 0.000 abstract description 3
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 abstract description 3
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 abstract description 2
- 125000000753 cycloalkyl group Chemical group 0.000 abstract description 2
- 125000001188 haloalkyl group Chemical group 0.000 abstract description 2
- 125000003884 phenylalkyl group Chemical group 0.000 abstract description 2
- 239000000543 intermediate Substances 0.000 abstract 2
- 125000006193 alkinyl group Chemical group 0.000 abstract 1
- 125000004663 dialkyl amino group Chemical group 0.000 abstract 1
- 238000004519 manufacturing process Methods 0.000 abstract 1
- -1 alkylthio triazole Chemical class 0.000 description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 20
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- WFJRIDQGVSJLLH-UHFFFAOYSA-N methyl n-aminocarbamate Chemical compound COC(=O)NN WFJRIDQGVSJLLH-UHFFFAOYSA-N 0.000 description 13
- 239000000203 mixture Substances 0.000 description 13
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 11
- 239000011591 potassium Substances 0.000 description 11
- 229910052700 potassium Inorganic materials 0.000 description 11
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 239000003513 alkali Substances 0.000 description 8
- 239000012752 auxiliary agent Substances 0.000 description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 6
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 6
- 229910052736 halogen Inorganic materials 0.000 description 6
- 150000002367 halogens Chemical class 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 5
- 239000002243 precursor Substances 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 4
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 4
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 4
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 4
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 239000011575 calcium Substances 0.000 description 4
- 229910052791 calcium Inorganic materials 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- 125000004093 cyano group Chemical group *C#N 0.000 description 4
- 238000003810 ethyl acetate extraction Methods 0.000 description 4
- 229940043265 methyl isobutyl ketone Drugs 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 229910052708 sodium Inorganic materials 0.000 description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- 235000011152 sodium sulphate Nutrition 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 125000000304 alkynyl group Chemical group 0.000 description 3
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- KVNRLNFWIYMESJ-UHFFFAOYSA-N butyronitrile Chemical compound CCCC#N KVNRLNFWIYMESJ-UHFFFAOYSA-N 0.000 description 3
- OWIUPIRUAQMTTK-UHFFFAOYSA-N carbazic acid Chemical compound NNC(O)=O OWIUPIRUAQMTTK-UHFFFAOYSA-N 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- RHUYHJGZWVXEHW-UHFFFAOYSA-N 1,1-Dimethyhydrazine Chemical compound CN(C)N RHUYHJGZWVXEHW-UHFFFAOYSA-N 0.000 description 2
- WNWOTMKHOLCHRJ-UHFFFAOYSA-N 1,4-dihydrotriazol-5-one Chemical compound O=C1CN=NN1 WNWOTMKHOLCHRJ-UHFFFAOYSA-N 0.000 description 2
- NFDXQGNDWIPXQL-UHFFFAOYSA-N 1-cyclooctyldiazocane Chemical compound C1CCCCCCC1N1NCCCCCC1 NFDXQGNDWIPXQL-UHFFFAOYSA-N 0.000 description 2
- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 description 2
- QDFXRVAOBHEBGJ-UHFFFAOYSA-N 3-(cyclononen-1-yl)-4,5,6,7,8,9-hexahydro-1h-diazonine Chemical compound C1CCCCCCC=C1C1=NNCCCCCC1 QDFXRVAOBHEBGJ-UHFFFAOYSA-N 0.000 description 2
- SYBYTAAJFKOIEJ-UHFFFAOYSA-N 3-Methylbutan-2-one Chemical compound CC(C)C(C)=O SYBYTAAJFKOIEJ-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- FKNQCJSGGFJEIZ-UHFFFAOYSA-N 4-methylpyridine Chemical compound CC1=CC=NC=C1 FKNQCJSGGFJEIZ-UHFFFAOYSA-N 0.000 description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- CSKNSYBAZOQPLR-UHFFFAOYSA-N benzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=C1 CSKNSYBAZOQPLR-UHFFFAOYSA-N 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 2
- 239000012973 diazabicyclooctane Substances 0.000 description 2
- XXBDWLFCJWSEKW-UHFFFAOYSA-N dimethylbenzylamine Chemical compound CN(C)CC1=CC=CC=C1 XXBDWLFCJWSEKW-UHFFFAOYSA-N 0.000 description 2
- 125000004494 ethyl ester group Chemical group 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000001640 fractional crystallisation Methods 0.000 description 2
- 150000004702 methyl esters Chemical class 0.000 description 2
- UAEPNZWRGJTJPN-UHFFFAOYSA-N methylcyclohexane Chemical compound CC1CCCCC1 UAEPNZWRGJTJPN-UHFFFAOYSA-N 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 1
- LZDKZFUFMNSQCJ-UHFFFAOYSA-N 1,2-diethoxyethane Chemical compound CCOCCOCC LZDKZFUFMNSQCJ-UHFFFAOYSA-N 0.000 description 1
- WIHIUTUAHOZVLE-UHFFFAOYSA-N 1,3-diethoxypropan-2-ol Chemical compound CCOCC(O)COCC WIHIUTUAHOZVLE-UHFFFAOYSA-N 0.000 description 1
- OCJBOOLMMGQPQU-UHFFFAOYSA-N 1,4-dichlorobenzene Chemical compound ClC1=CC=C(Cl)C=C1 OCJBOOLMMGQPQU-UHFFFAOYSA-N 0.000 description 1
- RRQYJINTUHWNHW-UHFFFAOYSA-N 1-ethoxy-2-(2-ethoxyethoxy)ethane Chemical compound CCOCCOCCOCC RRQYJINTUHWNHW-UHFFFAOYSA-N 0.000 description 1
- MTVUDFBYBPMGMR-UHFFFAOYSA-N 1-ethyl-2-propylhydrazine Chemical compound CCCNNCC MTVUDFBYBPMGMR-UHFFFAOYSA-N 0.000 description 1
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-Lutidine Substances CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 1
- SBASXUCJHJRPEV-UHFFFAOYSA-N 2-(2-methoxyethoxy)ethanol Chemical compound COCCOCCO SBASXUCJHJRPEV-UHFFFAOYSA-N 0.000 description 1
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 1
- ZNQVEEAIQZEUHB-UHFFFAOYSA-N 2-ethoxyethanol Chemical compound CCOCCO ZNQVEEAIQZEUHB-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 1
- NTSLROIKFLNUIJ-UHFFFAOYSA-N 5-Ethyl-2-methylpyridine Chemical compound CCC1=CC=C(C)N=C1 NTSLROIKFLNUIJ-UHFFFAOYSA-N 0.000 description 1
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical class CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- CMEWLCATCRTSGF-UHFFFAOYSA-N N,N-dimethyl-4-nitrosoaniline Chemical compound CN(C)C1=CC=C(N=O)C=C1 CMEWLCATCRTSGF-UHFFFAOYSA-N 0.000 description 1
- SVYKKECYCPFKGB-UHFFFAOYSA-N N,N-dimethylcyclohexylamine Chemical compound CN(C)C1CCCCC1 SVYKKECYCPFKGB-UHFFFAOYSA-N 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical class CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 125000002723 alicyclic group Chemical group 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- SMZOGRDCAXLAAR-UHFFFAOYSA-N aluminium isopropoxide Chemical compound [Al+3].CC(C)[O-].CC(C)[O-].CC(C)[O-] SMZOGRDCAXLAAR-UHFFFAOYSA-N 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 229910052728 basic metal Inorganic materials 0.000 description 1
- 150000003818 basic metals Chemical class 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
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- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C281/00—Derivatives of carbonic acid containing functional groups covered by groups C07C269/00 - C07C279/00 in which at least one nitrogen atom of these functional groups is further bound to another nitrogen atom not being part of a nitro or nitroso group
- C07C281/02—Compounds containing any of the groups, e.g. carbazates
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C281/00—Derivatives of carbonic acid containing functional groups covered by groups C07C269/00 - C07C279/00 in which at least one nitrogen atom of these functional groups is further bound to another nitrogen atom not being part of a nitro or nitroso group
- C07C281/02—Compounds containing any of the groups, e.g. carbazates
- C07C281/04—Compounds containing any of the groups, e.g. carbazates the other nitrogen atom being further doubly-bound to a carbon atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
- C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles 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
- C07D249/12—Oxygen or sulfur atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
本发明涉及制备通式(I)三唑啉酮的新方法,及制备这些三唑啉酮用新中间体和这些中间体的制备方法,所述通式(I)如下,式中R1代表卤代烷基,和R2代表氢,羟基或氨基,或代表烷基,链烯基,炔基,烷氧基,烷基氨基,二烷基氨基,环烷基,环烷基烷基,苯基或苯基烷基,它们均可被可选地取代。
Description
本申请系申请日为1996年2月13日、申请号为96103533.1、发明名称为“制备三唑啉酮的方法和新的中间体”的发明专利申请的分案申请。
本发明涉及制备三唑啉酮所用的新中间体及其制备方法,所述三唑啉酮大体上是公知的,可用作制备除莠剂和杀虫剂的中间体。
人们知道某些取代的三唑啉酮例如化合物4-甲基-5-三氟甲基-2,4-二氢-3H-1,2,4-三唑-3-酮可这样获得:首先使相应的三唑啉硫酮例如化合物4-甲基-5-三氟甲基-2,4-二氢-3H-1,2,4-三唑-3-硫酮与烷基化剂例如甲基碘在酸结合剂例如甲醇钠存在下反应,并将生成的烷硫基三唑衍生物按常规方法分离,然后在乙酸存在下与过氧化氢一同加热,冷却后中和,并按常规方法后处理(参见US-P3780052-实施例2)。
此外还知道,上述化合物4-甲基-5-三氟甲基-2,4-二氢-3H-1,2,4,-三唑-3-酮还可以如下获得:将1-三氟乙酰基-4-四基氨基脲于160-180℃加热,随后用乙酸乙酯萃取并进行柱层析(参见US-P3780052-实施例3)。
然而在这两个所引的合成方法中所生成的产物的收率和质量均令人十分不满意。
制备三唑啉酮的另外的方法是在先但尚未公开的申请(参见DE-4339412和DE-4342190)的主题。
本发明涉及制备通式(I)三唑啉酮的新方法:
式中
R1代表卤代烷基,和
R2代表氢,羟基或氨基,或代表烷基,链烯基,炔基,烷氧基,烷基
氨基,二烷基氨基,环烷基,环烷基烷基,苯基或苯基烷基,所述方法的特征在于:使通式(II)肼羧酸酯和/或式(II)化合物的互变异构化合物在碱性反应助剂和稀释剂存在下在0-150℃之间的温度进行反应;所述通式(II)如下:
式中
R1和R2的定义同上,和
R代表烷基或芳基,它们均可被可选地取代。
令人惊讶的是,用所述新方法,通式(I)三唑啉酮可以简便的方式和非常高的收率获得,而且取代基可以在宽范围内变动。
同时,安全问题例如在以前的方法中使用过氧化氢和实质性的废液问题,如在以前的方法中存在的涉及含硫废液的问题得以避免。
因而该新方法是对现有技术有价值的补充。
按照该新方法,优选制备取代基如下定义的式(I)化合物:
R1代表具有1至6个碳原子的卤代烷基,和
R2代表氢,羟基或氨基;代表烷基、链烯基、炔基、烷氧基、烷基氨基或二烷基氨基,它们均可被氰基、卤素或C1-C4烷氧基可选地取代并且在所述烷基、链烯基或炔基基团上均具有至多6个碳原子;或者代表C3-C6环烷基、C3-C6环烷基-C1-C2烷基、苯基或苯基-C1-C2烷基,它们均可被氰基、卤素、C1-C4烷基、C1-C4烷氧基或C1-C4烷氧基羰基可选地取代。
在基团定义中所述的烃基例如烷基是直链的或支链的,即使是在未明确指明的情况下,例如它们与杂原子结合如烷氧基、烷硫基或烷氨基的情况下亦是一样。
一般来讲,卤素代表氟、氯、溴或碘、最好代表氟,氯或溴,特别是代表氟或氯。
按照该新方法,更优选制备式中取代基如下定义的式(I)化合物:
R1代表甲基、乙基、正丙基、异丙基、正丁基、异丁基或仲丁基,它们均被氟和/或氯取代,和
R2代表甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、烯丙基、炔丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基、甲氨基、乙氨基、正丙氨基、异丙氨基、正丁氨基、异丁氨基、仲丁氨基、二甲氨基或二乙氨基,它们均可被氟、氯、氰基、甲氧基或乙氧基可选地取代;或者代表环丙基、环丁基、环戊基、环己基、苯基或苄基,它们均可被氟、氯、溴、氰基、甲基、乙基、正丙基、异丙基、甲氧羰基或乙氧羰基可选地取代。
可用所述新方法制备的特别优选的化合物是式中取代基如下定义的式(I)化合物:
R1代表甲基或乙基,它们均相应地被氟和/或氯1次、2次、3次、4次或5次取代,和
R2代表甲基,乙基,正丙基异丙基甲氧基,乙氧基,甲氨基,乙氨基,二甲氨基或环丙基。
上面所列的一般的基团定义或在优选范围内给出的基团定义均适用于式(I)的最终产物并且相应地,也适用于该制备所需的所有起始化合物或中间体。这些基团定义之间可随意组合,这也适用于在优选化合物的给定范围之间。
若将例如2-(2,2-二氟-1-乙基亚氨基-乙基)肼-1-羧酸乙酯用作起始化合物,则新方法的反应过程可用以下化学式图解概括:
在所述用于制备通式(I)化合物的新方法中用作起始化合物的肼羧酸酯一般用式(II)表示。在式(II)中,R1至R2优选或特别优选具有上面已经指出的与对于R1和R2是优选的或特别优选的式(I)化合物的描述有关的那些意义;R优选代表可任选地被卤素或C1-C4烷氧基取代的具有1至4个碳原子的烷基或优选代表可任选地被卤素或C1-C4烷基取代的苯基,且特别是代表甲基,乙基,甲氧基乙基,乙氧基乙基或苯基。
式(II)肼羧酸酯尚未在文献中披露;作为新化合物,它们属于本申请的要点。
通式(II)新化合物可以这样来获得:使相应的通式(III)肼羧酸酯在0-100℃之间的温度与通式(IV)氨基化合物反应,若合适,反应在酸接受剂例如三乙胺存在下,并且若合适,在稀释剂例如乙腈或二氧六环存在下进行(参见制备实施例);所述通式(III)和(IV)化合物如下:
式中R和R1的定义同上,
H2N-R2 (IV)
式中R2的定义同上。
用作前体的肼羧酸酯通常用式(III)表示,在式(III)中,R1和R优选或特别优选具有上面已经指出的与对于R1和R是优选的或特别优选的式(I)或式(II)化合物的描述有关的那些意义。
式(III)肼羧酸酯尚未在文献中披露;作为新化合物,它们属于本申请的要点。
通式(III)新化合物这样来获得:使相应的通式(V)肼羧酸酯在0-100℃之间的温度与磺酰氯例如甲磺酰氯、乙磺酰氯、苯磺酰氯或对甲苯磺酰氯反应,该反应若合适,在酸接受剂例如三乙胺或N,N-二甲基苄胺存在下,并且若合适,在稀释剂存在下进行(参见制备实施例);所述稀释剂有例如二甲氧基乙烷,二氧六环,四氢呋喃,二氯甲烷,乙酸乙酯,甲苯,氯苯,丙酮,甲基·乙基酮,甲基·异丙基酮,甲基·异丁基酮,乙腈,丙腈或丁腈;所述通式(V)化合物如下:
式中R和R1的定义同上。
在这里用作前体的肼羧酸酯一般用通式(V)表示。在式(V)中,R1和R优选或特别优选具有上面已经指出的与对于R1和R是优选的或特别优选的式(I)或式(II)化合物的描述有关的那些意义。
式(V)肼羧酸酯是已知的和/或可用已知方法(参见Synthesis 1991,350-352;FR-2123205)来制备。
式(Va)肼羧酸酯尚未在文献中披露,作为新化合物,属于本申请的要点;所述式(Va)如下:
式中
A1代表二氯甲基,三氯甲基,二氟甲基或三氟甲基,和
R的定义同上。
式(Va)新的肼羧酸酯这样来获得:使式(VI)肼羧酸酯在0-150℃之间的温度与通式(VII)羧酸或其衍生物反应,该反应若合适,在稀释剂例如乙醚、乙腈、丙腈、丁腈、氯苯、二甲苯或甲苯存在下进行(参见制备实施例);所述式(VI)和通式(VII)如下:
式中R的定义同上,
A1-CO-X (VII)
式中
A1的定义同上,和
X代表羟基,卤素(特别是氟或氯)或基团-O-CO-A1。
式(VI)和(VII)前体是已知的合成化学制品。
所述新方法在碱性反应助剂存在下进行。所有常规无机或有机碱均适宜用作这样的助剂。这些碱包括例如碱金属或碱土金属氢化物、氢氧化物、氨化物、醇化物、乙酸盐、碳酸盐或碳酸氢盐,例如氢化锂、钠、钾或钙,氢氧化锂、钠、钾或钙,氨基化锂、钠或钾,甲醇钠或钾、乙醇钠或钾、丙醇钠或钾、异丙醇铝、叔丁醇钠或钾,氢氧化钠或钾、氢氧化铵,乙酸钠、钾或钙、乙酸铵、碳酸钠、钾或钙、碳酸铵或碳酸氢钠或钾,以及碱性有机含氮化合物,例如三甲胺,三乙胺,三丙胺,三丁胺,乙基二异丙基胺,N,N-二甲基环己胺,二环己基胺,乙基二环己基胺,N,N-二甲基苯胺,N,N-二甲基苄基胺,吡啶,2-甲基、3-甲基和4-甲基吡啶,2,4-二甲基、2,6-二甲基、3,4-二甲基和3,5-二甲基吡啶,5-乙基-2-甲基吡啶,N-甲基哌啶,4-二甲氨基吡啶,二氮杂二环辛烷(DABCO),二氮杂二环壬烯(DBN)或二氮杂二环十一碳烯(DBU)。
作为该新方法的碱性反应助剂,特别优选碱金属氢氧化物例如氢氧化钠或氢氧化钾,或醇的碱金属盐例如甲醇钠。
用于制备式(II)起始化合物的式(IV)氨基化合物(见上述)也可用作碱性反应助剂代替上述的碱性反应助剂。
除水以外,常规有机溶剂适宜用作实施该新方法的稀释剂。这些溶剂尤其包括脂族、脂环族、芳族的可选地被卤代的烃类,例如戊烷,己烷,庚烷,石油醚,溶剂轻油(ligroin),汽油(benZine),苯,甲苯,二甲苯,氯苯,二氯苯,环己烷,甲基环己烷,二氯甲烷,氯仿或四氯甲烷;醚类,例如乙醚,二异丙基醚,叔丁基甲基醚,叔戊基甲基醚,二氧六环,四氢呋喃,乙二醇二甲醚,乙二醇二乙醚,二甘醇二甲醚或二甘醇二乙醚;酮类,例如丙酮,丁酮或甲基·异丁基酮;腈类,例如乙腈,丙腈,丁腈或苄腈;酰胺类,例如N,N-二甲基甲酰胺,N,N-二甲基乙酰胺,N-甲基甲酰苯胺,N-甲基吡咯烷酮或六甲基磷酸三酰胺;酯类,例如乙酸甲酯、乙酯、正丙酯、异丙酯、正丁酯、异丁酯或仲丁酯;亚砜类,例如二甲亚砜;醇类,例如甲醇,乙醇,正或异丙醇,正、异、仲或叔丁醇、乙二醇单甲醚,乙二醇单乙醚,二甘醇单甲醚或二甘醇单乙醚;和它们与水的混合物,或纯水。
特别优选水和甲醇用作该新方法中的稀释剂。
在实施该新方法时,反应温度可在相当宽的范围内变动。一般采用0-150℃之间的温度,优选10-120℃之间的温度,特别是20-110℃之间的温度。
一般来讲,该新方法在标准压力下实施。但亦可在加压或减压下实施,压力一般在0.1-10巴之间。
要实施该制备式(I)化合物的新方法,一般每摩尔式(II)肼羧酸酯使用1-3mol、优选1.5-2.5mol碱性反应助剂。
在该新方法的优选的实施方案中,将式(II)肼羧酸酯于室温(大约20℃)溶于适宜的稀释剂中,加入碱性反应助剂后,将此混合物在升高的温度下搅拌直至反应完毕。然后将混合物再冷却至室温(大约20℃),并用强酸例如盐酸或硫酸酸化。若式(I)产物在这些条件下结晶析出,可将其吸滤分离。或者将式(I)产物用基本上与水不混溶的有机溶剂例如乙酸乙酯萃取,并且若合适,在将有机相干燥并过滤后,将溶剂从有机相中减压蒸馏出去,于是式(I)产物留在残留物中。
在所述新方法的另一个优选的实施方案一“一步变异法”中,需要用作起始化合物的式(II)肼羧酸酯按下述方法制备:使式(III)肼羧酸酯按上述与式(IV)氨基化合物反应,然后不经中间体分离“就地”转化为式(I)三唑啉酮。
为此,最好在开始时将式(III)肼羧酸酯于温和升高的温度、最好在25-35℃之间的温度加至包含过量式(IV)氨基化合物(一般在2-10mol之间,优选在2.5-5.0mol之间)和适宜的稀释剂最好是水的混合物中。然后将此反应混合物在升温下加热,温度一直上升直至反应完毕,然后按上述进行后处理。
用该新方法制得的式(I)三唑啉酮可用作用于制备具有农业用价值的活性化合物的中间体(参见US-P-3780052,US-P-3780053,US-P-3780054和EP-A-341489)。
制备实施例
实施例1
将36g(185mmol)2-(2,2,2-三氟-1-甲基亚氨基-乙基)肼-1-羧酸甲酯悬浮于200ml水中,加入37.5g 45%氢氧化钠水溶液(相当于370mmol的NaOH)后,将混合物加热回流3小时。将其冷却至室温(大约20℃)后,用浓盐酸酸化,并用乙酸乙酯萃取3次,每次100ml。将合并的有机萃取溶液用硫酸钠干燥并过滤。将溶剂在水抽真空条件下由该滤液中仔细蒸出。
得到28.9g(收率为93.5%)4-甲基-5-三氟甲基-2,4-二氢-3H-1,2,4-三唑-3-酮,为固体残留物。
1H-NMR(DMSO-D6,δ):3.256ppm(s,3H),12.655ppm(s,1H)
实施例2
将25.4g(110mmol)2-(2,2,2-三氟-1-二甲氨基-亚乙基)肼-1-羧酸甲酯悬浮于200ml水中,加入19.8g 45%氢氧化钠水溶液(相当于223mmol的NaOH)后,将混合物加热回流3小时。将其冷却至室温(大约20℃)后,用浓盐酸酸化,并将已结晶析出的产物吸滤分离。
得到19.1g(收率为89%)4-二甲氨基-5-三氟甲基-2,4-二氢-3H-1,2,4-三唑-3-酮,熔点为138℃。
实施例3
将10.2g(50mmol)2-(1-氯-2,2,2-三氟-亚乙基)肼-1-羧酸甲酯一次加至由50ml水和22.5g 34%甲胺水溶液(相当于250mmol甲胺)组成的混合物中,该混合物的温度被维持在25-35℃之间。随后将反应混合物加热回流2小时,然后在冷却至室温(大约20℃)后用浓盐酸酸化。然后将其用乙酸乙酯萃取3次。将合并的萃取溶液用硫酸钠干燥并过滤。然后将溶剂在水抽真空条件下由滤液中仔细蒸出。
得到7.3g(收率:85%)4-甲基-5-三氟甲基-2,4-二氢-3H-1,2,4-三唑-3-酮,为固体残留物(纯度:97.0%)。
按与实施例1至3类似的方法和所述新制备方法的总述,还可例如制得下表1中所列的式(I)化合物。
表1:按照本发明获得的式(I)化合物的实施例
实施例 R1 R2
序号 收率(%) 物理数据
4 CF3 (CH2)2OCH3 92 nD 20=1.4290
5 CF3 (CH2)3OCH3 90 nD 20=1.4320
6 CHF2 CH3
7 CF2Cl CH3
8 CF3 H 70 m.p.:198℃
式(II)起始化合物
实施例(II-1)
将39.6g(185mmol)2-(1-氯-2,2,2-三氟-亚乙基)肼-1-羧酸甲酯溶于220ml二氧六环中,将50g 34.5%甲胺水溶液(相当于556mmol甲胺)于20℃用30分钟时间滴加至该溶液中,同时将内部温度维持在25-35℃之间。然后将混合物在大约30℃再搅拌2小时,此后将其在水抽真空的条件下浓缩。将残余物与150ml水一起搅拌,并将结晶析出的产物吸滤分离。
得到36g(收率:98%)2-(2,2,2-三氟-1-甲基亚氨基-乙基)肼-1-羧酸甲酯。
1H-NMR(DMSO-D6,δ):2.817ppm(m,3H),3.641ppm(s,3H),6.483ppm(br.s,1H),9.527ppm(s,1H)
实施例(II-2)
将8.06g(134mmol)N,N-二甲基肼和17ml(122mmol)三乙胺先引入120ml乙腈中,在大约55℃的内部温度和搅拌下滴加25g(122mmol)2-(1-氯-2,2,2-三氟-亚乙基)肼-1-羧酸甲酯的乙腈(30ml)溶液,然后将混合物于60℃再搅拌1小时,此后在水抽真空条件下将其浓缩。该残留物用乙酸乙酯溶解并将此溶液用水洗,以硫酸钠干燥并过滤。所得滤液在水抽真空条件下浓缩并且通过用二异丙醚溶解使残余物结晶,将结晶产物吸滤分离。
得到16.1g(收率:58%)2-(2,2,2-三氟-1-(N,N-二甲基肼基)乙基)肼-1-羧酸甲酯,熔点为124℃。
按与实施例(II-1)和(II-2)类似的方法还可例如制得下表2中所列的式(II)化合物。
表2:式(II)化合物的实施例
实施例
R1 R2 R
序号 收率(%) 熔点(℃)
II-3 CF3 CH3 CH3 88 213
II-4 CF3 (CH2)2OCH3 CH3 68 150
II-5 CF3 (CH2)3OCH3 CH3 84 148
II-6 CF3 OH CH3 63 183
II-7 CF3 OCH3 CH3 27 104
II-8 CHF2 CH3 CH3
II-9 CF2Cl CH3 CH3
式(III)前体
实施例(III-1)
将65.1g(350mmol)2-三氟乙酰基肼-1-羧酸甲酯和66.2g(375mmol)苯磺酰氯先加至450ml丙酮中,并在50-55℃之间的内部温度和搅拌下滴加48.7ml(350mmol)三乙胺的丙酮(50ml)溶液。将反应混合物于50-55℃搅拌1小时后,向其中加入2.5ml三乙胺,并再继续搅拌30分钟。将混合物在冰浴中冷却后,将结晶析出的氯化三乙基铵吸滤分离。将滤液在水抽真空条件下浓缩,并将残余物溶于300ml乙酸乙酯中。将此溶液用水洗涤3次,每次100ml,用硫酸钠干燥并过滤。将溶剂在水抽真空条件下从滤液中仔细蒸出。
得到72.5g(纯度:92.2%,收率:93%)2-(1-氯-2,2,2-三氟亚乙基)肼-1-羧酸甲酯,为固体产物。
1H-NMR(DMSO-D6,δ):3.78ppm(s,3H),11.59ppm(s,1H)
按与实施例(III-1)类似的方法例如还可制得下表3中所列的式(III)化合物。
表3:式(III)化合物的实施例
实施例
R1 R
序号 收率(%) 熔点(℃)
III-2 CHF2 CH3
III-3 CF2Cl CH3
式(V)前体:
实施例(V-1)
将121.5g(1.28mol)肼基甲酸甲酯(肼羧酸甲酯)先加至1200ml乙醚中,并于0℃用2小时时间滴加310g(1.48mol)三氟乙酸酐。然后将混合物于0-20℃再搅拌约90分钟。此后将其在水抽真空条件下浓缩。将残余物与500ml甲苯一起搅拌,吸滤分离结晶产物。
得到219g(纯度:94.4%,收率:94%)2-三氟乙酰基肼-1-羧酸甲酯,熔点为105℃。
1H-NMR(DMSO-D6,δ):3.647ppm(s,3H),9.649ppm(s,1H),11.429ppm(s,1H).
实施例(V-2)
将18.5g(0.20mol)肼基甲酸甲酯(肼羧酸甲酯先加至150ml甲苯中。在80℃的内部温度下用35分钟时间滴加23.1ml(0.30mol)三氟乙酸。然后将此混合物于80℃再搅拌约30分钟。此后将其在水分离器上加热1小时,然后在水抽真空条件下浓缩。将残余物与500ml甲苯一起搅拌,吸滤分离结晶产物。
得到36.4g(纯度:90.1%,收率:88.2%)2-三氟乙酰基肼-1-羧酸甲酯,熔点为105℃。
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CN1281848A (zh) | 2001-01-31 |
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US5817863A (en) | 1998-10-06 |
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TW425384B (en) | 2001-03-11 |
EP0726258A1 (de) | 1996-08-14 |
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US5965768A (en) | 1999-10-12 |
HU9600320D0 (en) | 1996-04-29 |
EP1172357A1 (de) | 2002-01-16 |
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US5977401A (en) | 1999-11-02 |
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