CN1532199A - Process of 2-methyl-thiophene benzodinitro heterotropilidene - Google Patents
Process of 2-methyl-thiophene benzodinitro heterotropilidene Download PDFInfo
- Publication number
- CN1532199A CN1532199A CNA031363881A CN03136388A CN1532199A CN 1532199 A CN1532199 A CN 1532199A CN A031363881 A CNA031363881 A CN A031363881A CN 03136388 A CN03136388 A CN 03136388A CN 1532199 A CN1532199 A CN 1532199A
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- Prior art keywords
- compound
- salt
- alkyl
- chemical formula
- replaces
- Prior art date
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- 238000000034 method Methods 0.000 title claims description 58
- 230000008569 process Effects 0.000 title claims description 7
- XQQBUAPQHNYYRS-UHFFFAOYSA-N 2-methylthiophene Chemical compound CC1=CC=CS1 XQQBUAPQHNYYRS-UHFFFAOYSA-N 0.000 title 1
- QENGPZGAWFQWCZ-UHFFFAOYSA-N Methylthiophene Natural products CC=1C=CSC=1 QENGPZGAWFQWCZ-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 72
- 150000003839 salts Chemical class 0.000 claims description 37
- 239000000126 substance Substances 0.000 claims description 33
- 125000000217 alkyl group Chemical group 0.000 claims description 31
- -1 alkyl sulfide Chemical compound 0.000 claims description 23
- 229910052794 bromium Inorganic materials 0.000 claims description 22
- 229910052801 chlorine Inorganic materials 0.000 claims description 22
- 238000002360 preparation method Methods 0.000 claims description 22
- 229910052731 fluorine Inorganic materials 0.000 claims description 21
- 229910052740 iodine Inorganic materials 0.000 claims description 21
- 229910052736 halogen Inorganic materials 0.000 claims description 18
- 150000002367 halogens Chemical class 0.000 claims description 18
- 125000002769 thiazolinyl group Chemical group 0.000 claims description 18
- 125000003118 aryl group Chemical group 0.000 claims description 17
- 150000001412 amines Chemical class 0.000 claims description 16
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 14
- 229910052760 oxygen Inorganic materials 0.000 claims description 14
- FDDDEECHVMSUSB-UHFFFAOYSA-N sulfanilamide Chemical compound NC1=CC=C(S(N)(=O)=O)C=C1 FDDDEECHVMSUSB-UHFFFAOYSA-N 0.000 claims description 14
- 229940124530 sulfonamide Drugs 0.000 claims description 14
- 125000006239 protecting group Chemical group 0.000 claims description 12
- 125000000304 alkynyl group Chemical group 0.000 claims description 11
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 11
- 125000003545 alkoxy group Chemical group 0.000 claims description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- 239000001257 hydrogen Substances 0.000 claims description 9
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 9
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- 239000002841 Lewis acid Substances 0.000 claims description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 4
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- 230000008878 coupling Effects 0.000 claims description 4
- 238000010168 coupling process Methods 0.000 claims description 4
- 238000005859 coupling reaction Methods 0.000 claims description 4
- 125000005842 heteroatom Chemical group 0.000 claims description 4
- 150000007517 lewis acids Chemical class 0.000 claims description 4
- CUONGYYJJVDODC-UHFFFAOYSA-N malononitrile Chemical compound N#CCC#N CUONGYYJJVDODC-UHFFFAOYSA-N 0.000 claims description 4
- 229910052717 sulfur Inorganic materials 0.000 claims description 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 3
- 239000005864 Sulphur Substances 0.000 claims description 3
- CNPURSDMOWDNOQ-UHFFFAOYSA-N 4-methoxy-7h-pyrrolo[2,3-d]pyrimidin-2-amine Chemical compound COC1=NC(N)=NC2=C1C=CN2 CNPURSDMOWDNOQ-UHFFFAOYSA-N 0.000 claims description 2
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 claims description 2
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 claims description 2
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical group C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 2
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 2
- PUJDIJCNWFYVJX-UHFFFAOYSA-N benzyl carbamate Chemical compound NC(=O)OCC1=CC=CC=C1 PUJDIJCNWFYVJX-UHFFFAOYSA-N 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 150000002460 imidazoles Chemical class 0.000 claims description 2
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 claims description 2
- 150000003053 piperidines Chemical class 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 150000003233 pyrroles Chemical class 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 2
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 claims 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims 1
- 150000004683 dihydrates Chemical group 0.000 claims 1
- 150000004885 piperazines Chemical group 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 238000006243 chemical reaction Methods 0.000 description 30
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 17
- 239000002585 base Substances 0.000 description 17
- 239000000203 mixture Substances 0.000 description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 14
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 239000002253 acid Substances 0.000 description 12
- HTZCNXWZYVXIMZ-UHFFFAOYSA-M benzyl(triethyl)azanium;chloride Chemical compound [Cl-].CC[N+](CC)(CC)CC1=CC=CC=C1 HTZCNXWZYVXIMZ-UHFFFAOYSA-M 0.000 description 12
- 230000031709 bromination Effects 0.000 description 11
- 238000005893 bromination reaction Methods 0.000 description 11
- 239000003513 alkali Substances 0.000 description 10
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 10
- 239000001301 oxygen Substances 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 239000003444 phase transfer catalyst Substances 0.000 description 9
- 206010013786 Dry skin Diseases 0.000 description 7
- 238000001035 drying Methods 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- 239000000460 chlorine Substances 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 238000002425 crystallisation Methods 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- 238000005660 chlorination reaction Methods 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 230000008025 crystallization Effects 0.000 description 5
- 239000012442 inert solvent Substances 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- 239000003960 organic solvent Substances 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 4
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 4
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 4
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 4
- 150000001335 aliphatic alkanes Chemical class 0.000 description 4
- 125000003435 aroyl group Chemical group 0.000 description 4
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 description 4
- 229910052500 inorganic mineral Inorganic materials 0.000 description 4
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 239000011707 mineral Substances 0.000 description 4
- 235000010755 mineral Nutrition 0.000 description 4
- 150000007524 organic acids Chemical class 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 238000007363 ring formation reaction Methods 0.000 description 4
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 description 4
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 3
- 125000002723 alicyclic group Chemical group 0.000 description 3
- 229910021529 ammonia Inorganic materials 0.000 description 3
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 3
- 239000006227 byproduct Substances 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 229910017604 nitric acid Inorganic materials 0.000 description 3
- 239000003495 polar organic solvent Substances 0.000 description 3
- 230000001737 promoting effect Effects 0.000 description 3
- 239000012429 reaction media Substances 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 3
- UWYVPFMHMJIBHE-OWOJBTEDSA-N (e)-2-hydroxybut-2-enedioic acid Chemical compound OC(=O)\C=C(\O)C(O)=O UWYVPFMHMJIBHE-OWOJBTEDSA-N 0.000 description 2
- QSSXJPIWXQTSIX-UHFFFAOYSA-N 1-bromo-2-methylbenzene Chemical group CC1=CC=CC=C1Br QSSXJPIWXQTSIX-UHFFFAOYSA-N 0.000 description 2
- AIDLAEPHWROGFI-UHFFFAOYSA-N 2-methylbenzene-1,3-dicarboxylic acid Chemical compound CC1=C(C(O)=O)C=CC=C1C(O)=O AIDLAEPHWROGFI-UHFFFAOYSA-N 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 2
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 2
- FXQYYFYMDDANJO-UHFFFAOYSA-N C(CCCCCCCCCCCCCCC)[P](CCCC)(CCCC)CCCC Chemical compound C(CCCCCCCCCCCCCCC)[P](CCCC)(CCCC)CCCC FXQYYFYMDDANJO-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-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
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 2
- NBBJYMSMWIIQGU-UHFFFAOYSA-N Propionic aldehyde Chemical compound CCC=O NBBJYMSMWIIQGU-UHFFFAOYSA-N 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-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
- 230000002378 acidificating effect Effects 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 239000000164 antipsychotic agent Substances 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 150000001557 benzodiazepines Chemical class 0.000 description 2
- CUBCNYWQJHBXIY-UHFFFAOYSA-N benzoic acid;2-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=CC=C1.OC(=O)C1=CC=CC=C1O CUBCNYWQJHBXIY-UHFFFAOYSA-N 0.000 description 2
- VBQDSLGFSUGBBE-UHFFFAOYSA-N benzyl(triethyl)azanium Chemical compound CC[N+](CC)(CC)CC1=CC=CC=C1 VBQDSLGFSUGBBE-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- JHXKRIRFYBPWGE-UHFFFAOYSA-K bismuth chloride Chemical compound Cl[Bi](Cl)Cl JHXKRIRFYBPWGE-UHFFFAOYSA-K 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical compound ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 2
- 229960003280 cupric chloride Drugs 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- 238000001212 derivatisation Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 239000001530 fumaric acid Substances 0.000 description 2
- DCAYPVUWAIABOU-UHFFFAOYSA-N hexadecane Chemical compound CCCCCCCCCCCCCCCC DCAYPVUWAIABOU-UHFFFAOYSA-N 0.000 description 2
- 125000001183 hydrocarbyl group Chemical group 0.000 description 2
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 2
- 229910052742 iron Inorganic materials 0.000 description 2
- HWSZZLVAJGOAAY-UHFFFAOYSA-L lead(II) chloride Chemical compound Cl[Pb]Cl HWSZZLVAJGOAAY-UHFFFAOYSA-L 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical compound C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 2
- 239000011664 nicotinic acid Substances 0.000 description 2
- 229960003512 nicotinic acid Drugs 0.000 description 2
- 235000001968 nicotinic acid Nutrition 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-O phosphonium Chemical compound [PH4+] XYFCBTPGUUZFHI-UHFFFAOYSA-O 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 235000015320 potassium carbonate Nutrition 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 201000000980 schizophrenia Diseases 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 229940095064 tartrate Drugs 0.000 description 2
- YJBKVPRVZAQTPY-UHFFFAOYSA-J tetrachlorostannane;dihydrate Chemical compound O.O.Cl[Sn](Cl)(Cl)Cl YJBKVPRVZAQTPY-UHFFFAOYSA-J 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- RMZAYIKUYWXQPB-UHFFFAOYSA-N trioctylphosphane Chemical compound CCCCCCCCP(CCCCCCCC)CCCCCCCC RMZAYIKUYWXQPB-UHFFFAOYSA-N 0.000 description 2
- 239000011592 zinc chloride Substances 0.000 description 2
- 235000005074 zinc chloride Nutrition 0.000 description 2
- BBUPDLILCKMSEN-UHFFFAOYSA-N 1-bromododecane;pyridine Chemical compound C1=CC=NC=C1.CCCCCCCCCCCCBr BBUPDLILCKMSEN-UHFFFAOYSA-N 0.000 description 1
- REACWASHYHDPSQ-UHFFFAOYSA-N 1-butylpyridin-1-ium Chemical compound CCCC[N+]1=CC=CC=C1 REACWASHYHDPSQ-UHFFFAOYSA-N 0.000 description 1
- ZJIWOPLUFMVUTO-UHFFFAOYSA-N 10-benzyl-2-methylthieno[2,3-b][1,5]benzodiazepin-4-amine Chemical compound S1C(C)=CC(C(=NC2=CC=CC=C22)N)=C1N2CC1=CC=CC=C1 ZJIWOPLUFMVUTO-UHFFFAOYSA-N 0.000 description 1
- ZVAPWJGRRUHKGP-UHFFFAOYSA-N 1h-1,5-benzodiazepine Chemical compound N1C=CC=NC2=CC=CC=C12 ZVAPWJGRRUHKGP-UHFFFAOYSA-N 0.000 description 1
- DYCPESWJKDONHC-UHFFFAOYSA-N 2-heptylpyridine Chemical compound CCCCCCCC1=CC=CC=N1 DYCPESWJKDONHC-UHFFFAOYSA-N 0.000 description 1
- KHXIELCFAHVRAL-UHFFFAOYSA-N 2-methylthieno[2,3-i][1,2]benzodiazepine Chemical compound C12=NN(C)C=CC=C2C=CC2=C1C=CS2 KHXIELCFAHVRAL-UHFFFAOYSA-N 0.000 description 1
- ZGNLVJRZVTXROW-UHFFFAOYSA-N C(C)N(CC)CC[N+](C1=CC=CC=C1)(C1=CC=CC=C1)C1=CC=CC=C1 Chemical compound C(C)N(CC)CC[N+](C1=CC=CC=C1)(C1=CC=CC=C1)C1=CC=CC=C1 ZGNLVJRZVTXROW-UHFFFAOYSA-N 0.000 description 1
- WXJVQQPLIMTRFK-UHFFFAOYSA-N C(CCC)[P](CCCC)(CCCC)CCCC Chemical compound C(CCC)[P](CCCC)(CCCC)CCCC WXJVQQPLIMTRFK-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- LZZYPRNAOMGNLH-UHFFFAOYSA-M Cetrimonium bromide Chemical compound [Br-].CCCCCCCCCCCCCCCC[N+](C)(C)C LZZYPRNAOMGNLH-UHFFFAOYSA-M 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- QMMADBSIIFAORD-UHFFFAOYSA-N Cl.Cc1cc2c(s1)N(Cc1ccccc1)c1ccccc1N=C2N Chemical compound Cl.Cc1cc2c(s1)N(Cc1ccccc1)c1ccccc1N=C2N QMMADBSIIFAORD-UHFFFAOYSA-N 0.000 description 1
- SZGKPLJMVQEZMM-UHFFFAOYSA-N N1N=CC=CC2=C1C=CC=C2.CC=2SC=CC2 Chemical class N1N=CC=CC2=C1C=CC=C2.CC=2SC=CC2 SZGKPLJMVQEZMM-UHFFFAOYSA-N 0.000 description 1
- 208000028017 Psychotic disease Diseases 0.000 description 1
- CMESGULQGSXOMR-UHFFFAOYSA-N S(=O)(=O)=O.S(=O)(=O)(C)OC.C1=CC=CC=C1 Chemical compound S(=O)(=O)=O.S(=O)(=O)(C)OC.C1=CC=CC=C1 CMESGULQGSXOMR-UHFFFAOYSA-N 0.000 description 1
- 208000020186 Schizophreniform disease Diseases 0.000 description 1
- UXMAWJKSGBRJKV-UHFFFAOYSA-N [SiH3][O] Chemical compound [SiH3][O] UXMAWJKSGBRJKV-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- SWLVFNYSXGMGBS-UHFFFAOYSA-N ammonium bromide Chemical compound [NH4+].[Br-] SWLVFNYSXGMGBS-UHFFFAOYSA-N 0.000 description 1
- 229940005529 antipsychotics Drugs 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 229910052785 arsenic Inorganic materials 0.000 description 1
- RQNWIZPPADIBDY-UHFFFAOYSA-N arsenic atom Chemical compound [As] RQNWIZPPADIBDY-UHFFFAOYSA-N 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 1
- 229940049706 benzodiazepine Drugs 0.000 description 1
- 229940053197 benzodiazepine derivative antiepileptics Drugs 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 125000001231 benzoyloxy group Chemical group C(C1=CC=CC=C1)(=O)O* 0.000 description 1
- 238000004166 bioassay Methods 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 229960000800 cetrimonium bromide Drugs 0.000 description 1
- WOWHHFRSBJGXCM-UHFFFAOYSA-M cetyltrimethylammonium chloride Chemical compound [Cl-].CCCCCCCCCCCCCCCC[N+](C)(C)C WOWHHFRSBJGXCM-UHFFFAOYSA-M 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000012937 correction Methods 0.000 description 1
- 150000003983 crown ethers Chemical group 0.000 description 1
- 125000000392 cycloalkenyl group Chemical group 0.000 description 1
- FMGOXRYKYRAOGN-UHFFFAOYSA-N decyl(triethyl)azanium Chemical compound CCCCCCCCCC[N+](CC)(CC)CC FMGOXRYKYRAOGN-UHFFFAOYSA-N 0.000 description 1
- HVMLGVVFRKCJOV-UHFFFAOYSA-N dibutyl(dimethyl)azanium Chemical compound CCCC[N+](C)(C)CCCC HVMLGVVFRKCJOV-UHFFFAOYSA-N 0.000 description 1
- 238000007599 discharging Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- DGJUONISEWDPFO-UHFFFAOYSA-N dodecyl(triethyl)azanium Chemical compound CCCCCCCCCCCC[N+](CC)(CC)CC DGJUONISEWDPFO-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 150000002466 imines Chemical class 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 230000003340 mental effect Effects 0.000 description 1
- 229940050176 methyl chloride Drugs 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- YCWSUKQGVSGXJO-NTUHNPAUSA-N nifuroxazide Chemical group C1=CC(O)=CC=C1C(=O)N\N=C\C1=CC=C([N+]([O-])=O)O1 YCWSUKQGVSGXJO-NTUHNPAUSA-N 0.000 description 1
- 150000005181 nitrobenzenes Chemical class 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- QWVGKYWNOKOFNN-UHFFFAOYSA-N o-cresol Chemical compound CC1=CC=CC=C1O QWVGKYWNOKOFNN-UHFFFAOYSA-N 0.000 description 1
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 238000003408 phase transfer catalysis Methods 0.000 description 1
- 150000003008 phosphonic acid esters Chemical class 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- LFGREXWGYUGZLY-UHFFFAOYSA-N phosphoryl Chemical group [P]=O LFGREXWGYUGZLY-UHFFFAOYSA-N 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-N picric acid Chemical compound OC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-N 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 230000007096 poisonous effect Effects 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 229910000105 potassium hydride Inorganic materials 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- WGYKZJWCGVVSQN-UHFFFAOYSA-O propan-1-aminium Chemical compound CCC[NH3+] WGYKZJWCGVVSQN-UHFFFAOYSA-O 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 208000020016 psychiatric disease Diseases 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000013049 sediment Substances 0.000 description 1
- 150000003346 selenoethers Chemical class 0.000 description 1
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 description 1
- YMBCJWGVCUEGHA-UHFFFAOYSA-M tetraethylammonium chloride Chemical compound [Cl-].CC[N+](CC)(CC)CC YMBCJWGVCUEGHA-UHFFFAOYSA-M 0.000 description 1
- DDFYFBUWEBINLX-UHFFFAOYSA-M tetramethylammonium bromide Chemical compound [Br-].C[N+](C)(C)C DDFYFBUWEBINLX-UHFFFAOYSA-M 0.000 description 1
- IUVXCVGGLRYGFE-UHFFFAOYSA-N tetraphenyl-lambda5-arsane hydrochloride Chemical compound C1=CC=C(C=C1)[AsH](C2=CC=CC=C2)(C3=CC=CC=C3)C4=CC=CC=C4.Cl IUVXCVGGLRYGFE-UHFFFAOYSA-N 0.000 description 1
- WAGFXJQAIZNSEQ-UHFFFAOYSA-M tetraphenylphosphonium chloride Chemical compound [Cl-].C1=CC=CC=C1[P+](C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 WAGFXJQAIZNSEQ-UHFFFAOYSA-M 0.000 description 1
- OSBSFAARYOCBHB-UHFFFAOYSA-N tetrapropylammonium Chemical compound CCC[N+](CCC)(CCC)CCC OSBSFAARYOCBHB-UHFFFAOYSA-N 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- KHMOASUYFVRATF-UHFFFAOYSA-J tin(4+);tetrachloride;pentahydrate Chemical compound O.O.O.O.O.Cl[Sn](Cl)(Cl)Cl KHMOASUYFVRATF-UHFFFAOYSA-J 0.000 description 1
- GCRCSLNXFKCFHB-UHFFFAOYSA-N triethyl(hexyl)azanium Chemical compound CCCCCC[N+](CC)(CC)CC GCRCSLNXFKCFHB-UHFFFAOYSA-N 0.000 description 1
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a novel multistep process for preparing thienobenzodiazepine derivatives having the following structure.
Description
With reference to relevant application/by with reference to incorporating into
The application requires the right of priority of the U.S. Patent Application Serial Number 60/456,270 of submission on March 20th, 2003, and its content is incorporated this paper into by reference.
The file and the reference of quote every application of this paper and patent and every application and patent citation (are included in during every published patent action; " application reference document "), and corresponding these applications arbitrarily and patent and/or by every U.S. and the foreign application or the patent of these applications and patent opinion right of priority arbitrarily, with every quote and each piece file that mention of application citing document, clearly incorporate this paper into by reference thus.More generally, this paper or the reference list before claims are perhaps at reference document of text own and reference; And, these files and reference (" reference that this paper quotes ") every piece, and the file of quoting in the reference quoted of every piece of this paper and reference (comprise any manufacturer's specification sheets, operational guidance, or the like), thus by with reference to clearly incorporating this paper into.In enforcement of the present invention, can adopt the file of incorporating this paper by reference into.
Technical field
The invention provides, especially, the preparation method of thieno-benzodiazepine derivative.Summarized conventional reaction scheme in the scheme 1.
Scheme 1. is used for thieno-benzodiazepine derivative synthetic popular response scheme.
Technical background
Antipsychotics is known to be suitable for treatment as psychotic cacopathia disease, includes but not limited to schizophrenia and schizophreniform diseases.These medicines comprise the thieno-benzodiazepine with following structure nuclear:
1,2,5-8 and 10 several analogues with various substituent said structures have shown interesting biologic activity.Published a large amount of patents, wherein United Kingdom's patent 980 853; 1 291 684; 1 380 242; 1 380 243; 1 380 244 and United States Patent (USP) 2,983,992; 3,102,116; 3,109,843; 3,136,815; 3,474,099; 3,654,286; 3,749,786 and 3,842,082, they only represent a little by with reference to incorporating this paper into.In addition, English Patent 1 533 235 discloses 7-fluoro-2-methyl isophthalic acid 0-(4-methyl isophthalic acid-piperazinyl)-4H-thieno-[2,3-b] [1,5]-benzodiazepine , and it develops into suffering from the stage of schizoid mental patient's clinical administration.US6,008,216 is open, 2-methyl-4-(4-methyl isophthalic acid-piperazinyl)-10H-thieno-[2,3-b] [1,5] benzodiazepine , it is sold as the antipsychotic agent that is suitable for the treatment of schizophrenia and two phasic property mental disorders in the U.S. at present.
Conventional reaction scheme needs synthesizing thiofuran and benzodiazepine derivative, wherein has indefinite substituent analogue and prepares in mode easily and accept biological assessment.English Patent 1,533,235 and 980,853 disclose several thieno-benzodiazepine derivatives, and incorporate this paper into by reference.This reaction scheme should comprise the ordinary method of synthesizing thiofuran and benzodiazepine derivative, and it is compatible with multiple substituting group.In addition, ordinary method should allow thieno-benzodiazepine derivative to prepare by combined method.As for relevant combination synthetic summary, referring to E.M.Gorden etc., J.Med.Chem., 37; 1385-1401 (1994); R.A.Houghten, Curr.Biol., 4; 564-567 (1994); R.Frank, J.Biotechnol., 41; 259-72 (1995); And P.M.Doyle, J.Chem.Technol.Biotechnol., 64; 317-324 (1995).United States Patent (USP) 5,229,382 disclose the method for a kind of 2-methyl-thiophene-benzodiazepine derivative and this derivative of preparation.This method comprises 4-amino-2-methyl-10H-thiophene [2,3-b] [1,5] benzodiazepine and N methyl piperazine reaction.This method has also been used toluene, methyl-sulphoxide and other compounds in technological process.
Summary of the invention
The present invention relates to a kind of rapid method of general multistep that is used to prepare the thieno-benzodiazepine derivative of Formula I
Especially, the invention provides a kind of method, wherein the phenyl amino of Formulae II-nitrilthiophene derivative through protected, cyclisation, derive and go to protect so that the thieno-benzodiazepine derivative of Formula I to be provided.The present invention also provides the preparation method of the phenyl amino-nitrilthiophene derivative of Formulae II by preparation precursor thieno-benzene derivative and the described derivative of coupling to nitrobenzene derivative.Also provide product by method preparation described herein.
Detailed Description Of The Invention
The invention provides the thieno-benzodiazepine derivative of Formula I or the preparation method of its salt
Wherein
R
1And R
2Be alternative alkyl or the cyclic hydrocarbon radical that replaces, perhaps R
1And R
2Add that adjacent nitrogen-atoms forms alternative 5-to a 8-unit ring that replaces, one or more carbon atoms can optionally be replaced by the heteroatoms that is selected from O, S and N on the ring,
R
3, R
4, R
5, and R
6Be alkyl, thiazolinyl, cycloalkyl, alkoxyl group, amino, alkyl sulfide (alkythio), aryl, the sulfanilamide (SN) that hydrogen, selectivity replace independently, perhaps be selected from the halogen of F, Cl, Br and I, or hydroxyl, perhaps two adjacent substituting groups, i.e. R
4And R
5, form the alternative many cyclic groups of 5-to 8-unit that replace,
R
7Be alkyl, thiazolinyl, alkynyl, alkyloyl, aryl, nitro, phenyl that optionally replaces or the halogen that is selected from F, Cl, Br and I;
Described method comprises
(1) with chemical formula R
8The compound of the protecting group protection Formulae II of-Y
R wherein
8Be nitrogen atom protecting group, Y is a leavings group, with first midbody compound or its salt of generation Formulae II I,
(2) with catalyzer cyclisation first midbody compound, second midbody compound of preparation Formula I V
Or its salt,
(3) chemical formula HNR
1R
2Amine add to second midbody compound, obtain the 3rd midbody compound or its salt of chemical formula V,
R wherein
1And R
2Definition as above; With
(4) remove to protect the 3rd midbody compound, obtain the compound of Formula I.
The popular response scheme of the reaction of this order is shown in scheme 1.
When being used for the application, the aliphatics substituting group of only forming of term " alkyl " expression unit price, straight or branched by carbon and hydrogen.Hydrocarbyl group can be saturated or undersaturated in one or more positions.Hydrocarbyl group comprises the alkyl group that contains 1 to 30 carbon atom and contains the thiazolinyl and the alkynyl group of 2 to 30 carbon atoms.Alkyl; thiazolinyl; or alkynyl group be unsubstituted or one or more on, preferred 1 to 7 replaces with low alkyl group, perhaps 1 to 3 replaces with lower alkoxy, hydroxyl, oxygen base, acetalation oxygen base, low-grade alkane acidyl, aroyl, low-grade alkane acidyl oxygen base or aroyl oxygen groups.
Unit price, list or how alicyclic or aryl substituent that term " cyclic hydrocarbon radical " expression only is made up of carbon and hydrogen.Alicyclic group can be saturated or undersaturated in one or more positions.Term " cyclic hydrocarbon radical " also comprises how alicyclic substituting group, promptly condenses the group of naphthene base of one or more saturated or unsaturated groups of naphthene base.Cyclic hydrocarbon radical is unsubstituted or replaces with low alkyl group, lower alkoxy, hydroxyl, oxygen base, acetalation oxygen base, low-grade alkane acidyl, aroyl, low-grade alkane acidyl oxygen base or aroyl oxygen groups in one or more positions.
Term " many rings " or " many cyclic groups " refer to two or more rings (for example, cycloalkyl, cycloalkenyl group, cycloalkynyl radical, aryl and/or heterocycle), and the ring that wherein two or more carbon atoms are two adjacency is total, and for example ring is " fused rings ".The ring term that atom by non-vicinity connects is called as " bridge " ring.Each ring of polycyclic can be replaced by aforesaid substituting group; for example, halogen, alkyl, thiazolinyl, alkynyl, hydroxyl, alkoxyl group, silyl oxygen base, amino, nitro, thiol, amine, imines, acid amides, phosphonic acid ester, phosphine, carbonyl, carboxyl, silyl, ether, thioether, alkylsulfonyl, selenide, ketone, aldehyde or ester etc.
Nitrogen atom protecting group is defined as any nitrogen-atoms that can prevent and stands the protecting group of derivatization reaction.Derivatization reaction comprises alkylation, acylations, displacement, replacement, cancellation, oxidation etc.T.W.Greene and G.M.Wuts; Protecting Groups in Organic Synthesis; second edition; Wiley; New York; 1991 and the reference wherein quoted, to describe the suitable blocking group and the protection of suitable amine and gone to protect the suitable condition of amine, they are by with reference to incorporating Ben Wenben into.Preferred blocking group comprises alternative carboxylamine methyl ester or the benzyl ester that replaces, benzyl, or benzoyl.
Going to protect is the method for removing protecting group.Different protecting groups needs the different reaction conditionss that they remove usefulness that is suitable for.T.W.Greene and G.M.Wuts, Protecting Groupsin Organic Synthesis, second edition; Wiley, New York, 1991; the reference of wherein quoting has been described and has been suitable for carrying out de-protected various reaction conditions, and they are by with reference to incorporating this paper into.
Leavings group comprises the halogen of being made up of F, Cl, Br and I; the alkylsulfonyl oxygen base that replaces; for example to benzene mesyloxy, methane sulfonyl oxygen base or trifluoromethane sulfonyl group oxygen base; benzoyloxy with replacement of one or more electron-withdrawing substituents (for example nitro or chlorine); the trifluoracetic acid base; or diaryl phosphoryl oxygen base; phenylbenzene-phosphoryl oxygen base halogen for example; trinitride and azo derivative; nitro; with two amine that are selected from the group replacement of low alkyl group or aromatic hydrocarbons and low alkyl group four derivatives thereof, and pyridyl.
Catalyzer helps improve speed of reaction.The catalyzer that is fit to comprises Lewis acid, for example bismuth chloride, cupric chloride, iron(ic) chloride, lead chloride, tin chloride and zinc chloride.
Reported the phase-transfer catalysis notion that is suitable for many reactions in the document.In the two-phase solvent system, phase-transfer catalyst is enough to carry alkali from the waterbearing stratum and enters organic layer.A.W.Herriott etc., J.Am Chem.Soc., 97; 2345-2349 (1975); E.V.Dehmlow, Angew.Chem., Internat.Edit., 13; 170-179 (1974); C.M.Starks, J.Am.Chem.Soc., 93; 195-199 (1971); And J.Dock, Synthesis, 441-456 (1973) has listed several phase-transfer catalysts and condition.
Phase-transfer catalyst is quaternary salt or crown ether preferably.More preferably; phase-transfer catalyst is selected from following a kind of in listed: the bromination butyl-pyridinium; the hydrogen sulfate TBuA; bromination benzyl triethyl ammonium; benzyltriethylammonium chloride; fluoridize the benzyl triethyl ammonium; the cetyltriethylphosphobromide bromide ammonium; bromination hexadecane base San Yi Ji Phosphonium; cetrimonium bromide, cetyltrimethylammonium chloride, chlorination dibutyl Dimethyl Ammonium; bromination decyl triethyl ammonium; bromination hexadecyl tributyl phosphorus, bromination heptyl pyridine, chlorination hexadecyl tributyl phosphorus; bromination hexyl triethyl ammonium; dodecyl bromide pyridine, bromination dodecyl triethyl ammonium, methyl chloride three nonyl ammoniums; Diethylaminoethyl triphenyl ammonium; bromination or hydrogen sulfate TBuA, tetrabutylammonium chloride, cyaniding TBuA; tetrabutylammonium; tetrabutylammonium iodide, tetrabutylammonium, chlorination tetrabutyl phosphorus; chlorination three capryloyl ammonium methyls; etamon chloride, tetramethylammonium bromide, bromination trioctylphosphine Yi Ji Phosphonium; tricaprylylmethylammchloride chloride; chlorination trioctylphosphine propyl ammonium, bromination tetrapropyl ammonium, tetraphenylarsonium chloride base arsenic; the Xiuization tetraphenylphosphoniphenolate; tetraphenylphosphonium chloride, hydroxide benzyltrimethylammon.um, 18-hat-6; dibenzo-18-hat-6, dicyclohexyl-18-hat-6 or their mixture.
The step of this method (1) comprises with chemical formula R
8The phenyl amino nitrilthiophene derivative of the protecting group protection Formulae II of-Y.T.W.Greene and G.M.Wuts, Protecting Groupsin Organic Synthesis, second edition, Wiley, New York, 1991 have described the various reagent that carry out this protection.Preferred protecting group comprises these, wherein R
8Be selected from alkyl carbamate or benzyl carbamate, perhaps alternative benzyl or the benzoyl benzyl that replaces, and Y is selected from F, Cl, Br, I, and N
3Most preferred protecting group is a bromotoluene, in other words, works as R
8Y is Br when being benzyl.This being reflected under the situation that has alkali, phase-transfer catalyst and organic solvent carried out.The alkali that is fit to includes, but not limited to carbonate, for example yellow soda ash or salt of wormwood, oxyhydroxide, for example sodium hydroxide or potassium hydroxide, and hydride, for example sodium hydride.A kind of preferred alkali is potassium hydroxide.A kind of preferred phase-transfer catalyst is a benzyltriethylammonium chloride.Suitable organic solvent includes, but not limited to polar proton inert solvent, for example methylene dichloride, chloroform, acetonitrile, dimethyl sulfoxide (DMSO) or N, dinethylformamide.A kind of preferred organic is a methylene dichloride.
The step of this method (2) comprises the cyclisation of the compound of Formulae II I with catalyzer.Suitable catalyzer comprises, but is not limited to Lewis acid, for example bismuth chloride, cupric chloride, iron(ic) chloride, lead chloride, tin chloride and zinc chloride.In an embodiment preferred of the present invention, catalyzer is the hydrated form tin chloride, comprise, for example, tin chloride dihydrate and tin chloride pentahydrate.Have that high temperature carries out this reaction under the situation of acidic conditions and polar organic solvent.Acidic conditions comprises use, but is not limited to, aqueous hydrochloric acid, trifluoroacetic acid, sulfuric acid, nitric acid, perchloric acid and hydrofluoric acid.Preferred aqueous hydrochloric acid (18%).Polar organic solvent, perhaps the aqueous mixture of polar organic solvent includes, but not limited to alcohol, for example methyl alcohol and ethanol, diethyl ether, tetrahydrofuran (THF), ethyl acetate, acetone and acetonitrile.Preferred aqueous 95% ethanol.High temperature for example up to 100 ℃, can be used for promoting reaction that the preferred temperature range of carrying out this reaction is 78 ℃ to 100 ℃.
The step of this method (3) comprises the midbody compound of Formula I V and the HNR of chemical formula
1R
2Reaction between the amine.In an embodiment of the present invention, R
1And R
2Add adjacent nitrogen-atoms, form alternative replace be selected from tetramethyleneimine, piperidines, morpholine, send piperazine, the ring of pyrroles, pyridine, pyrazine, thiazole, oxazole, isoxazole and imidazoles.Preferably, R
1And R
2Add that adjacent nitrogen-atoms forms the alternative piperazine ring that replaces.More preferably, the ring of this selectivity replacement is the 1-methylpiperazine.When can at high temperature using excess amine, this reaction carries out.Amine is under the situation of liquid substance, and amine can serve as reaction medium.If amine is solid matter, so suitable organic solvent, for example toluene, methyl-phenoxide or chlorobenzene can be used as reaction medium.If wish, high temperature for example up to 200 ℃, can be used for promoting reaction that the preferred temperature range of carrying out this reaction is 80 ℃ to 120 ℃.
The step of this method (4) comprises the compound of protecting Formulae II I, generates the target compound of Formula I.T.W.Greene and G.M.Wuts, Protecting Groups inOrganic Synthesis, second edition, Wiley, New York, 1991 have described and have been suitable for carrying out de-protected various reaction conditions.The progress of reaction can be by thin-layer chromatography or high performance liquid chromatography (HPLC) monitoring.In embodiment preferred of the present invention, when protecting group is chemical formula R
8The compound of-Y, and R is benzyl when Y is bromine, comprises and uses mineral acid and organic acid mixture under the high temperature so be suitable for carrying out the preferred reaction conditions of protective reaction.The example of mineral acid includes, but not limited to hydrochloric acid, Hydrogen bromide, nitric acid, sulfuric acid or phosphoric acid.The organic acid example comprises, but be not limited to, formic acid, oxyacetic acid, toxilic acid, hydroxymaleic acid, fumaric acid, oxysuccinic acid, tartrate, citric acid, Whitfield's ointment, o-acyloxy phenylformic acid, nicotinic acid or Yi Yansuan, perhaps organic sulfonic acid, for example methanesulfonic, ethane sulfonic acid, 2-hydroxyethanesulfonic acid, toluene-p-sulfonic acid or naphthalene-2 sulfonic acid.Preferred mineral acid is a hydrochloric acid, and preferred organic acid is an acetate.High temperature for example up to 100 ℃, can be used for promoting reaction, and the preferred temperature that is suitable for carrying out this reaction is 60 ℃ to 70 ℃.The compound of Formula I self adopts ordinary method to separate or transforms salify, and this is understandable.
The term pharmacy acceptable salt is defined as nontoxic acid salt, for example have those of mineral acid, example hydrochloric acid, Hydrogen bromide, nitric acid, sulfuric acid or phosphoric acid, perhaps have organic acid those, as organic carboxylic acid, for example formic acid, oxyacetic acid, toxilic acid, hydroxymaleic acid, fumaric acid, oxysuccinic acid, tartrate, citric acid, Whitfield's ointment, o-acyloxy phenylformic acid, nicotinic acid or Yi Yansuan, perhaps organic sulfonic acid, for example methanesulfonic, ethane sulfonic acid, 2-hydroxyethanesulfonic acid, toluene-p-sulfonic acid or naphthalene-2 sulfonic acid.Except pharmaceutically-acceptable acid addition, other salt is also included within the scope of acid salt, for example, illustrates, and has those of picric acid or oxalic acid; They can serve as in the compound purifying or other intermediate in the preparation of pharmaceutically-acceptable acid addition for example, perhaps be applicable to evaluation, sign or the purifying of this alkali.
Another aspect of the present invention provides a kind of method, wherein the compound of chemical formula VI
By sulphur, the compound of propane dinitrile and chemical formula VIII
R
7-CH
2-CHO VIII
R wherein
7Definition is (referring to scheme 1) as above.The mixture of alkali and organic solvent is carried out and comprises in this method cooling.This alkali is selected from but is not limited to n-butyllithium, sodium hydroxide, sodium hydride, sodium amide, triethylamine and salt of wormwood.Preferred alkali is triethylamine.Organic solvent is polar proton inert solvent preferably, and it is selected from but is not limited to acetonitrile, dimethyl sulfoxide (DMSO) and N, dinethylformamide.Most preferred solvent is N, dinethylformamide.Reaction mixture remains on cooling during adding alkali, and cooling preferably remains between 0 and 10 ℃, more preferably between 5 and 10 ℃.After alkali adds, make temperature of reaction reach 16 to 20 ℃, preferably to 18 ℃.
Another aspect of the present invention provides a kind of method, wherein the compound by coupling chemical formula VI
R wherein
7Definition as above and the compound of chemical formula VII
R wherein
3, R
4, R
5, and R
6Define as above, X is leavings group (referring to a scheme 1), the compound of preparation Formulae II, or its salt.Thieno-benzene raw materials or known compound that method of the present invention is used, referring to, for example, Chem.Berichte, 99; 94-100 (1966), J.Am.Chem.Soc., 68; 2232 (1946) and Netherlands patent applications 66 04742, perhaps can prepare by known compound by routine techniques.Leavings group X preferably is selected from F, Cl, and the halogen atom of Br and I more preferably is F.Exist under the situation of phase-transfer catalyst and in polar proton inert solvent, carry out this reaction.Preferred polar proton inert solvent is acetonitrile, dimethyl sulfoxide (DMSO) and N, dinethylformamide.Preferred polar proton inert solvent is N, dinethylformamide.Preferred phase-transfer catalyst is a quaternary salt.On the one hand, preferred phase-transfer catalyst benzyltriethylammonium chloride.
According to the present invention, at first use nitrogen atom protecting group group that the nitrogen-atoms of 4-position in the compound shown in the formula II is protected, form compound shown in the formula III; Formula III shown in compound carried out cyclization thereafter.Compound shown in the formula III is carried out cyclization and forms reduzate than compound shown in the formula II is carried out cyclization and forms reduzate, not only very big difference is being arranged all on the technology but also on technique effect.Production technique of the present invention is compared with the production technique of prior art, and the yield that the result shows reduzate among the present invention product behind the cyclization of compound shown in the formula III in other words is more stable, and by product obviously reduces.For example, the yield of reduzate is about 75%-95% among the present invention, and by product is few.Thereby the product productive rate improves in next step reaction of the present invention, and formula HNR
1R
2Shown in amine, improve as the utilization ratio of methylpiperazine.
In addition, in a preferred embodiment of the present invention, formula HNR
1R
2Shown in amine, use simultaneously as methylpiperazine as reactant and solvent.When just reaction medium is amine, allows second intermediate shown in the formula VI and amine react and form the 3rd intermediate shown in the formula V.Because the by product in the reactions steps of front reduces, thereby reaction system becomes simply, wherein residual amine can be recycled by comparatively simple method (as distillation method).So not only the utilization ratio of amine improves, and has reduced final refuse.
Moreover method of the present invention avoids using poisonous and harmful solvents such as toluene, methyl-sulphoxide, has reduced the discharging of the three wastes, helps protecting environment.
Except above-mentioned advantage, those skilled in the art can make various variations after having read disclosure of the present invention, also can figure out other advantage of the present invention.
Provide following embodiment to illustrate but do not limit desired invention.
Embodiment
Embodiment 1:2-amino-5-thiotolene-3-nitrile
Sulphur (21.8g), propionic aldehyde (47.3g) and N, the mixture of dinethylformamide (135mL) place the 500mL flask and cool off at ice bath.Dropwise added triethylamine (57.6mL) in 30 minutes to the reaction mixture that stirred, temperature remains between 5-10 ℃.Jar is warming up to 18 ℃, and stirs 50 minutes at 18 ± 2 ℃.At 18 ± 2 ℃ of N that dropwise add propane dinitrile (45g), dinethylformamide (90mL) solution.After dripping end, mixture stirred 45 minutes at 18 ± 2 ℃.Mixture stirs and has a down dip to ice/water (1.2L).Solid sediment thoroughly washs with water by filter collecting, and 70 ℃ of dryings whole night (perhaps at 45 ℃ of fan-dryings) to obtain 2-amino-5-thiotolene-3-nitrile (58.5g).Yield: 62.3%.
Embodiment 2:2-(the nitrated anilino of 2-)-5-thiotolene-3-nitrile
Potassium hydroxide in the 250mL flask (59.1g), benzyltriethylammonium chloride (1.2g) and N, the N that dropwise adds 2-amino-5-thiotolene-3-nitrile (73g) and 1-fluoro-2-oil of mirbane (74.5g) in the mixture of dinethylformamide (70mL), dinethylformamide (175mL) solution maintains the temperature between 20-25 ℃ with water/salt bath simultaneously.After adding end, mixture stirred 5 hours between 20-25 ℃, then inclined to ice/water (400mL), and extracted with methylene dichloride (480mL).Separate organic layer, water layer is with methylene dichloride (240mL * 2) extracting twice.Water (400mL) adds in the blended organic extract, regulates between the pH to 8-9 with 2N hydrochloric acid.Isolate organic layer and wash with water (400mL).Removal of solvent under reduced pressure produces resistates, and it produces 2-(2-oil of mirbane amido)-5-thiotolene-3-nitrile (82.2g) from ethanol (300mL) crystallization.Yield: 60%.
Embodiment 3:2-[2-nitrophenyl-(N-benzyl) amino]-5-thiotolene-3-nitrile
In the 2L flask, stir 2-(2-oil of mirbane amido)-5-thiotolene-3-nitrile (100g), methylene dichloride (915mL), bromotoluene (69.8g), and benzyltriethylammonium chloride (BTEA) is (1.8g).Slowly add 50% potassium hydroxide (200g) in the temperature that is lower than 25 ℃.Add after the end, mixture stirred 5 hours between 25-30 ℃.Add entry (300g), separate organic layer.Organic layer is mixed with dichloromethane extraction (200mL * 2) in the waterbearing stratum, and with water washing (400mL * 2), and decompression is removed.In resistates, add toluene (110mL), heated mixt, and add activated carbon.Mixture filters, cooling, and crystallization produces (6g).Crystallization is filtered, and with washing with alcohol, and 45 ℃ of dryings, produces 2-[2-nitrophenyl-(N-benzyl) amino]-5-thiotolene-3-nitrile.Yield: 55-60%.
Embodiment 4:4-amino-2-methyl-10-benzyl-thieno-[2,3-b] [1,5] benzodiazepine , hydrochloride
In the flask of 2L, stir 2-[2-nitrophenyl-(N-benzyl) amino]-5-thiotolene-3-nitrile (150g) and 95% ethanol (720mL).18% hydrochloric acid (720mL) solution that adds tin chloride dihydrate (304.5g).Mixture refluxes and stirred 5 hours, then is cooled to 20-25 ℃.Solid leaches, and with ethanol (1200mL) and water (200ml * 2) washing, then 45 ℃ of dryings, produces 4-amino-2-methyl-10-benzyl-thieno-[2,3-b] [1,5] benzodiazepine , hydrochloride (122.4g).Yield: 80%.
Embodiment 5:2-methyl isophthalic acid 0-benzyl-4-(4-methyl isophthalic acid-piperazinyl)-thieno-[2,3-b] [1,5] benzodiazepine
4-amino-2-methyl-10-benzyl-thieno-[2,3-b] [1,5] benzodiazepine hydrochloride (100g) and N methyl piperazine (500mL) stir at the 1000mL flask, and 120 ± 2 ℃ of heating 4 hours.Remove piperazine under the decompression, resistates stirs and has a down dip to ice/water (2Kg).Throw out passes through filtering separation, with water washing (2L * 2), and 45 ℃ of dryings.Raw product and acetone (500mL) mix at the 1000mL flask, and reflux is then filtered.Leach thing and be concentrated into nearly 100mL, crystallisation by cooling.Crystallization leaches, and with acetone (50mL * 2) washing, 45 ℃ of dryings produce title product (50.9g).Yield: 45%.
Embodiment 6:2-methyl-4-(4-methyl isophthalic acid-piperazinyl)-10H-thieno-[2,3-b] [1,5] benzodiazepine
Mix 2-methyl isophthalic acid 0-benzyl-4-(4-methyl isophthalic acid-piperazinyl)-thieno-[2,3-b] [1,5] benzodiazepine (15g) in the 250mL flask, acetate (15mL) and 36% hydrochloric acid (80mL) slowly were heated to 60 ℃ in 2-2.5 hour.Reaction mixture kept 4 hours in this temperature.The sample that takes out reaction mixture is so that efficient liquid phase chromatographic analysis.Surpass 70% o'clock stopped reaction at material content little 15% or product content.28% ammonia soln dropwise adds chilled mixture, reaches 6 until pH, and mixture stirred 30 minutes.By the filtering separation solid, then wash with methylene dichloride (50mL).Add entry (300mL) to this solid, heated mixt, and dropwise add 28% ammonia soln and be about 6.5 until pH.With methylene dichloride (50ml * 2) extraction mixture.Add 28% ammonia soln to the waterbearing stratum and reach 9 until pH.Leach solid,, and, produce raw product 45 ℃ of dryings with water washing.Produce a kind of material from ethyl acetate (70mL) crystallization, it can be from 95% ethanol (70mL) recrystallization, produce title compound.Yield: 20-30%.
For the purpose that is aware and understand, although by way of example the explanation and embodiment aforesaid invention has been described, for a person skilled in the art, it is conspicuous implementing some variation and correction.Therefore, specification sheets and embodiment should not be construed limitation of the scope of the invention, and scope of the present invention is described in the appended claims.
Claims (28)
1. the method for preparing the compound or its salt of Formula I,
Wherein
R
1And R
2Be alternative alkyl or the cyclic hydrocarbon radical that replaces, perhaps R
1And R
2Add that adjacent nitrogen-atoms forms alternative 5-to a 8-unit ring that replaces, one or more carbon atoms can optionally be replaced by the heteroatoms that is selected from O, S and N on the ring,
R
3, R
4, R
5, and R
6Be hydrogen, alternative alkyl, thiazolinyl, cycloalkyl, alkoxyl group, amino, alkyl sulfide (alkythio), aryl, the sulfanilamide (SN) that replaces independently, perhaps be selected from the halogen of F, Cl, Br and I, or hydroxyl,
R
7Be alkyl, thiazolinyl, alkynyl, alkyloyl, aryl, nitro, phenyl that optionally replaces or the halogen that is selected from F, Cl, Br and I,
Described method comprises
(1) with chemical formula R
8The compound of the protecting group protection Formulae II of-Y
R wherein
8Be nitrogen atom protecting group, Y is a leavings group, generates first midbody compound of Formulae II I
Or its salt,
(2) with catalyzer cyclisation first midbody compound, second midbody compound of preparation Formula I V
Or its salt,
(3) chemical formula HNR
1R
2Amine contact second midbody compound, obtain the 3rd midbody compound of chemical formula V
R wherein
1And R
2Definition as above; Or its salt,
(4) go to protect the 3rd midbody compound to obtain the compound of Formula I.
2. according to the method for claim 1, it further comprises the compound by the compound Formulae II of the compound of coupling chemical formula VI and chemical formula VII, perhaps its salt,
R wherein
7Define as above,
R wherein
3, R
4, R
5, and R
6Define as above, and X is a leavings group.
3. according to the method for claim 2, it further comprises the compound by the compound chemical formula VI of reacting thiourea, propane dinitrile and chemical formula VIII,
R
7-CH
2-CHO VIII
R wherein
7Definition as above.
4. according to the process of claim 1 wherein R
1And R
2Add adjacent nitrogen-atoms, form alternative 5-to the 8-unit ring that is selected from tetramethyleneimine, piperidines, morpholine, piperazine, pyrroles, pyridine, pyrazine, thiazole, oxazole, isoxazole and imidazoles that replaces,
R
3, R
5, R
5, and R
6Be hydrogen,
R
7Be alkyl,
R
8Be selected from alkyl carbamate or benzyl carbamate, perhaps alternative benzyl or the benzoyl benzyl that replaces, and Y is selected from F, Cl, Br, I, and N
3
5. according to the method for claim 4, R wherein
1And R
2Add that adjacent nitrogen-atoms forms with methyl substituted piperazine ring, R
7Be methyl, R
8Be benzyl, and Y is Br.
6. according to the method for claim 2, wherein X is selected from F, Cl, Br, and I.
7. according to the method for claim l, catalyzer wherein is a Lewis acid.
8. according to the method for claim 7, wherein Lewis acid is SnQ
2, wherein Q is selected from by F, Cl, the halogen atom of Br and I.
9. according to the process of claim 1 wherein that the compound of Formulae II is
Or its salt.
10. according to the process of claim 1 wherein that first midbody compound is
Or its salt.
11. according to the process of claim 1 wherein that second midbody compound is
Or its salt.
12. according to the process of claim 1 wherein that the 3rd midbody compound is
Or its salt.
13. have the preparation method of the compound or its salt of following formula
Described method comprises
(1) with the compound of protecting group benzyl-Cl protection Formula I X,
Produce first midbody compound or its salt of chemical formula X,
(2) use SnCl
2Cyclisation first midbody compound, with second midbody compound or its salt of generation chemical formula XI,
(3) amine of chemical formula XIV
Contact with second midbody compound, obtain the 3rd midbody compound or its salt of chemical formula XII,
(4) remove to protect the 3rd midbody compound, obtain the compound of chemical formula XIII.
14. according to the method for claim 13, wherein SnCl
2Be aqueous.
15. according to the method for claim 14, wherein SnCl
2It is dihydrate.
16. according to the method for claim 13, wherein Formula I X is by the compound of coupling chemical formula XV
Compound with chemical formula XVI
17. according to the method for claim 16, wherein the compound of chemical formula XV is by the compound of sulphur, propane dinitrile and chemical formula XVII
CH
3-CH
2-CHO XVII
18. the compound of Formula I,
Or its salt, by according to claim 1, the preparation of the method for any one of 4,5,7 and 8,
Wherein
R
1And R
2Be alternative alkyl or the cyclic hydrocarbon radical that replaces, perhaps R
1And R
2Add that adjacent nitrogen-atoms forms alternative 5-to the 8-unit ring that replaces, one or more here carbon atoms can be replaced by the heteroatoms selectivity that is selected from O, S and N,
R
3, R
4, R
5, and R
6Be hydrogen atom independently, alternative alkyl, thiazolinyl, cycloalkyl, alkoxyl group, amino, alkyl sulfide, aryl, the sulfanilamide (SN) that replaces, or be selected from F, and Cl, the halogen of Br and I, or hydroxyl,
R
7Be alternative alkyl, thiazolinyl, alkynyl, alkyloyl, aryl, nitro, the phenyl that replaces, or be selected from F, Cl, the halogen of Br and I.
19. the compound of Formulae II,
Or its salt, by according to any one the method preparation in claim 2 and 6,
Wherein
R
3, R
4, R
5, and R
6Be alkyl, thiazolinyl, cycloalkyl, alkoxyl group, amino, alkyl sulfide (alkythio), aryl, the sulfanilamide (SN) that hydrogen, selectivity replace independently, or be selected from F, Cl, the halogen of Br and I, or hydroxyl,
R
7Be alternative alkyl, thiazolinyl, alkynyl, alkyloyl, aryl, nitro, the phenyl that replaces, or be selected from F, Cl, the halogen of Br and I.
20. the compound of Formulae II I, or its salt, by according to claim 1, the method preparation of any one in 4,5,7 and 8,
Wherein
R
3, R
4, R
5, and R
6Be alkyl, thiazolinyl, cycloalkyl, alkoxyl group, amino, alkyl (alkythio), aryl, the sulfanilamide (SN) that hydrogen, selectivity replace independently, or be selected from F, Cl, the halogen of Br and I, or hydroxyl,
R
7Be alternative alkyl, thiazolinyl, alkynyl, alkyloyl, aryl, nitro, the phenyl that replaces, or be selected from F, Cl, the halogen of Br and I,
R
8It is nitrogen-protecting group.
21. the compound of Formula I V,
Or its salt, by according to claim 1, the preparation of the method for any one of 4,5,7 and 8,
Wherein
R
3, R
4, R
5, and R
6Be hydrogen, alternative alkyl, thiazolinyl, cycloalkyl, alkoxyl group, amino, alkyl (alkythio), aryl, the sulfanilamide (SN) that replaces independently, or be selected from F, Cl, the halogen of Br and I, or hydroxyl,
R
7Be alternative alkyl, thiazolinyl, alkynyl, alkyloyl, aryl, nitro, the phenyl that replaces, or be selected from F, Cl, the halogen of Br and I,
R
8It is nitrogen-protecting group.
22. the compound of chemical formula V,
Or its salt, by according to claim 1, the preparation of the method for any one of 4,5,7 and 8,
Wherein
R
1And R
2Be alkyl or the cyclic hydrocarbon radical that selectivity replaces, perhaps R
1And R
2Add that adjacent nitrogen-atoms forms 5-to the 8-unit ring that selectivity replaces, one or more here carbon atoms can be replaced by the heteroatoms selectivity that is selected from by O, S and N,
R
3, R
4, R
5, and R
6Be alkyl, thiazolinyl, cycloalkyl, alkoxyl group, amino, alkyl (alkythio), aryl, the sulfanilamide (SN) that hydrogen, selectivity replace independently, or be selected from F, Cl, the halogen of Br and I, or hydroxyl,
R
7Be alternative alkyl, thiazolinyl, alkynyl, alkyloyl, aryl, nitro, the phenyl that replaces, or be selected from F, Cl, the halogen of Br and I,
R
8It is nitrogen-protecting group.
23. the compound of chemical formula VI,
Or its salt, by method preparation according to claim 3,
R wherein
7Be alternative alkyl, thiazolinyl, alkynyl, alkyloyl, aryl, nitro, the phenyl that replaces, or be selected from F, Cl, the halogen of Br and I.
24. the compound of Formula I X,
Or its salt, by any one method preparation according to claim 2 and 6.
25. the compound of chemical formula X,
Or its salt, by according to claim 1,4,5,7,8, the method preparation of any one of 13,14 and 15.
26. the compound of chemical formula XI,
Or its salt, by according to claim 1,4,5,7,8, the method preparation of any one of 13,14 and 15.
27. the compound of chemical formula XII,
Or its salt, by according to claim 1,4,5,7,8, the method preparation of any one of 13,14 and 15.
28. the compound of chemical formula XIII,
Or its salt, by according to claim 1,4,5,7,8, the method preparation of any one of 13,14 and 15.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US45627003P | 2003-03-20 | 2003-03-20 | |
| US60/456,270 | 2003-03-20 |
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| Publication Number | Publication Date |
|---|---|
| CN1532199A true CN1532199A (en) | 2004-09-29 |
| CN1233646C CN1233646C (en) | 2005-12-28 |
Family
ID=33310658
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 03136388 Ceased CN1233646C (en) | 2003-03-20 | 2003-06-12 | Process of 2-methyl-thiophene benzodinitro heterotropilidene |
Country Status (3)
| Country | Link |
|---|---|
| CN (1) | CN1233646C (en) |
| AU (1) | AU2003243143A1 (en) |
| WO (1) | WO2004094390A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101061124B (en) * | 2004-11-22 | 2010-07-28 | 阿达梅德公司 | A process for the preparation of n-demethylolanzapine |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2551806A1 (en) * | 2003-12-22 | 2005-07-14 | Teva Pharmaceutical Industries, Ltd. | Methods of preparing olanzapine |
| CN102250116B (en) * | 2011-07-12 | 2013-11-27 | 江西富祥药业股份有限公司 | Preparation method of olanzapine |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| US5627178A (en) * | 1991-04-23 | 1997-05-06 | Lilly Industries Limited | 2-methyl-thieno-benzodiazepine |
-
2003
- 2003-04-16 WO PCT/US2003/011688 patent/WO2004094390A1/en not_active Application Discontinuation
- 2003-04-16 AU AU2003243143A patent/AU2003243143A1/en not_active Abandoned
- 2003-06-12 CN CN 03136388 patent/CN1233646C/en not_active Ceased
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101061124B (en) * | 2004-11-22 | 2010-07-28 | 阿达梅德公司 | A process for the preparation of n-demethylolanzapine |
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| AU2003243143A1 (en) | 2004-11-19 |
| CN1233646C (en) | 2005-12-28 |
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