FR2526423A1 - NOVEL UNSATURATED AMINES, THEIR PREPARATION AND THEIR USE AS MEDICAMENTS - Google Patents
NOVEL UNSATURATED AMINES, THEIR PREPARATION AND THEIR USE AS MEDICAMENTS Download PDFInfo
- Publication number
- FR2526423A1 FR2526423A1 FR8307400A FR8307400A FR2526423A1 FR 2526423 A1 FR2526423 A1 FR 2526423A1 FR 8307400 A FR8307400 A FR 8307400A FR 8307400 A FR8307400 A FR 8307400A FR 2526423 A1 FR2526423 A1 FR 2526423A1
- Authority
- FR
- France
- Prior art keywords
- group
- formula
- lower alkyl
- compounds
- hydrogen
- 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.)
- Granted
Links
- 239000003814 drug Substances 0.000 title claims description 8
- 238000002360 preparation method Methods 0.000 title claims description 4
- 150000001412 amines Chemical class 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 64
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 18
- 239000001257 hydrogen Substances 0.000 claims abstract description 17
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical class [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 13
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 8
- 150000002367 halogens Chemical class 0.000 claims abstract description 8
- 150000003555 thioacetals Chemical group 0.000 claims abstract description 4
- 239000002543 antimycotic Substances 0.000 claims abstract description 3
- -1 cyano, formyl Chemical group 0.000 claims description 29
- 125000000217 alkyl group Chemical group 0.000 claims description 21
- 238000000034 method Methods 0.000 claims description 17
- 150000003839 salts Chemical class 0.000 claims description 14
- 239000002253 acid Substances 0.000 claims description 11
- 239000012458 free base Substances 0.000 claims description 11
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
- 230000001857 anti-mycotic effect Effects 0.000 claims description 5
- 230000000973 chemotherapeutic effect Effects 0.000 claims description 5
- 239000004480 active ingredient Substances 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 claims description 3
- 125000004414 alkyl thio group Chemical group 0.000 claims description 3
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 3
- 125000000524 functional group Chemical group 0.000 claims description 3
- 125000006239 protecting group Chemical group 0.000 claims description 3
- 230000001225 therapeutic effect Effects 0.000 claims description 3
- 150000001768 cations Chemical class 0.000 claims description 2
- 229940079593 drug Drugs 0.000 claims description 2
- 125000000262 haloalkenyl group Chemical group 0.000 claims description 2
- 125000001188 haloalkyl group Chemical group 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 125000001382 thioacetal group Chemical group 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 241001331845 Equus asinus x caballus Species 0.000 claims 2
- 150000001721 carbon Chemical group 0.000 claims 2
- 125000002777 acetyl group Chemical class [H]C([H])([H])C(*)=O 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- 150000001241 acetals Chemical group 0.000 abstract description 4
- 239000002246 antineoplastic agent Substances 0.000 abstract description 3
- 229940127089 cytotoxic agent Drugs 0.000 abstract description 3
- 229910052760 oxygen Inorganic materials 0.000 abstract 1
- 229910052717 sulfur Inorganic materials 0.000 abstract 1
- 239000000203 mixture Substances 0.000 description 37
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 33
- 239000003921 oil Substances 0.000 description 31
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 28
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 28
- 239000000243 solution Substances 0.000 description 23
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 20
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- 239000012074 organic phase Substances 0.000 description 17
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- 125000004432 carbon atom Chemical group C* 0.000 description 13
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 12
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 239000003480 eluent Substances 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- 238000006243 chemical reaction Methods 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 239000007858 starting material Substances 0.000 description 8
- 239000007864 aqueous solution Substances 0.000 description 7
- 229920006395 saturated elastomer Polymers 0.000 description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000000460 chlorine Substances 0.000 description 6
- 238000004821 distillation Methods 0.000 description 6
- 239000011780 sodium chloride Substances 0.000 description 6
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 229910052801 chlorine Inorganic materials 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 239000012230 colorless oil Substances 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 4
- 238000004809 thin layer chromatography Methods 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 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 3
- 238000009835 boiling Methods 0.000 description 3
- 239000012141 concentrate Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 208000015181 infectious disease Diseases 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- CNWRSWRKEKCKCX-UHFFFAOYSA-N 1-bromo-6,6-bis(methylsulfanyl)hex-2-en-4-yne Chemical compound CSC(SC)C#CC=CCBr CNWRSWRKEKCKCX-UHFFFAOYSA-N 0.000 description 2
- IBXNCJKFFQIKKY-UHFFFAOYSA-N 1-pentyne Chemical compound CCCC#C IBXNCJKFFQIKKY-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-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- HGINCPLSRVDWNT-UHFFFAOYSA-N Acrolein Chemical compound C=CC=O HGINCPLSRVDWNT-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- 241000222120 Candida <Saccharomycetales> Species 0.000 description 2
- PHSPJQZRQAJPPF-UHFFFAOYSA-N N-alpha-Methylhistamine Chemical compound CNCCC1=CN=CN1 PHSPJQZRQAJPPF-UHFFFAOYSA-N 0.000 description 2
- ATHHXGZTWNVVOU-UHFFFAOYSA-N N-methylformamide Chemical compound CNC=O ATHHXGZTWNVVOU-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 238000002329 infrared spectrum Methods 0.000 description 2
- 239000013067 intermediate product Substances 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- KPZGRMZPZLOPBS-UHFFFAOYSA-N 1,3-dichloro-2,2-bis(chloromethyl)propane Chemical compound ClCC(CCl)(CCl)CCl KPZGRMZPZLOPBS-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- GXXOUZXFLFWGRY-WTKPLQERSA-N 1-[(Z)-6-methoxy-6-methylhept-2-en-4-ynyl]-2-naphthalen-1-ylpiperidine Chemical compound CC(C#C\C=C/CN1C(CCCC1)C1=CC=CC2=CC=CC=C12)(C)OC GXXOUZXFLFWGRY-WTKPLQERSA-N 0.000 description 1
- ZKCZKZMOTFBBJO-UHFFFAOYSA-N 1-bromo-6,6-bis(methylsulfanyl)hept-2-en-4-yne Chemical compound CSC(C)(SC)C#CC=CCBr ZKCZKZMOTFBBJO-UHFFFAOYSA-N 0.000 description 1
- JTDDJEILCRWRPK-UHFFFAOYSA-N 1-bromo-6-ethoxy-6-methylhept-2-en-4-yne Chemical compound CCOC(C)(C)C#CC=CCBr JTDDJEILCRWRPK-UHFFFAOYSA-N 0.000 description 1
- DWRSXKGOOJIPSZ-UHFFFAOYSA-N 1-bromo-6-methoxy-6-methylhept-2-en-4-yne Chemical compound COC(C)(C)C#CC=CCBr DWRSXKGOOJIPSZ-UHFFFAOYSA-N 0.000 description 1
- DXRYKNGQPQCBQQ-UHFFFAOYSA-N 1-bromo-8-chlorooct-2-en-4-yne Chemical compound ClCCCC#CC=CCBr DXRYKNGQPQCBQQ-UHFFFAOYSA-N 0.000 description 1
- YLGANAAHLWDLIB-UHFFFAOYSA-N 1-bromo-8-fluoro-6,6-dimethyloct-2-en-4-yne Chemical compound FCCC(C)(C)C#CC=CCBr YLGANAAHLWDLIB-UHFFFAOYSA-N 0.000 description 1
- CKDCIPHHNCOFKS-UHFFFAOYSA-N 1-bromo-8-methoxy-6,6-dimethyloct-2-en-4-yne Chemical compound COCCC(C)(C)C#CC=CCBr CKDCIPHHNCOFKS-UHFFFAOYSA-N 0.000 description 1
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- IENMSBIFJDBWBZ-UHFFFAOYSA-N 3,3-bis(methylsulfanyl)but-1-ynyl-trimethylsilane Chemical compound CSC(C)(SC)C#C[Si](C)(C)C IENMSBIFJDBWBZ-UHFFFAOYSA-N 0.000 description 1
- KQIIKSQUHGGYCU-UHFFFAOYSA-N 3,3-dimethylpent-1-yne Chemical compound CCC(C)(C)C#C KQIIKSQUHGGYCU-UHFFFAOYSA-N 0.000 description 1
- JTTOZPWKPVPIQY-UHFFFAOYSA-N 3,3-dimethylpent-4-yn-1-ol Chemical compound C#CC(C)(C)CCO JTTOZPWKPVPIQY-UHFFFAOYSA-N 0.000 description 1
- CWORKEUBPFOPPV-UHFFFAOYSA-N 3,3-dimethylpent-4-ynal Chemical compound C#CC(C)(C)CC=O CWORKEUBPFOPPV-UHFFFAOYSA-N 0.000 description 1
- XYWDDMKNNFGLDD-UHFFFAOYSA-N 3-methylsulfanylbut-1-yne Chemical compound CSC(C)C#C XYWDDMKNNFGLDD-UHFFFAOYSA-N 0.000 description 1
- YTXIGMLQHXRSEC-UHFFFAOYSA-N 3-methylsulfanylprop-1-yne Chemical compound CSCC#C YTXIGMLQHXRSEC-UHFFFAOYSA-N 0.000 description 1
- YELHIAZMUNXSMB-UHFFFAOYSA-N 5-methoxy-3,3-dimethylpent-1-yne Chemical compound COCCC(C)(C)C#C YELHIAZMUNXSMB-UHFFFAOYSA-N 0.000 description 1
- NBGCRXRNNRNISZ-UHFFFAOYSA-N 6-ethylsulfanylhex-1-en-4-yn-3-ol Chemical compound CCSCC#CC(O)C=C NBGCRXRNNRNISZ-UHFFFAOYSA-N 0.000 description 1
- LTOMFDQMEUOANP-UHFFFAOYSA-N 6-methylsulfanylhept-1-en-4-yn-3-ol Chemical compound CSC(C)C#CC(O)C=C LTOMFDQMEUOANP-UHFFFAOYSA-N 0.000 description 1
- MLWNBCZDXMZNPH-UHFFFAOYSA-N 7-bromo-1,1-difluoro-2-methylhepta-1,5-dien-3-yne Chemical compound FC(F)=C(C)C#CC=CCBr MLWNBCZDXMZNPH-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- MNNDTZDERFJQLL-UHFFFAOYSA-N 8-methoxy-6,6-dimethyloct-1-en-4-yn-3-ol Chemical compound COCCC(C)(C)C#CC(O)C=C MNNDTZDERFJQLL-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 241000228212 Aspergillus Species 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- RNIQUDALTOSNFN-UHFFFAOYSA-N CCOC(OCC)C#CC(O)C=C Chemical compound CCOC(OCC)C#CC(O)C=C RNIQUDALTOSNFN-UHFFFAOYSA-N 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- 241000700199 Cavia porcellus Species 0.000 description 1
- 239000005046 Chlorosilane Substances 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 206010017533 Fungal infection Diseases 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241001480037 Microsporum Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- 238000007126 N-alkylation reaction Methods 0.000 description 1
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical compound [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 208000002474 Tinea Diseases 0.000 description 1
- 241000223238 Trichophyton Species 0.000 description 1
- 206010067409 Trichophytosis Diseases 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- JAWMENYCRQKKJY-UHFFFAOYSA-N [3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-ylmethyl)-1-oxa-2,8-diazaspiro[4.5]dec-2-en-8-yl]-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]methanone Chemical compound N1N=NC=2CN(CCC=21)CC1=NOC2(C1)CCN(CC2)C(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F JAWMENYCRQKKJY-UHFFFAOYSA-N 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 1
- 150000008041 alkali metal carbonates Chemical class 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000005278 alkyl sulfonyloxy group Chemical group 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- WFKAJVHLWXSISD-UHFFFAOYSA-N anhydrous dimethyl-acetamide Natural products CC(C)C(N)=O WFKAJVHLWXSISD-UHFFFAOYSA-N 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- HQABUPZFAYXKJW-UHFFFAOYSA-O butylazanium Chemical compound CCCC[NH3+] HQABUPZFAYXKJW-UHFFFAOYSA-O 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- KOPOQZFJUQMUML-UHFFFAOYSA-N chlorosilane Chemical compound Cl[SiH3] KOPOQZFJUQMUML-UHFFFAOYSA-N 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 239000010779 crude oil Substances 0.000 description 1
- 150000004292 cyclic ethers Chemical class 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- LTUTVFXOEGMHMP-UHFFFAOYSA-N dibromofluoromethane Chemical compound FC(Br)Br LTUTVFXOEGMHMP-UHFFFAOYSA-N 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 1
- 230000002500 effect on skin Effects 0.000 description 1
- 239000012259 ether extract Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 208000024386 fungal infectious disease Diseases 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- MHZYPAQJDPALGT-UHFFFAOYSA-N hept-2-en-4-yn-1-amine Chemical compound CCC#CC=CCN MHZYPAQJDPALGT-UHFFFAOYSA-N 0.000 description 1
- SXMXMYYLWULGGN-UHFFFAOYSA-N hept-2-en-4-yne Chemical compound CCC#CC=CC SXMXMYYLWULGGN-UHFFFAOYSA-N 0.000 description 1
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 125000005948 methanesulfonyloxy group Chemical group 0.000 description 1
- XVDBWWRIXBMVJV-UHFFFAOYSA-N n-[bis(dimethylamino)phosphanyl]-n-methylmethanamine Chemical compound CN(C)P(N(C)C)N(C)C XVDBWWRIXBMVJV-UHFFFAOYSA-N 0.000 description 1
- XTEGVFVZDVNBPF-UHFFFAOYSA-L naphthalene-1,5-disulfonate(2-) Chemical compound C1=CC=C2C(S(=O)(=O)[O-])=CC=CC2=C1S([O-])(=O)=O XTEGVFVZDVNBPF-UHFFFAOYSA-L 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- DEDXOXBKCFZRJB-UHFFFAOYSA-N oct-3-en-5-yne Chemical compound CCC=CC#CCC DEDXOXBKCFZRJB-UHFFFAOYSA-N 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- TWJDCTNDUKKEMU-UHFFFAOYSA-N pent-2-en-4-yn-1-ol Chemical compound OCC=CC#C TWJDCTNDUKKEMU-UHFFFAOYSA-N 0.000 description 1
- LJBVEDFVUPAXCV-UHFFFAOYSA-N pent-2-en-4-ynoxysilane Chemical compound [SiH3]OCC=CC#C LJBVEDFVUPAXCV-UHFFFAOYSA-N 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 229910000077 silane Inorganic materials 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 239000002689 soil Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- MRSJQCJTLMLQSC-UHFFFAOYSA-N tert-butyl-dimethyl-pent-2-en-4-ynoxysilane Chemical compound CC(C)(C)[Si](C)(C)OCC=CC#C MRSJQCJTLMLQSC-UHFFFAOYSA-N 0.000 description 1
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 1
- DCGLONGLPGISNX-UHFFFAOYSA-N trimethyl(prop-1-ynyl)silane Chemical compound CC#C[Si](C)(C)C DCGLONGLPGISNX-UHFFFAOYSA-N 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- IIYTXTQVIDHSSL-UHFFFAOYSA-N trimethylsilylmethanethiol Chemical compound C[Si](C)(C)CS IIYTXTQVIDHSSL-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
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- C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
- C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- C07C29/09—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by hydrolysis
- C07C29/10—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by hydrolysis of ethers, including cyclic ethers, e.g. oxiranes
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/132—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group
- C07C29/136—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH
- C07C29/14—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH of a —CHO group
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C33/00—Unsaturated compounds having hydroxy or O-metal groups bound to acyclic carbon atoms
- C07C33/40—Halogenated unsaturated alcohols
- C07C33/42—Halogenated unsaturated alcohols acyclic
- C07C33/426—Halogenated unsaturated alcohols acyclic containing only triple bonds as unsaturation
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- C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
- C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes 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 carbon atoms of the hetero ring
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Abstract
L'INVENTION CONCERNE LES COMPOSES DE FORMULE (CF DESSIN DANS BOPI) DANS LAQUELLE R REPRESENTE UN GROUPE (CF DESSIN DANS BOPI) OU R ET R SONT L'HYDROGENE, UN HALOGENE, CF, ALKYLE, ALCOXY, S SIGNIFIE 3, 4 OU 5, X SIGNIFIE O, S, CH, OCH, SCH OU NR OU R EST L'HYDROGENE OU ALKYLE, R EST L'HYDROGENE OU ALKYLE, OU BIEN R ET R REPRESENTENT (CF DESSIN DANS BOPI) OU P SIGNIFIE 1, 2 OU 3, R ET R SONT L'HYDROGENE OU ALKYLE ET R REPRESENTE UN HALOGENE, UN GROUPE ACETAL, THIOACETAL, HALOGENOALCENYLE, HALOGENOCYCLOALKYLE, ALKYLCYCLOALKYLE OU ALKYLE SUBSTITUE OU BIEN R ET R FORMENT ENSEMBLE -(CH)- OU N SIGNIFIE 3, 4 OU 5. CES COMPOSES PEUVENT ETRE UTILISES COMME AGENTS CHIMIOTHERAPEUTIQUES, NOTAMMENT COMME ANTIMYCOTIQUES.THE INVENTION RELATES TO COMPOUNDS OF FORMULA (CF DRAWING IN BOPI) IN WHICH R REPRESENTS A GROUP (CF DRAWING IN BOPI) OR R AND R ARE HYDROGEN, A HALOGEN, CF, ALKYL, ALCOXY, S MEANS 3, 4 OR 5, X MEANS O, S, CH, OCH, SCH OR NR OR R IS HYDROGEN OR ALKYL, R IS HYDROGEN OR ALKYL, OR R AND R REPRESENT (CF DRAWING IN BOPI) OR P MEANS 1, 2 OR 3, R AND R ARE HYDROGEN OR ALKYL AND R REPRESENTS A HALOGEN, ACETAL GROUP, THIOACETAL, HALOGENOALCENYL, HALOGENOCYCLOALKYL, ALKYLCYCLOALKYL OR ALKYL SUBSTITUTE (SIGNIFICANTLY 3 - OR RALLY 4 - OR R - AND R) OR 5. THESE COMPOUNDS MAY BE USED AS CHEMOTHERAPEUTIC AGENTS, ESPECIALLY AS ANTIMYCOTICS.
Description
La présente invention a pour objet de nouvelles amines insaturées, leurThe subject of the present invention is new unsaturated amines, their
préparation et leur utilisation en thérapeutique, à titre de principes actifs de médicaments L'invention concerne plus particulièrement les amines de formule I PREPARATION AND THEIR USE IN THERAPEUTICS, AS ACTIVE INGREDIENTS OF MEDICAMENTS The invention relates more particularly to the amines of formula I
R 1 R 4R 1 R 4
R 2 C N CH 2 CH = CH C C R 8 ()R 2 C N CH 2 CH = CH C C R 8 ()
R 3 dans laquelle a) R 1 représente un groupe de formule I Ia, I Ib ou I Ic, R 3 in which a) R 1 represents a group of formula I Ia, I Ib or I Ic,
RF R RRF R R
R 6 9 (CH C)56R 6 9 (CH C) 56
(I Ia) (I Ib) (I Ic) dans lesquelles R et R représentent chacun, indépendamment l'un de rersetn l'autre, l'hydrogène, un halogène ou un groupe (I Ia) (I Ib) (I Ic) in which R and R each independently represent a hydrogen or a halogen or a group;
trifluorométhyle, alkyle inférieur ou alcoxy infé- trifluoromethyl, lower alkyl or lower alkoxy
rieur, s signifie 3, 4 ou 5 et X représente -0-, -S-, -CH 2-, -OCH 2-, SCH 2 ou -N(R 7) o R 7 signifie l'hydrogène ou un groupe alkyle inférieur, et R représente l'hydrogène ou un groupe alkyle inférieur, ou bien ou bien s is 3, 4 or 5 and X is -O-, -S-, -CH 2, -OCH 2, SCH 2 or -N (R 7) o R 7 is hydrogen or an alkyl group lower, and R represents hydrogen or a lower alkyl group, or else
R 1 et R 2 représentent, avec l'atome de carbone adja- R 1 and R 2 represent, with the adjacent carbon atom,
cent auquel ils sont attachés, un groupe de formule I Id to which they are attached, a group of formula I Id
(CH)p-(CH) p-
52 p (I Id) dans laquelle p signifie 1, 2 ou 3, R 3 et R 4 représentent chacun, indépendamment l'un de l'autre, l'hydrogène ou un groupe alkyle inférieur et Wherein p is 1, 2 or 3, R 3 and R 4 are each, independently of one another, hydrogen or a lower alkyl group and
R 8 représente un halogène, un groupe-acétal ou thio- R 8 represents a halogen, a group-acetal or thio-
acétal éventuellement substitués par alkyle inférieur, un groupe halogénoalcényle, un groupe acetal optionally substituted with lower alkyl, a haloalkenyl group, a
halogénocycloalkyle, un groupe (alkyle inférieur)- halogenocycloalkyl, a lower alkyl group
cycloalkyle, ou un groupe alkyle substitué par alcoxy inférieur, cycloalkyl, or an alkyl group substituted by lower alkoxy,
alkylthio inférieur, halogénoalkyle inférieur, acé- lower alkylthio, lower haloalkyl, aceto
tal, thioacétal, cyano, formyle ou hydroxy, l'atome de carbone en a de la triple liaison ne devant pas comporter de groupe hydroxy, ou bien b)R 3 et R 4 forment ensemble un groupe -(CH 2)u o u signifie 3, 4 ou 5, R 1 représente un groupe de formule I Ia, I Ib ou I Ic, R 2 représente l'hydrogène ou un groupe alkyle inférieur et R 5 à R 8 ont les significations données précédemment, tal, thioacetal, cyano, formyl or hydroxy, the carbon atom in a of the triple bond must not have a hydroxy group, or b) R 3 and R 4 together form a group - (CH 2) u or means 3 , 4 or 5, R 1 represents a group of formula I Ia, Ib or Ic, R 2 represents hydrogen or a lower alkyl group and R 5 to R 8 have the meanings given above,
à l'état de base libre ou sous forme d'un sel d'addi- in the free base state or in the form of an additive salt
tion d'acide.acid.
Conformément au procédé de l'invention, pour préparer les composés de formule I on fait réagir un composé de formule III R 1 According to the process of the invention, to prepare the compounds of formula I a compound of formula III R 1 is reacted
R 2 C NH R 4R 2 C NH R 4
R 3 (III)R 3 (III)
avec un composé de formulewith a compound of formula
A 5 CH 2 CH = CH C C R 8A 5 CH 2 CH = CH C C R 8
dans lequel un groupe fonctionnel éventuellement pré- in which a functional group optionally
sent est sous forme protégée, formules dans lesquelles R 1, R 2, R 3, R 4 et R ont les significations données 4 8 précédemment,et A représente un groupe éliminable, /présent / et,si nécessaire,on élimine tout groupe protecteur éventuellement Le procédé peut être effectué selon les méthodes is in protected form, formulas in which R 1, R 2, R 3, R 4 and R have the meanings given above, and A represents an eliminable group, / present / and, if necessary, eliminates any protecting group The process may be carried out according to the methods
classiques, par exemple dans un solvant, inerte sous les condi- classics, for example in a solvent, inert under the conditions
tions de la réaction, tel qu'un alcanol inférieur comme par exem- of the reaction, such as a lower alkanol such as
ple l'éthanol, éventuellement en mélange avec de l'eau, un hydro- ethanol, possibly mixed with water, a hydro-
carbure aromatique tel que le benzène ou le toluène, un éther cyclique tel que le dioxanne, ou un dialkylamide d'acide carboxylique tel que le diméthylformamide On opère à une température comprise entre la température ambiante et le point d'ébullition du mélange réactionnel, de aromatic carbide such as benzene or toluene, a cyclic ether such as dioxane, or a dialkylamide of carboxylic acid such as dimethylformamide is carried out at a temperature between room temperature and the boiling point of the reaction mixture,
préférence à la température ambiante Le groupe A éli- preferably at room temperature Group A elects
minable peut être par exemple un halogène comme par shabby can be for example a halogen as per
exemple le chlore ou le brome, ou un groupe sulfonyl- chlorine or bromine, or a sulphonyl group
oxy organique contenant de 1 à 10 atomes de carbone, comme par exemple un groupe alkylarylsulfonyloxy tel que p-toluènesulfonyloxy ou un groupe alkylsulfonyloxy tel que méthanesulfonyloxy Lorsque cela est approprié, la réaction est effectuée avantageusement en présence d'un agent accepteur d'acide comme par exemple un carbonate de métal alcalin tel que le carbonate de sodium ou de potassium Lorsque organic oxy containing from 1 to 10 carbon atoms, for example an alkylarylsulfonyloxy group such as p-toluenesulfonyloxy or an alkylsulfonyloxy group such as methanesulfonyloxy. When appropriate, the reaction is advantageously carried out in the presence of an acid-accepting agent such as for example an alkali metal carbonate such as sodium carbonate or potassium carbonate when
cela est approprié, les groupes fonctionnels éventuel- this is appropriate, the possible functional groups
lement présents dans le produit de départ peuvent être prôtégés par des groupes protecteurs appropriés qui peuvent, après la réaction, être éliminés selon contained in the starting material may be protected by suitable protecting groups which may, after the reaction, be removed according to
les méthodes connues.known methods.
Les composés de formule I ainsi obtenus The compounds of formula I thus obtained
peuvent ensuite être isolés et purifiés selon les mé- can then be isolated and purified according to the
thodes habituelles.usual methods.
Les composés de formule I peuvent être récupérés selon les méthodes connues, à l'état de The compounds of formula I can be recovered according to the known methods, in the form of
base libre ou sous forme d'un sel d'addition d'acide. free base or as an acid addition salt.
Les bases libres peuvent être transformées selon les Free bases can be transformed according to
méthodes connues en sels, et inversement. known methods in salts, and vice versa.
Les composés de formule I et leurs inter- The compounds of formula I and their
médiaires peuvent être obtenus sous forme de mélanges des différents isomères cis/trans qui peuvent être mediates can be obtained as mixtures of different cis / trans isomers which can be
séparés selon les méthodes connues. separated according to known methods.
Sauf indication contraire, les restes alkyle sont de préférence à chaîne linéaire ou ramifiée contenant de 1 à 12 atomes de carbone, spécialement de 1 Unless otherwise indicated, the alkyl radicals are preferably straight or branched chain containing from 1 to 12 carbon atoms, especially from 1 to 12 carbon atoms.
à 8 atomes de carbone, en particulierde là 6 et spécia- to 8 carbon atoms, especially 6 and especially
lement delà 4 atomes de carbone Un groupe particulier de tels reste alkyle comprend les restes alkyle ayant A particular group of such alkyl radicals includes alkyl radicals having
2 atomes de carbone ou plus Les groupes alkyle infé- 2 or more carbon atoms The lower alkyl groups
rieurs présents comme substituantsau dans un substi- present as substituents in a substitute
tuant sont à chaîne linéaire ou ramifiée et contiennent de préférence de l à 4 atomes de carbone, spécialement are linear or branched and preferably contain 1 to 4 carbon atoms, especially
1 ou 2 atomes de carbone Les restes alcényle con- 1 or 2 carbon atoms The alkenyl con-
tiennent de préférence de 3 à 6 atomes de carbone, spécialement 3 ou 4 atomes de carbone comme par exemple le groupe allyle ou propényle Les groupes cycloalkyle sont de préférence des groupes cyclohexyle, cyclopentyle ou cyclopropyle Par halogène, on entend le fluor, le preferably contain 3 to 6 carbon atoms, especially 3 or 4 carbon atoms such as for example the allyl or propenyl group. The cycloalkyl groups are preferably cyclohexyl, cyclopentyl or cyclopropyl. Halogen refers to fluorine,
chlore, le brome ou l'iode.chlorine, bromine or iodine.
Les groupes acétals et thioacétals contiennent de préfé- The acetals and thioacetals groups preferably contain
rence de 1 à 4 atomes de carbone, spécialement 1 ou 2 atomes de carbone dans leurs restes alkyle respectifs, 1 to 4 carbon atoms, especially 1 or 2 carbon atoms in their respective alkyl radicals,
ou peuvent également être cycliques. or can also be cyclic.
Les produits de départ de formule III sont partiellement nouveaux et peuvent être préparés en faisant réagir un composé de formule V R 2 C Hal (V) The starting materials of formula III are partially new and can be prepared by reacting a compound of formula V R 2 C Hal (V)
RR
avec un composé de formule VIwith a compound of formula VI
R 14,'H 2 (VI>R 14, H 2 (VI)
formules dans lesquelles R 1, R 2, R 3 et R 4 ont les formulas in which R 1, R 2, R 3 and R 4 have the same
significations données précédemment. meanings previously given.
Les produits de départ de formule IV sont partiellement nouveaux et peuvent être préparés par exemple selon le schéma réactionnel suivant 9, R 8 C 3 CH R 8 C C Me +CH 2 CH CHO The starting materials of formula IV are partially new and can be prepared, for example, according to the following reaction scheme: ## STR2 ##
R 8 C C CH CH = CH 2 +PA 3 (HA) IVR 8 C CH CH = CH 2 + PA 3 (HA) IV
OH dans lequel R 8 et A ont les significations données OH in which R 8 and A have the given meanings
précédemment et Me représente le cation d'un métal. previously and Me represents the cation of a metal.
Les conditions de réaction sont celles utilisées habituellement pour de telles réactions, les différents produits intermédiaires pouvant, lorsque cela est approprié, être mis à réagir ultérieurement sans isolement préalable Si on le désire, on peut The reaction conditions are those customarily used for such reactions, the various intermediate products being able, where appropriate, to be reacted subsequently without prior isolation.
isoler les produits intermédiaires selon les méthodes connues. isolate the intermediate products according to known methods.
Les autres produits de départ et produits intermédiaires sont connus ou peuvent être préparés Other starting materials and intermediates are known or can be prepared
selon des méthodes connues.according to known methods.
Les composés de formule I possèdent d'in- The compounds of formula I possess
téressantes propriétés chimiothérapeutiques et peuvent interesting chemotherapeutic properties and can
par conséquent être utilisés comime médicaments. therefore be used as drugs.
En particulier, les composés de formule I exercent une action antimycotique comme il ressort des essais de dilution en série effectués invitro sur des familles et types variés de mycètes, comnprenant Trichophyton spp, Aspergillus spp, Microsporum spp, Sporotrix schenkii et Candida spp, à des concentrations comprises par In particular, the compounds of Formula I exert an antimycotic action as shown by invitro serial dilution tests on various families and types of fungi, including Trichophyton spp., Aspergillus spp., Microsporum spp., Sporotrix schenkii, and Candida spp. concentrations included by
exemple entre 0,003 et 50 ug/ml.example between 0.003 and 50 μg / ml.
L'activité anti-mycotique des composés de formule I a été également mise en évidence in vivo dans le modèle expérimental de mycose dermique chez le cobaye 24 heures après l'infection, on administre quotidiennement la substance à essayer aux animaux pendant 7 jours, soit par application locale en frictionnant l'endroit infecté, la substance à essayer étant dans ce cas dans du polyéthylèneglycol, soit par voie orale, _______________ L'activité contre Candida, présentée spécialement par les composés de formule I dans laquelle R 1 est un groupe de formule I Ib, a été mnise en évidence in vivo à l'aide des modèles expérimentaux classiques, comme le modèle d'infection disséminé ou d'infection The anti-mycotic activity of the compounds of formula I was also demonstrated in vivo in the experimental model of dermal mycosis in guinea pigs 24 hours after infection, the substance to be tested is administered daily to animals for 7 days, or by local application by rubbing the infected place, the substance to be tested being in this case in polyethylene glycol, or orally, the activity against Candida, presented especially by the compounds of formula I in which R 1 is a group of Formula Ib, was demonstrated in vivo using conventional experimental models, such as the model of disseminated infection or infection.
intravaginale/intra-utérin chez la souris ou le rat. intravaginal / intrauterine in mice or rats.
On constate une nette activité anti-mycotique lorsque les composés de formule I sont appliqués par voie topique à une concentration comprise par exemple entre 0,01 et 0,2 % L'activité par voie orale a été constatée in vivo sur la trichophytose du cobaye à des A marked anti-mycotic activity is observed when the compounds of formula I are applied topically to a concentration of, for example, between 0.01 and 0.2%. Oral activity has been observed in vivo on guinea pig trichophytosis. Has
doses comprises par exemple entre 2 et 70 mg/kg. doses for example between 2 and 70 mg / kg.
Grâce à ces propriétés, les composés de formule I peuvent être utilisés en thérapeutique comme agents chimiothérapeutiques, en particulier comme agents anti-mycotiques Pour cette utilisation, une dose quotidienne appropriée sera comprise entre environ et 2000 mg de substance active que l'on administrera avantageusement sous forme de doses unitaires contenant chacune entre environ 17,5 et 1000 mg de substance Thanks to these properties, the compounds of formula I can be used therapeutically as chemotherapeutic agents, in particular as anti-mycotic agents. For this use, an appropriate daily dose will be between about 2000 mg of active substance that will be advantageously administered. in unit dose form each containing between about 17.5 and 1000 mg of substance
active 2 à 4 fois par jour, ou sous une forme à libé- active 2 to 4 times a day, or in free-form
ration retardée.delayed ration.
Les composés de formule I peuvent être utilisés à l'état de base libre ou sous forme d'un sel The compounds of formula I can be used in the free base state or in the form of a salt
d'addition d'acide acceptable du point de vue chimio- addition of chemically acceptable acid
thérapeutique De tels sels présentent le même ordre d'activité que les bases libres correspondantes Les sels appropriés sont par exemple le chlorhydrate, These salts have the same order of activity as the corresponding free bases. The appropriate salts are, for example, the hydrochloride,
l'hydrogénofumarate ou le naphtalène-l,5-disulfonate. hydrogenofumarate or naphthalene-1,5-disulfonate.
L'invention concerne donc les composés de formule I, à l'état de base libre ou sous forme d'un sel d'addition d'acide acceptable du point de vue chimiothérapeutique,pour l'utilisation comme médicaments, en particulier comme agents chimiothérapeutiques, The invention therefore relates to the compounds of formula I, in the free base state or in the form of a chemically acceptable acid addition salt, for use as medicaments, in particular as chemotherapeutic agents. ,
notamment anti-mycotiques.including anti-mycotics.
L'invention concerne également un médicament contenant, à titre de principe actif, un composé de formule I à l'état de base libre ou sous forme d'un sel d'addition d'acide acceptable du point de vue chimiothérapeutique. Pour leur utilisation en thérapeutique, les composés de formule I peuvent être mélangés à des diluants et véhicules acceptables du point de vue chimiothérapeutique et, éventuellement, à d'autres excipients Ils peuvent être administrés par voie The invention also relates to a medicament containing, as active ingredient, a compound of formula I in the free base state or as a chemically acceptable acid addition salt. For their therapeutic use, the compounds of formula I may be admixed with chemotherapeutically acceptable diluents and carriers and, optionally, other excipients.
orale sous forme de comprimés ou de capsules. oral form of tablets or capsules.
Les composés peuvent également être appliqués par voie topique, par exemple sous forme d'onguents ou de crèmes, The compounds can also be applied topically, for example in the form of ointments or creams,
ou par voie parentérale ou intraveineuse La concentra- parenteral or intravenous
tion de la substance active dépend du composé utilisé, du traitement envisagé, du type de formulation etc. En général, on obtient des résultats satisfaisants lorsque les formulations destinées à l'application of the active substance depends on the compound used, the treatment envisaged, the type of formulation, etc. In general, satisfactory results are obtained when the formulations intended for application
topique contiennent le principe actif à une concentra- topically contain the active ingredient at a concentration
tion comprise par exemple entre 0,05 et 5 % en poids, for example between 0.05 and 5% by weight,
en particulier entre 0,1 et 1 % en poids. in particular between 0.1 and 1% by weight.
De telles compositions font également Such compositions also make
partie de l'invention.part of the invention.
Les significations préférées des substhi tuants présents dans les composés de formule I sont les suivantes R = a) I Ia b) I Ib R 2 et R 3 = H R 4 = alkyle inférieur, spécialement méthyle R 5 et R 6 = a) l'hydrogène b) un halogène, spécialement le chlore R 8 = a) alkyle inférieur substitué par alcoxy ou alkylthio The preferred meanings of the substituents present in the compounds of formula I are R = a) I b) I Ib R 2 and R 3 = HR 4 = lower alkyl, especially methyl R 5 and R 6 = a) hydrogen b) halogen, especially chlorine R 8 = a) lower alkyl substituted by alkoxy or alkylthio
b) un groupe acétal ou thioacétal (éventuel- (b) an acetal or thioacetal group (
lement substitués par alkyle inférieur) substituted by lower alkyl)
ainsi que leurs combinaisons.as well as their combinations.
Les composés préférés sont ceux dans les- The preferred compounds are those in
quels la double liaison adjacente à l'atome d'azote a which the double bond adjacent to the nitrogen atom has
la configuration (E) trans.the configuration (E) trans.
Un composé particulièrement préféré est A particularly preferred compound is
la (E)-N-(l-naphtyl-méthyl)-N-méthyl-6-éthoxy-6-mnéthyl- (E) -N- (1-Naphthyl-methyl) -N-methyl-6-ethoxy-6-methyl
hept-2-ènè-4-ynylamine. Les exemples suivants illustrent la présente invention sans aucunement en limiter la portée Les hept-2-ene-4-ynylamine. The following examples illustrate the present invention without in any way limiting its scope.
températures sont toutes indiquées en degrés Celsius. all temperatures are in degrees Celsius.
Exemple 1Example 1
(E) et (Z)-N-méthyl-N-(l-naphtylméthyl)-6-méthoxy-6- (E) and (Z) -N-methyl-N- (1-naphthylmethyl) -6-methoxy-6-
méthyl-hept-2-ène-4-ynyl-aminemethyl-hept-2-ene-4-ynyl-amine
A un mélange de 16,1 g de N-méthyl-(l- To a mixture of 16.1 g of N-methyl- (l-
naphtyl)méthylamine, de 16,5 9 de carbonate de sodium et de 100 ml de diméthylformamide, on ajoute goutte à naphthyl) methylamine, 16.5% of sodium carbonate and 100 ml of dimethylformamide,
goutte une solution de 16,9 g de 1-bromo-6-méthoxy-6- drop a solution of 16.9 g of 1-bromo-6-methoxy-6-
méthylhept-2-ène-4-yne (mélange E/Z) dans de l'éther. methylhept-2-ene-4-yne (E / Z mixture) in ether.
Après avoir agité pendant la nuit, on filtre le mélange réactionnel et on élimine le solvant sous pression réduite On répartit le résidu d'évaporation entre une solution aqueuse saturée de bicarbonate de sodium et du dichlorométhane, on sèche la phase organique, on la concentre et on chromatographie sur gel de silice After stirring overnight, the reaction mixture is filtered and the solvent is removed under reduced pressure. The evaporation residue is partitioned between a saturated aqueous solution of sodium bicarbonate and dichloromethane, the organic phase is dried, concentrated and chromatography on silica gel
(éluant: miélange 4:1 de toluène et d'acétate d'éthyle). (eluent: 4: 1 mixture of toluene and ethyl acetate).
On obtient d'abord l'isomère (E) puis l'isomère (Z) We obtain first the isomer (E) then the isomer (Z)
sous forme d'huiles.in the form of oils.
En procédant de manière analogue ou comme décrit précédemment, on obtient les composés de formule I suivant dans lesquels R 2 et R 3 signifient l'hydrogène By proceeding in a similar manner or as described above, the following compounds of formula I are obtained in which R 2 and R 3 denote hydrogen.
et R 4 signifie un groupe méthyle.and R 4 is a methyl group.
(Tableau voir pages suivantes)(Table see following pages)
Exemple R 1 R 8 Conf 4 Données ph'y- Example R 1 R 8 Conf 4 Data ph'y-
guraiion sico-chimicues 2 3 E nuileguraiion sico-chimicues 2 3 E nuile
-C-OCH 3-C-OCH 3
,s éH ci, s eH c
4 E4 E
zz
6 CH6 CH
-C-OCH 2 CH 3 E-C-OCH 2 CH 3 E
CH 3CH 3
7 37 3
-C-OCH CH-C-OCH CH
1 2 31 2 3
-CH 3 '_-CH 3 '_
8 E 154-156 'E 154-156
Chlorhydrate)hydrochloride)
-CH -S-CH CH E il--CH -S-CH CH E il-
2 2 32 2 3
1 1 il lo z Il-1 1 he lo z He-
l Hl H
12 le 3 1 1 E il-12 the 3 1 1 E il-
-C'rl -S-CH 3 i-C'rl -S-CH 3 i
T A B L E A UBOARD
il- il- z huile ilhe- he- z oil he
R T Données physico-R T Physical data
Exemple R _________fonfi 'chimiques ___ ___ ___ ___ __ uratio C 2 H 5 E huile 13 ' O c 2 H 5 EXAMPLE R _______________________________________ Chemicals C 2 H 5 E Oil 13 'O c 2 H 5
14 H 3 E F 131714 H 3 E F 1317
-C-CH CH N 6317-C-CH CH N 6317
Ca I 2 (dhlorliydr 3;te); Z huile 16 E -'n Ca I 2 (dhlorliydr 3; te); Z oil 16 E -'n
17 -i-Z-17 -i-Z-
18 E18 E
___--CH 3-C___-- CH 3-C
19 H 3 E19 H 3 E
-C-CH -CHO-C-CH -CHO
C 3C 3
C 3 EC 3 E
-CH-CH 2 CH 2 OH-CH-CH 2 CH 2 OH
21 "21 "
/c 2 E -CH /C 2/ c 2 E -CH / C 2
22 II E22 II E
1 _________________I F= 145-148 o1 _________________I F = 145-148 o
I (chlorhydratei-I (hydrochloride
R R Con f 1 Donées physico: Exemple 1 8 gu ra t i ofnich 1 m i g ues CH R R Con f 1 Physical Data: Example 1 8 gu ra t i ofnich 1 m i g ues CH
23 3 CH23 3 CH
2 E -F = 150-155 '2 E-F = 150-155 '
-C C 12 (chlorhydfate) 24 z huile-C 12 C (chlorhydrate) 24 z oil
F = 130-1350F = 130-1350
issu (chiorhydratel 26 z -huileissued (chiorhydratel 26 z-oil
27 E27 E
s 28 zs 28 z
29 H 329 H 3
_CH 2 CH 2 OCH 3 E_CH 2 CH 2 OCH 3 E
CH 3 z HCH 3 z H
31 331 3
-C-OCH 3 E-C-OCH 3 E
3 ' 32 z -SCH3 '32 z -SCH
-CH 3 E-CH 3 E
-SCH 3-SCH 3
m i, 1 2m i, 1 2
-CH-CH-CH-CH
'-s C 3 Jq E -il - il- il- z -1 il- Confi 1 Données physico '-s C 3 Jq E -il - il- il- z -1 il- Confi 1 Physical data
Exemple R R guration chimiques-Example R Chemical R & D-
36 -CH CH CH Ci E huile 2 2 236 -CH CH CH Ci E oil 2 2 2
37 Z37 Z
38 -C-CH CH Ci E 2 2 & 338 -C-CH CH Ci E 2 2 & 3
39 H 339 H 3
CH 2 CH 2 F ECH 2 CH 2 F E
CH 3CH 3
Exemple 40Example 40
(E)-I-( 6-méthyl-6-méthoxyhe Dt-2-ène-4-ynyl)-2-(l-naphtyjl- (E) -I- (6-methyl-6-methoxyhe-2-en-4-ynyl) -2- (1-naphthyl)
pipéridîne huile.piperidine oil.
Exemple 41Example 41
(Z)-I-( 6-méthyl-6-méthoxyhept-2-ène-4-ynyl) 2-(I naphtyl)-_ pipéridîne h u i 1 e Spectres RMN 1 3 ( CDC 1 3 " TMS, température ambiante, 90 M Hz) (Z) -1- (6-methyl-6-methoxyhept-2-en-4-ynyl) -2- (1-naphthyl) piperidine, NMR Spectra 13 (CDCl 3 TMS, room temperature, 90.degree. M Hz)
ExempleExample
I(E) 8,2-8,35 (M, IH); 7,65-7 95 (m, 2 H); 7,35-7 i 6 (ni, 4 H); 6,26 (dt, J = 16 & 2 x O 595 Pz, IH), 5,72 (dt, J = 16 2 x',5 Hz, IH); 3,9 (s, 2 H); 3)36 (s, 3 HI'; 3115 (ddy J = 675 & 115 Hz, I (E) 8.2-8.35 (M, 1H); 7.65-7.95 (m, 2H); 7.35-7 (6n, 4H); 6.26 (dt, J = 16 & 2 x 0 595 Pz, 1H), 5.72 (dt, J = 16 2 x, 5Hz, 1H); 3.9 (s, 2H); 3) 36 (s, 3H, 3115 (ddy J = 675 & 115 Hz,
2 H); 2,2-" (s, 3 H); 154-6 (s, 6 P). 2H); 2.2- (s, 3H); 154-6 (s, 6 P).
I(Z) 8,1-8,25 (rn, 1 H), 7,65-7,8 (m, 2 "); - 25-7,5 (rn, 4 M); 6,04 (dt, J = 11 & 2 x 6,5 Hz 1 H); 5, 6 (dt, J = Il li 2 xl Fiz, IH); 3,84 (SI 2 P 'i; 3 y 3 -(s, 3-Li); 3,3 (dd, J 6 5 & 1 'riz, 2 Li); 2718 I (Z) 8.1-8.25 (m, 1H), 7.65-7.8 (m, 2 "); 25-7.5 (m, 4 M); , J = 11 & 2 x 6.5 Hz 1 H), 5.6 (dt, J = 11 Li 2 x Fiz, 1H), 3.84 (Si 2 P 'i; 3 y 3 - (s, 3 -Li); 3.3 (dd, J 6 5 & 1 rice, 2 Li); 2718
(SI 3 P,);(SI 3 P,);
2 7,8 (dd, J-= 7 2,5 Hz, 1 H); 7,2-7,55 (m, 4 Fn,; 6,3 (dt, J Io' & ' 2 x 6 Hz, 1 H); 5 $ 74 (dt, 3 16 & 2 xl,5 Fiz, 1 H); 3,P, (SI 2 H); 3,36 (SI 31 H); 3,15 (dd, J 6 & 1,5 Hz, 2 i-1): 2115 (si 7.8 (dd, J = 7.5 Hz, 1H); 7.2-7.55 (m, 4 Fn, 6.3 (dt, J = 2 x 6 Hz, 1H), $ 74 (dt, 3 16 & 2 × 15, Fiz, 1). H); 3, P, (SI 2 H); 3.36 (Si 31 H); 3.15 (dd, J 6 & 1.5 Hz, 2 i-1): 2115 (if
3 H,%; 1,46 (SI 9 H).3H,%; 1.46 (SI 9H).
3 7,8 (dd, 3 - 7 & 2,5 -11 z, IH); 7 2-7,515 (m, 4-Hj' 692 (dt, J Il 2 x 6 Hz" IH); 5,7 (dt, J = Il&2 xl,5 H, IP); ""le (SI 2 H); 3,38 (SI 3 H); 3,36 (dd, J 6 & 1,5 Hz, 2 H); 2 ,2-,I (s, 7.8 (dd, 3-7 & 2.5-11, 1H); 2-7,515 (m, 4-H, 692 (dt, JI 2 x 6 Hz-1H), 5.7 (dt, J = 11 & 2 x 1.5H, IP); 3.38 (SI 3 H), 3.36 (dd, J 6 & 1.5 Hz, 2H), 2, 2-, I (s,
3 H); 1148 Cs, 6 H).3H); 1148 Cs, 6H).
4 7,77 (CI J = 7 & 2 Hz, IPO; 7,I 5-7 5 (rn, 3 H); 6,25 1 (dt, J 16 & 6, 5 HZ, IH); 5,7 (dt, J = 16&2 x'L,,5 '14 z, IH'; 31,76 2 M); 3133 (s, 3 H) j 3,1 (dd i 6 5 & 1,5 Hz, 2 H); 2 e'l' (SI 3 H% 7.77 (Cl J = 7 & 2 Hz, IPO; 7, I 5-7 (rn, 3H); 6.25 (dt, J 16 & 6.5HZ, 1H); 5.7; (dt, J = 16 & 2 x 'L ,, 5' 14 z, 1H ', 31.76 2 M), 3133 (s, 3H), 3.1 (dd i 6 5 & 1.5 Hz, 2H); ) 2% (SI 3%)
l 44 (SI 6 H).l 44 (SI 6 H).
1,7 77 (dd, J = 72 1-1 z, 1 H); 7,2 -7,5 (m-Z %4 (dt, J Il & 6,5 Hz, l Hè; 5,C 5 (dt, -J & -2 xl,5 111 z, 11-i), 3 e 79 (SI 2 H); 3 j,34 (SI 3 H); 3,3 Icldj i 6,5 & 13 5 Hz, 2 P)i 2 > 22 (s, 1.777 (dd, J = 72-100, 1H); 7.2 -7.5 (mZ% 4 (dt, J11 & 6.5 Hz, 1He; 5, C 5 (dt, -J & -2xl, 5111, 11-i), 3 e 79 (SI 2 H), 3 d, 34 (ss 3 H), 3.3 Icldj i 6.5 & 13 5 Hz, 2 P) i 2> 22 (s,
3 H 1,; 1,44 (s, 6 H).3H 1 ,; 1.44 (s, 6H).
BD 2-8; 4 (m, IH); 7 ,7-7395 (,n, 21 H); 7 315-7 %M, 14 H); 6 24 (dt, J 16 & 2 x 6,5 Hz, 1 H); 5,7 (dt, J 16 & 2 xl,5 Hz, 1 H); 3 e 8 B (SI 2 H); 3,53 (qua, J = 7 Hz, 2 H); 3,14 (dd, J = 6 5 & BD 2-8; 4 (m, 1H); 7, 7-7395 (, n, 21H); 7,315-7% M, 14H); 24 (dt, J 16 & 2 x 6.5 Hz, 1H); 5.7 (dt, J16 & 2 xl, 5 Hz, 1H); 3 e 8 B (SI 2 H); 3.53 (qua, J = 7 Hz, 2H); 3.14 (dd, J = 6 & 5)
1,5 Hz, 2 iri); 2,22 (SI 3 H); 1,45 (s, 6 H); le I 8 (t, J 7 Hz, 3 H). 1.5 Hz, 2 iri); 2.22 (SI 3H); 1.45 (s, 6H); I 8 (t, J 7 Hz, 3 H).
7 8,2-8,4 2 H); 7,7-7,95 (rn, 2 H); 7 e 35-7,6 (m, 4-H); 6)ECI (dt, J = 11 2 x 6,5 Hz, 1 H); 5)67 (dt, J = 11 à 2 x 195 Hz, IH); 319 (s, 2 P 1; 3, 62 (qua, J = 7 Hz, 2 H); 3,36 (dd, J = 6,5 & 7 8.2-8.4 2H); 7.7-7.95 (m, 2H); 7e 35-7.6 (m, 4-H); 6) ECI (dt, J = 11 2 x 6.5 Hz, 1H); 5) 67 (dt, J = 11 at 2 x 195 Hz, 1H); 319 (s, 2 P 1; 3, 62 (qua, J = 7Hz, 2H); 3.36 (dd, J = 6.5);
1,5 Hz, 2 H); 2525 (SI 3 H); 1,-1-B (s, 6 F-i); 1 > 2 (t, J = 7 Hz, 3 H). 1.5 Hz, 2H); 2525 (SI 3H); 1, -1-B (s, 6 F-1); 1> 2 (t, J = 7 Hz, 3H).
8 7,77 (dd, J 7 & 2 Hz, IH); 7 t 3-7,6 (m, 4 H); 6,20 (dt, J 16 & 2 x 6,5 Hz, IH); 5 72 ( (det, J = 16 & 2 xl,5 Hz, IH); 3,78 %"S, 21-i); 3,6 (qua, J = 7 Hz, 2 H), 3 14 (dd, J = 6,5 & 7.77 (dd, J 7 & 2 Hz, 1H); 3-7.6 (m, 4H); 6.20 (dt, J 16 & 2 x 6.5 Hz, 1H); 72 ((det, J = 16 & 2 x 1.5 Hz, 1H), 3.78% (S, 21-1), 3.6 (qua, J = 7 Hz, 2H), 3 (dd , J = 6.5 &
Hz, 2 H); 2 e 2 l', fls, 3 H); 1,46 (s, 611); 1,2 (t, J = 7 Pz, 31-i). Hz, 2H); 2 e 2,,, 3 H); 1.46 (s, 611); 1.2 (t, J = 7 Pz, 31-i).
7,76 (dd, J = 7 & 2 Hz, 11-i); 7,2-7,5 (in, 4 H); 6,16 (dt, J 9 Il & 2 x 6,5 Hz, IH); 5 e 66 (dt, J Il & 2 xl,5 Pz, 1 H); 3,78 (s, 2 H); 3,6 (qua, J = 7 Hz, 2 F-1); 39 5 (dd, J = 6,5 7.76 (dd, J = 7 & 2 Hz, 11-1); 7.2-7.5 (in, 4H); 6.16 (dt, J 9 Il & 2 x 6.5 Hz, 1H); 5 e 66 (dt, J11 & 2 xl, 5 Pz, 1H); 3.78 (s, 2H); 3.6 (qua, J = 7 Hz, 2 F-1); 39 5 (dd, J = 6.5
1,5 Pz, 2 H); 2,26 (t, 31-i); 1,46 (s, 6 H); 1; 2 "t, J = 7 Hz, 3 H'J. 1.5 Pz, 2H); 2.26 (t, 31-1); 1.46 (s, 6H); 1; 2 "t, J = 7 Hz, 3HJ.
8,2-8 4 (m, 1 H), 7,7-7,95 (in, 2 H); 7,35-7,6 (m, 4 H); 6 3 (dt, J = 16 & 2 x 6 Hz, 1 H); 6572 (dm, J = 16 Hz, IH); 3,9 (s, 2 H); 3,4 (d, J = 2 Hz, 2 H%#; 3,15 (d, J 6 Hz, 2 H); 2,,7 (qua, J 8.2-8 (m, 1H), 7.7-7.95 (in, 2H); 7.35-7.6 (m, 4H); 6 3 (dt, J = 16 & 2 x 6 Hz, 1H); 6572 (dm, J = 16Hz, 1H); 3.9 (s, 2H); 3.4 (d, J = 2 Hz, 2H% #; 3.15 (d, J 6 Hz, 2H); 2,, 7 (qua, J
7 'Hz, 2 H); 2,24 (s, 3 H); lj ft, J = 7 Hz, 3 H). 7 Hz, 2H); 2.24 (s, 3H); ft, J = 7 Hz, 3H).
8,2-8,4 (m, IH); 7,65-7,95 Cm, 211); 7,35-7,65 (m, 4 H); 6 12 (dt, J 11 & 2 x 6 Hz, l H); 6,66 (dm J 11 Hz, IH); 3192 (s, 21-i); 3 4 (d, J = 2 Pz, 2 H'l; 3 36 (dd, J 6 & 1 Hz, 2 H); 2,7 8.2-8.4 (m, 1H); 7.65-7.95 cm, 211); 7.35-7.65 (m, 4H); 6 12 (dt, J 11 & 2 x 6 Hz, 1H); 6.66 (dm J 11 Hz, 1H); 3192 (s, 21-1); 3 4 (d, J = 2 Pz, 2H'l; 36 (dd, J 6 & 1 Hz, 2H); 2.7
(qua, J 7 Hz, 2 H); 2; 27 (s, 3 H); li 3 (t, J = 7 Hz, 3 H). (qua, J 7 Hz, 2H); 2; 27 (s, 3H); li 3 (t, J = 7 Hz, 3H).
12 8,2-8,4 (in, l Hï, 7 65-7,,95 m, 2 MJ%; 7,4-7,65 (in, -,',H); 6,3 (dt, J = 1 6 à 2 x 6 Pz, 1 P); 5,75 (dm, J 16 Hz, 1 H); 3,92 (s, H); 3,7 (dm J = 7 Hz, 1 H); 3,1 B (c;,-Il J 6 & 2 xl,5 Hz, 2 H),; 8.2-8.4 (in, 1H, 7 65-7, 95m, 2MJ%, 7.4-7.65 (in, -, ', H), 6.3 (dt, J = 16 at 2 x 6 Pz, 1 P) 5.75 (dm, J 16 Hz, 1H) 3.92 (s, H) 3.7 (dm J = 7 Hz, 1H) ; 3.1 B (c 1, - J 6 & 2 x 1, 5 Hz, 2 H) ,;
2,26 (s, 3 H" 0, 2 ,25 (s, 3 H); 1 5-1 (d, J = 7 Hz, 3 H). 2.26 (s, 3H-O, 2, 25 (s, 3H); 1 5-1 (d, J = 7Hz, 3H).
1 3 8,2-8,35 (rn, IH); 7,7-7 j 95 (in, 2 H); 7,35-7,65 (in, 4 Hï; 6,38 (dt, J = 16 & 2 x 6 Hz, IH); 5,7 ', (dm, J = 16 Hz, IHI); 5,4 (d, Jwl,5 Hz, 1 H); 3 y 9 (s, 2 H); 3,4-3,95 'partie AB du système ABX 3 JAB = le Hz, 4-H); 3,15 (dd, J = 6 & 1,5 Hz, 2 H); 8.2-8.35 (m, 1H); 7.7-7 to 95 (in, 2H); 7.35-7.65 (in, 4H, 6.38 (dt, J = 16 & 2 x 6Hz, 1H), 5.7 ', (dm, J = 16Hz, 1H), 5.4; (d, Jw1, 5 Hz, 1H); 3 y 9 (s, 2H); 3,4-3,95 'AB part of ABX system 3 JAB = Hz, 4-H); 3.15 (dd, J = 6 & 1.5 Hz, 2H);
2;,24 3 H); 1)25 (t, J = 7 Hz, 6 H). 2; 24 3H); 1) (t, J = 7 Hz, 6H).
14 8 15-8,35 (in, 1 H)I; 7,65-7 95 (in, 2 P); 7,3-7,6 (m, I H); 6,2 (dt, 16; 2 x 6,5 Hz, IH); 5 65 (dt, J = 16 Co( 2 xl,5 Hz, 1 F-i"; M 6, f's, 2 H); 3,1 (dd, J = 6 ,5 1 > 5 -Hz, 2 H); 2,4-8 (s, 2 H)/; 2 14.8 15-8.35 (in, 1H) I; 7.65-7.95 (in, 2 P); 7.3-7.6 (m, 1H); 6.2 (dt, 16, 2 x 6.5 Hz, 1H); 65 (dt, J = 16Co (2x1.5Hz, 1Fe, M6, fs, 2H), 3.1 (dd, J = 6.5, 5Hz, 2H); 2,4-8 (s, 2H) /; 2
(s, 3 H); 1,36 (s, 6 H).(s, 3H); 1.36 (s, 6H).
812-8)4 (rr-, 111 î); 7 '65-71,9 (rn, 211 A"i 7 3 7 O (m, 4 H); 6 12 (dt, J = 11 & 2 x 6,5 Hlz, IH); 5 62 (dt, J = il 2 xl,5 Pz, IH); 319 (s, 2 H); 3,35 (dd, J = 655 1,5 Hz, 2 H); 2,46 (s 2 ")$, 812-8) 4 (rr-, 111 '); 7, 65-71.9 (mp, 211 A, 7H (m, 4H), 612 (dt, J = 11 & 2 x 6.5H, 1H), 62 (dt, J); = 2 μl, 5 Pz, 1H), 319 (s, 2H), 3.35 (dd, J = 655 1.5 Hz, 2H), 2.46 (s 2 "),,
252,5 %f S, 31 il; I 36 (s, 6 H).252.5%, 31%; I 36 (s, 6H).
7,65-7 85 (rn, IH), 7 e I-7 5 (M, 4 H); 6,24 (dt, J 16 & 2 x 6,5 HZ, IH) ; 5166 (dt, J = 16 & 2 xl,5 Hz, 1 H), 3,75 (s, 2 H); 3 l (dd, J = 6 5 & 1,5 Hz, 2 H); 2 e 5 (S, 2 H); 2,2 (s, 3 H); 7.65-785 (m, 1H), 7H (M, 4H); 6.24 (dt, J 16 & 2 x 6.5HZ, 1H); 5166 (dt, J = 16 & 2 x 1.5 Hz, 1H), 3.75 (s, 2H); Λ (dd, J = 65 & 1.5 Hz, 2H); 2 e 5 (S, 2H); 2.2 (s, 3H);
1 36 (s, 6 H).36 (s, 6H).
17 7 65-7,85 IH)I; 7 1-75 (m, 4 H,; 5; 16 (dt, J = Il S 2 x 6 '5 Hz, 1 H); 5,6 (dt, J = Il2 xl)5 Hz',,B (s, 2 H); là 1 1 -M); 'Z 3533 (dd, J = 6 5 115 Hz, 2 H); 2 e 4 g (s, 2 H); 2,25 (s, 3-Li); 17 7 65-7.85 IH) I; 1-75 (m, 4H, 5; 16 (dt, J = 11 S 2 x 6 '5 Hz, 1H); 5.6 (dt, J = 11 x 1) 5 Hz', s, 2H); there 1 1 -M); Z 3533 (dd, J = 655 Hz, 2H); 2 e 4 g (s, 2H); 2.25 (s, 3-Li);
1 JS Cs, 6 H).1 JS Cs, 6H).
8,2-8,4 (m, 1 H); 7)7-830 %fm, 21 H); 7,35-7,6 (m, 4 H), 61,3 (dt, J ='1 6 ct 6 > 5 Hz, 1 H); 6 7 (dt, J = 16 & 2 xl,5 Hz, IH); 3;,9 (s, 2 H); 3 l 5 (%dit, J = 6 5 & 1,5 Hz, 2 H), 2; 2-4 (s, 3 H); 1)74 8.2-8.4 (m, 1H); 7) 7-830% fm, 21H); 7.35-7.6 (m, 4H), 61.3 (dt, J = 16 and 6 Hz, 1H); 6.7 (dt, J = 16.2 x 1.5 Hz, 1H); 3; 9 (s, 2H); 3% (% said, J = 65 & 1.5 Hz, 2H), 2; 2-4 (s, 3H); 1) 74
(t, i = 315 Hz, 3 H).(t, i = 315 Hz, 3H).
19 919 (t, J = 3 Hz, IH); 852-M r 1 m; 1 'A'#; 7; 7-7 p 5 (m, 29-0; 7,35- 19 919 (t, J = 3 Hz, 1H); 852-M r 1 m; 1 'A' #; 7; 7-7 p 5 (m, 29-0;
7 6 (fr, 4 H); 6; 2 (dt, J = 16 & 2 x 6 Pz, IHII; 517 (dt, J = 16 & 7 xi,5 Pz, 1 H'/; 3 9 (s, 21- ); 3,14 (dd, J = 6 à 2 1,5 Hz, 7 (fr, 4H); 6; 2 (dt, J = 16 & 2 x 6 Pz, IHII; 517 (dt, J = 16 & 7 xi, 5 Pz, 1 H '/; 3 9 (s, 21-); 3.14 (dd, J); = 6 to 2 1.5 Hz,
2 H); 2- 4 (d, J = 3 Hz, 2 H); 2 24 (s, 3-Li); Ip (s, 6 H). 2H); 2-4 (d, J = 3 Hz, 2H); 24 (s, 3-Li); Ip (s, 6H).
8,15-8,35 (m, I Hi;:7 e 65 1; 95 (M, 2 H); 7; 3-7 6 (m, 4 H); 6,18 (dt, J = 16 & 2 x 6,,5 Hz, IH); 5965 (dt, J = 16 & 2 xl,5 Hz, 1 H); 3,9 (s, 2 H); 3,84 (t, J = 7 Hz, 2 F-11); 3,12 %tdd, J = 6,5 & 1,5 Hz, 2 H); 2 22 (s, 3 H); 117 (t, J = 7 Hz, 2 H); 1,7 (br, OH); 8.15-8.35 (m, 1 H; 7 e 65 1; 95 (M, 2H); 7; 3-7 6 (m, 4H); 6.18 (dt, J = 16 & 2 x 6,, 5 Hz, 1H), 5965 (dt, J = 16 & 2 x 1.5 Hz, 1H), 3.9 (s, 2H), 3.84 (t, J = 7 Hz, 2 F-11), 3.12% tdd, J = 6.5 & 1.5 Hz, 2H); 22 (s, 3H); 117 (t, J = 7 Hz, 2H); 1.7 (br, OH);
1124 (s, 6 H).1124 (s, 6H).
21 8112-8,4 (rn, 1 H)I; 7,7-7,95 (m, 2 H); 7 35-7,65 (m, 4 H); 6; 3 (dt, J = 16 & 2 x 6 Hz, 1 H); 5,72 (dm, 3 16 Hz, IH): 5,23 (di, J 2 Hz, IH), 3, 88 (s, 2 H); 3,15-3, 65 (m, 4 H); 3 , 14 (dd, J = 6 & 8112-8.4 (m, 1H); 7.7-7.95 (m, 2H); 35-7.65 (m, 4H); 6; 3 (dt, J = 16 & 2 x 6 Hz, 1H); 5.72 (dm, 36 Hz, 1H): 5.23 (di, J 2 Hz, 1H), 3.88 (s, 2H); 3.15-3.65 (m, 4H); 3, 14 (dd, J = 6 &
*Hz, 2 H); 2,22 (s, 3 H).* Hz, 2H); 2.22 (s, 3H).
1 7 22 8,15-8,3 (m, 1 H); 7165-7,9 (m, 21 H); 7,3-7 6 (m, 4 HJ%; 673 (et, J = 16 & 2 x 6 15 Hz, 1 H); 5,8 (d't, J = 16 & 2 xl Hz, IH); 8.15-8.3 (m, 1H); 7165-7.9 (m, 21H); 7.3-7 6 (m, 4 HJ%; 673 (and, J = 16 & 2 x 6 15 Hz, 1H); 5.8 (from t, J = 16 & 2 xl Hz, 1H);
3,88 (s, 2 H); 3 14 (dd i = 6 5 & 1 Hz, 2 H'i; 2,2 (s, 3 H). 3.88 (s, 2H); 14 (dd i = 65 & 1 Hz, 2Hi, 2.2 (s, 3H).
23 8,2-8,4 (m, li); 7 7-8 j O (M, 2 H); 7;"- -7765 (m, Z -H); 6 3 (de, J = 16 & 2 x 6,5 Hz, 1 H); 5; 7 (dt, J = 16 &2 x l 5 Hz, 1 H), M (s 2 H); 3 I 4 (dd J = 6,5 & 1 5 liz, 2 H; 2 8.2-8.4 (m, Li); 7-8% (M, 2H); ## EQU1 ## where: J = 16 & 2 × 6.5 Hz, 1H); 5; 7 (dt, J = 16 & 2 × 15 Hz, 1H); ), M (s 2 H); 3 I 4 (dd J = 6.5 & 1, liz, 2H; 2);
3 H); 1; 74 (d, J = 7 Hz,'IH); 1,65 (s, 3 M); 1;,43 (d, J = 7 Hz, 1 H). 3H); 1; 74 (d, J = 7 Hz, 1H); 1.65 (s, 3 M); 1;, 43 (d, J = 7 Hz, 1H).
24 812-814 (m, IH); 7,7-8,0 (rn, 2 P "#; 7,4-7,65 (rr,, 4 F-1); 6; 16 (dts J = 105 & 2 x 6; 5 Hz, 1 H'; 5;( 56 (dt, J= lo,5 2 x 115 Hz, IH); 3, 92 (s, 2 H'; 3138 (dd, J = 6; 5 1; 5 Hz, 2 H'; 2124 (s, 3 H); le 76 (d, J = 7 Hz, l H); Ifi (s, 3 H); 1; 52 (d, J 812-814 (m, 1H); 7.7-8.0 (mp, n = 7.4-7.65 (m, 4 F-1); 6; 16 (d = J = 105 & 2 x 6; 5 Hz, 1H); (56 (dt, J = 0, 2 x 115 Hz, 1H); 3, 92 (s, 2 H '; 3138 (dd, J = 6; 5 1; 5 Hz, 2 H'; 2124 (s, 3H), 76 (d, J = 7 Hz, 1H), Ifi (s, 3H), 1, 52 (d, J);
7 Hz, 1 H).7 Hz, 1 H).
7178 (dd, J 7 & 2 Hz, 1 H'J; 7,2-7,5 (n-, 4,H'); 6 e 32 (dt, J 16 & 2 x 6, 5 Hz, 1 H); 5 72 (dt, J = 1 O' & 115 Hz, 1 1-i'; 3,78 1 5 (s, 2 H); 3) 14 dd, J = 6 5 & 115 Pz, 2 '); 2,22 (s, le 76 7178 (dd, J 7 & 2 Hz, 1HJ; 7.2-7.5 (n-, 4, H '); 6e 32 (dt, J 16 & 2 x 6.5 Hz, 1H); 72 (dt, J = 100, 115 Hz, 11.78 (s, 2H), 3) 14dd, J = 65 & 115 Pz, 2 '); ; 2.22 (s, the 76
(d, J = 7 Hz, l H) 11,58 (s, 31-i); 'L 46 (d, J 7 Hz, 1 H). (d, J = 7Hz, 1H) 11.58 (s, 31-1); L 46 (d, J 7 Hz, 1H).
26 7 > 76 (dd, J = 7 & 2 Hz, IH); 7 l I-715 (M, 4 P); 6318 (dt, J 1015 & 2 x 6,5 Pz, IH); 5,65 (jt, J = 10,5 & 2 x 11,5 Hzy 1 H); 3,80 (s, 2 H); 3 34 (dd, J = 615 & 1,5 Hz, 2 H)-, 2; 25 (s, 3 H); l 74 (d, J 7 Hz, IH'-; 1758 (s, 31-INI; 1148 (d, J 7 HZ, 27 7 j B (dd, J 7 F 4 2 Hz, IH); 7142 (ts 3 7 Hz, IHl; 7 j 2-7 45 (M, 2 H), O ' 28 (c 1 t, J = 16 2 x 6 5 Hz, X; 517 (dt, J = 16 2 x 1,5 Hz, IH); 3 7 B (s, 21-i); 3 l (dd, J = 615 & 1,5 Hz, 74 (d, J 7 Hz, 1 H); L 55 (s, 3 F-' 'J; 1146 (d, 2 H); 212 (s, 3 H); Il 26 7> 76 (dd, J = 7 & 2 Hz, 1H); I-715 (M, 4 P); 6318 (dt, J 1015 & 2 x 6.5 Pz, 1H); 5.65 (Jt, J = 10.5 & 2 x 11.5 H 1 H); 3.80 (s, 2H); 34 (dd, J = 615 & 1.5Hz, 2H) -, 2; 25 (s, 3H); 1 74 (d, J 7 Hz, 1H-1, 1758 (s, 31-INI; 1148 (d, J 7 HZ, 27 7 B (dd, J 7 F 4 2 Hz, 1H); 7142 (ts 3 7 Hz, 7 H 2-7 45 (M, 2 H), O '28 (c 1 t, J = 16 2 x 6 5 Hz, X, 517 (dt, J = 16 2 x 1.5 Hz) , 1H); B (s, 21-i); 3 1 (dd, J = 615 & 1.5Hz, 74 (d, J 7Hz, 1H); L 55 (s, 3H); J; 1146 (d, 2H); 212 (s, 3H);
J = 7 Hz, 1 H).J = 7 Hz, 1H).
28 7178 (dd, J = 7-and 2 Hz, IH); 7,42 (t, J 7 Hz, l Li); 752-7 45 (m., 2 F-i); 6316 (dt, J = l Oe 5 & 2 x 6 5 Hz, IH); 5,62 (d-t J 1075 & 2 x 1, 5 Hz, 11-4); 3178 (à, 2 H; 3 22 Cd, J = 6 5 Hz, 2 H); 2 2 (s, 3 -i"j; l 72 (d, J 71 Pz, IP); 1155 's, 3 H); 7178 (dd, J = 7 and 2 Hz, 1H); 7.42 (t, J 7 Hz, 1 Li); 752-7 (m, 2 F-1); 6316 (dt, J = 1 Oe 5 & 2 x 6 5 Hz, 1H); 5.62 (d 1075 & 2 x 1.5 Hz, 11-4); 3178 (at, 2H, 3 Cd, J = 65 Hz, 2H); 72 (d, J 71 Pz, IP); 1155 's, 3H);
1 * 48 (d, J 7 Hz, 1 H).1 * 48 (d, J 7 Hz, 1H).
29 8 2-8 4 1-M); 7 7-si O2 i-41,; 7 35-7,65 fm, 44 "; ke'19 (dt, J 1 6 & 2 x C- 5 Mz, 11-l'); 5-YB (dt, J In' 2 x 1 5 Hz, Ifi); 3,9 (s, 2 '-'); 3 55 (I-, iî Fiz, 3,3 '+ (s, 3:-'I; 3; 12 (ddy J = 6 5 & 1 5 Hz, 2 P, /'; 2; 1)2 (s, -3 H); 1 7 (t, J 7 H::, 2 H); 29 8 2-8 4 1-M); 7- if O2 i-41 ,; 7 35-7.65 fm, 44 "; ke'19 (dt, J 1 6 & 2 x C-5 Mz, 11-l '); 5-YB (dt, J In' 2 x 15 Hz, Ifi 3.9 (s, 2 '-'); 3 55 (I), Fiz, 3,3 '+ (s, 3: -'; 3; 12 (ddy J = 65 & 15 Hz , 2 P, '; 2; 1) 2 (s, -3 H); 17 (t, J 7 H :: 2H);
1,2 (s, 6 H).1.2 (s, 6H).
8 2-8 4 IH); 7,7-8 O 2 H'; 7 -7,1)5 (r 6 OER (dit )5 2 x 6 5 Hz, l Hl; 5; 66 (dt, J1015 2 x 1,5 Hz, 1 H); 3 92 (s, 2 H); 3; 6 (t, J = 7 Pz, 2 H'J; 3 4 (dd, J = 615 & 1 5 Hz, 2 H); 3 43 (s, 3 FA); 2 2 f es, 3 H); 1 74 't' J = 8 2-8 4H1); 7.7-8 O 2 H; 7-7.1) 5 (r 6 OER (dit) 2 x 6 5 Hz, 1Hl; 5; 66 (dt, J1015 2 x 1.5 Hz, 1H); 3 92 (s, 2H); ; 3; 6 (t, J = 7 Pz, 2H'J; 34 (dd, J = 615 & 15 Hz, 2H); 43 (s, 3 FA); 2 2 f es, 3H; 1 74 't' J =
7 Hz, 21-1); 1124 (s, 6 H).7 Hz, 21-1); 1124 (s, 6H).
31 6,9-7,17 (m, 3 H); 6 22 (dt, J m 16 & 2 x 5 Hz, 1 1-i/'; 5 7 (dt, 16 2 x 1,5 Hz, l Fi); 37 5 (s, 31-i; 3,05 (dd, J = 6,5 o ú 6.9-7.17 (m, 3H); 6 22 (dt, J m 16 & 2 x 5 Hz, 1 1-i / '; 5 7 (dt, 16 2 x 1.5 Hz, 1 Fi); 37 5 (s, 31-i; 3.05 (dd, J = 6.5 o ú
1,5 Pz, 2 H); 2 6-2 95 40 '; 2 2 (s, Y 1 'l; ' 65- 1.5 Pz, 2H); 2, 6-2, 95, 40 '; 2 2 (s, Y 1 ''; 65-
11,05 4 H), l 6 (s, 6 H).11.05 H), 16 (s, 6H).
32 6,9-7,3 31-iï; 6,09 (dt, J 11 ou 7 x 6,5 Hz, l H; 5,66 (dt, 32 6.9-7.3 31-ii; 6.09 (dt, J 11 or 7 x 6.5 Hz, 1H, 5.66 (dt,
J = 11 2 x 11,5 Hz, IHJ; 3 4-4 '(s, 2 H); 3,40 (S' ir); 3,3 (dd,- J = 11 2 x 11.5 Hz, 1HJ; 3-4 '(s, 2H); 3.40 (S 'ir); 3.3 (dd, -
J = 6 5 1,5 Pz, 2 H; 2,6-2,9 (m, 4 H; 2,22 (s, 3 H'; 1,6-2 P J = 6.51 Pb, 2H; 2.6-2.9 (m, 4H, 2.22 (s, 3H, 1.6-2P)
4 H); 1,5 (s, 6 H).4H); 1.5 (s, 6H).
33 8 2-8 4IH); 757-BO 2 P); 714-7,65 (m, 4 H); 6)34 '(dt, 33 8 2-8 4IH); 757-BO 2 P); 714-7.65 (m, 4H); 6) 34 '(dt,
J = 16 & 2 x 6,5 Hz, IH); 5177 (ddd, J = 16, 2 & '1,,5 Hz,- J = 16 & 2 x 6.5 Hz, 1H); 5177 (ddd, J = 16, 2 & 1, 5 Hz, -
1 H); 4,65 (d, J = 2 Hz, 1 H'i; 3,9 (s, 21-i); 3 15 (dd, J = 6,,5 1H); 4.65 (d, J = 2 Hz, 1H, 3,9 (s, 21-i); 3d (dd, J = 6, 5
l, 5 Hz, 2 H)-, 2 22 (s, 9 H).1.5 Hz, 2H) -, 22 (s, 9H).
34 8 2-8,4 (m, 1 H); 7 > 7-810 (m, 2 H); 7,3-717 (m, 4 H); 6 3 (dt, J 16 Et 2 x 6,5 Hz, 1 H); 5,76 (dt, J = là O 2 x 1,5 Hz, IH); 3,9 (s, 2 H), 3 14 (dd, J = 615 & 115 Hz, 2 H); 2,22 (% 9 F); 2-8.4 (m, 1H); 7> 7-810 (m, 2H); 7.3-717 (m, 4H); 6 3 (dt, J 16 and 2 x 6.5 Hz, 1H); 5.76 (dt, J = 0, 2 x 1.5 Hz, 1H); 3.9 (s, 2H), 34 (dd, J = 615 & 115 Hz, 2H); 2.22 (% 9F);
1)84 (st 3 H).1) 84 (st 3 H).
8,2-8,4 (m, IH); 757-BC (m, 2 H); 7 3-7 65 (m, 4 H); 6 e 18 (dt, 3 = 10,5 & 2 x 6,5 Hz, 1 H); 5175 (dt, J = 10 5 & 2 x 1,5 Hz, 1 H); 3,,95 (s, 2 H); 3 4 (dd, J = 6,5 & I 5 Hz, 2 H); 8.2-8.4 (m, 1H); 757-BC (m, 2H); 3-7 65 (m, 4H); 6 e 18 (dt, 3 = 10.5 & 2 x 6.5 Hz, 1H); 5175 (dt, J = 10 5 & 2 x 1.5 Hz, 1H); 3, 95 (s, 2H); 34 (dd, J = 6.5 & 1 Hz, 2H);
2,28 '(s, 3 H); 2 26 (s, 6 H); 1 88 (s, 3 H). 2.28 '(s, 3H); 26 (s, 6H); 88 (s, 3H).
36 852-854 (m, 1 H); 757-8,0 (m, 2 H); 74-7,6 (m, 4 H); 6; 24 (dt, J = 16 & 2 x 6,5 Hz, 1 H); 5,66 (dm, J = 16 Hz, 1 H); 3,9 (s, 2 H); 3 j 66 (t, J = 7 Hz, 2 H); 3,15 (dd, J = 6 5 & 1 Hz, 2 H); 36, 852-854 (m, 1H); 757-8.0 (m, 2H); 74-7.6 (m, 4H); 6; 24 (dt, J = 16 & 2 x 6.5 Hz, 1H); 5.66 (dm, J = 16Hz, 1H); 3.9 (s, 2H); 66 (t, J = 7 Hz, 2H); 3.15 (dd, J = 65 & 1 Hz, 2H);
2.,5 (tbr, J = 7 Hz, 2 H); 2,22 (s, 3 H); 2,0 (qu, J = 7 Hz, 2 H). 2., 5 (tbr, J = 7 Hz, 2H); 2.22 (s, 3H); 2.0 (that, J = 7 Hz, 2H).
37 8,2-8,4 (m, IH); 7,7-8,0 (m, 2 H); 7,4-7,65 (m, 4 H); 6,1 (dt, j = 10) 5 & 635 Hz, IH); 5566 (dm J = 10,5 Hz, IH); 3,94 (s, 2 H); 68 (t, J = 7 Hz, 2 H); 3,38 (dd, J = 6,5 à 1,5 Hz, 2 H); 8.2-8.4 (m, 1H); 7.7-8.0 (m, 2H); 7.4-7.65 (m, 4H); 6.1 (dt, j = 10) δ & 635 Hz, 1H); 5566 (dm J = 10.5 Hz, 1H); 3.94 (s, 2H); 68 (t, J = 7 Hz, 2H); 3.38 (dd, J = 6.5 to 1.5 Hz, 2H);
2,55 (tbr, J = 7 Hz, 2 H); IP 26 (s, 3 H); 2,,03 (qui, J = 7 Hz, 2 H). 2.55 (tbr, J = 7 Hz, 2H); IP 26 (s, 3H); 2,, 03 (which, J = 7 Hz, 2 H).
38 6,2-8,4 (m, IH); 7,65-8)0 (M' 2 H); 7 3-7 6 (m, 4 H); 6 J 24 (dt, J = 16 & 2 x 6,5 Hz, IH); 5,67 (dt, J = 16 & 2 x 1,,5 Hz, là 1 H); 3,9 (s, 2 H); 3,55-3,8 (m,24);31,12 (dd, J = 6: 5 6.2-8.4 (m, 1H); 7.65-8) 0 (M '2H); 3-7 (m, 4H); J 24 (dt, J = 16 & 2 x 6.5 Hz, 1H); 5.67 (dt, J = 16 & 2 x 1, 5 Hz, 1H); 3.9 (s, 2H); 3.55-3.8 (m, 24); 31.12 (dd, J = 6: 5;
I.,5 Hz, 2 H); 2,22 (s, 3 H); 1 8-2,0 2 H); 1 24 (s, 6 H). I., 5 Hz, 2H); 2.22 (s, 3H); 1 8-2.0 2H); 1 24 (s, 6H).
39 8 2-8 A 1 H); 7,,65-8 0 (m, 2 H); 7,3-7,6 (m, 4 H); 6 22 (dt, J = 16 2 x 6,5 Hz, 1 H); 5,65 (dm, J = 16 Hz, 1 H); 45,7 (dt, J = 47 2 x 7 Hz, 2 H); 3; 9 (s, 2 H); 3,12 (dd, J = 6 e 5 45 Hz, 2 H); 2,2 (s, 3 H); 1, 3 (dt, J= 24 2 x 7 Hz, 2 H); 1 22 (s, 6 H). Ei 2-SB (br, IP NJ; 7,2-7,9 Cr-, 6 H); 6,1 (clt',d, J = 16, P, & 6 Hz, 1 H); 5,5-1 (e-m, J = 16 Hz, 1 H'; 3,6-4 Il ( % 3 dy 39 8 2-8 A 1H); 7, 65-80 (m, 2H); 7.3-7.6 (m, 4H); 22 (dt, J = 16 2 x 6.5 Hz, 1H); 5.65 (dm, J = 16Hz, 1H); 45.7 (dt, J = 47 2 x 7 Hz, 2H); 3; 9 (s, 2H); 3.12 (dd, J = 6 and 45 Hz, 2H); 2.2 (s, 3H); 1, 3 (dt, J = 24 2 x 7 Hz, 2H); 1 22 (s, 6H). EI 2-SB (br, IP NJ; 7.2-7.9 Cr-, 6H); 6.1 (clt ', d, J = 16, P, & 6 Hz, 1H); 5.5-1 (e-m, J = 16Hz, 1H ', 3.6-4It (% 3 dy)
in, IH); 3 36 fs 3 H)-in, 1H); 3 36 fs 3 H) -
1,1-3,4 (m, ' 'H), 2 4-2,7 (m, 1 H?; 172-233 m, 7-Li); 1144 (s, 1.1-3.4 (m, H), 24-2.7 (m, 1H172-233m, 7-Li); 1144 (s,
6 H).6H).
41 8 4-8 9 (br, l H'; 732-7 9 en, 61-i); 5,96 J = 11, 8 6 Hz-, 11-i; 5, 42 %'d -n, J = Il Hz, IH'i; 3; 6-4 O (m, -1 1-i); 26 41 8 4-8 9 (br, 1 H '; 732-7-9, 61-1); 5.96 J = 11.86 Hz-, 11-1; 5, 42% d-n, J = 11 Hz, 1H'i; 3; 6-4 O (m, -1-1-i); 26
31 i'; 8-3 4 fn-i, 31-11; 112-2,,4 (m, 7-t-î; lli (s, 61-0. 31 i '; 8-3 4 fn-1, 31-11; 112-2, 4 (m, 7-t-1; 1H (s, 61-0.
s = singulet, d = doublet, t = triplet, qu = quadriplet, m = multiplet, s = singlet, d = doublet, t = triplet, qu = quadriplet, m = multiplet,
br = large.br = large.
Les produits de départ nécessaires à la préparation des composés de formule I peuvent être préparés par exemple comme suit: A) l-bromo-6méthoxy-6-méthylhept-2-ène-4-yne& a) 6-méthoxy-6-méthylhept-1-ène-4-yne 3-ol The starting materials necessary for the preparation of the compounds of the formula I can be prepared for example as follows: A) 1-bromo-6-methoxy-6-methylhept-2-en-4-yne (a) 6-methoxy-6-methylhept- 1-en-4-yl 3-ol
A 127 ml d'une solution -1,6 X de n-butylli- To 127 ml of a -1.6% solution of n-butyllithium
thium dans de l'hexane, on ajoute goutte à goutte, sous atmosphère de gaz inerte et à -20 , 20 g thium in hexane is added dropwise under an inert gas atmosphere and at -20.20 g
de 3-méthoxy-3-méthyl-1 l-butynedans 200 ml de tétra- of 3-methoxy-3-methyl-1-butynedan in 200 ml of tetrachloride
hydrofuranne anhydre On refroidit la solution à -70 et on ajoute goutte à goutte 11,4 g d'acroléine dans du tétrahydrofuranne On chauffe le mélange réactionnel à la température ambiante, on le verse dans une solution aqueuse saturée de chlorure d'ammonium, on l'extrait à l'éther, anhydrous hydrofuran The solution is cooled to -70 and 11.4 g of acrolein in tetrahydrofuran are added dropwise. The reaction mixture is heated to room temperature, poured into a saturated aqueous solution of ammonium chloride, the extract with ether,
on sèche la phase organique et on la concentre. the organic phase is dried and concentrated.
Par distillation à 58 sous 0,2 mbar, on obtient By distillation at 58 at 0.2 mbar, we obtain
le produit pur à l'état huileux.the pure product in the oily state.
b) l-bromo:6 m__thoxy-6-mthylhe Et-2-ne-4:yne (mélange E/Z) b) 1-bromo: 6-methoxy-6-methyl-Et-2-ne-4: yne (E / Z mixture)
On dissout 12 g de 6-méthoxy-6-méthylhept- 12 g of 6-methoxy-6-methylhept-
1-ène-4-yne-3-ol dans de l'éther et on ajoute 1-en-4-yn-3-ol in ether and added
goutte à goutte à O 10; 5 g de tribromure de phosphore. dropwise at 0-10; 5 g of phosphorus tribromide.
On continue d'agiter pendant 1 heure et demie puis on verse le mélange dans de la glace, on Stirring is continued for 1 hour and then poured into ice,
l'extrait à l'éther et on sèche la phase organique. the ether extract and the organic phase is dried.
Le produit brut ainsi obtenu ne contient plus de produit de départ (chromatographie en couche mince: mélange 9/1 de toluène et d'acétate d'éthyle comme éluant; Rf du produit = O,8; Rf du produit de départ = 0,1) et est utilisé directement comme The crude product thus obtained no longer contains starting material (thin layer chromatography: 9/1 mixture of toluene and ethyl acetate as eluent, Rf of the product = 0.8, Rf of the starting product = 0, 1) and is used directly as
solution àt,)iêré&e pour la N-alkylation. This solution is used for N-alkylation.
En Deocédant de manière analogue à celle décrite sous Aa) ou comme décrit précédemment, on peut préparer les composés suivants 6-éthoxy-5-méthyl hept- 11-ène-4-yne-3-ol (h uil e; spectre RMN 5,7-6,2 (m,l H); 5,0-5,6 (ni, 2 H); 4,85 (d, J 4,5 Hz, 1 H); 3,7 (br, OH); 3,6 (qua, J =:7 By proceeding analogously to that described under Aa) or as previously described, the following compounds can be prepared: 6-ethoxy-5-methylhept-11-en-4-yn-3-ol , 7-6.2 (m, 1 H), 5.0-5.6 (nl, 2H), 4.85 (d, J 4.5 Hz, 1H), 3.7 (br, OH); ) 3.6 (qua, J =: 7
Hz, 2 H); 1,5 (s, 6 H); 1,2 (t, J= 7 Hz, 3 H). Hz, 2H); 1.5 (s, 6H); 1.2 (t, J = 7 Hz, 3H).
6-éthylthiohex-1-ène-4-yne-3-ol (huile: chromatographie en couche mince: mélange 9/1 de toluène 6-ethylthiohex-1-en-4-yn-3-ol (oil: thin-layer chromatography: 9/1 toluene mixture
et d'acétate d'éthyle comme éluant, Rf = 0,26). and ethyl acetate as eluent, Rf = 0.26).
6-rnéthylthiohept-1-ène-4-yne-3-ol (E = 1200 6-methylthiohept-1-en-4-yn-3-ol (E = 1200
sous 16 mbar dans un tube à boules). under 16 mbar in a bulb tube).
6,6-di éthoxyhex-l -ène-4-yne-3-ol. 6,6-di-ethoxyhex-1-en-4-yn-3-ol.
7-cyano-6,6-diméthylhept- 11-ène-4-yne-3-ol <huile; spectre RMN: 5,7-6,3 (mi, 1 H); 5,0-5,6 (ni, 2 H); 4,85 (d, J = 4,5 Hz, 1 H); 3,1-3,8 (br, OH); 2,55 (s,2 H); 7-cyano-6,6-dimethylhept-11-en-4-yn-3-ol <oil; NMR spectrum: 5.7-6.3 (mi, 1H); 5.0-5.6 (nl, 2H); 4.85 (d, J = 4.5 Hz, 1H); 3.1-3.8 (br, OH); 2.55 (s, 2H);
1,4 (s, 6 H).1.4 (s, 6H).
6,6-dithioéthylènehex-l-ène-4-yne-3-ol. 6,6-dithioéthylènehex-l-ene-4-yn-3-ol.
5-(l-méthyl-2,2-dichlorocyclopropyl)pent-1- 5- (l-methyl-2,2-dichlorocyclopropyl) pent-1-
ène-4-yne-3-ol (huile; chromatographie en couche mince: toluè-ne cornue éluant, Rf= 0,15) 6,6-diméthyl-8-méthoxyoct-1-ène-4-yne-3-ol. En procédant de manière analogue à celle décrite sous Ab) ou comme décrit précédemment, on peut préparer les composés suivants 6-éthoxy-1 -bromo-6- méthyl hept-2-ène-4-yne 6-éthyl thio- 11-bromohex-2-ène-4-yne 1-bromo-6- méthylthiohept-2-ène-4-yne 1-bromo-6,6-diéthoxyhex-2-ène-4-yne 1 -bromo7-cyano-6,6-di méthyl hept-2-êne-4-yne 1-bromo-6-di thioéthylèniehex-2ène-4-yne 1 -bromo-5-iodopent-2-ène-4-yne ene-4-yn-3-ol (oil, thin layer chromatography: eluted toluene-eluent, Rf = 0.15) 6,6-dimethyl-8-methoxyoct-1-en-4-yn-3-ol . By proceeding in a manner analogous to that described under Ab) or as described above, the following compounds can be prepared 6-ethoxy-1-bromo-6-methylhept-2-en-4-yne 6-ethylthio-11-bromohex -2-en-4-yne 1-bromo-6-methylthiohept-2-en-4-yne 1-bromo-6,6-diethoxyhex-2-en-4-yne 1-bromo-7-cyano-6,6- methyl-hept-2-en-4-yl-1-bromo-6-di-thioethylenhex-2-en-4-yl-bromo-5-iodopent-2-en-4-yne
1-bromo-5-( 1-méthyl-2,2-dichlorocyclopropyl)pent-2- 1-bromo-5- (1-methyl-2,2-dichlorocyclopropyl) pent-2-
ène-4-yne, et l-bromo-6,6-diméthyl-8-méthoxyoct-2-ène-4-yne. B) l-bromo-7, 7-difluoro-6-méthylhepta-2,6-diène-4-yne a) 1-tert -butyldiméthylsilyloxy4-pentyne-2-ène A une solution de 5 g de 4-pentyne-2-ène-l-ol ene-4-yne, and 1-bromo-6,6-dimethyl-8-methoxyoct-2-ene-4-yne. B) 1-Bromo-7,7-difluoro-6-methylhepta-2,6-dien-4-yne a) 1-tert-butyldimethylsilyloxy-4-pentyne-2-ene To a solution of 5 g of 4-pentyne-2 -ene-l-ol
et de 9,3 ml de triéthylamine dans du diméthylfor- and 9.3 ml of triethylamine in dimethylformate
mamide, on ajoute goutte à goutte à la température mamide, add drop by drop to the temperature
ambiante 10,1 g de tert -butyldiméthylchloro- 10.1 g of tert-butyldimethylchloride
silane On continue d'agiter pendant 1 heure, on verse le mélange dans de la glace et on silane Stirring is continued for 1 hour, the mixture is poured into ice and
l'extrait avec de l'hexane On lave la phase or- the extract with hexane The washing phase is washed
ganique, on la sèche et on la concentre Le produit brut huileux ainsi obtenu est utilisé dried, and concentrated. The oily crude product thus obtained is used
directement pour la réaction suivante. directly for the next reaction.
b) 1-tert -butyldiméthylsilyloxy-6-hydroxyhept-2- b) 1-tert-butyldimethylsilyloxy-6-hydroxyhept-2-
ène:l:yntene: l: YNT
On dissout 10,7 9 de l-tert -butyldiméthyl- 10.7% of 1-tert-butyldimethyl
silyloxy-4-pentyne-2-ène dans du tétrahydrofuranne anhydre-et on ajoute goutte à goutte, à -50 , 44 ml d'une solution 1,6;M de n-butyllithium silyloxy-4-pentyne-2-ene in anhydrous tetrahydrofuran-and dropwise at -50, 44 ml of a 1.6 M solution of n-butyllithium
dans de l'hexane puis, à -70 , 4 ml d'acétal- in hexane and then at -70.4 ml of acetal-
déhyde On retire le bain réfrigérant et on conti- dehyde The cooling bath is removed and
nue d'agiter pendant la nuit à la température ambiante On verse ensuite le mélange dans de la glace, on l'extrait à l'éther et on effectue le traitement ultérieur habituel Le produit brut huileux ainsi obtenu est chromatographié sur gel de silice en utilisant, comme éluant, un mélange 95/5 de toluène et d'acétate d'éthyle On obtient The mixture is then poured overnight at room temperature. The mixture is then poured into ice, extracted with ether and the usual after-treatment is carried out. The oily crude product thus obtained is chromatographed on silica gel using as eluent, a 95/5 mixture of toluene and ethyl acetate is obtained
ainsi le l-tert -butyldiméthylsilyloxy-6-hydroxy- thus 1-tert-butyldimethylsilyloxy-6-hydroxy-
hept-2-ène-4-yne sous forme d'une huile incolore. hept-2-ene-4-yne as a colorless oil.
Spectre RMN: 6,2 (dt, J = 16 et 2 x 3,5 Hz, 1 H); ,75 (dm, J = 16 Hz, 1 H) ; 4,5-4,8 (m, 1 H); 4,2 (dd, J = 3,54; 2 Hz, 2 H); 1,8 (d, J= 5,5 Hz,OH); NMR spectrum: 6.2 (dt, J = 16 and 2 x 3.5 Hz, 1H); , 75 (dm, J = 16 Hz, 1H); 4.5 - 4.8 (m, 1H); 4.2 (dd, J = 3.54, 2 Hz, 2H); 1.8 (d, J = 5.5 Hz, OH);
1,45 (d, J = 7 Hz, 3 H); 0,9 (s, 9 H); 0,05 (s 6 H). 1.45 (d, J = 7 Hz, 3H); 0.9 (s, 9H); 0.05 (s 6H).
c) I:tert -butyldiméthylsilyloxyhept-2-ène-4-yne- c) I: tert-butyldimethylsilyloxyhept-2-ene-4-yne
6-one On agite pendant la nuit à la température 6-one Shake overnight at room temperature
ambiante, un mélange de 6 g de l-tert -butyl- ambient, a mixture of 6 g of 1-tert-butyl-
diméthylsilyloxy-6-hydroxyhept-2-êne-4-yne et de 21 9 de Mn O 2 dans du dichlorométhane, puis on filtre le mélange et on le concentre Le produit ainsi obtenu sous forme d'une huile est utilisé dimethylsilyloxy-6-hydroxyhept-2-ene-4-yne and 21% MnO 2 in dichloromethane, then the mixture is filtered and concentrated. The product thus obtained in the form of an oil is used.
directement pour l'étape suivante.directly for the next step.
Spectre IR: 1665 cm 1 (C= 0),2180 cm 1 (C-C) Spectre NMR: 6,6 (dt,J = 16 et 2 x 3,5 Hz, 1 H); ,95 (dt, J = 16 et 2 x 2 Hz, 1 H); 4,3 (dd, J = 3,5 et 2 Hz, 2 H); IR spectrum: 1665 cm 1 (C = O), 2180 cm 1 (C-C) NMR spectrum: 6.6 (dt, J = 16 and 2 x 3.5 Hz, 1H); , 95 (dt, J = 16 and 2 x 2 Hz, 1H); 4.3 (dd, J = 3.5 and 2 Hz, 2H);
2,4 (s, 3 H)' 0,95 (s, 9 H); 0,1 (s,6 H). 2.4 (s, 3H); 0.95 (s, 9H); 0.1 (s, 6H).
d) l-tert:butyldiméthylsilyl 2 xy:7,7-difluoro-6- d) l-tert: butyldimethylsilyl 2 xy: 7,7-difluoro-6-
Methy 1 hejta-2,6-diêne-4-yneMethy 1 hejta-2,6-diene-4-yne
A une solution de 1 g de l-tert -butyl-diméthyl- To a solution of 1 g of 1-tert-butyl-dimethyl
silyloxyhept-2-éne-4-yne-6-one et de 0,77 ml de dibromofluorométhane dans'du diméthylacétamide anhydre, on ajoute goutte à goutte à O une solution de 1,52 ml de tris(diméthylamino)phosphine dans du diméthylacétamide On continue d'agiter pendant 1 heure et demie à la température ambiante et on ajoute 0,55 g de poudre de zinc On agite le mélange pendant 1 heure à 100 , on le filtre, on le verse dans de la glace et on l'extrait avec de l'hexane On lave la phase organique avec une solution aqueuse saturée de chlorure de sodium, on la sèche et on la concentre Le résidu est chromatographié sur gel de silice en utilisant, comme éluant, un mélange 100:5 d'hexane et d'acétate d'éthyle On obtient ainsi le composé du titre silyloxyhept-2-en-4-yn-6-one and 0.77 ml of dibromofluoromethane in anhydrous dimethylacetamide, a solution of 1.52 ml of tris (dimethylamino) phosphine in dimethylacetamide is added dropwise at 0.degree. Stirring is continued for 1.5 hours at room temperature and 0.55 g of zinc powder is added. The mixture is stirred at 100 for 1 hour, filtered, poured into ice and dried. Extracted with hexane The organic phase is washed with saturated aqueous sodium chloride solution, dried and concentrated. The residue is chromatographed on silica gel using a 100: 5 hexane mixture as eluent. and ethyl acetate The title compound is thus obtained
sous forme d'une huile incolore.in the form of a colorless oil.
Spectre IR: 1720 cm 1 Spectre RMN: 6,22 (dt, J = 16 et 3,5 Hz, 1 H); 5,85 (dm, J = 16 Hz, 1 H); 4,24 (dd, J = 3,5 et 2 Hz, 2 H); 1,73 (t, J =- 3 Hz, IR spectrum: 1720 cm -1 NMR spectrum: 6.22 (dt, J = 16 and 3.5 Hz, 1H); 5.85 (dm, J = 16Hz, 1H); 4.24 (dd, J = 3.5 and 2 Hz, 2H); 1.73 (t, J = -3 Hz,
3 H); 0,9 (s, 9 H); 0,06 (s, 6 H).3H); 0.9 (s, 9H); 0.06 (s, 6H).
e) 1-bromo-7,7-difluoro-6-méthylhelta-2,6-diène-4-:yne e) 1-bromo-7,7-difluoro-6-methylhelta-2,6-diene-4-: yne
On dissout 3 g de l-tert -butyldiméthylsilyl- 3 g of 1-tert-butyldimethylsilyl are dissolved
oxy-7,7-difluoro-6-méthylhepta-2,6-di ne-4-yne dans du tétrahydrofuranne et on ajoute à O oxy-7,7-difluoro-6-methylhepta-2,6-di-4-yne in tetrahydrofuran and added to O
16,5 ml d'une solution 1 M de fluorure de tétra- 16.5 ml of a 1 M solution of tetrahydrofluoride
butylammonium dans du tétrahydrofuranne Apres butylammonium in tetrahydrofuran After
unedemi-heure, la réaction est terminée (chroma- one half hour, the reaction is over (chromatic
tographie en couche mince: toluène comme éluant, thin layer graph: toluene as eluent,
Rf = 0,1 comparé au Rf = 0,9 du produit de départ). Rf = 0.1 compared to Rf = 0.9 of the starting material).
On verse le mélange dans de la glace et on extrait à plusieurs reprises avec de l'éther On lave la phase organique avec une solution aqueuse saturée de chlorure de sodium, on la sèche et on The mixture is poured into ice and extracted several times with ether. The organic phase is washed with saturated aqueous sodium chloride solution and dried.
la concentre On dissout le 7,7-difluoro-6-méthyl- the concentrate is dissolved 7,7-difluoro-6-methyl-
hepta-2,6-diène-4-yne-l-ol ainsi obtenu dans de l'éther et on ajoute goutte à goutte à O une hepta-2,6-diene-4-yn-1-ol thus obtained in ether and added dropwise to O
solution de 0,5 ml de tribromure de phosphore dans l'éther. 0.5 ml solution of phosphorus tribromide in ether.
La réaction est terminée après une demi-heure (chromatographie en couche mince: toluène comme éluant, Rf = 0,9 comparé au Rf = 0,1 du produit de départ) On verse le mélange dans de la glace, on isole la phase éthérée, on la lave et on la The reaction is complete after half an hour (thin-layer chromatography: toluene as eluent, Rf = 0.9 compared to Rf = 0.1 of the starting material). The mixture is poured into ice, the ethereal phase is isolated. we wash it and we
sèche La solution éthérée de l-bromo-7,7-difluoro- The ethereal solution of 1-bromo-7,7-difluoro-
6-méthylhepta-2,6-diène-4-yne ainsi obtenueest 6-methylhepta-2,6-dien-4-yne thus obtained is
utilisée directement pour l'alkylation ultérieure. used directly for subsequent alkylation.
C) 3-méthylthio-l-butyne A 15 g de 3-méthylthio-1 l-propyne dans du tétrahydrofuranne anhydre, on ajoute goutte à goutte à -40 113 ml d'une solution 1,6 M 1 de n-butyllithium C) 3-methylthio-1-butyne To 15 g of 3-methylthio-1-propyn in anhydrous tetrahydrofuran was added dropwise to -40 113 ml of a 1.6 M 1 solution of n-butyllithium
dans de l'hexane puis,à -70 ,23,3 ml de triméthyl- in hexane and then at -70.23 ml of trimethyl-
chlorosilane On retire le bain réfrigérant, on chauffe le mélange réactionnel à la température ambiante et on le verse sur de la glace On extrait Chlorosilane The cooling bath is removed, the reaction mixture is heated to room temperature and poured onto ice.
le mélange avec de l'éther, on sèche la phase orga- the mixture with ether, the organic phase is dried
nique et on la concentre Le 3-méthylthio-1- and concentrates it 3-methylthio-1-
trimêthylsilyl-l-propyne brut ainsi obtenu est dissous; dans du tétrahydrofuranne anhydre; on le fait réagir à -70 avec 80 ml d'une solution 1,6 M de n-butyllithium dans de l'hexane et on ajoute goutte à goutte 8,7 ml d'iodure de méthyle On retire le bain réfrigérant et une heure plus tard on verse 16 le mélange sur de la glace On extrait le mélange Trimethylsilyl-1-propyn crude thus obtained is dissolved; in anhydrous tetrahydrofuran; It is reacted at -70 with 80 ml of a 1.6 M solution of n-butyllithium in hexane and 8.7 ml of methyl iodide are added dropwise. The cooling bath is removed and dried for one hour. later, the mixture is poured onto ice. The mixture is extracted
à l'éther, on lave la phase organique avec une solu- with ether, the organic phase is washed with a solution of
tion aqueuse de bicarbonate de sodium, on la sèche et on la concentre Par distillation à 70 sous aqueous solution of sodium bicarbonate, dried and concentrated by distillation at 70 ° C.
9 m bar dans un tube à boules, on obtient le 3-méthyl- 9 m bar in a bulb tube, 3-methyl-
thio-l-triméthylsilyl-l-butyne sous forme d'une huile On agite cette huile pendant 45 minutes à la température ambiante dans une solution de 3, 3 g d'hydroxyde de sodium dans du méthanol et on répartit ensuite entre du pentane et une solution saturée de chlorure de sodium On lave la phase organique, Thio-1-trimethylsilyl-1-butyne in the form of an oil This oil is stirred for 45 minutes at room temperature in a solution of 3.3 g of sodium hydroxide in methanol and then partitioned between pentane and a saturated solution of sodium chloride The organic phase is washed,
on la sèche et on élimine le pentane par distilla- it is dried and the pentane is distilled off
tion sur colonne à la pression normale Par distilla- column pressure at normal pressure By distillation
tion à 98-102 , on obtient le composé du titre at 98-102, we obtain the title compound
sous forme d'une huile incolore.in the form of a colorless oil.
D) N-( 7-benzolblthiénylméthyl)méthylamine a) 7bromométhylbenzolblthiophène On chauffe pendant 6 heures au reflux 7 g D) N- (7-benzolblthienylmethyl) methylamine a) 7-bromomethylbenzolblthiophene 7 g of refluxing are heated for 6 hours
de 7-méthylbenzolblthiophène avec 8,5 g de N- of 7-methylbenzolblthiophene with 8.5 g of N-
bromosuccinimide et une pointe de spatule d'a,a'- bromosuccinimide and a spatula tip of a, a'-
azoisobutyronitrile dans 50 ml de tétrachlorure de carbone On refroidit ensuite le mélange, azoisobutyronitrile in 50 ml of carbon tetrachloride The mixture is then cooled,
on le filtre et on le concentre Le 7-bromométhyl- filtered and concentrated 7-bromomethyl-
benzolblthiophène brut ainsi obtenu peut être utilisé directement dans l'étape suivante. b) N:7 benzolblthiénylméthyl),néthylamine On dissout le 7-bromométhylbenzo Eblthiophène dans du dichlorométhane, on ajoute la solution sous agitation à 40 ml d'une solution éthanolique à 33 % de méthylamine et on laisse reposer pendant la nuit On concentre le mélange, on reprend le résidu dans du dichlorométhane et on extrait avec de l'acide chlorhydrique 2 N On alcalinise fortement la phase aqueuse avec de l'hydroxyde The crude benzolblthiophene thus obtained can be used directly in the next step. b) N: 7 benzolblthienylmethyl), ethylamine 7-bromomethylbenzo [b] thiophene is dissolved in dichloromethane, the stirring solution is added to 40 ml of a 33% ethanol solution of methylamine and allowed to stand overnight The mixture is concentrated The residue is taken up in dichloromethane and extracted with 2N hydrochloric acid. The aqueous phase is made alkaline with hydroxide.
de sodium et on agite avec du dichlorométhane. of sodium and stirred with dichloromethane.
On sèche la phase organique sur carbonate de potassium, on la concentre et on distille sous vide le résidu,ce qui donne le composé du titre sous forme d'une huile bouillant à 1030 sous The organic phase is dried over potassium carbonate, concentrated and the residue is distilled off in vacuo to give the title compound as a boiling oil at 1030 ° C.
1,3 m bar.1.3 m bar.
E) N-( 3-chloro-7-benzolblthiénylméthyl)méthylamine a) 2,3-dichloro-7méthylbenzoblthiioehène On dissout 20 g de 7-méthylbenzolblthiopène dans du tétrachlorure de carbone et on sature a la température ambiante avec du chlore Apres E) N- (3-chloro-7-benzol-1-thienylmethyl) methylamine a) 2,3-dichloro-7-methylbenzo-1-thiothene 20 g of 7-methylbenzolblthiopene are dissolved in carbon tetrachloride and saturated at room temperature with chlorine After
2 heures, on élimine l'excès de chlore, on concen- 2 hours, the excess chlorine is removed,
tre le melange et on reprend le résidu dans du dichlorométhane On lave la phase organique avec une solution aqueuse saturée de bicarbonate The mixture is washed and the residue is taken up in dichloromethane. The organic phase is washed with a saturated aqueous solution of bicarbonate.
de sodium, on la sèche et on la concentre. of sodium, dried and concentrated.
Apres recristallisation dans le méthanol, on obtient le composé du titre sous forme de cristaux After recrystallization from methanol, the title compound is obtained in the form of crystals
incolores fondant à 45-47 .colorless melting at 45-47.
b) 3:chllro 7 Zméthylbenzolblthioehène b) 3: chllro 7 Zmethylbenzolblthioehene
On dissout 10 g de 2,3-dichloro-7-méthyl- 10 g of 2,3-dichloro-7-methyl-
benzo Eblthiophène dans 200 ml d'éther et on benzoethiophene in 200 ml of ether and
ajoute goutte à goutte à O 28,8 ml d'une solu- added dropwise to 28.8 ml of a solution
tion 1,6 M de n-butyllithium dans de l'hexane. Apres environ 1 heure, on verse le mélange dans une solution aqueuse diluée d'acide chlorhydrique, on sépare la phase organique, on la lave, on la sèche et on la concentre Par distillation sous vide, on obtient le composé du titre à l'état pur, sous forme d'une huile E = 60-62 / 1.6 M n-butyllithium in hexane. After about 1 hour, the mixture is poured into a dilute aqueous solution of hydrochloric acid, the organic phase is separated off, washed, dried and concentrated by distillation in vacuo to give the title compound of the title compound. pure state, in the form of an oil E = 60-62 /
0,13 m bar.0.13 m bar.
c) N-:3:chloro-7-benzo Eblthiénylméthyl 2 méthylamine Le produit est obtenu en procédant de manière analogue à celle décrite sous D) E = 130132 /1,3 m bar (le chlorhydrate fond c) N-: 3: chloro-7-benzo-E-thienylmethyl-2-methylamine The product is obtained by proceeding in a manner analogous to that described under D) E = 130132 / 1.3 m bar (the hydrochloride
à 250-255 ).at 250-255).
Spectre RMN: 7,78 (dd, J = 7 et 2,5 Hz, 1 H); 7,25-7,55 (m, 3 H); 4,05 (s, 2 H); NMR spectrum: 7.78 (dd, J = 7 and 2.5 Hz, 1H); 7.25-7.55 (m, 3H); 4.05 (s, 2H);
2,45 (s, 3 H); 184 (s, NH).2.45 (s, 3H); 184 (s, NH).
F) 3,3,-dii éthyl-5-méthoxy-l-pentyne a) 3,:3:iméthy 11-:2:tyne-5-ol On dissout 6 g de 3,3-diméthyl-l-pentyne-5-al F) 3,3, -diiethyl-5-methoxy-1-pentyne a) 3, 3: imethyldi-2-tyne-5-ol 6 g of 3,3-dimethyl-1-pentyne- 5-al
dans de l'éthanol et on fait réagir sous agita- in ethanol and reacted under stirring.
tion avec 1,3 g de borohydrure de sodium Apres avoir agité pendant encore 2 heures, on distille le solvant et on répartit le résidu entre de l'éther With 1.3 g of sodium borohydride After stirring for a further 2 hours, the solvent is distilled off and the residue is partitioned between ether.
et une solution aqueuse de chlorure de sodium. and an aqueous solution of sodium chloride.
On sèche la phase organique et on la concentre sous pression normale Apres distillation dans dans un tube à boules, on obtient le composé du titre sous forme d'une huile incolore b) 3,3-diméthyl-5-méthoxy-l-pentyne A une suspension de 3,5 g de Na H (à 80 %) dans du tétrahydrofuranne, on ajoute goutte à goutte à O 7 g de 3,3-diméthyl-l-pentyne-5-ol et, après 30 minutes d'agitation, on ajoute lentement Il ml de sulfate de diméthyle On retire le bain réfrigérant et on continue d'agiter à la tempéra- ture ambiante pendant 3 heures On détruit l'excès de Na H avec de l'acide acétique glacial et on évapore le solvant sous pression normale On répartit le résidu entre de l'eau et de l'hexane, on lave la phase organique, on la sèche et on The organic phase is dried and concentrated under normal pressure. After distillation in a Kugelrohr tube, the title compound is obtained in the form of a colorless oil. B) 3,3-Dimethyl-5-methoxy-1-pentyne A A suspension of 3.5 g of NaH (80%) in tetrahydrofuran is added dropwise to O 7 g of 3,3-dimethyl-1-pentyne-5-ol and after 30 minutes of stirring. Dimethyl sulfate is slowly added. The cooling bath is removed and stirring is continued at room temperature for 3 hours. The excess NaH is destroyed with glacial acetic acid and the solvent is evaporated off. under normal pressure The residue is partitioned between water and hexane, the organic phase is washed, dried and
la concentre sous pression normale Par distilla- Concentrate under normal pressure
tion-à 113-115 dans un tube à boules,on obtient tion-to 113-115 in a tube to balls, we get
le composé du titre sous forme d'une huile inco- the title compound as an inconsistent oil
lore. G) l-bromo-6,6-diméthylthiohex-2-ène-4-yne a) l-tert butyldiehhénylsil loxyent-2-êne-4-yne On procède comme décrit sous Ba) On obtient ainsi lore. G) 1-Bromo-6,6-dimethylthiohex-2-ene-4-yne a) 1-tert butyldiethyl-phenyloxy-2-ene-4-yne The procedure is as described under (B).
le composé du titre sous forme d'une huile. the title compound as an oil.
Spectre RMN: 7,3-7,8 (m, 1 H); 6,34 (dt, J = 16 et 2 x 4 Hz, 1 H); 5,9 (dm, J = 16 Hz, 1 H); NMR spectrum: 7.3-7.8 (m, 1H); 6.34 (dt, J = 16 and 2x4 Hz, 1H); 5.9 (dm, J = 16Hz, 1H);
4,24 (m, 2 H); 2,9 (m, 1 H); 1,04 (s, 9 H). 4.24 (m, 2H); 2.9 (m, 1H); 1.04 (s, 9H).
b) l-tert -buttldihhénylsilyloxy-6-hydroxyhex-2-êne- b) 1-tert-butyl-diphenylsilyloxy-6-hydroxyhex-2-ene
4-yne On procède comme décrit sous Bb) On obtient 4-yne We proceed as described under Bb) We get
ainsi le composé du titre sous forme d'une huile. thus the title compound as an oil.
Spectre RMN: 7,3-7,8 (m, 10 H); 6,24 (dt,J= 16 et 2 x 4 Hz, 1 H); 5,9 (dm, J = 16 Hz, 1 H); 4,4 (dbr, 2 H); 4,25 (m, 2 H); 1,7 NMR spectrum: 7.3-7.8 (m, 10H); 6.24 (dt, J = 16 and 2x4 Hz, 1H); 5.9 (dm, J = 16Hz, 1H); 4.4 (dbr, 2H); 4.25 (m, 2H); 1.7
(t, J = 7 Hz, 1 H); 1,04 (s, 9 H).(t, J = 7 Hz, 1H); 1.04 (s, 9H).
c) 1-tert -butyldiphénylsilyloxyhex-2-éne-4-yne-6-al On procède comme décrit sous Bc) On obtient le composé du titre sous forme de cristaux fondant c) 1-tert-butyldiphenylsilyloxyhex-2-en-4-yne-6-al The procedure is carried out as described under Bc). The title compound is obtained in the form of melting crystals.
à 51-59 .at 51-59.
spectre RMN: 9,35 (d, J = 1,5 Hz, 1 H); 7,3-7,8 (m, 10 Hz); 6,62 (dt, J = 16 et 2 x 4 Hz, 1 H); 6,18 (dm, J = 16 Hz, NMR spectrum: 9.35 (d, J = 1.5 Hz, 1H); 7.3-7.8 (m, 10 Hz); 6.62 (dt, J = 16 and 2x4 Hz, 1H); 6.18 (dm, J = 16 Hz,
1 H); 4,34 (m, 2 H); 1,06 (s, 9 H).1H); 4.34 (m, 2H); 1.06 (s, 9H).
d) 1-tert -butyldiehénylsilyloxy-6,6-diméthylthio- hex-2-ène-4 ne d) 1-tert-butyldienylsilyloxy-6,6-dimethylthio-hex-2-ene-4
A un mélange de 2 g de 1-tert -butyldiphényl- To a mixture of 2 g of 1-tert-butyldiphenyl-
silyloxy-2-ène-4-yne-6-al et de 170 mg de Zn I 2 dans de l'éther anhydre, on ajoute goutte à goutte 2,4 ml silyloxy-2-en-4-yne-6-al and 170 mg of Zn I 2 in anhydrous ether, 2.4 ml is added dropwise.
de S(triméthylsilyl)méthanethiol et on agite le mé- of S (trimethylsilyl) methanethiol and the mixture is stirred
lange pendant la nuit à la température ambiante On verse ensuite le mélange dans de l'eau, on lave la overnight at room temperature The mixture is then poured into water, washed with
phase étherée, on la sèche et on l'évapore Le pro- ether phase, dried and evaporated.
duit brut huileux ainsi obtenu est utilisé directe- oily crude oil thus obtained is used directly
ment dans l'étape suivante.in the next step.
Spectre RMN: 7,3-7,8 (m, l OH); 6,26 (dt, J = 16 et 2 x 4 Hz, 1 H); 5,98 (dm, J = 16 Hz, 1 H); 4,66 (m, 1 H); 4,24 (m, 2 H); NMR spectrum: 7.3-7.8 (m, 1H); 6.26 (dt, J = 16 and 2x4 Hz, 1H); 5.98 (dm, J = 16Hz, 1H); 4.66 (m, 1H); 4.24 (m, 2H);
2,26 (s, 6 H); 1,06 (s, 9 H).2.26 (s, 6H); 1.06 (s, 9H).
e) 1:bromo-6,6-diméthyl thiohex-2-êne-4-yne On procède comme décrit sous Be) On obtient e) 1: bromo-6,6-dimethylthiohex-2-ene-4-yne The procedure is as described under Be)
ainsi le composé du titre sous forme d'une huile. thus the title compound as an oil.
Spectre RMN: 6,35 (dt, J = 16 et 2 x 5 Hz, 1 H); ,84 (ddd, J = 16,5 et 2 Hz, 1 H); 4,67 (d, J = 2 Hz, 1 H); 4,24 (dd, J = 5 et 2 Hz, 2 H); 2,24 (s, 6 H); NMR spectrum: 6.35 (dt, J = 16 and 2 x 5 Hz, 1H); 84 (ddd, J = 16.5 and 2 Hz, 1H); 4.67 (d, J = 2 Hz, 1H); 4.24 (dd, J = 5 and 2 Hz, 2H); 2.24 (s, 6H);
1,82 (s, 1 H).1.82 (s, 1H).
H) 1-bromo-6,6-diméthylthiohept-2-ène-4-yne a) 1 trmts 1 btnei 3:o On procède comme décrit sous Bb) On obtient ainsi le composé du titre sous forme d'une huile H) 1-bromo-6,6-dimethylthiohept-2-en-4-yne a) 1 trmts 1 btnei 3: The procedure is carried out as described under Bb). The title compound is thus obtained in the form of an oil.
bouillant à 100-101 sous 85 m bar. boiling at 100-101 under 85 m bar.
b) I:Iriméthelsilyl-l-u:tyne-1-oneb) I: Irimethylsilyl-1-u: tyne-1-one
On procède comme décrit sous Bc) On ob- We proceed as described under Bc) We ob-
tient le composé du titre sous forme d'une huile. holds the title compound as an oil.
Spectre RMN: 2,24 (s, 3 H); 0,23 (s, 9 H). NMR spectrum: 2.24 (s, 3H); 0.23 (s, 9H).
c) 1:triméth lsilyl:3,3:diméth 1 lthio-i -but'y c) 1: trimethylsilyl: 3,3: dimethylthio-i-buty
On procède comme décrit sous Gd) On ob- We proceed as described under Gd) We ob-
tient le composé du titre sous forme d'une huile. holds the title compound as an oil.
Spectre RMN: 2,3 (s, 6 H); 1,9 (s, 3 H); 0,3 (s, 9 H). NMR spectrum: 2.3 (s, 6H); 1.9 (s, 3H); 0.3 (s, 9H).
d) 3,3-diméthlthioo-i-butlned) 3,3-dimethylthio-i-butyl
On agite pendant 1/2 heure à O 1 g de 1- Stirring is carried out for 1/2 hour at 0 g of
triméthylsilyl-3,3-diméthylthio-1-butyne dans trimethylsilyl-3,3-dimethylthio-1-butyne in
une solution de 180 mgde Na OH dans du méthanol. a solution of 180 mg of NaOH in methanol.
Après addition d'une solution aqueuse saturée After addition of a saturated aqueous solution
de chlorure de sodium, on extrait avec du pen- sodium chloride, extracted with
tane, on sèche la phase organique sur sulfate tane, the organic phase is dried over sulfate
de sodium et on élimine avec précaution le sol- sodium and carefully remove the soil
vant par distillation sur une colonne Vigreux. by distillation on a Vigreux column.
Le produit brut huileux ainsi obtenu est utilisé The oily crude product thus obtained is used
directement dans l'étape suivante.directly in the next step.
Spectre RMN: 2,65 (s, 1 H); 2,2 (s, 6 H); NMR spectrum: 2.65 (s, 1H); 2.2 (s, 6H);
1,8 (s, 3 H).1.8 (s, 3H).
e) 6,6-diméthylthioheet-l-ène-4-yne-3-ol e) 6,6-dimethylthiohe-1-en-4-yn-3-ol
On procède de manière analogue à celle décri- The procedure is analogous to that described
te sous Aa) On obtient le composé du titre under Aa) We get the title compound
sous forme d'une huile.in the form of an oil.
Spectre RMN: 5,7-6,0 (m 1 H); 4,9-5,6 (m, 3 H); NMR spectrum: 5.7-6.0 (m H); 4.9-5.6 (m, 3H);
2,2 (s, 6 H); 1,9 (s, 3 H); 1,5 (O-H). 2.2 (s, 6H); 1.9 (s, 3H); 1.5 (O-H).
f) 1:bromo-6,6-diméth Xlthioheet-2-ène-4-:ne f) 1: bromo-6,6-dimethylthioheet-2-ene-4-: ne
On procède comme décrit sous Ab).We proceed as described under Ab).
1) 1-bromo-8-chloroct-2-êne-4-yne a) _ -bu _i_ ___ St 1) 1-bromo-8-chloroct-2-ene-4-yne a) _bu_i_ ___ St
On procède comme décrit sous Ba) On ob- We proceed as described under Ba) We ob-
tient le composé du titre sous forme d'une huile. holds the title compound as an oil.
Spectre RMN: 5,76-6,1 (m, 1 H); 5,06-5,55 (mn, 2 H); 4,8-5,0 (m, 1 H); 2, 48 (d, J = 2 Hz, 1 H); 0,9 (s, 9 H); 0,1 (s, 6 H). NMR spectrum: 5.76-6.1 (m, 1H); 5.06-5.55 (min, 2H); 4.8-5.0 (m, 1H); 2.48 (d, J = 2 Hz, 1H); 0.9 (s, 9H); 0.1 (s, 6H).
b) 3:tert -:butldimé tylsil 12 oy-: :-h-loroct-1-ène- b) 3: tert -: butldimethylsil 12 oy-:: -h-loroct-1-ene
4 ne4 do not
On dissout 2 g de 3-tert -butyldiméthylsilylo- 2 g of 3-tert-butyldimethylsilylol are dissolved
xypent-l-ène-4-yredans un mélange 10:1 de tétra- xypent-1-ene-4-yr in a 10: 1 mixture of tetra-
hydrofuranne et d'hexaméthyl-phosphotriamide et hydrofuran and hexamethyl-phosphotriamide and
on ajoute goutte à goutte à -30 6,2 ml d'une so- 6.2 ml of a solution is added dropwise to
lution 1,6 M de n-butyllithium dans de l'hexane. 1.6 M n-butyllithium in hexane.
On ajoute ensuite 0,98 ml de 1-bromo-3-chloropro- 0.98 ml of 1-bromo-3-chloropropyl is then added.
pane et on agite le mélange réactionnel pendant la nuit à la température ambiante On verse ensuite le mélange dans une solution aqueuse de chlorure de sodium, on extrait avec du pentane, on sèche la The mixture is then stirred overnight at room temperature. The mixture is then poured into aqueous sodium chloride solution, extracted with pentane and dried.
phase organique et on la concentre On chromato- organic phase and concentrated on
graphie le résidu sur gel de silice (éluant: mé- the residue on silica gel (eluent:
lange 98/2 d'hexane et d'acétate d'éthyle) et on 98/2 hexane and ethyl acetate) and
isole le composé du titre sous forme d'une huile. isolates the title compound as an oil.
* Spectre RMN: 5,7-6,1 (m, 1 H); 4,8-5,5 (m, 3 H); 3,6 (t, J = 7 Hz, 2 H); 2,5 (t, 2 H);NMR spectrum: 5.7-6.1 (m, 1H); 4.8-5.5 (m, 3H); 3.6 (t, J = 7 Hz, 2H); 2.5 (t, 2H);
2,1 (m, 2 H); 0,9 (s, 9 H); 0,1 (s, 6 H). 2.1 (m, 2H); 0.9 (s, 9H); 0.1 (s, 6H).
c) :ct 12 roct-l-ene-4-yq 2:2:ol On procède comme décrit sous Be) On obtient c): ct 12 roct-l-ene-4-yq 2: 2: ol We proceed as described under Be) We obtain
le composé du titre sous forme d'un huile. the title compound as an oil.
Rf (éluant: mélange 4/1 de toluene et d'acetate Rf (eluent: 4/1 mixture of toluene and acetate
d'éthyle) = 0,35.of ethyl) = 0.35.
d) 1-brono-8-chloroct-2-êne-4-Yn d) 1-Brono-8-chloroct-2-ene-4-Yn
On procède comme décrit sous Ab).We proceed as described under Ab).
J) 1-bromo-8-chloro-6,6-diméthyvioct-2-ène-4-yne a) _ _ u _ _ _ J) 1-Bromo-8-chloro-6,6-dimethyl-2-en-4-yne a) _ _ u _ _ _
On dissout 3 g de 3,3-diméthylpent-1-yne- 3 g of 3,3-dimethylpent-1-yne are dissolved
-ol et 2,7 g de triéthylamine dans du dichlo- rométhane et on ajoute goutte à goutte à O ,1 g de chlorure de p-toluènesulfonyle On continue d'agiter pendant 3 heures à la tem- pérature ambiante et on verse le mélange dans de l'acide chlorhydrique aqueux 0,1 N refroidi par de la glace On lave la phase organique à neutralité, on la sèche et on la concentre Le and 2.7 g of triethylamine in dichloromethane are added dropwise to 0.1 g of p-toluenesulfonyl chloride. Stirring is continued for 3 hours at room temperature and the mixture is poured into the mixture. in ice-cold 0.1 N aqueous hydrochloric acid. The organic phase is washed neutral, dried and concentrated.
produit brut ainsi obtenu peut être utilisé di- The raw product thus obtained can be used
rectement dans l'étape suivante ou chromatogra- in the next step or chromatogra-
phié sur gel de silice (éluant: toluène). on silica gel (eluent: toluene).
Spectre RMN: 7,8-7,95 (m, 2 H); 7,25-7,5 (m, 2 H); 4,28 (t, J= 7 Hz, 2 H); 2,45 (s,3 H); 2,06 (s,l H); NMR spectrum: 7.8-7.95 (m, 2H); 7.25-7.5 (m, 2H); 4.28 (t, J = 7 Hz, 2H); 2.45 (s, 3H); 2.06 (s, 1H);
1,8 (t, J = 7 Hz, 2 H); 1,2 (s, 6 H). 1.8 (t, J = 7 Hz, 2H); 1.2 (s, 6H).
b) 5-chloro-3,3-dimethylet:-l:neb) 5-chloro-3,3-dimethylet: -1
A l'abri de l'humidité, on agite à 50 pen- In the absence of moisture, stirring at 50
dant la nuit 2 g de 3,3-diméthyl-5-(p-toluènesul- at night 2 g of 3,3-dimethyl-5- (p-toluenesulphon)
fonyloxy)pent-l-yne avec 1 g de Li Cl dans du di- fonyloxy) pent-1-yne with 1 g of LiCl in di-
méthylformamide On distille le mélange réaction- methylformamide The reaction mixture is distilled
nel; le produit obtenu entre 115 et 130 est uti- nel; the product obtained between 115 and 130 is used
lisé directement dans l'étape suivante. directly in the next step.
Spectre RMN: 3,55-3,8 (m, 2 H);; 2,1 (s, 1 H); NMR spectrum: 3.55-3.8 (m, 2H); 2.1 (s, 1H);
1,8 -2,0 (m, 2 H);; 1,2 (s, 6 H).1.8 -2.0 (m, 2H); 1.2 (s, 6H).
c) 8-chloro-6,6-diméthyloct-1:-ène-4-yne-3-o 121 On procède comme décrit sous Aa) On obtient c) 8-chloro-6,6-dimethyloct-1: -ene-4-yn-3-o 121 The procedure is as described under Aa)
le composé du titre sous forme d'une huile. the title compound as an oil.
d) 1-bromo-8-chloro-6,6-diméthïl:ct-2-ène:4-:ne d) 1-bromo-8-chloro-6,6-dimethyl: α-2-ene: 4-:
On procède comme décrit sous Ab) Le compo- We proceed as described under Ab).
sé du titre est obtenu sous forme d'une huile. The title is obtained in the form of an oil.
K) l-bromo-6,6-diméthyl-8-fluorooct-2-ène-4-yne a) 3,3-diméth Xl:-5fluorent:ne K) 1-Bromo-6,6-dimethyl-8-fluorooct-2-ene-4-yl a) 3,3-dimethyl-5-fluorine: ne
On chauffe pendant la nuit au reflux un mé- During the night at reflux a mixture of
lange de 266 mg de 3,3-diméthyl-5-(p-toluène- 266 mg of 3,3-dimethyl-5- (p-toluene)
sulfonyloxy)pent-l-yne, de 5 ml de fluorure de tétrabutylammonium 1 N dans du tétrahydrofuranne sulfonyloxy) pent-1-yne, 5 ml of 1 N tetrabutylammonium fluoride in tetrahydrofuran
et de 2 ml d'acétonitrile On mélange la solu- and 2 ml of acetonitrile.
tion réactionnelle avec de l'eau et on extrait reaction with water and extracted
à plusieurs reprises avec de l'éther diéthyli- repeatedly with diethyl ether
que On lave la phase organique, on la sèche et that the organic phase is washed, dried and
on élimine le solvant par distillation sous pres- the solvent is distilled off under pressure.
sion normale Le produit brut ainsi obtenu est The gross product thus obtained is
utilisé directement dans l'étape suivante. used directly in the next step.
Spectre RMN: 4,70 (dt, J = 47 et 2 x 7 Hz, 2 H); 2,05 (s, 1 H); 1,8 (dt, J = 24 et NMR spectrum: 4.70 (dt, J = 47 and 2 x 7 Hz, 2H); 2.05 (s, 1H); 1.8 (dt, J = 24 and
2 x 7 Hz, 2 H); 1,2 (s, 6 H).2 x 7 Hz, 2H); 1.2 (s, 6H).
b) 6,6-dirnéthvl-8-fluorooct-1-ène-4-lyne-3-ol b) 6,6-dimethyl-8-fluorooct-1-ene-4-lyne-3-ol
On procède comme décrit sous Aa) On ob- We proceed as described under Aa) We ob-
tient le composé du titre sous forme d'une huile. holds the title compound as an oil.
c) 1:bromo-6,6-diméthyl-8-fluorooct-2-ène-4-yne c) 1: bromo-6,6-dimethyl-8-fluorooct-2-en-4-yne
On procède comme décrit sous Ab) On ob- We proceed as described under Ab) We ob-
tient le composé du titre sous forme d'un huile. holds the title compound as an oil.
Claims (10)
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CH285182 | 1982-05-07 |
Publications (2)
Publication Number | Publication Date |
---|---|
FR2526423A1 true FR2526423A1 (en) | 1983-11-10 |
FR2526423B1 FR2526423B1 (en) | 1987-07-10 |
Family
ID=4243003
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
FR8307400A Expired FR2526423B1 (en) | 1982-05-07 | 1983-05-02 | NOVEL UNSATURATED AMINES, THEIR PREPARATION AND THEIR USE AS MEDICINES |
Country Status (5)
Country | Link |
---|---|
JP (1) | JPS58208252A (en) |
DE (1) | DE3316093A1 (en) |
FR (1) | FR2526423B1 (en) |
GB (1) | GB2120663B (en) |
IT (1) | IT1197645B (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0251574A2 (en) * | 1986-06-25 | 1988-01-07 | E.R. Squibb & Sons, Inc. | Antifungal derivatives of N-(6,6-dimethyl-2-hepten-4-ynyl)-1-naphthalenemethanamine and method of using same |
EP0254677A1 (en) * | 1986-07-08 | 1988-01-27 | Sandoz Ag | Antimycotic 6-phenyl-2-hexen-4-ynamines |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
NZ227042A (en) | 1987-11-27 | 1991-05-28 | Banyu Pharma Co Ltd | Substituted alkylamine derivatives and pharmaceutical compositions |
JP3116364B2 (en) * | 1989-10-02 | 2000-12-11 | 萬有製薬株式会社 | Method for producing enyne derivatives |
GB0003360D0 (en) | 2000-02-14 | 2000-04-05 | Novartis Ag | Monoclonal antibodies |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0024587A1 (en) * | 1979-08-22 | 1981-03-11 | Sandoz Ag | Propenylamines, processes for their production, pharmaceutical compositions containing them and their use as pharmaceuticals |
GB2089348A (en) * | 1980-12-15 | 1982-06-23 | Sandoz Ltd | Benzopyran and benzothiapyran derivatives |
-
1983
- 1983-05-02 FR FR8307400A patent/FR2526423B1/en not_active Expired
- 1983-05-03 DE DE3316093A patent/DE3316093A1/en not_active Withdrawn
- 1983-05-04 GB GB08312160A patent/GB2120663B/en not_active Expired
- 1983-05-06 JP JP58080004A patent/JPS58208252A/en active Pending
- 1983-05-06 IT IT48233/83A patent/IT1197645B/en active
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0024587A1 (en) * | 1979-08-22 | 1981-03-11 | Sandoz Ag | Propenylamines, processes for their production, pharmaceutical compositions containing them and their use as pharmaceuticals |
GB2089348A (en) * | 1980-12-15 | 1982-06-23 | Sandoz Ltd | Benzopyran and benzothiapyran derivatives |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0251574A2 (en) * | 1986-06-25 | 1988-01-07 | E.R. Squibb & Sons, Inc. | Antifungal derivatives of N-(6,6-dimethyl-2-hepten-4-ynyl)-1-naphthalenemethanamine and method of using same |
EP0251574A3 (en) * | 1986-06-25 | 1989-01-04 | E.R. Squibb & Sons, Inc. | Antifungal derivatives of n-(6,6-dimethyl-2-hepten-4-ynyl)-1-naphthalenemethanamine and method of using same |
EP0254677A1 (en) * | 1986-07-08 | 1988-01-27 | Sandoz Ag | Antimycotic 6-phenyl-2-hexen-4-ynamines |
Also Published As
Publication number | Publication date |
---|---|
GB2120663A (en) | 1983-12-07 |
IT1197645B (en) | 1988-12-06 |
IT8348233A0 (en) | 1983-05-06 |
GB8312160D0 (en) | 1983-06-08 |
GB2120663B (en) | 1985-08-29 |
FR2526423B1 (en) | 1987-07-10 |
JPS58208252A (en) | 1983-12-03 |
DE3316093A1 (en) | 1983-11-10 |
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