EP1812386A1 - Process for alkyl aryl sulfide derivatives and new sulfide compounds - Google Patents
Process for alkyl aryl sulfide derivatives and new sulfide compoundsInfo
- Publication number
- EP1812386A1 EP1812386A1 EP05808625A EP05808625A EP1812386A1 EP 1812386 A1 EP1812386 A1 EP 1812386A1 EP 05808625 A EP05808625 A EP 05808625A EP 05808625 A EP05808625 A EP 05808625A EP 1812386 A1 EP1812386 A1 EP 1812386A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- group
- chemical formula
- mmol
- mhz
- nmr
- 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.)
- Withdrawn
Links
- -1 alkyl aryl sulfide derivatives Chemical class 0.000 title claims abstract description 54
- 238000000034 method Methods 0.000 title abstract description 83
- 150000003568 thioethers Chemical class 0.000 title description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 94
- 239000000126 substance Substances 0.000 claims abstract description 52
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims abstract description 31
- 239000011593 sulfur Substances 0.000 claims abstract description 16
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 16
- 125000001424 substituent group Chemical group 0.000 claims abstract description 14
- 229910052744 lithium Inorganic materials 0.000 claims abstract description 13
- 238000004519 manufacturing process Methods 0.000 claims abstract description 11
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 25
- 125000005843 halogen group Chemical group 0.000 claims description 23
- 239000002253 acid Substances 0.000 claims description 19
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 17
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- 125000003118 aryl group Chemical group 0.000 claims description 7
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 claims description 7
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 6
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 5
- 125000004705 ethylthio group Chemical group C(C)S* 0.000 claims description 5
- LNPNXWKVAFKIBX-UHFFFAOYSA-N hex-5-en-2-ol Chemical compound CC(O)CCC=C LNPNXWKVAFKIBX-UHFFFAOYSA-N 0.000 claims description 5
- WGOPGODQLGJZGL-UHFFFAOYSA-N lithium;butane Chemical compound [Li+].CC[CH-]C WGOPGODQLGJZGL-UHFFFAOYSA-N 0.000 claims description 5
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
- QRLABRQRPREVFF-UHFFFAOYSA-N (4-benzylsulfanylphenyl)methanol Chemical compound C1=CC(CO)=CC=C1SCC1=CC=CC=C1 QRLABRQRPREVFF-UHFFFAOYSA-N 0.000 claims description 3
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 3
- QBKWYERFEMZUES-UHFFFAOYSA-N 2-(cyclohexylmethylsulfanyl)-4-fluorophenol Chemical compound OC1=CC=C(F)C=C1SCC1CCCCC1 QBKWYERFEMZUES-UHFFFAOYSA-N 0.000 claims description 3
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 claims description 3
- FJCARKSRYNNDOY-UHFFFAOYSA-N 4-benzylsulfanyl-2-chlorophenol Chemical compound C1=C(Cl)C(O)=CC=C1SCC1=CC=CC=C1 FJCARKSRYNNDOY-UHFFFAOYSA-N 0.000 claims description 3
- ADOLAPWZCLMBGJ-UHFFFAOYSA-N 4-fluoro-2-(2-hydroxyhex-5-enylsulfanyl)phenol Chemical compound C=CCCC(O)CSC1=CC(F)=CC=C1O ADOLAPWZCLMBGJ-UHFFFAOYSA-N 0.000 claims description 3
- XGNMFQWGRPOOCI-UHFFFAOYSA-N 4-fluoro-2-(5-phenylpentylsulfanyl)phenol Chemical compound OC1=CC=C(F)C=C1SCCCCCC1=CC=CC=C1 XGNMFQWGRPOOCI-UHFFFAOYSA-N 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 125000005907 alkyl ester group Chemical group 0.000 claims description 3
- 150000004791 alkyl magnesium halides Chemical class 0.000 claims description 3
- 125000003277 amino group Chemical group 0.000 claims description 3
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 claims description 3
- 125000005265 dialkylamine group Chemical group 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 3
- NJDWJGHGDJMKLA-UHFFFAOYSA-N 1-benzylsulfanyl-2-(trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC=C1SCC1=CC=CC=C1 NJDWJGHGDJMKLA-UHFFFAOYSA-N 0.000 claims description 2
- TZFDIWVKNFJGDH-UHFFFAOYSA-N 1-benzylsulfanyl-2-methoxybenzene Chemical compound COC1=CC=CC=C1SCC1=CC=CC=C1 TZFDIWVKNFJGDH-UHFFFAOYSA-N 0.000 claims description 2
- YCGVEPZZZJBWDF-UHFFFAOYSA-N 2-(3-benzylsulfanylphenyl)ethanol Chemical compound OCCC1=CC=CC(SCC=2C=CC=CC=2)=C1 YCGVEPZZZJBWDF-UHFFFAOYSA-N 0.000 claims description 2
- VRYXAKDSWJEOJQ-UHFFFAOYSA-N 4-benzylsulfanyl-2-methylaniline Chemical compound C1=C(N)C(C)=CC(SCC=2C=CC=CC=2)=C1 VRYXAKDSWJEOJQ-UHFFFAOYSA-N 0.000 claims description 2
- JHHLRJMCWICPPM-UHFFFAOYSA-N 4-benzylsulfanyl-4-fluorocyclohexa-1,5-dien-1-ol Chemical compound C1=CC(O)=CCC1(F)SCC1=CC=CC=C1 JHHLRJMCWICPPM-UHFFFAOYSA-N 0.000 claims description 2
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 2
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 claims description 2
- VXWPONVCMVLXBW-UHFFFAOYSA-M magnesium;carbanide;iodide Chemical compound [CH3-].[Mg+2].[I-] VXWPONVCMVLXBW-UHFFFAOYSA-M 0.000 claims description 2
- FRIJBUGBVQZNTB-UHFFFAOYSA-M magnesium;ethane;bromide Chemical compound [Mg+2].[Br-].[CH2-]C FRIJBUGBVQZNTB-UHFFFAOYSA-M 0.000 claims description 2
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 claims description 2
- WSTKYJOCODCJIS-UHFFFAOYSA-N tert-butyl 2-(4-hydroxyphenyl)sulfanylacetate Chemical compound CC(C)(C)OC(=O)CSC1=CC=C(O)C=C1 WSTKYJOCODCJIS-UHFFFAOYSA-N 0.000 claims description 2
- UDPTYBFJUZDKNR-UHFFFAOYSA-N tert-butyl 2-[4-(2-aminoethyl)phenyl]sulfanylacetate Chemical compound CC(C)(C)OC(=O)CSC1=CC=C(CCN)C=C1 UDPTYBFJUZDKNR-UHFFFAOYSA-N 0.000 claims description 2
- 125000004496 thiazol-5-yl group Chemical group S1C=NC=C1* 0.000 claims description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims 2
- DBUWGNBHZQOVFD-UHFFFAOYSA-N (4-pent-2-ynylsulfanylphenyl)methanol Chemical compound CCC#CCSC1=CC=C(CO)C=C1 DBUWGNBHZQOVFD-UHFFFAOYSA-N 0.000 claims 1
- DBZUVZVJGQNQFQ-UHFFFAOYSA-N 1-[4-(hydroxymethyl)phenyl]sulfanylhex-5-en-2-ol Chemical compound OCC1=CC=C(SCC(O)CCC=C)C=C1 DBZUVZVJGQNQFQ-UHFFFAOYSA-N 0.000 claims 1
- GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 claims 1
- 150000003973 alkyl amines Chemical class 0.000 claims 1
- 239000000852 hydrogen donor Substances 0.000 claims 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims 1
- QKZIRQOJSZCNGO-UHFFFAOYSA-N tert-butyl 2-[4-(hydroxymethyl)phenyl]sulfanylacetate Chemical compound CC(C)(C)OC(=O)CSC1=CC=C(CO)C=C1 QKZIRQOJSZCNGO-UHFFFAOYSA-N 0.000 claims 1
- 238000000746 purification Methods 0.000 abstract description 53
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 11
- 230000035484 reaction time Effects 0.000 abstract description 5
- 239000007818 Grignard reagent Substances 0.000 abstract description 4
- 150000004795 grignard reagents Chemical class 0.000 abstract description 4
- 238000005580 one pot reaction Methods 0.000 abstract description 4
- 238000000926 separation method Methods 0.000 abstract description 3
- 238000002360 preparation method Methods 0.000 description 69
- 238000005160 1H NMR spectroscopy Methods 0.000 description 61
- 238000006243 chemical reaction Methods 0.000 description 58
- 239000000203 mixture Substances 0.000 description 53
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 50
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 48
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 42
- 235000013350 formula milk Nutrition 0.000 description 35
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 28
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 28
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 26
- 239000012074 organic phase Substances 0.000 description 26
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 25
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 24
- VADKRMSMGWJZCF-UHFFFAOYSA-N 2-bromophenol Chemical compound OC1=CC=CC=C1Br VADKRMSMGWJZCF-UHFFFAOYSA-N 0.000 description 23
- 239000002904 solvent Substances 0.000 description 23
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 22
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 18
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 18
- 238000003756 stirring Methods 0.000 description 16
- 239000011541 reaction mixture Substances 0.000 description 15
- 235000019270 ammonium chloride Nutrition 0.000 description 14
- 229940093499 ethyl acetate Drugs 0.000 description 14
- 235000019439 ethyl acetate Nutrition 0.000 description 14
- 238000001914 filtration Methods 0.000 description 14
- 239000012299 nitrogen atmosphere Substances 0.000 description 14
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 12
- 235000019341 magnesium sulphate Nutrition 0.000 description 12
- 238000010791 quenching Methods 0.000 description 12
- 238000010898 silica gel chromatography Methods 0.000 description 12
- IUYHWZFSGMZEOG-UHFFFAOYSA-M magnesium;propane;chloride Chemical compound [Mg+2].[Cl-].C[CH-]C IUYHWZFSGMZEOG-UHFFFAOYSA-M 0.000 description 10
- 239000011780 sodium chloride Substances 0.000 description 9
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical class [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 6
- 229960004132 diethyl ether Drugs 0.000 description 6
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 5
- 229910052740 iodine Inorganic materials 0.000 description 5
- VEDDBHYQWFOITD-UHFFFAOYSA-N para-bromobenzyl alcohol Chemical group OCC1=CC=C(Br)C=C1 VEDDBHYQWFOITD-UHFFFAOYSA-N 0.000 description 5
- MEYRABVEYCFHHB-UHFFFAOYSA-N 2-bromo-4-fluorophenol Chemical group OC1=CC=C(F)C=C1Br MEYRABVEYCFHHB-UHFFFAOYSA-N 0.000 description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 4
- 229910052801 chlorine Inorganic materials 0.000 description 4
- 125000001309 chloro group Chemical group Cl* 0.000 description 4
- 229910052751 metal Inorganic materials 0.000 description 4
- 239000002184 metal Substances 0.000 description 4
- 238000006467 substitution reaction Methods 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- RWXUNIMBRXGNEP-UHFFFAOYSA-N 1-bromo-2-(trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC=C1Br RWXUNIMBRXGNEP-UHFFFAOYSA-N 0.000 description 3
- UBPDKIDWEADHPP-UHFFFAOYSA-N 2-iodoaniline Chemical group NC1=CC=CC=C1I UBPDKIDWEADHPP-UHFFFAOYSA-N 0.000 description 3
- GZFGOTFRPZRKDS-UHFFFAOYSA-N 4-bromophenol Chemical group OC1=CC=C(Br)C=C1 GZFGOTFRPZRKDS-UHFFFAOYSA-N 0.000 description 3
- VLVCDUSVTXIWGW-UHFFFAOYSA-N 4-iodoaniline Chemical group NC1=CC=C(I)C=C1 VLVCDUSVTXIWGW-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000010949 copper Substances 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- LIGACIXOYTUXAW-UHFFFAOYSA-N phenacyl bromide Chemical group BrCC(=O)C1=CC=CC=C1 LIGACIXOYTUXAW-UHFFFAOYSA-N 0.000 description 3
- BNWCETAHAJSBFG-UHFFFAOYSA-N tert-butyl 2-bromoacetate Chemical compound CC(C)(C)OC(=O)CBr BNWCETAHAJSBFG-UHFFFAOYSA-N 0.000 description 3
- 229940124597 therapeutic agent Drugs 0.000 description 3
- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical compound SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 description 3
- GJNKKSZJGJWUST-UHFFFAOYSA-N 2-(4-benzylsulfanylphenyl)ethanol Chemical compound C1=CC(CCO)=CC=C1SCC1=CC=CC=C1 GJNKKSZJGJWUST-UHFFFAOYSA-N 0.000 description 2
- MUUOUUYKIVSIAR-UHFFFAOYSA-N 2-but-3-enyloxirane Chemical compound C=CCCC1CO1 MUUOUUYKIVSIAR-UHFFFAOYSA-N 0.000 description 2
- HFHFGHLXUCOHLN-UHFFFAOYSA-N 2-fluorophenol Chemical compound OC1=CC=CC=C1F HFHFGHLXUCOHLN-UHFFFAOYSA-N 0.000 description 2
- APXFJBZKWPUYKC-UHFFFAOYSA-N 4-benzylsulfanyl-2,6-dimethylphenol Chemical compound CC1=C(O)C(C)=CC(SCC=2C=CC=CC=2)=C1 APXFJBZKWPUYKC-UHFFFAOYSA-N 0.000 description 2
- FXXGFMDQNJINJT-UHFFFAOYSA-N 4-fluoro-2-pent-2-ynylsulfanylphenol Chemical compound CCC#CCSC1=CC(F)=CC=C1O FXXGFMDQNJINJT-UHFFFAOYSA-N 0.000 description 2
- QICUPOFVENZWSC-UHFFFAOYSA-N 5-bromopentylbenzene Chemical compound BrCCCCCC1=CC=CC=C1 QICUPOFVENZWSC-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- YGPZYYDTPXVBRA-RTDBHSBRSA-N [(2r,3s,4r,5r,6s)-2-[[(2r,3r,4r,5s,6r)-3-[[(3r)-3-dodecanoyloxytetradecanoyl]amino]-6-(hydroxymethyl)-5-phosphonooxy-4-[(3r)-3-tetradecanoyloxytetradecanoyl]oxyoxan-2-yl]oxymethyl]-3,6-dihydroxy-5-[[(3r)-3-hydroxytetradecanoyl]amino]oxan-4-yl] (3r)-3-hydr Chemical compound O1[C@H](CO)[C@@H](OP(O)(O)=O)[C@H](OC(=O)C[C@@H](CCCCCCCCCCC)OC(=O)CCCCCCCCCCCCC)[C@@H](NC(=O)C[C@@H](CCCCCCCCCCC)OC(=O)CCCCCCCCCCC)[C@@H]1OC[C@@H]1[C@@H](O)[C@H](OC(=O)C[C@H](O)CCCCCCCCCCC)[C@@H](NC(=O)C[C@H](O)CCCCCCCCCCC)[C@@H](O)O1 YGPZYYDTPXVBRA-RTDBHSBRSA-N 0.000 description 2
- 125000003282 alkyl amino group Chemical group 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- UUWSLBWDFJMSFP-UHFFFAOYSA-N bromomethylcyclohexane Chemical compound BrCC1CCCCC1 UUWSLBWDFJMSFP-UHFFFAOYSA-N 0.000 description 2
- 230000007812 deficiency Effects 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 125000001153 fluoro group Chemical group F* 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 229960001866 silicon dioxide Drugs 0.000 description 2
- 150000003573 thiols Chemical class 0.000 description 2
- NAWXUBYGYWOOIX-SFHVURJKSA-N (2s)-2-[[4-[2-(2,4-diaminoquinazolin-6-yl)ethyl]benzoyl]amino]-4-methylidenepentanedioic acid Chemical compound C1=CC2=NC(N)=NC(N)=C2C=C1CCC1=CC=C(C(=O)N[C@@H](CC(=C)C(O)=O)C(O)=O)C=C1 NAWXUBYGYWOOIX-SFHVURJKSA-N 0.000 description 1
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 1
- FLYKDBVJMFJUQH-UHFFFAOYSA-N 1-benzylsulfanyl-3-methoxybenzene Chemical compound COC1=CC=CC(SCC=2C=CC=CC=2)=C1 FLYKDBVJMFJUQH-UHFFFAOYSA-N 0.000 description 1
- GZRAXWKQMHUSCT-UHFFFAOYSA-N 1-benzylsulfanyl-4-(trifluoromethyl)benzene Chemical compound C1=CC(C(F)(F)F)=CC=C1SCC1=CC=CC=C1 GZRAXWKQMHUSCT-UHFFFAOYSA-N 0.000 description 1
- XLQSXGGDTHANLN-UHFFFAOYSA-N 1-bromo-4-(trifluoromethyl)benzene Chemical group FC(F)(F)C1=CC=C(Br)C=C1 XLQSXGGDTHANLN-UHFFFAOYSA-N 0.000 description 1
- PKJBWOWQJHHAHG-UHFFFAOYSA-N 1-bromo-4-phenylbenzene Chemical group C1=CC(Br)=CC=C1C1=CC=CC=C1 PKJBWOWQJHHAHG-UHFFFAOYSA-N 0.000 description 1
- MPPPKRYCTPRNTB-UHFFFAOYSA-N 1-bromobutane Chemical compound CCCCBr MPPPKRYCTPRNTB-UHFFFAOYSA-N 0.000 description 1
- VDHGRVFJBGRHMD-UHFFFAOYSA-N 1-bromopent-2-yne Chemical compound CCC#CCBr VDHGRVFJBGRHMD-UHFFFAOYSA-N 0.000 description 1
- UKHKZGJCPDWXQY-UHFFFAOYSA-N 1-methoxy-4-(4-methoxyphenyl)sulfanylbenzene Chemical compound C1=CC(OC)=CC=C1SC1=CC=C(OC)C=C1 UKHKZGJCPDWXQY-UHFFFAOYSA-N 0.000 description 1
- LGERTTXLZNHNAI-UHFFFAOYSA-N 1-methoxy-4-propylsulfanylbenzene Chemical compound CCCSC1=CC=C(OC)C=C1 LGERTTXLZNHNAI-UHFFFAOYSA-N 0.000 description 1
- DYSRXWYRUJCNFI-UHFFFAOYSA-N 2,4-dibromoaniline Chemical group NC1=CC=C(Br)C=C1Br DYSRXWYRUJCNFI-UHFFFAOYSA-N 0.000 description 1
- FEYDZHNIIMENOB-UHFFFAOYSA-N 2,6-dibromopyridine Chemical compound BrC1=CC=CC(Br)=N1 FEYDZHNIIMENOB-UHFFFAOYSA-N 0.000 description 1
- RCHJKOKWVCYWNW-UHFFFAOYSA-N 2-(2-benzylsulfanylphenyl)ethanol Chemical compound OCCC1=CC=CC=C1SCC1=CC=CC=C1 RCHJKOKWVCYWNW-UHFFFAOYSA-N 0.000 description 1
- ADLOWZRDUHSVRU-UHFFFAOYSA-N 2-(2-bromophenyl)ethanol Chemical group OCCC1=CC=CC=C1Br ADLOWZRDUHSVRU-UHFFFAOYSA-N 0.000 description 1
- PTTFLKHCSZSFOL-UHFFFAOYSA-N 2-(3-bromophenyl)ethanol Chemical group OCCC1=CC=CC(Br)=C1 PTTFLKHCSZSFOL-UHFFFAOYSA-N 0.000 description 1
- ZSZCXAOQVBEPME-UHFFFAOYSA-N 2-(4-bromophenyl)ethanamine Chemical compound NCCC1=CC=C(Br)C=C1 ZSZCXAOQVBEPME-UHFFFAOYSA-N 0.000 description 1
- PMOSJSPFNDUAFY-UHFFFAOYSA-N 2-(4-bromophenyl)ethanol Chemical group OCCC1=CC=C(Br)C=C1 PMOSJSPFNDUAFY-UHFFFAOYSA-N 0.000 description 1
- JDKYYLZVBXMRPN-UHFFFAOYSA-N 2-(4-methoxyphenyl)sulfanyl-1-phenylethanone Chemical compound C1=CC(OC)=CC=C1SCC(=O)C1=CC=CC=C1 JDKYYLZVBXMRPN-UHFFFAOYSA-N 0.000 description 1
- YOLYJTSQMGIQOP-UHFFFAOYSA-N 2-benzylsulfanylaniline Chemical compound NC1=CC=CC=C1SCC1=CC=CC=C1 YOLYJTSQMGIQOP-UHFFFAOYSA-N 0.000 description 1
- OWZPCVGKLYOVLV-UHFFFAOYSA-N 2-benzylsulfanylphenol Chemical compound OC1=CC=CC=C1SCC1=CC=CC=C1 OWZPCVGKLYOVLV-UHFFFAOYSA-N 0.000 description 1
- RRTLQRYOJOSPEA-UHFFFAOYSA-N 2-bromo-1,3,5-trimethylbenzene Chemical compound CC1=CC(C)=C(Br)C(C)=C1 RRTLQRYOJOSPEA-UHFFFAOYSA-N 0.000 description 1
- ULVUNGFGSQHMSZ-UHFFFAOYSA-N 2-bromo-6-[2-(1,3-dioxolan-2-yl)ethylsulfanyl]pyridine Chemical compound BrC1=CC=CC(SCCC2OCCO2)=N1 ULVUNGFGSQHMSZ-UHFFFAOYSA-N 0.000 description 1
- XRXMNWGCKISMOH-UHFFFAOYSA-N 2-bromobenzoic acid Chemical compound OC(=O)C1=CC=CC=C1Br XRXMNWGCKISMOH-UHFFFAOYSA-N 0.000 description 1
- LQAMJDLEUKJGME-UHFFFAOYSA-N 3-(2-hydroxyhex-5-enylsulfanyl)benzoic acid Chemical compound C=CCCC(O)CSC1=CC=CC(C(O)=O)=C1 LQAMJDLEUKJGME-UHFFFAOYSA-N 0.000 description 1
- LKBRQRWYVAPXBG-UHFFFAOYSA-N 3-benzylsulfanylphenol Chemical compound OC1=CC=CC(SCC=2C=CC=CC=2)=C1 LKBRQRWYVAPXBG-UHFFFAOYSA-N 0.000 description 1
- USEGQJLHQSTGHW-UHFFFAOYSA-N 3-bromo-2-methylprop-1-ene Chemical compound CC(=C)CBr USEGQJLHQSTGHW-UHFFFAOYSA-N 0.000 description 1
- VOIZNVUXCQLQHS-UHFFFAOYSA-N 3-bromobenzoic acid Chemical group OC(=O)C1=CC=CC(Br)=C1 VOIZNVUXCQLQHS-UHFFFAOYSA-N 0.000 description 1
- UMLFTCYAQPPZER-UHFFFAOYSA-N 4-(bromomethyl)benzonitrile Chemical compound BrCC1=CC=C(C#N)C=C1 UMLFTCYAQPPZER-UHFFFAOYSA-N 0.000 description 1
- RFSULXKAMWZYQJ-UHFFFAOYSA-N 4-[(4-aminophenyl)sulfanylmethyl]benzonitrile Chemical compound C1=CC(N)=CC=C1SCC1=CC=C(C#N)C=C1 RFSULXKAMWZYQJ-UHFFFAOYSA-N 0.000 description 1
- UXMOBLWTCSCLLR-UHFFFAOYSA-N 4-benzylsulfanylphenol Chemical compound C1=CC(O)=CC=C1SCC1=CC=CC=C1 UXMOBLWTCSCLLR-UHFFFAOYSA-N 0.000 description 1
- ZLVFYUORUHNMBO-UHFFFAOYSA-N 4-bromo-2,6-dimethylphenol Chemical group CC1=CC(Br)=CC(C)=C1O ZLVFYUORUHNMBO-UHFFFAOYSA-N 0.000 description 1
- VIBJPUXLAKVICD-UHFFFAOYSA-N 4-bromo-2-chlorophenol Chemical group OC1=CC=C(Br)C=C1Cl VIBJPUXLAKVICD-UHFFFAOYSA-N 0.000 description 1
- TUXYZHVUPGXXQG-UHFFFAOYSA-N 4-bromobenzoic acid Chemical group OC(=O)C1=CC=C(Br)C=C1 TUXYZHVUPGXXQG-UHFFFAOYSA-N 0.000 description 1
- DXVMFHFKEKYGGW-UHFFFAOYSA-N 5-butyl-5-(1-butyl-4-methoxycyclohexa-2,4-dien-1-yl)sulfanyl-2-methoxycyclohexa-1,3-diene Chemical compound C1C=C(OC)C=CC1(CCCC)SC1(CCCC)CC=C(OC)C=C1 DXVMFHFKEKYGGW-UHFFFAOYSA-N 0.000 description 1
- FWVQJNYIEFAZOP-UHFFFAOYSA-N 6-benzylsulfanylnaphthalen-2-ol Chemical compound C1=CC2=CC(O)=CC=C2C=C1SCC1=CC=CC=C1 FWVQJNYIEFAZOP-UHFFFAOYSA-N 0.000 description 1
- YLDFTMJPQJXGSS-UHFFFAOYSA-N 6-bromo-2-naphthol Chemical group C1=C(Br)C=CC2=CC(O)=CC=C21 YLDFTMJPQJXGSS-UHFFFAOYSA-N 0.000 description 1
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 1
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- PSXLCTPHDAEPLK-UHFFFAOYSA-N CC(C)[Mg] Chemical compound CC(C)[Mg] PSXLCTPHDAEPLK-UHFFFAOYSA-N 0.000 description 1
- 208000020446 Cardiac disease Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- RAPBNVDSDCTNRC-UHFFFAOYSA-N Chlorobenzilate Chemical compound C=1C=C(Cl)C=CC=1C(O)(C(=O)OCC)C1=CC=C(Cl)C=C1 RAPBNVDSDCTNRC-UHFFFAOYSA-N 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 208000035150 Hypercholesterolemia Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical compound [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 description 1
- QEMNYLZJYHIEDN-UHFFFAOYSA-N [4-[2-(1,3-dioxolan-2-yl)ethylsulfanyl]phenyl]methanol Chemical compound C1=CC(CO)=CC=C1SCCC1OCCO1 QEMNYLZJYHIEDN-UHFFFAOYSA-N 0.000 description 1
- 125000002877 alkyl aryl group Chemical group 0.000 description 1
- BHELZAPQIKSEDF-UHFFFAOYSA-N allyl bromide Chemical group BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- OTKPPUXRIADSGD-PPRNARJGSA-N avoparcina Chemical compound O([C@@H]1C2=CC=C(C(=C2)Cl)OC=2C=C3C=C(C=2O[C@H]2C([C@@H](O)[C@H](O)[C@@H](CO)O2)O[C@@H]2O[C@@H](C)[C@H](O)[C@H](N)C2)OC2=CC=C(C=C2)[C@@H](O)[C@H](C(N[C@H](C(=O)N[C@H]3C(=O)N[C@H]2C(=O)N[C@@H]1C(N[C@@H](C1=CC(O)=CC(O)=C1C=1C(O)=CC=C2C=1)C(O)=O)=O)C=1C=CC(O)=CC=1)=O)NC(=O)[C@H](NC)C=1C=CC(O[C@H]2[C@@H]([C@H](O)[C@@H](O)[C@H](C)O2)O)=CC=1)[C@H]1C[C@@H](N)[C@@H](O)[C@H](C)O1 OTKPPUXRIADSGD-PPRNARJGSA-N 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 125000004799 bromophenyl group Chemical group 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000007806 chemical reaction intermediate Substances 0.000 description 1
- BULLHNJGPPOUOX-UHFFFAOYSA-N chloroacetone Chemical group CC(=O)CCl BULLHNJGPPOUOX-UHFFFAOYSA-N 0.000 description 1
- 229940126142 compound 16 Drugs 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 150000002366 halogen compounds Chemical class 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 125000002524 organometallic group Chemical group 0.000 description 1
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 125000003356 phenylsulfanyl group Chemical group [*]SC1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229910000077 silane Inorganic materials 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 230000002311 subsequent effect Effects 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- IGVNJALYNQVQIT-UHFFFAOYSA-N tert-butyl 2-bromo-2-methylpropanoate Chemical compound CC(C)(C)OC(=O)C(C)(C)Br IGVNJALYNQVQIT-UHFFFAOYSA-N 0.000 description 1
- 125000000101 thioether group Chemical group 0.000 description 1
Classifications
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
- C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
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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
- C07C323/01—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and halogen atoms, or nitro or nitroso groups bound to the same carbon skeleton
- C07C323/09—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and halogen atoms, or nitro or nitroso groups bound to the same carbon skeleton having sulfur atoms of thio groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
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- C—CHEMISTRY; METALLURGY
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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
- C07C323/10—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C323/11—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
- C07C323/14—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and unsaturated
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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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- C07C323/19—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton with singly-bound oxygen atoms bound to acyclic carbon atoms of the carbon skeleton
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- 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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- 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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- C07C323/21—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton with the sulfur atom of the thio group bound to a carbon atom of a six-membered aromatic ring being part of a condensed ring system
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- C07C323/22—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and doubly-bound oxygen atoms bound to the same carbon skeleton
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- C07C323/31—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
- C07C323/32—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton having at least one of the nitrogen atoms bound to an acyclic carbon atom of the carbon skeleton
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- C07C323/31—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
- C07C323/33—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton having at least one of the nitrogen atoms bound to a carbon atom of the same non-condensed six-membered aromatic ring
- C07C323/35—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton having at least one of the nitrogen atoms bound to a carbon atom of the same non-condensed six-membered aromatic ring the thio group being a sulfide group
- C07C323/36—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton having at least one of the nitrogen atoms bound to a carbon atom of the same non-condensed six-membered aromatic ring the thio group being a sulfide group the sulfur atom of the sulfide group being further bound to an acyclic carbon atom
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- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/36—Sulfur atoms
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- C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
- C07D317/32—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
- C07F7/1872—Preparation; Treatments not provided for in C07F7/20
- C07F7/1892—Preparation; Treatments not provided for in C07F7/20 by reactions not provided for in C07F7/1876 - C07F7/1888
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
Definitions
- the present invention relates to a process for preparing sulfide compounds from aryl halogen compounds having various electron- donating, electron-withdrawing or hydrogen-donating substituents via one-step reaction , and the sulfide derivatives prepared therefrom i o More specifically, the invention relates to a process for preparing various alkyl aryl sulfides represented by Formula (III) which have important roles in syntheses of organic chemistry and medicinal chemistry, via one-step reaction
- Alkyl aryl sulfide compounds represented by Formula (III) have very wide utility spectrum in organic chemistry and medicinal chemistry Thus, a variety of processes for preparing such sulfide compounds have very wide utility spectrum in organic chemistry and medicinal chemistry. Thus, a variety of processes for preparing such sulfide compounds have
- Form ula (10) in Reaction Scheme (3) is troublesome because a thiol compound (8) m ust be prepared according to the Scheme and then separated and purified before subseq uent reaction 5)
- a thiol of Chemical Formula (13) is prepared from the compound of Chemical Formula (12) via reduction with LiAIH 4
- this process also has problems in that a disulfide compound is readily formed, and LiAIH 4 employed in the reduction is unstable in the air to give trouble in the production in a large scale
- an alkyl aryl sulfide of Chemical Formula (I I I) is obtained by substituting a halogen from an aryl halogen compound with alkyl lithium organometallic reagent when the compound of Chemical Formula (I) has an electron-donating or an electron-withdrawing substitue ⁇ t, and continuously reacting with the compound of Chemical Formula (II) and sulfur, or by reacting the aryl halogen compound of Chemical Formula (I) containing a hydrogen-donating substituent ⁇ -OH , -NH 2 , -NRH, - COOH) with an alkylmagnesium halide (Grignard reagent) to protect the hydrogen-donating substituent; substituting the halogen with alkyl lithium organometallic reagent, and continuously reacting with the compound of Chemical Formula (II) and sulfur, to complete the invention.
- A represents CH or a nitrogen atom
- Xi represents a halogen atom
- X 2 represents a halogen atom or a leaving group
- X 3 represents a halogen atom
- Ri represents a hydrogen atom, a halogen atom, a Ci-C 7 alkyl group, a C1-C7 alkyloxy group, a C1-C7 alkylthiooxy group, an aryl group, a hydroxyl group, a hydroxymethyl group, a hydroxyethyl group, an amine group, an aminomethyl group, an aminoethyl group, an alkylamine group, a dialkylamine group or a carboxy group, wherein the alkyl group may be substituted by one or more substituent(s) selected from the group consisting of halogen atoms and a hydroxyl group,
- R 2 represents a C1-C1 0 alkyl group, an aryl group, a C1-C10 alkylester group, a C 1 -C 10 alkylketone group or an arylketone group
- R 3 and R 4 independently represents a C1-C4 alkyl group
- n represents an integer of 1 to 3
- the present invention provides a process for easily and economically preparing various alkyl aryl sulfide derivatives of Chemical
- novel compounds are 2-(pent-2-ynylsulfanyl)-4-fluorophenol, 2-(5- phenylpentylsulfanyl)-4-fluorophenol, 2-(cyclohexylmethylsulfanyl)-4- fluorophenol, 4-((2-(1 ,3-d ⁇ oxolan-2-yl)ethylsulfanyl)phenol, 2-(2- hydroxyhex-5-enylsulfanyl)-4-fluorophenol, 4-((tert- butoxycarbonyl)methylsulfanyl)benzo ⁇ c acid, 3-(2-(1 ,3-d ⁇ oxolan-2- yl)ethylsulfanyl)benzo ⁇ c acid , 3-(2-hydroxyhex-5-enylsulfany I) benzoic acid, 2-(4-(benzyls
- A represents CH or a i s nitrogen atom contained in the aryl compound having a resonance structure.
- Xi represents a halogen atom.
- the halogen atom mentioned can be a fluorine atom, chlorine atom, bromine atom, and iodine atom . Among them, a bromine atom or an iodine atom is 20 preferable.
- X 2 means a leaving group.
- a conventional leaving group specifically a halogen atom, a methansulfonyl oxy group, a p- toluenesulfonyloxy group may be employed.
- the halogen atoms include a fluorine atom, a chlorine atom, a bromine atom and an iodine
- a halogen atom is preferable, a chlorine atom, a bromine atom, or an iodine atom being more preferable
- X 3 a halogen atom of G ⁇ gnard reagent represents a chlorine atom , a bromine atom or an iodine atom
- Ri represents a hydrogen atom, a halogen atom, a C- 1 -C 7 alkyl r > group, a C1-C7 alkyloxy group, a C1-C7 alkylthiooxy group, an aryl group, a hydroxyl group, a hydroxymethyl group, a hydroxyethyl group, an amine group, an aminomethyl group, an aminoethyl group, an alkylamine group, a dialkylamine group or a carboxy group, where in the alkyl group may be substituted by one or more subst ⁇ tuent(s) selected
- Each substituent Ri may have ortho-, meta- or para-position with respect to the halogen atom (Xi), and number of the subst ⁇ tuent(s) is from 1 to 3
- R 2 represents a C1-C10 alkyl group, an aryl group, a C1-C10 I 1 J alkylester group, a C 1 -C 10 alkylketo ⁇ e group or an arylketone group
- R 3 and R4 independently represent a C 1 -C 4 alkyl group, such as methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl and tert-butyl group
- the compound of Chemical Formula (I) employed as raw material is well ZO known in the art and commercially available
- alkyl aryl sulfide compound represented by Chemical Formula (II I) having (an) electron-donating or 2 ⁇ 5 electron-withdrawing subst ⁇ tuent(s)
- An alkyl aryl sulfide compound represented by Chemical Formula (II I) is obtained by reacting a compound represented by Chemical Formula (I) with an alkyl lithium organometallic reagent and sulfur, and then with a compound represented by Chemical Formula (II) Dry solvent such as diethyl ether, tetrahydrofuran, hexane and heptane is used in this process either alone or in a mixture of the two or more Among them , diethylether, tetrahydrofuran , and a mixture of diethyl ether and tetrahydrofuran are the most preferable
- alkyl lithium organometallic reagents employed in the halogen-metal substitution include n-butyl lithium, sec-butyl lithium, tert- butyl lithium, and the like
- the amount of alkyl lithium organometallic reagent employed is usually from 1 to 3 equivalents with respect to the compound of Chemical Formula (I), most preferably from 1 to 1 2 equivalents in case of n-butyl lithi um or sec-butyl lithium, and from 2 to 2 2 equivalents in case of tert-butyl lithium
- Sulfur used in this process is in a powdery state colored pale yellow, and the amou nt is usually from 1 to 3 equivalents, preferably from 1 to 1 2 equivalents with respect to the compound of Chemical Form ula (I )
- the reaction temperature varies dependi ng upon the solvent employed , but usually is from -1 00 ° C to 25 T: Preferably the substitution of halogen with metal and introduction of sulfur are carried out at -75 ° C , and the reaction with compound of Chemical Formula (I I) at room temperature (25 ° C )
- the reaction time varies depending on the reaction temperature and the type of solvent employed , but usually is from 30 minutes to 6 hours, preferably 1 hour or less.
- a hydrogen-donating substituent -OH, -CH 2 OH, -CH 2 CH 2 OH, -NH 2 , -NRH, -CH 2 NH 2 , -CH 2 CH 2 NH 2 , -COOH
- diethyl ether, tetrahydrofuran, hexane or heptane may be used alone or in a combination of the two or more.
- diethyl ether, tetrahydrofuran, or a mixture of diethyl ether and tetrahydrofuran are preferable.
- the Grignard reagent which protects the hydrogen-donating substituent (-OH , -CH 2 OH, -CH 2 CH 2 OH, -NH 2 , -NRH, -CH 2 N H 2 , - CH 2 CH 2 NH 2 , -COOH), employed may be CH 3 MgCI, CH 3 MgBr, CH 3 MgI , CH 3 CH 2 MgCI, CH 3 CH 2 MgBr, CH 3 CH 2 MgI, CH 3 CH 2 CH 2 MgCI,
- alkyl lithium organometallic reagents which can be employed in halogen-metal substitution reaction include n-butyl lithium, sec-butyl lithium , tert-butyl lithium, and the like
- the amount of alkyl lithium 5 organometallic reagent employed is usually from 1 to 3 equivalents, more preferably from 1 to 1 2 equivalents in case of n-butyl lithium or sec-butyl lithium , from 2 to 2 2 eq uivalents in case of tert-butyl lithium
- Sulfur used in this process is in a powdery state colored pale yellow, and the amount is usually from 1 to 3 equivalents, preferably i o from 1 to 1 2 equivalents with respect to the compound of Chemical Form ula (I)
- reaction temperature varies depending upon the solvent em ployed , but usually is from -10CTC to 25 ° C
- protection of the hyd rogen-donating substituent is carried out at 0 ° C to 25 ° C , the
- reaction time varies depending on the reaction temperature and the type of solvent employed, but usually is from 30 minutes to 6 hours, preferably 2 hours or less
- mesityl bromide 300 ⁇ l (2 mmol) was completely dissolved in dry tetrahydrofuran 15 ml under nitrogen atmosphere, and the mixture was cooled to -78 t: .
- butyl lithium 1 .25 ml (1 .6M in hexane, 1 .0 equivalent) was slowly added for 1 minute.
- sulfur powder 64 mg (2 mmol, 1.0 equivalent) was added at c> once at the same temperature.
- phenacyl bromide 398 mg (2 mmol, 1 .0 equivalent) was slowly added.
- alkyl aryl sulfide derivatives represented by Chemical Formula (III) can be prepared in a simple process with high yield.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Thiazole And Isothizaole Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Description
Claims
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KR20040085011 | 2004-10-22 | ||
PCT/KR2005/003528 WO2006043797A1 (en) | 2004-10-22 | 2005-10-21 | Process for alkyl aryl sulfide derivatives and new sulfide compounds |
KR1020050099926A KR100723828B1 (en) | 2004-10-22 | 2005-10-21 | Process for alkyl aryl sulfide derivatives and new sulfide compounds |
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CN115260050B (en) * | 2022-08-04 | 2023-08-22 | 常州大学 | Method for preparing 3-bromo-N-aryl propionamide by using NBS |
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- 2005-10-21 WO PCT/KR2005/003528 patent/WO2006043797A1/en active Application Filing
- 2005-10-21 EP EP05808625A patent/EP1812386A4/en not_active Withdrawn
Non-Patent Citations (3)
Title |
---|
J. DUPONT ET AL: "Reactions of Cyclopalladated Compounds. Part 21. Various Examples of Sulphur-assisted Intramolecular Palladation of Aryl and Alkyl Groups" J. CHEM. SOC. DALTON TRANS., 1989, pages 1715-1720, XP002556950 * |
JUNGYEOB HAM AND HEONJOONG KANG: "A highly efficient synthesis of antiobestic ligand GW501516 for the peroxisome proliferator-activated receptor deltha through in situ protection of the phenol group by reaction with a Grignard reagent" TETRAHEDRON LETTERS, vol. 46, 2005, pages 6683-6686, XP002556904 * |
See also references of WO2006043797A1 * |
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