CN1341596A - 苯并[b]噻吩类化合物的合成方法 - Google Patents
苯并[b]噻吩类化合物的合成方法 Download PDFInfo
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- CN1341596A CN1341596A CN00130779A CN00130779A CN1341596A CN 1341596 A CN1341596 A CN 1341596A CN 00130779 A CN00130779 A CN 00130779A CN 00130779 A CN00130779 A CN 00130779A CN 1341596 A CN1341596 A CN 1341596A
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- 238000000034 method Methods 0.000 title claims abstract description 22
- -1 benz [b] thiophenes compound Chemical class 0.000 title claims description 84
- 230000002194 synthesizing effect Effects 0.000 title abstract 2
- 150000001875 compounds Chemical class 0.000 claims description 75
- 239000002253 acid Substances 0.000 claims description 33
- 229910052739 hydrogen Inorganic materials 0.000 claims description 20
- 125000003118 aryl group Chemical group 0.000 claims description 19
- 239000001257 hydrogen Substances 0.000 claims description 18
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 17
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 15
- 125000001843 C4-C10 alkenyl group Chemical group 0.000 claims description 11
- 238000005917 acylation reaction Methods 0.000 claims description 11
- 239000000460 chlorine Substances 0.000 claims description 11
- 229910052801 chlorine Inorganic materials 0.000 claims description 11
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 10
- 239000003377 acid catalyst Substances 0.000 claims description 8
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 7
- 230000010933 acylation Effects 0.000 claims description 6
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 6
- 125000000623 heterocyclic group Chemical group 0.000 claims description 5
- ODIGIKRIUKFKHP-UHFFFAOYSA-N (n-propan-2-yloxycarbonylanilino) acetate Chemical compound CC(C)OC(=O)N(OC(C)=O)C1=CC=CC=C1 ODIGIKRIUKFKHP-UHFFFAOYSA-N 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 238000007363 ring formation reaction Methods 0.000 claims description 3
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 230000020335 dealkylation Effects 0.000 claims description 2
- 238000006900 dealkylation reaction Methods 0.000 claims description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 2
- 125000001246 bromo group Chemical group Br* 0.000 claims 1
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims 1
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical class C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 abstract description 25
- 150000003462 sulfoxides Chemical class 0.000 abstract description 11
- 230000015572 biosynthetic process Effects 0.000 abstract description 5
- 238000003786 synthesis reaction Methods 0.000 abstract description 5
- 238000006243 chemical reaction Methods 0.000 description 43
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 30
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 30
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 30
- 239000000203 mixture Substances 0.000 description 30
- 239000000243 solution Substances 0.000 description 29
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 27
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 23
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 22
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 19
- 238000002360 preparation method Methods 0.000 description 19
- LUFPJJNWMYZRQE-UHFFFAOYSA-N benzylsulfanylmethylbenzene Chemical compound C=1C=CC=CC=1CSCC1=CC=CC=C1 LUFPJJNWMYZRQE-UHFFFAOYSA-N 0.000 description 18
- 239000011541 reaction mixture Substances 0.000 description 17
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 15
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 229910052799 carbon Inorganic materials 0.000 description 12
- 239000002904 solvent Substances 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 11
- 238000005481 NMR spectroscopy Methods 0.000 description 11
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 11
- 239000007859 condensation product Substances 0.000 description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 10
- 239000002585 base Substances 0.000 description 10
- 239000000047 product Substances 0.000 description 10
- 239000000376 reactant Substances 0.000 description 10
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 10
- UAYWVJHJZHQCIE-UHFFFAOYSA-L zinc iodide Chemical compound I[Zn]I UAYWVJHJZHQCIE-UHFFFAOYSA-L 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 150000001721 carbon Chemical group 0.000 description 9
- 150000002148 esters Chemical class 0.000 description 9
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 8
- 239000003513 alkali Substances 0.000 description 8
- 238000004364 calculation method Methods 0.000 description 8
- 239000003960 organic solvent Substances 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 125000003710 aryl alkyl group Chemical group 0.000 description 7
- 238000009833 condensation Methods 0.000 description 7
- 230000005494 condensation Effects 0.000 description 7
- 229960004756 ethanol Drugs 0.000 description 7
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- 150000002500 ions Chemical class 0.000 description 7
- 229910052751 metal Inorganic materials 0.000 description 7
- 239000002184 metal Substances 0.000 description 7
- 230000003647 oxidation Effects 0.000 description 7
- 238000007254 oxidation reaction Methods 0.000 description 7
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 6
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 6
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 6
- 239000002841 Lewis acid Substances 0.000 description 6
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 6
- HTMQZWFSTJVJEQ-UHFFFAOYSA-N benzylsulfinylmethylbenzene Chemical compound C=1C=CC=CC=1CS(=O)CC1=CC=CC=C1 HTMQZWFSTJVJEQ-UHFFFAOYSA-N 0.000 description 6
- 150000007517 lewis acids Chemical class 0.000 description 6
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 6
- 230000001590 oxidative effect Effects 0.000 description 6
- 238000001228 spectrum Methods 0.000 description 6
- 238000010189 synthetic method Methods 0.000 description 6
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 6
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 5
- 238000013459 approach Methods 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 238000001291 vacuum drying Methods 0.000 description 5
- BKOOMYPCSUNDGP-UHFFFAOYSA-N 2-methylbut-2-ene Chemical compound CC=C(C)C BKOOMYPCSUNDGP-UHFFFAOYSA-N 0.000 description 4
- MSHFRERJPWKJFX-UHFFFAOYSA-N 4-Methoxybenzyl alcohol Chemical compound COC1=CC=C(CO)C=C1 MSHFRERJPWKJFX-UHFFFAOYSA-N 0.000 description 4
- UOHBMRODJBFDPN-UHFFFAOYSA-N C(C)(C)(C)O.[Li] Chemical compound C(C)(C)(C)O.[Li] UOHBMRODJBFDPN-UHFFFAOYSA-N 0.000 description 4
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 4
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 4
- 239000012346 acetyl chloride Substances 0.000 description 4
- 150000001263 acyl chlorides Chemical class 0.000 description 4
- 150000004703 alkoxides Chemical class 0.000 description 4
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 4
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 4
- 229940093499 ethyl acetate Drugs 0.000 description 4
- 235000019439 ethyl acetate Nutrition 0.000 description 4
- 229910052744 lithium Inorganic materials 0.000 description 4
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 description 4
- WGOPGODQLGJZGL-UHFFFAOYSA-N lithium;butane Chemical compound [Li+].CC[CH-]C WGOPGODQLGJZGL-UHFFFAOYSA-N 0.000 description 4
- IHLVCKWPAMTVTG-UHFFFAOYSA-N lithium;carbanide Chemical compound [Li+].[CH3-] IHLVCKWPAMTVTG-UHFFFAOYSA-N 0.000 description 4
- AZVCGYPLLBEUNV-UHFFFAOYSA-N lithium;ethanolate Chemical compound [Li+].CC[O-] AZVCGYPLLBEUNV-UHFFFAOYSA-N 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
- 150000004965 peroxy acids Chemical class 0.000 description 4
- 238000012545 processing Methods 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 4
- 239000012312 sodium hydride Substances 0.000 description 4
- 229910000104 sodium hydride Inorganic materials 0.000 description 4
- FAQYAMRNWDIXMY-UHFFFAOYSA-N trichloroborane Chemical compound ClB(Cl)Cl FAQYAMRNWDIXMY-UHFFFAOYSA-N 0.000 description 4
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 4
- HQSMEHLVLOGBCK-UHFFFAOYSA-N 1-ethenylsulfinylethene Chemical class C=CS(=O)C=C HQSMEHLVLOGBCK-UHFFFAOYSA-N 0.000 description 3
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 3
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- UHBXGHADNVDXMM-UHFFFAOYSA-N C(C)(C)N(C(C)C)CC[Li] Chemical compound C(C)(C)N(C(C)C)CC[Li] UHBXGHADNVDXMM-UHFFFAOYSA-N 0.000 description 3
- 235000014493 Crataegus Nutrition 0.000 description 3
- 241001092040 Crataegus Species 0.000 description 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 125000002252 acyl group Chemical group 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- CSKNSYBAZOQPLR-UHFFFAOYSA-N benzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=C1 CSKNSYBAZOQPLR-UHFFFAOYSA-N 0.000 description 3
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 125000004473 dialkylaminocarbonyl group Chemical group 0.000 description 3
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 3
- FRYHCSODNHYDPU-UHFFFAOYSA-N ethanesulfonyl chloride Chemical compound CCS(Cl)(=O)=O FRYHCSODNHYDPU-UHFFFAOYSA-N 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 238000001819 mass spectrum Methods 0.000 description 3
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 description 3
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- ZRSNZINYAWTAHE-UHFFFAOYSA-N p-methoxybenzaldehyde Chemical compound COC1=CC=C(C=O)C=C1 ZRSNZINYAWTAHE-UHFFFAOYSA-N 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 3
- WMXCDAVJEZZYLT-UHFFFAOYSA-N tert-butylthiol Chemical compound CC(C)(C)S WMXCDAVJEZZYLT-UHFFFAOYSA-N 0.000 description 3
- 238000004809 thin layer chromatography Methods 0.000 description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 3
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 3
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 2
- RFFLAFLAYFXFSW-UHFFFAOYSA-N 1,2-dichlorobenzene Chemical compound ClC1=CC=CC=C1Cl RFFLAFLAYFXFSW-UHFFFAOYSA-N 0.000 description 2
- QOJVHSBENNSCHL-UHFFFAOYSA-N 1-(butylsulfanylmethyl)-4-methoxybenzene Chemical group CCCCSCC1=CC=C(OC)C=C1 QOJVHSBENNSCHL-UHFFFAOYSA-N 0.000 description 2
- ULQQGOGMQRGFFR-UHFFFAOYSA-N 2-chlorobenzenecarboperoxoic acid Chemical compound OOC(=O)C1=CC=CC=C1Cl ULQQGOGMQRGFFR-UHFFFAOYSA-N 0.000 description 2
- 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 2
- 239000007848 Bronsted acid Substances 0.000 description 2
- RBLVBKCIZRBTBF-UHFFFAOYSA-N C(C)(C)N(C(C)C)CC[Mg] Chemical compound C(C)(C)N(C(C)C)CC[Mg] RBLVBKCIZRBTBF-UHFFFAOYSA-N 0.000 description 2
- WATQCMFDEPQANR-UHFFFAOYSA-N C(CCl)Cl.S1C2=C(C=C1)C=CC=C2 Chemical compound C(CCl)Cl.S1C2=C(C=C1)C=CC=C2 WATQCMFDEPQANR-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000005864 Sulphur Substances 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 2
- 238000007171 acid catalysis Methods 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 2
- 229910052796 boron Inorganic materials 0.000 description 2
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- 238000001816 cooling Methods 0.000 description 2
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- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 2
- 239000007800 oxidant agent Substances 0.000 description 2
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- 238000001556 precipitation Methods 0.000 description 2
- 238000000746 purification Methods 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
- 239000012453 solvate Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 150000003568 thioethers Chemical class 0.000 description 2
- 150000003573 thiols Chemical class 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- VNDYJBBGRKZCSX-UHFFFAOYSA-L zinc bromide Chemical compound Br[Zn]Br VNDYJBBGRKZCSX-UHFFFAOYSA-L 0.000 description 2
- 239000011592 zinc chloride Substances 0.000 description 2
- 235000005074 zinc chloride Nutrition 0.000 description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
- WNRWEBKEQARBKV-UHFFFAOYSA-N 1-(2-chloroethyl)piperidine Chemical compound ClCCN1CCCCC1 WNRWEBKEQARBKV-UHFFFAOYSA-N 0.000 description 1
- LFPWGWSNPJDVCK-UHFFFAOYSA-N 1-(butylsulfinylmethyl)-4-methoxybenzene Chemical group CCCCS(=O)Cc1ccc(OC)cc1 LFPWGWSNPJDVCK-UHFFFAOYSA-N 0.000 description 1
- DYSJMQABFPKAQM-UHFFFAOYSA-M 1-benzothiophene-2-carboxylate Chemical compound C1=CC=C2SC(C(=O)[O-])=CC2=C1 DYSJMQABFPKAQM-UHFFFAOYSA-M 0.000 description 1
- XGXCKODMKQQVOU-UHFFFAOYSA-N 1-ethenyl-7-thiabicyclo[4.1.0]hepta-2,4-diene Chemical class C(=C)C12C(C=CC=C1)S2 XGXCKODMKQQVOU-UHFFFAOYSA-N 0.000 description 1
- 125000005976 1-phenylethyloxy group Chemical group 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 125000001917 2,4-dinitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C(=C1*)[N+]([O-])=O)[N+]([O-])=O 0.000 description 1
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 description 1
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- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 1
- 125000003119 4-methyl-3-pentenyl group Chemical group [H]\C(=C(/C([H])([H])[H])C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
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- 239000005591 Pendimethalin Substances 0.000 description 1
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical group C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 1
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- 238000000944 Soxhlet extraction Methods 0.000 description 1
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 description 1
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical class [H]C([H])([H])C(*)=O 0.000 description 1
- 102000011759 adducin Human genes 0.000 description 1
- 108010076723 adducin Proteins 0.000 description 1
- 125000004450 alkenylene group Chemical group 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 150000001446 angelic acids Chemical class 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzenecarboxaldehyde Natural products O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 1
- 125000005605 benzo group Chemical group 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 229960004217 benzyl alcohol Drugs 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- HRYZWHHZPQKTII-UHFFFAOYSA-N chloroethane Chemical compound CCCl HRYZWHHZPQKTII-UHFFFAOYSA-N 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000000975 co-precipitation Methods 0.000 description 1
- ONCCWDRMOZMNSM-FBCQKBJTSA-N compound Z Chemical class N1=C2C(=O)NC(N)=NC2=NC=C1C(=O)[C@H]1OP(O)(=O)OC[C@H]1O ONCCWDRMOZMNSM-FBCQKBJTSA-N 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 239000002178 crystalline material Substances 0.000 description 1
- 238000013016 damping Methods 0.000 description 1
- 238000005947 deacylation reaction Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000005595 deprotonation Effects 0.000 description 1
- 238000010537 deprotonation reaction Methods 0.000 description 1
- 238000003795 desorption Methods 0.000 description 1
- IJKVHSBPTUYDLN-UHFFFAOYSA-N dihydroxy(oxo)silane Chemical compound O[Si](O)=O IJKVHSBPTUYDLN-UHFFFAOYSA-N 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
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- 238000001035 drying Methods 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-N ethanesulfonic acid Chemical compound CCS(O)(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-N 0.000 description 1
- 229960003750 ethyl chloride Drugs 0.000 description 1
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- 238000000605 extraction Methods 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 238000004817 gas chromatography Methods 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 238000003402 intramolecular cyclocondensation reaction Methods 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 229910000474 mercury oxide Inorganic materials 0.000 description 1
- UKWHYYKOEPRTIC-UHFFFAOYSA-N mercury(ii) oxide Chemical compound [Hg]=O UKWHYYKOEPRTIC-UHFFFAOYSA-N 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- PYLWMHQQBFSUBP-UHFFFAOYSA-N monofluorobenzene Chemical compound FC1=CC=CC=C1 PYLWMHQQBFSUBP-UHFFFAOYSA-N 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 238000007243 oxidative cyclization reaction Methods 0.000 description 1
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- QARVLSVVCXYDNA-UHFFFAOYSA-N phenyl bromide Natural products BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- 150000003053 piperidines Chemical class 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 239000008057 potassium phosphate buffer Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000197 pyrolysis Methods 0.000 description 1
- 238000007348 radical reaction Methods 0.000 description 1
- MDGWZLQPNOETLH-UHFFFAOYSA-N raloxifene core Chemical compound C1=CC(O)=CC=C1C1=CC2=CC=C(O)C=C2S1 MDGWZLQPNOETLH-UHFFFAOYSA-N 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical class [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 235000014347 soups Nutrition 0.000 description 1
- 125000000542 sulfonic acid group Chemical group 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- FWMUJAIKEJWSSY-UHFFFAOYSA-N sulfur dichloride Chemical compound ClSCl FWMUJAIKEJWSSY-UHFFFAOYSA-N 0.000 description 1
- PUGUQINMNYINPK-UHFFFAOYSA-N tert-butyl 4-(2-chloroacetyl)piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCN(C(=O)CCl)CC1 PUGUQINMNYINPK-UHFFFAOYSA-N 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 150000003577 thiophenes Chemical class 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 238000007738 vacuum evaporation Methods 0.000 description 1
- 238000003809 water extraction Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 229940102001 zinc bromide Drugs 0.000 description 1
Classifications
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/50—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
- C07D333/56—Radicals substituted by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
- C07C317/16—Sulfones; Sulfoxides having sulfone or sulfoxide groups and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C317/18—Sulfones; Sulfoxides having sulfone or sulfoxide groups and singly-bound oxygen atoms bound to the same carbon skeleton with sulfone or sulfoxide groups bound to acyclic carbon atoms of the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- 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
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Addition Polymer Or Copolymer, Post-Treatments, Or Chemical Modifications (AREA)
- Saccharide Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及应用新的二芳基乙烯亚砜类化合物合成苯并[b]噻吩类化合物的新方法,以及新的二芳基乙烯亚砜类化合物及其合成的新方法。
Description
本申请是中国专利申请号为96196167.8、申请日为1996年6月4日。发明名称为《乙烯亚砜类化合物及其合成方法》的中国专利申请的分案申请。
本发明针对新型乙烯亚砜类化合物,及其新的合成方法,尤其是二芳基乙烯亚砜。本发明还针对将新型乙烯亚砜类化合物用于合成苯并[b]噻吩类化合物的的新方法。
苯并[b]噻吩由很多不同合成途径制备,一个广泛采用的方法是邻巯基肉桂酸的氧化环化反应。该途径被局限于制备苯并[b]噻吩-2-羧化物。2-苯基苯并[b]噻吩由2-苯基硫代乙醛二烷基缩醛经酸催化环化制备。未取代的苯并[b]噻吩由苯乙烯和硫催化缩合制备。3-取代苯并[b]噻吩由芳基硫代甲基酮酸催化环化制备,但该途径只局限于制备3-烷基苯并[b]噻吩。参见Campaigne,“Thiophenes and their Benzo Derivatives:(iii)Synthesis and Applications,”inComprehensive Heterocyclic Chemistry(Katritzky and Rees,eds.),Volume IV,PartIII,863-934(1984)。3-氯代2-苯基苯并[b]噻吩由二苯基乙炔与二氯化硫反应制得(Barton和Zika,J.Org.Chem.,35,1729-1733(1970))。苯并[b]噻吩也通过苯乙烯亚砜热解制备,但是由于产量很低,且需极高温度,使得该途径不适于大规模合成生产。参见Ando,J.Chem.Soc,Chem.Comm.,704-705(1975)。
6-羟基-2-(4-羟苯基)苯并[b]噻吩在U.S.专利4,133,814和4,380,635中有介绍。这些专利所述的一个方法是α-(3-甲氧苯基硫)-4-甲氧基苯乙酮的酸催化分子内环化/重排。所述原料化合物在纯多磷酸中,于约85℃-约90℃条件下反应,得到约3∶1的两种区域异构产物之混合物:6-甲氧基-2-(4-甲氧苯基)-苯并[b]噻吩和4-甲氧基-2(4-甲氧苯基)苯并[b]噻吩。这些异构苯并噻吩从反应混合物中共沉淀出,产生含两化合物的混合物。为了获得单一区域异构体,必需将其分离,例如采用色谱或分级结晶。因此,目前很需要一种从易获得原料,有效的区域特异性合成2-芳基苯并[b]噻吩的方法。而本发明化合物对于从易得原料有效的区域特异性合成2-芳基苯并[b]噻吩很有用。
本发明针对新的乙烯亚砜及其新的合成方法,尤其是二芳基乙烯亚砜。具体说来,本发明针对下式化合物:其中
R1是氢、C1-C4烷氧基、芳烷氧基、卤代基、或氨基;
R2是氢、C1-C4烷氧基、芳烷氧基、卤代基、或氨基;
R3是热不稳定性或酸不稳定性C2-C10烷基、C4-C10链烯基、或芳基(C1-C10烷基)。这样,本发明包括式II化合物的个体E和Z异构体或其混合物。这些E和Z区域异构体由下面的结构式代表:本发明的另一个方面是制备下式化合物的方法,其中
R1是氢、C1-C4烷氧基、芳烷氧基、卤代基、或氨基;
R2是氢、C1-C4烷氧基、芳烷氧基、卤代基、或氨基;
(其中R2和R3的定义同上)用氧化剂氧化,产生下式的苄亚砜:(其中R2和R3定义同上)(2)使所述苄亚砜与强碱反应,形成苄基阴离子化合物;(3)使所述苄基阴离子化合物与下式苯甲醛缩合,(其中R1定义同上)(4)将步骤3的缩合产物与酰基氯反应,产生下式的酯:其中
R1、R2、和R3定义同上;
R4是CO(C1-C6烷基)、CO(芳基)、CO(芳烷基)、SO2(C1-C6烷基)、SO2(芳基)、SO2(芳烷基)、CO2(C1-C6烷基)、CO2(芳基)、CO2(芳烷基)、或CON(C1-C6烷基)2;
(5)将上述酯用第二强碱处理。
R1是氢、C1-C4烷氧基、芳烷氧基、卤代基、或氨基;
R2是氢、C1-C4烷氧基、芳烷氧基、卤代基、或氨基;
R3是热不稳定性或酸不稳定性C2-C10烷基、C4-C10链烯基、或芳基(C1-C10烷基),这些基团有叔碳原子与硫原子邻接;
所述方法包括下面步骤:
(其中R2和R3定义同上)与强碱反应,形成苄基阴离子化合物;
(2)使所述苄基阴离子化合物与下式苯甲醛缩合,(其中R1定义同上)(3)将步骤2的缩合产物与酰基氯反应,产生下式的酯:其中
R1、R2和R3定义同上;
R4是CO(C1-C6烷基)、CO(芳基)、CO(芳烷基)、SO2(C1-C6烷基)、SO2(芳基)、SO2(芳烷基)、CO2(C1-C6烷基)、CO2(芳基)、CO2(芳烷基)、或CON(C1-C6烷基)2;
R8是氢、卤代基、氨基、或羟基;
R9是氢、卤代基、氨基、或羟基;
R5和R6各自是C1-C4烷基,或者R5和R6与其邻接的氮原子一起,形成杂环,所述杂环选自吡咯烷(1位基)、哌啶(1位基)、六亚甲基亚氨基、和吗啉(4位基);
HX是HCl或HBr;
所述方法包括下述步骤:
(a)在酸催化剂存在下,使下式化合物产生环化反应,
[其中R1是氢、C1-C4烷氧基、芳烷氧基、卤代基、或氨基;R2是氢、C1-C4烷氧基、芳烷氧基、卤代基、或氨基;而R3是热不稳定性或酸不稳定性C2-C10烷基、C4-C10链烯基、或烷基(C1-C10烷基)],制备下式苯并噻吩化合物:(其中R1和R2定义同上)(b)用下式酰化剂将所述苯并噻吩化合物酰基化,其中
R5、R6和HX定义同上;
R7是氯、溴或羟基;
该酰化反应是在BX′3(其中X′是氯或溴)存在下进行的;
(c)如果R1和/或R2是C1-C4烷氧基或芳烷氧基,则使步骤(b)的酰化产物与另外再加入的BX′3(其中X′同上面定义)反应,而使该酰化产物上的一个或多个酚基脱烷基化;
(d)分离式XII化合物。
所谓“C1-C6烷基”代表直链或支链的1-6碳烷基。一般的C1-C6烷基包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、正己基、2-甲基戊基等等。所谓“C1-C4烷基”代表直链或支链的1-4碳烷基,它包括甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基、和叔丁基。
所谓“C1-C4烷氧基”代表甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、叔丁氧基之类的基团。所谓“卤代基”指氟、氯、溴、或碘基团。
所谓“芳基”代表苯基和取代苯基之类的基团。所谓“取代苯基”代表由选自下述的基团一个或多个取代的苯基,即卤代基、羟基、硝基、C1-C4烷基、C1-C4烷氧基、三氯甲基、和三氟甲基取代的苯基。取代苯基的例子包括4-氯苯基、2,6-二氯苯基、2,5-二氯苯基、3,4-二氯苯基、3-氯苯基、3-溴苯基、4-溴苯基、3,4-二溴苯基、3-氯-4-氟苯基、2-氟苯基、4-羟苯基、3-羟苯基、2,4-二羟苯基、3-硝苯基、4-硝苯基、2,4-二硝苯基、4-甲苯基、4-乙苯基、4-甲氧苯基、4-丙苯基、4-正丁苯基、4-叔丁苯基、3-氟-2甲苯基、2,3-二氟苯基、2,6-二氟苯基、2,6-二甲苯基、2-氟-5-甲苯基、2,4,6-三氟苯基、2-三氟甲苯基、2-氯-5-三氟甲苯基、3,5-二(三氟甲基)苯基、2-甲氧苯基、3-甲氧苯基、3,5-二甲氧苯基、4-羟基-3-甲苯基、3,5-二甲基苯基、4-羟苯基、2-甲基-4-硝苯基、4-甲氧基-2-硝苯基等等。
所谓“芳烷基”表示带有一个或多个芳基的C1-C4烷基。有代表性的该基团包括苄基、邻硝基苯甲基、对硝基苯甲基、对卤代苯甲基(例如对氯代苯甲基、对溴代苯甲基、对-碘代苯甲基)、1-苯乙基、2-苯乙基、3-苯丙基、4-苯丁基、2-甲基-2-苯丙基、(2,6-二氯苯基)甲基、二(2,6-二氯苯基)甲基、(4-羟苯基)甲基、(2,4-二硝苯基)甲基、二苯甲基、三苯甲基、(对-甲氧苯基)二苯甲基、二(对甲氧苯基)甲基、二(2-硝苯基)甲基等等。
所谓“芳烷氧基”表示带有一个或多个芳基的C1-C4烷氧基。有代表性的该基团包括苄氧基、邻硝基苄氧基、对硝基苄氧基、对卤代苄氧基(例如对氯代苄氧基、对溴代苄氧基、对碘代苄氧基)、1-苯基乙氧基、2-苯基乙氧基、3-苯基丙氧基、4-苯基丁氧基、2-甲基-2-苯基丙氧基、(2,6-二氯苯基)甲氧基、二(2,6-二氯苯基)甲氧基、(4-羟苯基)甲氧基、(2,4-二硝基苯基)甲氧基、二苯甲氧基、三苯甲氧基、(对-甲氧苯基)-二苯甲氧基、二(对-甲氧苯基)甲氧基、二(2-硝苯基)甲氧基等等。
所谓“热不稳定性或酸不稳定性C2-C10烷基、C4-C10链烯基、或芳(C1-C10烷基)”表示在受热或以酸催化剂处理条件下,容易从亚砜(SO)基中除去的基团。所述热不稳定性或酸不稳定性C2-C10烷基是具2-10个碳原子,并有至少一个β-氢原子的直链或支链烷基链。有代表性的热不稳定性或酸不稳定性C2-C10烷基包括乙基、正丙基、异丙基、1,1-二甲丙基、正丁基、仲丁基、叔丁基、1,1-二甲丁基、2-甲丁基、3-甲丁基、1-甲丁基、1,2-二甲丁基、1,3-二甲丁基、2,4-二甲丁基、3,3-二甲丁基、正戊基、1-甲戊基、2-甲戊基、3-甲戊基、4-甲戊基、正己基等等。热不稳定性或酸不稳定性C4-C10链烯基是具4-10个碳原子,至少一个不饱和位,一个β-氢原子或δ-氢原子的直链或支链烯基链。代表性的热不稳定性或酸不稳定性C4-C10链烯基包括2-丁烯基、3-丁烯基、2-甲基-2-丁烯基、3-甲基-2-丁烯基、2-甲基-3-丁烯基、2-戊烯基、3-戊烯基、4-戊烯基、2-甲基-2-戊烯基、3-甲基-2-戊烯基、4-甲基-2-戊烯基、2-甲基-3-戊烯基、3-甲基-3-戊烯基、4-甲基-3-戊烯基、2-甲基-4-戊烯基、3-甲基-4-戊烯基、4-甲基-4-戊烯基、2-己烯基、3-己烯基、4-己烯基、5-己烯基等等。所谓热不稳定性或酸不稳定性芳基(C1-C10烷基)表示另外还含有一个或多个芳基和芳基取代甲基的热不稳定性或酸不稳定性C2-C10烷基。代表性的芳基(C1-C10烷基)包括苄基、二苯甲基、三苯甲基、对甲氧苄基、2-苯乙基、2-苯丙基、3-苯丙基等等。所谓“热不稳定性或酸不稳定性C2-C10烷基、C4-C10链烯基或芳基(C1-C10烷基),这些基团有叔碳原子与硫原子相邻接”,所述这类基团包括(但不限于)叔丁基、1,1-二甲丙基、1,1-二甲丁基、1-乙基-1-甲丙基、1,1-二甲戊基、1-乙基-1-甲丁基、1,1-二乙丙基、1,1-二甲己基、三苯甲基等等。
所谓“酰基氯”包括乙酰氯和苄酰氯之类的酰氯、甲磺酰氯、苯磺酰氯、1-丁磺酰氯、乙磺酰氯、异丙磺酰氯、和对甲苯磺酰氯之类的磺酰氯、甲氧羰基氯和苄氧羰基氯之类的烷氧羰基氯、N,N-二甲氨基羰基氯之类的二烷氨基羰基氯。优选酰氯是磺酰氯、更优选甲磺酰氯。
本发明化合物可用很多途径制备,制备式II化合物的一个方法如方案1所示。
一般来说,式IX化合物与式HSR3硫醇在路易斯酸存在下反应转化成苯乙烯硫醚。然后将该式III化合物氧化成苯乙烯亚砜,即式II化合物。
更具体地说,将式IX化合物(其中R1和R2定义同上),用路易斯酸处理(如氯化钛(IV)),该反应在无水四氢呋喃之类的无水有机溶剂中,约0℃-约35℃温度下进行。约15分钟-约1小时以后,用胺碱和式HSR3硫醇处理反应混合物,(其中R3定义同上)。优选硫醇和胺碱以反应溶剂的溶液形式加入。有代表性的胺碱是三乙胺。加入硫醇和氨碱之后,一般将反应物加热至约35℃-约65℃,优选约50℃。使用本化学领域已知技术,例如重结晶或色谱,将该反应产物提纯。
然后将式III化合物(其中R1、R2和R3定义同上)氧化,产生式II化合物。该反应相宜的氧化剂是过酸,例如过乙酸和间氯代过苯丁酸,以及过氧化氢。所述氧化反应一般在有机溶剂中,例如甲苯、二氯甲烷、氯仿、或四氯化碳中进行。如果用过酸作氧化剂,该反应一般在约-30℃-约15℃温度下进行,优选-20℃左右。该反应产物易于用重结晶提纯。如果R3是叔丁基,该反应所得结晶产物是式II的E型区域异构体。
如果R3有叔碳原子与硫原子邻接,则式II化合物的Z型区域异构体,可由方案2所示途径有选择地制备。
一般地说,使苄醇,即式V化合物,与式R3SH硫醇反应,生成苄硫醚,即式VI化合物。该苄硫醚与强碱反应,形成苄基阴离子,再与苯甲醛缩合。该缩合产物与酰基氯反应,并将所得中间体酯用第二强碱处理,产生苯乙烯硫醚,即式IIIZ化合物。然后将所述苯乙烯硫醚用氧化剂氧化,生成式IIZ化合物。
合成Z型苯乙烯亚砜化合物的第一步,是将苄醇转化为苄硫醚,即式VI化合物。式V化合物(其中R2定义同上)与式R3SH硫醇(其中R3是热不稳定性或酸不稳定性C2-C10烷基、C4-C10链烯基或芳基(C1-C10烷基),这些基团有叔碳原子与硫原子邻接),在路易斯酸存在下的反应产生苄硫醇,即式VI化合物。该转化的适宜路易斯酸是溴化锌、氯化锌、碘化锌、氯化铁、氯化钛(IV)、三氯化铝、和三溴化铝、优选碘化锌。该反应一般在有机溶剂,例如1,2-二氯乙烷或二氯甲烷中进行。如果反应在室温进行,则反应在约18小时之后完成。
苄硫醚与强碱反应形成苄基阴离子。适宜于该反应的强碱包括金属醇盐,例如甲醇钠、乙醇钠、乙醇锂、叔丁醇锂、和叔丁醇钾;包括氢化钠;以及包括烷基锂,例如正丁基锂、叔丁基锂、仲丁基锂和甲基锂。该反应优选的强碱是正丁基锂。该反应优选的溶剂是无水四氢呋喃。如果以正丁基锂作强碱,则该反应在约-35℃~约-15℃温度下进行。
苄基阴离子与笨甲醛缩合,制备中间缩合产物。所述苯甲醛通式为R1(C6H4)CHO,其中R1是氢、C1-C4烷氧基、芳烷氧基、卤代基或氨基。优选先制备苄基阴离子,并通过加入苯甲醛于苄基阴离子的冷溶液中,而原位形成缩合产物。
用酰基氯处理该缩合产物,产生中间体酯。代表性的酰基氯包括乙酰氯和苯甲酰氯之类的酰氯;甲磺酰氯、苯磺酰氯、1-丁磺酰氯、乙磺酰氯、异丙磺酰氯、和对甲苯磺酰氯之类的磺酰氯;甲氧羰基氯和苄氧羰基氯之类的烷氧羰基氯;以及N,N-二甲氨基羰基氯之类的二烷氨基羰基氯。优选在缩合产物形成之后很短时间内将甲磺酰氯加入反应混合物中。
该中间体酯与第二强碱反应,生成苯乙烯硫醚,即式IIIZ化合物,其中R1、R2和R3定义同上。适宜于该反应的强碱包括金属醇盐,例如甲醇钠、乙醇钠、乙醇锂、叔丁醇锂和叔丁醇钾;包括氢化钠;包括烷基锂,例如正丁基锂、叔丁基锂、仲丁基锂、和甲基锂;包括金属氨化物,例如氨基化钠、二异丙基氨基化镁、和二异丙基氨基化锂。该反应优选的强碱是叔丁醇钾。一般来说,该反应于约15℃-约室温下进行,优选在室温下进行。
该苯乙烯硫醚氧化制备相应的苯乙烯亚砜。适宜于该反应的氧化剂是过酸,例如过乙酸和间氯代过苯甲酸;是有机过氧化物,例如叔丁基过氧化物,以及是过氧化氢。优选氧化剂是过乙酸。该氧化反应一般在有机溶剂中进行,例如甲苯、苯、二甲苯、甲醇、乙醇、乙酸甲酯、乙酸乙酯、二氯甲烷、1,2-二氯乙烷、或氯仿;优选二氯甲烷。该氧化反应可在约-40℃~约0℃温度下进行。
此外,如果R3有与硫原子邻接的叔碳原子时,可用此种苄硫醚中间体(式VI化合物)生产苯乙烯亚砜的E型和Z型异构体,即式II化合物。该合成归纳如下方案3。
将如上所述制备的苄硫醚氧化,产生相应的苄亚砜。该苄亚砜与强碱反应,所得的阴离子产物与苯甲醛缩合。该缩合产物再与酰基氯反应,所得中间体酯与第二强碱反应,得到苯乙烯亚砜。
苄硫醚,即式VI化合物(其中R2定义同上,而R3是热不稳定性或酸不稳定性C2-C10烷基、C4-C10链烯基、或芳基(C1-C10烷基),这些基团有与硫原子邻接的叔碳原子)被氧化,产生相应的苄亚砜,即式X化合物。适宜于该反应的氧化剂是过酸,例如过乙酸及间氯代过苯甲酸;是有机过氧化物,例如叔丁基过氧化物;以及是过氧化氢。优选氧化剂是过乙酸。该氧化反应一般在有机溶剂,例如甲苯、苯、二甲苯、甲醇、乙醇、乙酸甲酯、乙酸乙酯、二氯甲烷、1,2-二氯乙烷、或氯仿中进行,优选温度约-30℃~约5℃。
苄亚砜,即式X化合物(其中R2和R3定义同上)与强碱反应,生产苄基阴离子产物。适宜该反应的强碱包括金属醇盐,例如甲醇钠、乙醇钠、乙醇锂、叔丁醇锂、和叔丁醇钾;包括氢化钠;包括烷基锂,例如正丁基锂、叔丁基锂、仲丁基锂,和甲基锂;以及包括金属氨化物,例如氨基化钠、二异丙基氨基化钠、和二异丙基氨基化锂。该转化优选的碱是正丁基锂。该去质子化反应在无水有机溶剂,例如四氢呋喃、或1,2-二甲氧基乙烷中进行,温度为-25℃左右。
该苄基阴离子产物无需分离,即与式p-R1(C6H4)CHO(其中R1定义同上)的苯甲醛化合物缩合。优选将约1当量苯甲醛加入到按前一段所述制备的冷却溶液中。所得非对映异构体混合缩合产物可以分离、或者优选不分离直接用于下步反应。
该缩合产物任意用碱,例如正丁基锂处理,并与酰基氯反应。代表性的酰基氯包括酰氯,例如乙酰氯和苄酰氯;包括磺酰氯,例如甲磺酰氯、苯磺酰氯、1-丁磺酰氯、乙磺酰氯、异丙磺酰氯、和对甲苯磺酰氯;包括烷氧基羰基氯,例如甲氧羰基氯和苄氧羰基氯;以及包括二烷氨基羰基氯,例如N,N-二甲氨基羰基氯;优选磺酰氟。将酰基氯加入到冷却的反应混合物中,然后使所得混合物升至室温。优选在缩合产物形成以后很短时间内将甲磺酰氯加入到反应混合物中,可以免加所需额外的碱。
所得中间体酯与第二强碱反应,产生E型和Z型苯乙烯亚砜,即式II化合物(其中R1、R2和R3定义同上)。该消除反应所需代表性第二强碱包括金属醇盐,例如甲醇钠、乙醇钠、乙醇锂、叔丁醇锂、和叔丁醇钾;包括氢化钠;包括烷基锂,例如正丁基锂、叔丁基锂、仲丁基锂、和甲基锂;包括金属氨化物,例如氨基化钠、二异丙基氨基化镁,和二异丙基氨基化锂。该转化反应优选的碱是叔丁醇钾。优选该第二强碱加入过量20%,例如1,2当量。一般情况下,该反应在约15℃-室温下进行,优选室温。
所述中间体苯乙烯亚砜用于合成2-芳基苯并[b]噻吩,如方案4所示。
一般是将中间体苯乙烯亚砜化合物加热,并用酸催化剂处理,产生式I化合物。适于该反应的酸催化剂包括路易斯酸或布朗斯台德酸。有代表性的路易斯酸包括氯化锌、碘化锌、氯化铝、和溴化铝。有代表性的布朗斯台德酸包括无机酸,例如硫酸和磷酸;包括羧酸,例如乙酸和三氟乙酸;包括磺酸,例如甲磺酸、苯磺酸、1-萘磺酸、1-丁磺酸、乙磺酸、4-乙基苯磺酸、1-己磺酸、1,5-萘磺酸、1-辛磺酸、樟脑磺酸、三氟甲磺酸、和对甲苯磺酸;以及包括聚合芳基磺酸,例如Nafion、Amberlyst、或Amberlite。更优选的酸催化剂是磺酸,例如甲磺酸、苯磺酸、樟脑磺酸、和对甲苯磺酸。最优选的酸催化剂是对甲苯磺酸。一般是将酸催化剂在有机溶剂中的溶液(例如在甲苯、苯、二甲苯、或1,1,2-三氯代乙烷之类的高沸点卤代烃溶剂中)加热至约80°-约140℃,并用同样溶剂中的苯乙烯亚砜溶液处理。使用过量酸催化剂,优选2当量酸。为得最佳结果,原料化合物的最终浓度是约0.01M~约0.2M,优选0.05M。而且,如果将苯乙烯亚砜在约20分钟-约3小时期间慢慢加入到加热的酸溶液中时获得的产量最高。为得到最佳结果,使用Dean-Stark阱或Soxhlet萃取剂从反应溶液中除去残留的水,并用纯氮清洗该反应物。
式I化合物是合成一系列3-芳酰基-2-芳基苯并[b]噻吩的中间体。U.S专利号4133814和4418068(引入本文作为参考)介绍了这些3-芳酰基-2-芳基苯并[b]噻吩,及其从式I化合物制备它们的方法。从式I化合物(其中R1和R2是氢、C1-C4烷氧基、或芳烷氧基)制备一组3-芳酰基-2-芳基苯并[b]噻吩的改进合成法归纳于方案5中。
方案5
在三氯化硼或三溴化硼存在下(优选三氯化硼),用式XI化合物(其中R7是氯或羟基)使式I苯并噻吩化合物(其中R1和R2是氢、C1-C4烷氧基、或芳烷氧基)酰基化。该反应可以在各种不同有机溶剂中,例如氯仿、二氯乙烷、1,2-二氯乙烷、1,2,3-二氯丙烷、1,1,2,2-四氯乙烷、1,2-二氯苯、氯苯、和氟苯中进行,该合成优选溶剂是1,2-二氯乙烷。该反应在约-10℃~约25℃温度下进行,优选0℃。该反应最好在式I苯并噻吩化合物浓度为约0.2M-约1.0M下进行。该酰化反应一般在2小时-8小时左右完成。
如果R1和/或R2是C1-C4烷氧基或芳烷氧基时,该酰基化的苯并噻吩被转化为R8和/或R9是羟基的式XII化合物,该产物无需从酰基化反应物中分离出来。该转化通过再加入三卤化硼或三溴化硼并加热而完成。优选加入2-5摩尔当量三卤化硼到反应混合物中,最优选3摩尔当量。该反应在约25℃-约40℃温度下进行,优选35℃。该反应一般在4-48小时左右完成。
用醇或醇混合物使该酰基化反应或酰基化/脱酰基反应骤停。用于骤停该反应的适宜醇包括甲醇、乙醇和异丙醇。优选该酰基化/脱酰基化反应混合物中加入95∶5乙醇和甲醇混合物(3A乙醇)。该3A乙醇可以是室温,或加热至回流,优选回流。当以这种方式骤停反应时,式XII化合物能很方便地从所得醇混合物中结晶出来。一般是每毫摩尔苯并噻吩原料用1.25ml-3.75ml醇。
下面的实施例进一步说明本发明。这些实施例并不试图从任何意义上来对本发明范围加以限制,也不应当作此种解释。所有实验在干燥氮气的正压下进行。所有溶剂和试剂均采用从外面获取来的。百分率一般以重量为基础计算(w/w),但高压液体色谱(HPLC)溶剂例外,它以体积为基础计算(v/v)。质子核磁共振光谱(1H NMR)和13C核磁共振光谱(13C NMR),在Bmker AC-300 FTNMR光谱仪上,于300.135MHz,或在GE QE-300光谱仪上,于300.15MHz获得。按Still等人所述,使用硅胶60(230-400目,E.Merck)进行硅胶快速色谱分析。参见Still等人,J.Org.Chem.,43,2923(1978)。在ControlEquipment Corporation 440元素分析仪上测定分析碳、氢、和氮元素。而硫元素分析则在Brirkman Colorimetric元素分析仪上测定。熔点在开口玻璃毛细管中,于Mel-Temp II熔点装置,或Mettler FP 62自动仪上测定,未校正过。使用Varian Instruments VG 70-SE或VG ZAB-3F质谱仪获得场解吸质谱(FDMS)。使用Varian Instruments VG ZAB-2SE质谱获得高分辨自由原子轰击质谱(FABMS)。
将原位获得的6-甲氧基-2-(4-甲氧苯基)苯并[b]噻吩用高压液体色谱(HPLC)测定,与用已公开发表的合成途径制备的该化合物可信样品进行比较。参见US专利4,133,814。一般是用乙腈稀释反应混合物样品,该稀释样品用Zorbax RX-C8柱(4.6mm×25cm),带有UV检测器(280nm)的HPLC进行检测。用下面的线性梯度溶剂系统进行该分析:
梯度溶剂系统
时间(分) A(%) B(%)
0 50 50
2 50 50
20 20 80
35 20 80
37 50 50
45 50 50
A:0.01M磷酸钠水溶液(pH2.0)
B:乙腈
用下述方法测定结晶物质中6-羟基-2-(4-羟苯基)-3-[4-(2-哌啶子基乙氧基)苄酰基]苯并[b]噻吩的百分含量。将结晶固体(5mg)称重加入100ml体积烧瓶中,并溶解于70/30(v/v)75mM磷酸钾缓冲液(pH2.0)和乙腈的混合物中。使用Zorbax RX-C8柱(25cm×4.6mm ID,5μ颗粒)和带有UV检测器(280nm)的高压液体色谱测试该溶液的等分样品(10μl)。采用下面的梯度溶剂系统:
梯度溶剂系统(浓度)时间(分) A(%) B(%)
0 70 30
12 70 30
14 25 75
16 70 30
25 70 30
A:75mM KH2PO4缓冲液(pH2.0)
B:乙腈
溶剂(例如1,2-二氯乙烷)在结晶物中含量(百分比)由气相色谱测定。将结晶固体样品称重(50mg)装入10ml体积烧瓶中,溶解于2-丁醇(0.025mg/ml)的二甲基亚砜溶液中。使用DB Wax柱(30m×0.53mm ID,1μ颗粒),以气相色谱分析该溶液样品,其柱流速10ml/分,并采用火焰离子检测器。在12分钟期间,将柱温从35℃升至230℃。通过与内标物(2-丁醇)比较,测定溶剂量。
实施例1
E~叔丁基4,4′-二甲氧基均二苯乙烯亚砜
A.制备E-叔丁基4,4′-二甲氧基均二苯乙烯硫醚
将脱氧茴香偶姻(12.82g)的四氢呋喃(100ml)溶液用氯化钛(IV)(10.43g)处理。滴加氯化钛(IV)期间,冷却反应混合物,使温度维持在35℃以下。当加完时,于30℃搅拌所得混合物。再过30分钟之后用2-甲基-2-丙硫醇(6.76ml)和三乙胺(16.70ml)的四氢呋喃(15ml)溶液处理该混合物。于50℃搅拌所得混合物。2小时之后,将该混合物加入到10%碳酸钠(500ml)中。用二氯甲烷提取所得混合物。合并二氯甲烷提取液,用硫酸镁干燥,过滤,真空浓缩,得到17.2g油状物,当冷至室温时结晶。该结晶物从热乙醇中重结晶,得到12.3g标题化合物。熔点71-73℃。
C20H24O2S的分析计算值:C,73.13;H,7.36;S,9.76。实验值:C,73.37;H,7.51;S,9.87。
B.制备E-叔丁基4,4′-二甲氧基均二苯乙烯亚砜
将实施例1A制备的结晶化合物溶于甲苯(150ml)中,所得溶液冷却至约-20℃。该冷溶液用过乙酸(32%w/w于稀乙酸中,1.24g)处理10分钟。用饱和亚硫酸钠和盐水提取所得混合物。真空浓缩有机相。从乙酸乙酯/庚烷中使残留物重结晶,得到14.11g标题化合物。熔点104℃(分解)。
C20H24O3S的分析计算值:C,69.74;H,7.02;S,9.31。实验值:C,69.47;H,7.04;S,9.54。
实施例2
Z-叔丁基4,4′-二甲氧基均二苯乙烯亚砜
A.制备叔丁基4-甲氧苄基硫醚
将4-甲氧苄醇(10.13g)和碘化锌(11.7g)在1,2-二氯乙烷(120ml)中的混合物,用一份2-甲基-2-丙硫醇(9.92ml)处理。所得混合物于室温下搅拌。约18小时之后,用水(100ml)和二氯甲烷(100ml)稀释该反应物。分出有机相,用硫酸钠干燥、过滤、并真空浓缩,得到14.4g油状物。
1H NMR(CDCl3):δ7.28(d,2H),6.85(d,2H),3.77(s,3H),3.73(s,2H),1.36(s,9H).
13C NMR(CDCl3):δ130,114,56,35,32.
C12H18OS的分析计算值:C,68.52;H,8.63。实验值:C,68.80;H,8.67。
B.制备Z-叔丁基4,4′-二甲氧基均二苯乙烯硫醚
将例2A制备的化合物(2.51g)在四氢呋喃(50ml)中的溶液冷却至-20℃左右。在10分钟期间,用正丁基锂的己烷(1.6M,7.47ml)溶液处理该冷却溶液。所得溶液在35分钟期间升至0℃左右。用对甲氧基苯甲醛(1.46ml)处理该冷溶液。再过15分钟后,用甲磺酰氯(0.95ml)处理该反应溶液。所得反应物升至室温,再过45分钟后,用叔丁醇钾的THF溶液(1.0M,12.0ml)处理反应混合物。再过45分钟后,加入1N盐酸(12.0ml)使反应骤停。分离出有机相,用硫酸镁干燥,过滤,浓缩得油状物(4.4g)。
1H NMR(CDCl3):δ7.95(d,H),7.05(s,H),6.9(d,H),6.8(dd,2H),3.75(s,3H),0.95(s,9H).
13C NMR(CDCl3):δ153,139,137,114,56,32.
C.制备Z-叔丁基4,4′-二甲氧基均二苯乙烯亚砜
使用与例1B所述基本相同的方法将例2B化合物转化为本标题化合物。
1H NMR(CDCl3):δ7.61(d,H),7.56(d,H),7.1(s,H),6.9(dd,2H),3.83(s,3H),1.05(s,9H).
13C NMR(CDCl3):δ142,132.5,131,118,117,56,24.
C20H24O3S的分析计算值:C,69.74;H,7.02。实验值:C,69.98;H,6.94。
实施例3
E和Z-叔丁基4,4′-二甲氧基均二苯乙烯亚砜
A.制备叔丁基4-甲氧基苄基硫醚
将4-甲氧苄醇(10.13g)和碘化锌(11.7g)在1,2-二氯乙烷(120ml)中的混合物用一份2-甲基-2-丙硫醇(9.92ml)处理。室温下搅拌该所得混合物。约18小时后,用水(100ml)和二氯甲烷(100ml)稀释该反应物。除去有机相,用硫酸镁干燥、过滤、真空浓缩,得到14.4g油状物。
1H NMR(CDCl3):δ7.28(d,2H),6.85(d,2H),3.77(s,3H),3.73(s,2H),1.36(s,9H).
13C NMR(CDCl3):δ130,114,56,35,32.
C12H18OS的分析计算值:C,68.52;H,8.63。实验值:C,68.8;H,8.67。
B.制备叔丁基4-甲氧基苄亚砜
将上述例3A制备的化合物(14.4g)的1,2-二氯乙烷(50ml)溶液冷却至5℃,在30分钟期间用过乙酸(32%w/w于稀乙酸中,14.2ml)处理该冷溶液。加完过乙酸后,再用盐水和碳酸氢钠处理该反应物。分出有机相,用硫酸镁干燥、过滤、浓缩至黄色沉淀。用己烷(100ml)处理该残留物,室温下搅拌所得混合物。约18小时之后,过滤该混合物,用己烷(100ml)洗涤该固体。真空干燥该固体物,得到14.07g标题化合物。熔点124-126℃。
1H NMR(CDCl3):δ7.26(d,2H),6.89(d,2H),3.79(d,H),3.78(s,3H),3.58(d,H),1.3(s,9H).
13C NMR(CDCl3):δ132,114,56,53,23.
C12H18O2S的分析计算值:C,63.68;H,8.02。实验值:C,63.72;H,7.93。
C.制备E和Z-叔丁基4,4′-二甲氧基均二苯乙烯亚砜
将例3B制得的化合物(10.0g)的THF(140ml)溶液冷至-30°~-25℃左右(干冰/丙酮浴)。在25分钟期间用正丁基锂的环己烷液(1.6M,27.65ml)处理该冷溶液。搅拌35分钟之后,用对甲氧基苯甲醛(5.4ml)处理反应混合物。撤去干冰/丙酮浴,反应物升至约20℃。用甲磺酰氯(3.5ml)处理反应混合物。当加入甲磺酰氯时,反应温度由约20℃升至约35℃。将混合物冷至约25℃,然后用THF中的叔丁醇钾(1M,50.9ml)处理。再搅拌35分钟之后,用1N盐酸(51.0ml)处理反应物。进行相分离,用硫酸镁干燥有机层,过滤、浓缩成油状物(16.67g)。不需进一步提纯,该物被用于下步反应。碳NMR光谱和质子NMR光谱与实施例1和2制得的该化合物之NMR光谱相似。
实施例4
Z-叔丁基4,4′-二甲氧基均二苯乙烯亚砜
将例3B制备的化合物(3.0g)的THF(40ml)溶液冷却至-15℃。在15分钟期间,用正丁基锂的环己烷液(1.6M,8.3ml)处理该冷溶液。搅拌10分钟之后,反应混合物升至0℃并用对甲氧基苯甲醛(1.6lml)处理。撤去冰浴,反应物升至室温,用乙酰氯(0.95ml)处理该混合物。约1小时后,用THF中的叔丁醇钾(1M,16.0ml)处理反应混合物。再搅拌1.5小时后,用1N盐酸(17.0ml)处理反应物。进行相分离,用硫酸镁干燥有机层,过滤、浓缩至油状物(5.26g)。不需进一步提纯,该物即能使用。碳NMR光谱和质子NMR光谱与实施例所制化合物之NMR光谱相似。
实施例5
6-甲氧基-2-(4-甲氧苯基)苯并[b]噻吩
将对甲苯磺酸一水合物(2.25g)的甲苯(60ml)溶液加热回流。除去水,使之收集入Dean-Stark阱中。采用通过冷凝器顶部排除的氮气清吹,将例1制得的化合物(2.04g)的甲苯(33ml)溶液在1.5小时期间加入到回流的酸溶液中。在氮气清吹条件下,所得混合物冷至约5℃,然后用水(8ml)处理。将所得浆状物搅拌3小时,过滤,用水(8ml)和丙酮(8ml)洗涤结晶产物。40℃真空干燥该结晶产物约18小时,得到1.30g浅褐色固态标题化合物。该化合物与由公知方法制备的化合物相同。熔点196-199℃。
实施例6
6-甲氧基-2-(4-甲氧苯基)苯并[b]噻吩
将对甲苯磺酸一水合物(2.49g)的甲苯(108ml)溶液加热回流,除去水份,使其收集入Dean-Stark阱中。将例1制得的化合物(9.00g)的甲苯(32ml)溶液在6小时期间加入到回流的酸溶液中。当加完时,再加入无水乙醇(35ml)到反应溶液中,将所得混合物降至室温。约18小时后,过滤分离出沉淀。用甲苯/无水乙醇(4∶1,29ml)洗涤沉淀,40℃真空干燥约18小时,得到4.86g固体。该化合物与公知方法合成的化合物相同。熔点199-200℃。
实施例7
盐酸6-羟基-2-(4-羟苯基)-3-[4-(2-哌啶
子基乙氧基)-苄酰基]苯并[b]噻吩1,2-二氯乙烷溶剂化物
A.制备4-(2-哌啶子基乙氧基)苯甲酸乙酯
将4-羟基苯甲酸乙酯(8.31g),1-(2-氯乙基)哌啶-盐酸盐(10.13g)、碳酸钾(16.59g)、和甲乙酮(60ml)的混合物加热至80℃。1小时后,该混合物冷却至55℃左右,并用另外的1-(2-氯乙基)哌啶-盐酸盐(0.92g)处理。所得混合物加热至80℃。用薄层色谱(TLC)监测该反应,所述薄层色谱是以硅胶板,和乙酸乙酯/乙腈/三乙胺(10∶6∶1,v/v)进行。再加入几份1-(2-氯乙基)哌啶盐酸盐,直至4-羟基苯甲酸乙酯原料消耗完为止。反应完成后,用水(60ml)处理反应混合物,并使其降至室温。弃去水层,40℃和40mmHg条件下将有机层真空浓缩。不进一步提纯,所得油状物可用于下步反应。
B.制备盐酸4-(2-哌啶子基乙氧基)苯甲酸
用5N氢氧化钠(15ml)处理实施例7A制备的化合物(约13.87g)的甲醇(30ml)溶液,并加热至40℃。41/2小时之后,加入水(40ml)所得混合物冷却至5-10℃,慢慢加入浓盐酸(18ml)。酸化期间,本标题化合物即结晶出。过滤收集该晶体产物,40-50℃真空干燥,得到83%产率的本标题化合物。熔点270-271℃。
C.制备盐酸4-(2-哌啶子基乙氧基)苄酰氯
将例7B制备的化合物(30.01g)和二甲基甲酰胺(2ml)的二氯甲烷(500ml)溶液在30-35分钟期间用草酰氯(10.5ml)处理。搅拌约18小时后,用HPLC分析检测反应是否完全。如果还存在羧酸原料,则再加入草酰氯于反应物中。反应完成时,该反应溶液真空蒸发至干。将残渣溶于二氯甲烷(200ml),并将所得溶液蒸发至干。重复该溶解/蒸发程序得到固态标题化合物。该化合物可以固态贮存,或可配成0.2M二氯甲烷溶液(500ml)。
D.制备盐酸6-羟基-2-(4-羟基苯基)-3-[4-(2-哌啶子基乙氧基)苄酰基]苯并[b]噻吩1,2-二氯乙烷溶剂化物
将例5或6制备的化合物(2.92g)、例7C制备的化合物(3.45g)、和1,2-二氯乙烷(52ml)的混合物冷却至0℃左右。将三氯化硼气体凝缩进冷量筒(2.8ml)中,并加入到上述冷混合物中。于0℃8小时后,该反应混合物再用三氯化硼(2.8ml)处理。将所得溶液加热至35℃。16小时后,反应完成。
用上述反应混合物以20分钟时间处理甲醇(30ml),使甲醇回流。于25℃搅拌所得浆液。1小时后,滤出结晶产物,用冷甲醇(8ml)洗涤,于40℃真空干燥,得到5.14g标题化合物。熔点225℃。
含量:86.8%
1,2-二氯乙烷:6.5%(气相色谱)
Claims (2)
R8是氢、卤代基、氨基、或羟基;
R9是氢、卤代基、氨基、或羟基;
R5和R6各自是C1-C4烷基,或者R5和R6与其邻接的氮原子一起形成杂环,所述杂环选自吡咯烷基(1位基)、哌啶子基、六亚甲基亚氨基、和吗啉代基;
HX是HCl或HBr;
所述方法包括下述步骤:
式中
R1是氢、C1-C4烷氧基、芳烷氧基、卤代基、或氨基;
R2是氢、C1-C4烷氧基、芳烷氧基、卤代基、或氨基;而
R3是热不稳定性或酸不稳定性C2-C10烷基、C4-C10链烯基、或芳基(C1-C10烷基),
R5、R6和HX的定义如上所述;
R7是氯代基、溴代基或羟基;
该酰化反应是在其式中的X′是氯或溴的BX′3存在下进行的;
(c)如果R1和/或R2是C1-C4烷氧基或芳烷氧基,则使步骤(b)的酰化产物与另外再加入的其式中X′的定义如上所述的BX′3进行反应,而使该酰化产物上的一个或多个酚基脱烷基化;
(d)任意选择地分离式XII化合物。
2.根据权利要求1的方法,其中所制备的式XII化合物是式中的R5和R6与邻接的氮原子一起形成一个哌啶子基环,而R8和R9两者是羟基以及HX是HCl的式XII化合物。
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US08/483,130 | 1995-06-07 | ||
US08/478,706 US5659087A (en) | 1995-06-07 | 1995-06-07 | Diarylvinyl sulfoxides |
US08/478,706 | 1995-06-07 | ||
US08/483,130 US6372945B1 (en) | 1995-06-07 | 1995-06-07 | Process for the synthesis of vinyl sulfoxides |
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BR9608579A (pt) | 1999-01-05 |
NO5987A (no) | 1997-12-03 |
AU6092096A (en) | 1996-12-30 |
NO20005987D0 (no) | 2000-11-27 |
NO975578D0 (no) | 1997-12-03 |
NO975578L (no) | 1997-12-03 |
TR199701510T1 (xx) | 1998-03-21 |
EA199800028A1 (ru) | 1998-08-27 |
NZ310179A (en) | 1999-09-29 |
EP0830361A4 (en) | 1998-12-30 |
HUP9900922A3 (en) | 2000-06-28 |
HUP9900922A2 (hu) | 1999-07-28 |
IL122090A0 (en) | 1998-04-05 |
CA2220145A1 (en) | 1996-12-19 |
TR199801495T2 (xx) | 1998-09-21 |
JPH11507061A (ja) | 1999-06-22 |
EP0830361A1 (en) | 1998-03-25 |
TR199801494T2 (xx) | 1998-09-21 |
PL324035A1 (en) | 1998-05-11 |
KR19990022362A (ko) | 1999-03-25 |
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