CN1230957A - 苯并噻吩的合成方法 - Google Patents
苯并噻吩的合成方法 Download PDFInfo
- Publication number
- CN1230957A CN1230957A CN97198100A CN97198100A CN1230957A CN 1230957 A CN1230957 A CN 1230957A CN 97198100 A CN97198100 A CN 97198100A CN 97198100 A CN97198100 A CN 97198100A CN 1230957 A CN1230957 A CN 1230957A
- Authority
- CN
- China
- Prior art keywords
- acid
- compound
- alkyl
- reaction
- zeo
- Prior art date
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- Granted
Links
- 238000000034 method Methods 0.000 title claims abstract description 45
- 230000008569 process Effects 0.000 title claims abstract description 12
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical class C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 title abstract description 39
- 230000015572 biosynthetic process Effects 0.000 title description 5
- 238000003786 synthesis reaction Methods 0.000 title description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 64
- 150000001875 compounds Chemical class 0.000 claims description 31
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 30
- 229920005989 resin Polymers 0.000 claims description 19
- 239000011347 resin Substances 0.000 claims description 19
- -1 pyrrolidyl Chemical group 0.000 claims description 17
- 150000003839 salts Chemical class 0.000 claims description 14
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 12
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 12
- 239000011541 reaction mixture Substances 0.000 claims description 9
- 238000002360 preparation method Methods 0.000 claims description 8
- 238000007363 ring formation reaction Methods 0.000 claims description 8
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 3
- 125000005936 piperidyl group Chemical group 0.000 claims description 2
- 239000012453 solvate Substances 0.000 claims description 2
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 claims description 2
- 239000003729 cation exchange resin Substances 0.000 abstract 1
- 229940023913 cation exchange resins Drugs 0.000 abstract 1
- 238000006243 chemical reaction Methods 0.000 description 32
- 239000002904 solvent Substances 0.000 description 24
- 239000002253 acid Substances 0.000 description 13
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 12
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
- 238000010520 demethylation reaction Methods 0.000 description 11
- 230000017858 demethylation Effects 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- 239000000203 mixture Substances 0.000 description 8
- 239000002994 raw material Substances 0.000 description 7
- 239000000376 reactant Substances 0.000 description 7
- 238000006462 rearrangement reaction Methods 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 6
- 230000008707 rearrangement Effects 0.000 description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 5
- 239000003377 acid catalyst Substances 0.000 description 5
- 239000006227 byproduct Substances 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 4
- 229920005654 Sephadex Polymers 0.000 description 4
- 239000012507 Sephadex™ Substances 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 4
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 4
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 229920001429 chelating resin Polymers 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 3
- 125000001931 aliphatic group Chemical group 0.000 description 3
- 239000001913 cellulose Substances 0.000 description 3
- 229920002678 cellulose Polymers 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 229910052500 inorganic mineral Inorganic materials 0.000 description 3
- 239000006210 lotion Substances 0.000 description 3
- 239000011707 mineral Substances 0.000 description 3
- 235000010755 mineral Nutrition 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- QPFMBZIOSGYJDE-UHFFFAOYSA-N 1,1,2,2-tetrachloroethane Chemical compound ClC(Cl)C(Cl)Cl QPFMBZIOSGYJDE-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- 239000002841 Lewis acid Substances 0.000 description 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
- 239000004793 Polystyrene Substances 0.000 description 2
- 229920002684 Sepharose Polymers 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000003849 aromatic solvent Substances 0.000 description 2
- 238000010533 azeotropic distillation Methods 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 238000005336 cracking Methods 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- DGXRZJSPDXZJFG-UHFFFAOYSA-N docosanedioic acid Chemical compound OC(=O)CCCCCCCCCCCCCCCCCCCCC(O)=O DGXRZJSPDXZJFG-UHFFFAOYSA-N 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 230000002349 favourable effect Effects 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 150000007517 lewis acids Chemical class 0.000 description 2
- 239000007791 liquid phase Substances 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- 238000006198 methoxylation reaction Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- XTEGVFVZDVNBPF-UHFFFAOYSA-N naphthalene-1,5-disulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1S(O)(=O)=O XTEGVFVZDVNBPF-UHFFFAOYSA-N 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- FDPIMTJIUBPUKL-UHFFFAOYSA-N pentan-3-one Chemical compound CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 description 2
- 229920002223 polystyrene Polymers 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
- 230000000171 quenching effect Effects 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000011877 solvent mixture Substances 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 125000000542 sulfonic acid group Chemical group 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 2
- UAYWVJHJZHQCIE-UHFFFAOYSA-L zinc iodide Chemical compound I[Zn]I UAYWVJHJZHQCIE-UHFFFAOYSA-L 0.000 description 2
- 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 1
- UWYVPFMHMJIBHE-OWOJBTEDSA-N (e)-2-hydroxybut-2-enedioic acid Chemical class OC(=O)\C=C(\O)C(O)=O UWYVPFMHMJIBHE-OWOJBTEDSA-N 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- HCSBTDBGTNZOAB-UHFFFAOYSA-N 2,3-dinitrobenzoic acid Chemical compound OC(=O)C1=CC=CC([N+]([O-])=O)=C1[N+]([O-])=O HCSBTDBGTNZOAB-UHFFFAOYSA-N 0.000 description 1
- HCVAHOALJPEBKZ-UHFFFAOYSA-N 2-acetyl-3-aminobenzoic acid Chemical class CC(=O)C1=C(N)C=CC=C1C(O)=O HCVAHOALJPEBKZ-UHFFFAOYSA-N 0.000 description 1
- HMGCGUWFPZVPEK-UHFFFAOYSA-N 2-naphthalen-2-ylbenzoic acid Chemical compound OC(=O)C1=CC=CC=C1C1=CC=C(C=CC=C2)C2=C1 HMGCGUWFPZVPEK-UHFFFAOYSA-N 0.000 description 1
- OFJWFSNDPCAWDK-UHFFFAOYSA-N 2-phenylbutyric acid Chemical class CCC(C(O)=O)C1=CC=CC=C1 OFJWFSNDPCAWDK-UHFFFAOYSA-N 0.000 description 1
- WHBMMWSBFZVSSR-UHFFFAOYSA-N 3-hydroxybutyric acid Chemical class CC(O)CC(O)=O WHBMMWSBFZVSSR-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 1
- 229920000936 Agarose Polymers 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 229920000742 Cotton Polymers 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- 206010013786 Dry skin Diseases 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- QIAFMBKCNZACKA-UHFFFAOYSA-N N-benzoylglycine Chemical compound OC(=O)CNC(=O)C1=CC=CC=C1 QIAFMBKCNZACKA-UHFFFAOYSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
- ZZXDRXVIRVJQBT-UHFFFAOYSA-M Xylenesulfonate Chemical compound CC1=CC=CC(S([O-])(=O)=O)=C1C ZZXDRXVIRVJQBT-UHFFFAOYSA-M 0.000 description 1
- FUYHPEFCMUFNLQ-UHFFFAOYSA-N [4-(2-aminoethoxy)phenyl]-[6-hydroxy-2-(4-hydroxyphenyl)-1-benzothiophen-3-yl]methanone Chemical compound C1=CC(OCCN)=CC=C1C(=O)C1=C(C=2C=CC(O)=CC=2)SC2=CC(O)=CC=C12 FUYHPEFCMUFNLQ-UHFFFAOYSA-N 0.000 description 1
- GVHFVTLDHBPKOF-UHFFFAOYSA-N [4-[2-(dimethylamino)ethoxy]phenyl]-[6-hydroxy-2-(4-hydroxyphenyl)-1-benzothiophen-3-yl]methanone Chemical compound C1=CC(OCCN(C)C)=CC=C1C(=O)C1=C(C=2C=CC(O)=CC=2)SC2=CC(O)=CC=C12 GVHFVTLDHBPKOF-UHFFFAOYSA-N 0.000 description 1
- CRPBGTFXFYXYBH-UHFFFAOYSA-N [4-[2-(ethoxymethylamino)ethoxy]phenyl]-[6-hydroxy-2-(4-hydroxyphenyl)-1-benzothiophen-3-yl]methanone Chemical compound C1=CC(OCCNCOCC)=CC=C1C(=O)C1=C(C=2C=CC(O)=CC=2)SC2=CC(O)=CC=C12 CRPBGTFXFYXYBH-UHFFFAOYSA-N 0.000 description 1
- SEPMRKANBJYIOT-UHFFFAOYSA-N [6-hydroxy-2-(4-hydroxyphenyl)-1-benzothiophen-3-yl]-[4-[3-methyl-2-(methylamino)pentoxy]phenyl]methanone Chemical compound C1=CC(OCC(C(C)CC)NC)=CC=C1C(=O)C1=C(C=2C=CC(O)=CC=2)SC2=CC(O)=CC=C12 SEPMRKANBJYIOT-UHFFFAOYSA-N 0.000 description 1
- JCHQKERCGIFPRD-UHFFFAOYSA-K [B+3].[I-].[I-].[I-] Chemical compound [B+3].[I-].[I-].[I-] JCHQKERCGIFPRD-UHFFFAOYSA-K 0.000 description 1
- WAIPAZQMEIHHTJ-UHFFFAOYSA-N [Cr].[Co] Chemical compound [Cr].[Co] WAIPAZQMEIHHTJ-UHFFFAOYSA-N 0.000 description 1
- IPBVNPXQWQGGJP-UHFFFAOYSA-N acetic acid phenyl ester Natural products CC(=O)OC1=CC=CC=C1 IPBVNPXQWQGGJP-UHFFFAOYSA-N 0.000 description 1
- CGIHPACLZJDCBQ-UHFFFAOYSA-N acibenzolar Chemical group SC(=O)C1=CC=CC2=C1SN=N2 CGIHPACLZJDCBQ-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
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- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 125000003289 ascorbyl group Chemical class [H]O[C@@]([H])(C([H])([H])O*)[C@@]1([H])OC(=O)C(O*)=C1O* 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 150000001555 benzenes Chemical class 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 238000007600 charging Methods 0.000 description 1
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- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- JOYKCMAPFCSKNO-UHFFFAOYSA-N chloro benzenesulfonate Chemical compound ClOS(=O)(=O)C1=CC=CC=C1 JOYKCMAPFCSKNO-UHFFFAOYSA-N 0.000 description 1
- KVSASDOGYIBWTA-UHFFFAOYSA-N chloro benzoate Chemical compound ClOC(=O)C1=CC=CC=C1 KVSASDOGYIBWTA-UHFFFAOYSA-N 0.000 description 1
- 229940114081 cinnamate Drugs 0.000 description 1
- GKIRPKYJQBWNGO-OCEACIFDSA-N clomifene Chemical compound C1=CC(OCCN(CC)CC)=CC=C1C(\C=1C=CC=CC=1)=C(\Cl)C1=CC=CC=C1 GKIRPKYJQBWNGO-OCEACIFDSA-N 0.000 description 1
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- 230000001186 cumulative effect Effects 0.000 description 1
- 230000020335 dealkylation Effects 0.000 description 1
- 238000006900 dealkylation reaction Methods 0.000 description 1
- GHVNFZFCNZKVNT-UHFFFAOYSA-M decanoate Chemical compound CCCCCCCCCC([O-])=O GHVNFZFCNZKVNT-UHFFFAOYSA-M 0.000 description 1
- HRKQOINLCJTGBK-UHFFFAOYSA-N dihydroxidosulfur Chemical compound OSO HRKQOINLCJTGBK-UHFFFAOYSA-N 0.000 description 1
- IJKVHSBPTUYDLN-UHFFFAOYSA-N dihydroxy(oxo)silane Chemical compound O[Si](O)=O IJKVHSBPTUYDLN-UHFFFAOYSA-N 0.000 description 1
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical class [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- GRWZHXKQBITJKP-UHFFFAOYSA-N dithionous acid Chemical compound OS(=O)S(O)=O GRWZHXKQBITJKP-UHFFFAOYSA-N 0.000 description 1
- 229950007655 esilate Drugs 0.000 description 1
- 239000000262 estrogen Substances 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-N ethanesulfonic acid Chemical compound CCS(O)(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-N 0.000 description 1
- DNJIEGIFACGWOD-UHFFFAOYSA-N ethanethiol Chemical compound CCS DNJIEGIFACGWOD-UHFFFAOYSA-N 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
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- 238000011156 evaluation Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000000434 field desorption mass spectrometry Methods 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
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Classifications
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- 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
-
- 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
Abstract
本发明提供利用阳离子交换树脂制备苯并噻吩的改进方法。
Description
本发明涉及药物化学领域，并提供由二烷氧基苯乙酮制备一组苯并噻吩类化合物的有利方法。该方法可大规模、高产率提供所需化合物。
通过二烷氧基苯并噻吩中间体制备苯并噻吩在U.S.4380635(该公开结合在此作为参考)中早有叙述，该公开提出了在多磷酸(PPA)存在下的α-(3-甲氧基苯基硫代)-4-甲氧基苯乙酮的分子内环化作用。在PPA存在下，于大约85℃加热苯乙酮原料约1小时可得到两种异构体：6-甲氧基-2-(4-甲氧基苯基)苯并[b]噻吩和4-甲氧基-2-(4-甲氧基苯基)苯并[b]噻吩的3∶1的混合物。然而，当该反应以生产规模进行时，所述异构的苯并噻吩会沉淀并产生一种用常用生产设备无法充分搅拌的粘稠糊状物。
Guy等(Synthesis，222(1980))已尝试使用溶剂以减轻糊状物在不同反应图式中引起的问题。然而，当该方法应用于本图式时，加入溶剂导致原料苯乙酮的不完全环化，6-甲氧基-3-(4-甲氧基苯基)苯并[b]噻吩的不完全重排，并大大增加了反应时间。
因此，需要一种运用可选择的催化剂使二烷氧基苯乙酮衍生物以适合的产率和可接收的反应时间转化为苯并噻吩的改进方法。
本发明提供使用阳离子交换树脂制备苯并噻吩的方法。本制备方法依赖二烷氧基苯乙酮衍生物的分子内环化作用以产生苯并噻吩。
因此，本发明提供在阳离子交换树脂的存在下制备式I化合物的方法：
其中R基团是相同的或不同的，并代表C1-C6烷基，该方法包括式II化合物的环化：
其中R基团如上定义。
在raloxifene(一种雌激素受体调节剂)或SERM的合成中，苯并噻吩是重要的中间体。本发明除了提供制备这种中间体的改进方法外，还提供制备式III化合物或其药学上可接受的盐或溶剂化物的改进方法：
其中：R1和R2独立为C1-C6烷基，或与它们连接的氮一起形成哌啶基、吡咯烷基、甲基-吡咯烷基、二甲基吡咯烷基或六亚甲基亚氨基，该方法包括在阳离子交换树脂的存在下，使式II化合物环化：
其中R基团是相同的或不同的，并代表C1-C6烷基。
在U.S.4133814和U.S.4380635中还提供用本发明方法制备的许多原料和化合物，这些公开结合在此作为参考。
在本文中，所有温度均以摄氏度表示。除溶剂比例用体积单位表示外，所有的用量、比率、浓度、比例等均用重量单位表示，除非另有所指。
用于本文的术语“酸催化剂”表示路易斯酸或Brnsted acid。代表性的路易斯酸为氯化锌、碘化锌、氯化铝和溴化铝。代表性的Brnsted acid包括无机酸，如硫酸和磷酸；羧酸，如乙酸和三氟乙酸；磺酸，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-萘二磺酸、1-辛磺酸、樟脑磺酸、三氟甲磺酸和对-甲苯-磺酸。另外，术语“酸催化剂”包括阳离子交换树脂，它也可称为树脂-基酸催化剂。这些阳离子交换树脂被定义为不溶性的酸性树脂。所述阳离子交换树脂包括(但不限于)葡聚糖阳离子交换剂，如CM Sephadex(羧甲基Sephadex)、SP Sephadex(磺丙基Sephadex)等；琼脂糖阳离子交换剂，如CM Sepharose、S Sepharose等；纤维素阳离子交换剂，如CM纤维素、磷酸纤维素、次硫酸乙基纤维素(Sulfoxyethyl cellulose)等；聚苯乙烯阳离子交换剂，如磺化的聚苯乙烯树脂(树脂上磺酸基团的总数一般不同)，包括AmberlystXN-1010、Amberlyst15、Amberlite、XE586等；磺化的多氟烃树脂，包括Nafion-H树脂；氧化纤维素；SP Trisacryl树脂，如SP Trisacryl PlusM和SP Trisacryl Plus LS；聚(N-三[羟甲基]甲基甲基丙烯酰胺树脂等。
术语“卤代”指氟、氯、溴或碘基团。
术语“C1-C6烷基”表示具有1-6个碳原子直链或支链烷基链。典型的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。术语“C1-C4烷基”表示具有1-4个碳原子直链或支链烷基链，并包括甲基、乙基、正-丙基、异丙基、正-丁基、仲-丁基、异丁基和叔-丁基。
本领域已知适合的活化酯基团。形成和除去保护基团的大量反应在许多标准著作包括，如Protective Groups in Organic Chemistry，PlenumPress(London and New York，1973)；Green，T.W.Protective Groups inOrganic Synthesis，Wiley，(New York，1981)；及The Peptides，Vol.I，Schrooder和Lubke，Academic Press(London and New York，1965)中有描述。本领域已知羟基保护基团，尤其是甲基的非区域选择性的除去方法。预先在6-和4-’位已经用甲氧基保护的式III化合物可以被选择性的裂解而生成具有4’-甲氧基的式III化合物。一般来说，裂解4’位甲氧基的方法包括使6-，4’-二甲氧基作用物与选自下列基团的脱甲基化试剂混合：三溴化硼、三氯化硼或三碘化硼，或者与三氯化铝和各种硫醇试剂如EtSH化合。在惰性气体如氮气环境下，每摩尔需裂解的甲氧基与一或数摩尔的所述试剂进行反应。
去保护反应的适合的溶剂为在脱甲基化反应过程中保持惰性的溶剂或溶剂的混合物。优选卤化溶剂如二氯甲烷、1，2-二氯乙烷和氯仿，或芳族溶剂如苯或甲苯。用于该反应的温度应足以完成脱甲基化反应。然而，为了最大限度地选择性裂解4’-甲氧基和避免形成不需要的副产物，尤其是因过量的脱甲基化作用而产生的6，4’-二羟基类似物，保持温度低于0℃比较有利。在优选的反应条件下，在搅拌该反应物约1-24小时后，将形成选择性的脱烷基化产物。优选的变化包括在氮气环境下、于-20℃、在二氯甲烷中，使用大约1.5摩尔量的三溴化硼和1摩尔6，4’-二甲氧基作用物反应1-4小时。
用于本发明方法的原料可以通过多种途径，包括U.S.4133814和U.S.4380635公开的途径获得。制备本发明提供的式I化合物方法见以下图式I所示：
图式I
整个反应过程包括首先的环化步骤和随后的重排步骤。式I化合物是所需的产物。第一步的环化反应在各种催化剂存在下发生，反应通常比随后的重排反应快约5-100倍。本发明使用阳离子交换树脂作为酸催化剂。
通过增加反应混合物中使用的树脂的量可以增加环化反应的速率。当A15树脂作阳离子交换树脂时，检验催化剂对反应物产率的影响。在5-33ml催化剂/g反应物范围内，对产率，或者说对脱甲基(desmethyl)形成的水平没有影响。然而，该反应速率与催化剂的用量成正比。
在环化步骤中可以使用任何阳离子交换树脂或阳离子交换树脂的组合。对于本发明的实施，优选聚苯乙烯基的阳离子交换树脂。特别优选聚苯乙烯基磺酸催化剂。
通过任何方法，包括(但不限于)过滤，可以从整个反应混合物中很容易分离阳离子交换树脂，且任何回收的树脂可以再用。通过任何方法，包括使用Whatman滤纸、100目筛、5-20微米滤筒等可以完成过滤。
该反应通常在回流下与共沸除去水进行。在某些反应中，水对磺酸树脂活性的影响早已由A.R.Pitochelli(Ion Exchange Catalysisand Matris Effects，Rohm和Haas出版的小册子，Inc.，1975)进行过讨论。也可参见G.Zundel，Hydration and IntermolecularInteraction Infrared Investigations with PolyelectroyteMembranes，Academic Press，New York，1969及G.Zundel等，Physik.Chem.，59，225，1968。
在反应期间可形成各种脱甲基副产物。下面图式II提供4种不同的脱甲基副产物的结构：
图式II
异构体A和异构体B由式Ia’化合物衍生，而异构体C和异构体D由式I化合物衍生。在通常的反应混合物中，异构体A∶B∶C∶D的比率大约为1∶1∶9∶9。异构体的鉴定通常经HPLC证实。异构体比率以及最终产率由动态控制的环化反应决定。在甲苯中使用阳离子交换树脂，在环化步骤中获得88∶12(I/Ia’)的优选异构体比率，而在环化步骤中使用多磷酸时，获得的异构体比率为75∶23。在该方法中未观察到邻位和对位异构体之间的进一步平衡。
所述重排反应是热力学控制反应。所述反应的平衡常数如下：K1为＞100，而K2为约7-9。使用阳离子交换树脂和甲苯/庚烷作为溶剂系统，当式Ia化合物在反应混合物中形成时会发生沉淀，因而使该反应完成。不需要的异构体，式Ib’化合物的重排比需要的化合物，式Ib化合物的重排快3-5倍。
用于本发明实施的溶剂(包括溶剂混合物和共溶剂)可以影响整个反应，包括反应产物和总收率。选择的溶剂是通常极弱的碱。而且，该溶剂应不能溶解树脂的磺酸质子。用于本发明实施的优选溶剂为芳族溶剂，脂族和氯化溶剂也获得合理的结果。溶剂的实例包括甲苯、庚烷、二甲苯、氯代苯、二甲氧基乙烷和四氯乙烷。优选用于本发明实施的溶剂为甲苯。特别优选的是加入甲磺酸的甲苯。加入的甲磺酸可以促进随后的重排反应。必须将足够的甲磺酸加入到甲苯中以便形成分离的MSA相。
庚烷是另一种优选的溶剂，它能影响苯并噻吩产物的结晶。这种结晶引起所述产物溶解度的显著降低，因而促使反应平衡。最好在平衡之前将庚烷加入到反应混合物。
根据本发明，所述环化反应在约50℃-约110℃，优选约75℃-110℃，最优选约80℃-110℃温度下进行。不管反应是在回流下进行，还是在70℃进行，环化反应的收率都相同。然而，通常优选回流，因为反应率要快10-20倍。在该反应中不需要采用更高的温度，因为这会导致脱甲基副产物水平的增加。
在阳离子交换树脂和甲苯存在下，加热苯乙酮原料至少30分钟，优选约60-180分钟。如本发明所实施的，苯乙酮于110℃、约3-5小时环化。在该初步的加热期后，使反应物冷却至约50℃-90℃，过滤除去阳离子交换树脂。如果该反应物冷却至50℃以下，可能会出现苯并噻吩的少量沉淀，它是发生在环化步骤期间重排的量的函数。通常，在环化反应期间，会发生1-7％的重排。
重排反应通常在甲磺酸和甲苯反应物的存在下发生。此时任选进一步加入庚烷，这可能提高反应产率。该反应期间加入庚烷后，没有必要使温度由90℃升高至106℃，因为这将对收率产生负影响。
在所述重排反应结束时，可以进一步加入适当的的溶剂或溶剂混合物以使该反应物骤冷。适当的溶剂的例子包括(但不限于)异丙醇(IPA)等。该溶剂的加入可降低所述产物的溶解度，并提高其纯度。
整个反应过程可以按“一罐”合成、分批、半连续、连续等方式进行。本领域技术人员将能理解这些操作方式之间的差异，包括为达到一定目的需采用何种反应。例如，在半连续或连续操作中，向固体酸树脂的填充柱中加入原料和溶剂。通过蒸馏可以回收和分离过量的溶剂和产物。而且，该反应可以任选在能与水形成共沸物的有机溶剂存在下进行，这样有利于在反应过程中通过共沸蒸馏除去副产物。可以采用的此类溶剂的实例包括芳香烃如苯、甲苯、二甲苯等。
采用标准提取步骤，通过加水、分离各层、任选用有机溶剂再次提取水层、合并有机层并浓缩合并的有机层来分离苯并噻吩产物。当原料为甲氧基衍生物时，所需的6-甲氧基化合物于浓缩的有机溶剂中结晶，而4-甲氧基异构体仍留在溶液中。经过滤可以收集所需的6-甲氧基化合物。
在根据本发明的优选的环化过程中，所述原料为α-(3-甲氧基苯基硫代)-4-甲氧基苯乙酮，经环化后处理，其可生成6-甲氧基-2-(4-甲氧基苯基)苯并[b]噻吩。接着将该物质转化为式III化合物，如6-羟基-2-(4-羟基苯基)-3-[4-(2-氨基乙氧基)苯甲酰基]苯并[b]噻吩。根据如U.S.4380635提供的反应可以实现6-烷氧基-2-(4-烷氧基苯基)苯并[b]噻吩向式III化合物的转化。
式III化合物常常以酸加成盐的形式给予。这些盐可以如有机化学中通常的那样，通过使根据本发明制备的化合物与适当的酸反应而方便地形成。所述盐在适中的温度下可以高产率的快速形成，且往往只要在该合成的最后步骤从适合的酸洗液分离所述化合物而制备。例如，可以用无机酸或有机酸形成盐。
用于形成此类盐的常用无机酸包括盐酸、氢溴酸、氢碘酸、硝酸、硫酸、磷酸、连二磷酸等。也可以使用由有机酸如脂族一和二羧酸、苯基取代的链烷酸。羟基链烷酸和羟基链烷二酸、芳族酸、脂族和芳族磺酸衍生的盐。因而，这些药学上可接受的盐包括乙酸盐、苯乙酸盐、三氟乙酸盐、丙烯酸盐、抗坏血酸盐、苯甲酸盐、氯代苯甲酸盐、二硝基苯甲酸盐、羟基苯甲酸盐、甲氧基苯甲酸盐、甲基苯甲酸盐、邻-乙酰氧基苯甲酸盐、萘-2-苯甲酸盐、溴化物、异丁酸盐、苯基丁酸盐、β-羟基丁酸盐、丁炔-1，4-二酸盐、己炔-1，4-二酸盐、癸酸盐、辛酸盐、氯化物、肉桂酸盐、柠檬酸盐、甲酸盐、富马酸盐、乙醇酸盐、庚酸盐、马尿酸盐、乳酸盐、苹果酸盐、马来酸盐、羟基马来酸盐、丙二酸盐、扁桃酸盐、甲磺酸盐、烟酸盐、异烟酸盐、硝酸盐、草酸盐、邻苯二甲酸盐、对苯二酸盐、磷酸盐、磷酸一氢盐、磷酸二氢盐、偏磷酸盐、焦磷酸盐、丙炔酸盐、丙酸盐、苯基丙炔酸盐、水杨酸盐、癸二酸盐、琥珀酸盐、辛二酸盐、硫酸盐、硫酸氢盐、焦硫酸盐、亚硫酸盐、亚硫酸氢盐、磺酸盐、苯磺酸盐、对-溴代苯磺酸盐、氯代苯磺酸盐、乙磺酸盐、2-羟基乙磺酸盐、甲磺酸盐、萘-1-磺酸盐、萘-2-磺酸盐、对-甲苯磺酸盐、二甲苯磺酸盐、酒石酸盐等。优选的盐为盐酸盐。
提供下列化合物作为对本文公开的整个方法的进一步说明：6-羟基-2-(4-羟基苯基)-3-[4-(2-二甲基氨基乙氧基)-苯甲酰基]苯并[b]噻吩；3-[4-(2-乙氧基甲基氨基乙氧基)-苯甲酰基]-6-羟基-2-(4-羟基苯基)苯并[b]噻吩；3-[4-(2-乙氧基异丙基氨基乙氧基)-苯甲酰基]-6-羟基-2-(4-羟基苯基)苯并[b]噻吩；3-[4-(2-二丁基氨基乙氧基)-苯甲酰基]-5-羟基-2-(4-羟基苯基)苯并[b]噻吩；3-[4-(2-(1-甲基丙基)甲基氨基乙氧基)-苯甲酰基]-6-羟基-2-(4-羟基苯基)苯并[b]噻吩；6-羟基-2-(4-羟基苯基)-3-[4-[2-二(2-甲基-丙基)氨基乙氧基]苯甲酰基]苯并[b]噻吩；6-羟基-2-(4-羟基苯基)-3-[4-(2-吡咯烷基-乙氧基]苯甲酰基]苯并[b]噻吩；6-羟基-2-(4-羟基苯基)-3-[4-(2-哌啶子基-乙氧基]苯甲酰基]苯并[b]噻吩；6-羟基-2-(4-羟基苯基)-3-[4-(2-吗啉代乙氧基]苯甲酰基]苯并[b]噻吩；3-[4-(2-六亚甲基亚氨基乙氧基)-苯甲酰基]-6-羟基-2-(4-羟基苯基)苯并[b]噻吩。
提供下列实施例以便更好地说明本发明的实施，而不应该认为是以任何方式限制本发明的范围。本领域技术人员应该认识到可以进行各种修改而不背离本发明的精神和范围。本说明书提及的所有出版物和专利申请是本发明相关领域技术人员水平的指标。
实施例
全部试验均在干燥氮气正压下进行。能获得的所有溶剂和试剂均可使用。百分比一般以重量(w/w)为基础进行计算，但用于高效液相(HPLC)的溶剂除外，此类溶剂以体积(v/v)为基础进行计算。质子核磁共振(1H NMR)谱和13C核磁共振谱(13C NMR)在Bruker AC-300FTNMR质谱仪上于300.135MHz处或在GE QE-300质谱仪上于300.15MHz处获得。硅胶快速层析可如Still等所述，用硅胶60(230-400目，E.Merck)进行(Still等，J.Org.Chem.，43，2923，(1978)。碳、氢和氮的元素分析在Control Equipment Corporation 440 ElementalAnalyzer上测定。至于硫的元素分析在Brinkman Colorimetric ElementalAnalyzer上测定。熔点在开口的玻璃毛细管在Gallenkamp热空气浴熔点仪或Mettler FP 62Automatic仪器上测定，并且未校正。场解析质谱(FDMS)用Varian Instruments VG 70-SE或VG ZAB-3F质谱仪获得。高分辨游离原子轰击质谱(FABMS)用Varian Instruments VG ZAB-2SE质谱仪获得。
6-甲氧基-2-(4-甲氧基苯基)苯并[b]噻吩的产率可通过高效液相(HPLC)与经公开的合成途径制得的该化合物的可靠样品比较后确定(见，如美国专利4133814号)。
实施例1
环化作用：
将40gα-(3-甲氧基苯基硫代)-4-甲氧基苯乙酮，4g干燥Amberlyst15(A15)树脂(由Rohm & Haas获得)和129ml Toluol(DrumStock)加入到配有回流冷凝器和迪安-斯达克榻分水器的3颈圆底烧瓶中。该分水器预先装有甲苯，或将过量的溶剂加入到反应器中。加热该混合物至回流并搅拌3-5小时，同时共沸除去水。然后冷却该混合物至50-70℃。用4.25cm瓷漏斗滤除该树脂，用20ml甲苯洗涤。记录滤液的总重量，计算将滤液转移到500ml重排烧瓶中用作洗液所需甲苯的量。[洗液体积＝(WT.-161.5)/0.866][注：该洗液体积表示(accoutts for)在热甲苯过滤中发生的蒸发损失]。
重排：
将该滤液移入装备有回流冷凝器的500ml圆底烧瓶中。用2-5分钟经滴料漏斗加入14g甲磺酸(MSA)。用3ml甲苯冲洗该混合物，并于90℃搅拌l小时。用5-20分钟加入56ml庚烷(Drum Stock)。然后于90℃搅拌该混合物l小时，于80℃搅拌3-4小时。用5-20分钟加入98ml异丙醇(IPA)(Drum Stock)，接着于约83℃回流30分钟。然后以每小时不超过50℃的速率使该混合物冷却至0℃。再于0℃搅拌至少1小时，过滤，用75ml 70/30(Toluol/IPA)洗涤两次，在完全真空下于60℃干燥。产率＝77-80.4％；100％效能；0.1％脱甲基；0.1％化合物D；0.3％TRS。
实施例2
在中试装置中进行下列反应。在50加仑Hastelloy C反应罐中进行环化和重排反应。除非另有所指，反应条件如实施例1所述。
环化作用：
α-(3-甲氧基苯基硫代)-4-甲氧基苯乙酮：14kg
A15树脂：1.4kg
甲苯：42L
环化回流时间：2.5小时
A15甲苯树脂：6L
A15树脂过滤温度：60℃
重排：
MSA：4.9kg
MSA/甲苯洗液：1L
加入庚烷前于90℃搅拌时间：3小时
加入庚烷后于90℃搅拌时间：1小时
加入庚烷后于80℃搅拌时间：3小时
庚烷：20L
加入庚烷时间：20分钟
IPA骤冷量：34L
加入IPA时间：17分钟
加入IPA后回流时间：30分钟
冷却速率：每小时50℃
产物过滤前最终温度：0℃
滤饼洗涤：2×26L 70/30甲苯/IPA
得到的结果是：
77.5％产率
100.1％效能
0.21％rel subs
0.08％脱甲基
实施例3
除了以下改变外，用于本实施例的反应条件与实施例2的反应条件相同：使用50加仑搪玻璃反应罐代替50加仑Hastelloy反应罐；庚烷加入前于90℃的搅拌时间增至4小时；及庚烷加入后于80℃的搅拌时间增至4小时。获得的结果如下：
55％产率
99.5％效能
0.30％rel subs
0.09％脱甲基
实施例4
在中试装置中进行下列反应：在50加仑搪玻璃反应罐中进行环化和重排反应。除非另有所指，本反应条件如实施例1中所述。α-(3-甲氧基苯基硫代)-4-甲氧基苯乙酮的量增至16.5kg，所有其它进料均相应接比例。因而，反应容器中的总体积增加。反应混合物的搅拌由95增至115rpm。获得的结果如下：
79.6％产率
100.6％效能
0.25％rel subs
0.08％desmethyl
Claims (12)
1.制备式Ib化合物的方法：
其中R基团是相同的或不同的，并代表C1-C6烷基，该方法包括使式II的二烷氧基化合物：
在阳离子交换树脂存在下环化。
2.权利要求1的方法，该方法还包括制备式I化合物：
其中R基团是相同的或不同的，并代表C1-C6烷基。
3.权利要求1的方法，其中R是甲基。
4.权利要求1的方法，其中所述阳离子交换树脂是聚苯乙烯-基的磺酸树脂。
5.权利要求1的方法，该方法还包括使所述反应混合物在甲苯中与甲磺酸接触。
6.权利要求5的方法，该方法还包括使所述反应混合物与庚烷接触。
7.权利要求6的方法，该方法还包括使所述反应混合物与异丙醇接触。
8.权利要求1的方法，其中所述环化反应在约70℃-约90℃的温度范围内进行。
9.权利要求1的方法，其中所述方法按批操作进行。
10.权利要求1的方法，其中所述方法按连续操作进行。
11.制备式III化合物或其药学上可接受的盐或溶剂化物的方法：
其中：R1和R2独立为C1-C6烷基，或与它们连接的氮一起形成哌啶基、吡咯烷基、甲基吡咯烷基，二甲基吡咯烷基或六亚甲基亚氨基，该改进包括在阳离子交换树脂的存在下，使式II化合物环化，其中R基团是相同的或不同的，并代表C1-C6烷基。
12.权利要求11的方法，其中R是甲基。
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