CN1253556A - 制备苯并噻吩的方法 - Google Patents
制备苯并噻吩的方法 Download PDFInfo
- Publication number
- CN1253556A CN1253556A CN98804576A CN98804576A CN1253556A CN 1253556 A CN1253556 A CN 1253556A CN 98804576 A CN98804576 A CN 98804576A CN 98804576 A CN98804576 A CN 98804576A CN 1253556 A CN1253556 A CN 1253556A
- Authority
- CN
- China
- Prior art keywords
- compound
- formula
- group
- acid
- salt
- 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.)
- Pending
Links
- 238000004519 manufacturing process Methods 0.000 title claims description 3
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical class C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 title abstract description 6
- 238000000034 method Methods 0.000 claims abstract description 29
- 150000001875 compounds Chemical class 0.000 claims description 75
- 238000006243 chemical reaction Methods 0.000 claims description 26
- 150000003839 salts Chemical class 0.000 claims description 20
- -1 pyrrolidyl Chemical group 0.000 claims description 15
- 238000002360 preparation method Methods 0.000 claims description 14
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 13
- 239000000460 chlorine Substances 0.000 claims description 12
- 229910052801 chlorine Inorganic materials 0.000 claims description 12
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 9
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 claims description 8
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 8
- 229910052796 boron Inorganic materials 0.000 claims description 8
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 8
- 229910052794 bromium Inorganic materials 0.000 claims description 8
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 7
- 229910005965 SO 2 Inorganic materials 0.000 claims description 7
- 239000011630 iodine Substances 0.000 claims description 7
- 229910052740 iodine Inorganic materials 0.000 claims description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 6
- 230000003213 activating effect Effects 0.000 claims description 6
- 125000002252 acyl group Chemical group 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- FAQYAMRNWDIXMY-UHFFFAOYSA-N trichloroborane Chemical compound ClB(Cl)Cl FAQYAMRNWDIXMY-UHFFFAOYSA-N 0.000 claims description 6
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 5
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 5
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 claims description 5
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- 150000003053 piperidines Chemical class 0.000 claims description 2
- 125000005936 piperidyl group Chemical group 0.000 claims description 2
- 239000012453 solvate Substances 0.000 claims description 2
- 239000000543 intermediate Substances 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 52
- 239000000203 mixture Substances 0.000 description 27
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 20
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 19
- 239000002904 solvent Substances 0.000 description 19
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 18
- 239000000047 product Substances 0.000 description 14
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- 239000002253 acid Substances 0.000 description 11
- 238000004128 high performance liquid chromatography Methods 0.000 description 11
- 238000003756 stirring Methods 0.000 description 11
- 239000003513 alkali Substances 0.000 description 10
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000000706 filtrate Substances 0.000 description 9
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- 239000003643 water by type Substances 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- 239000011541 reaction mixture Substances 0.000 description 7
- 238000005406 washing Methods 0.000 description 7
- 239000012065 filter cake Substances 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 235000015320 potassium carbonate Nutrition 0.000 description 6
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- 238000001291 vacuum drying Methods 0.000 description 6
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 5
- 229940095102 methyl benzoate Drugs 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 4
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 125000001309 chloro group Chemical group Cl* 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- 235000011152 sodium sulphate Nutrition 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 238000005917 acylation reaction Methods 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 3
- 239000006227 byproduct Substances 0.000 description 3
- 229910052792 caesium Inorganic materials 0.000 description 3
- TVFDJXOCXUVLDH-UHFFFAOYSA-N caesium atom Chemical compound [Cs] TVFDJXOCXUVLDH-UHFFFAOYSA-N 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 125000001033 ether group Chemical group 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 3
- 238000012544 monitoring process Methods 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- XPMZFKWAFWMRGF-UHFFFAOYSA-N 4-(2-chloroethoxy)benzoyl chloride Chemical compound ClCCOC1=CC=C(C(Cl)=O)C=C1 XPMZFKWAFWMRGF-UHFFFAOYSA-N 0.000 description 2
- FJKROLUGYXJWQN-UHFFFAOYSA-N 4-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- UYWQUFXKFGHYNT-UHFFFAOYSA-N Benzylformate Chemical compound O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 2
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical group COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- 241000294743 Gamochaeta Species 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical class CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 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
- 125000001931 aliphatic group Chemical group 0.000 description 2
- 125000005103 alkyl silyl group Chemical group 0.000 description 2
- 150000003842 bromide salts Chemical class 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 239000001569 carbon dioxide Substances 0.000 description 2
- 229910002092 carbon dioxide Inorganic materials 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000007810 chemical reaction solvent Substances 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- DGXRZJSPDXZJFG-UHFFFAOYSA-N docosanedioic acid Chemical compound OC(=O)CCCCCCCCCCCCCCCCCCCCC(O)=O DGXRZJSPDXZJFG-UHFFFAOYSA-N 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 235000010755 mineral Nutrition 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 238000005935 nucleophilic addition reaction Methods 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- IZUPBVBPLAPZRR-UHFFFAOYSA-N pentachlorophenol Chemical compound OC1=C(Cl)C(Cl)=C(Cl)C(Cl)=C1Cl IZUPBVBPLAPZRR-UHFFFAOYSA-N 0.000 description 2
- LCPDWSOZIOUXRV-UHFFFAOYSA-N phenoxyacetic acid Chemical compound OC(=O)COC1=CC=CC=C1 LCPDWSOZIOUXRV-UHFFFAOYSA-N 0.000 description 2
- 235000007715 potassium iodide Nutrition 0.000 description 2
- 229960004839 potassium iodide Drugs 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- NHOWDZOIZKMVAI-UHFFFAOYSA-N (2-chlorophenyl)(4-chlorophenyl)pyrimidin-5-ylmethanol Chemical compound C=1N=CN=CC=1C(C=1C(=CC=CC=1)Cl)(O)C1=CC=C(Cl)C=C1 NHOWDZOIZKMVAI-UHFFFAOYSA-N 0.000 description 1
- 125000004169 (C1-C6) alkyl group Chemical group 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
- ITFCEERPJPLHPQ-UHFFFAOYSA-N 1,3-dichloro-2-[(2,6-dichlorophenyl)methoxymethyl]benzene Chemical group ClC1=CC=CC(Cl)=C1COCC1=C(Cl)C=CC=C1Cl ITFCEERPJPLHPQ-UHFFFAOYSA-N 0.000 description 1
- WGAXJEXVOSVLFY-UHFFFAOYSA-N 1-(2,4-dinitrophenoxy)-2,4-dinitrobenzene Chemical compound [O-][N+](=O)C1=CC([N+](=O)[O-])=CC=C1OC1=CC=C([N+]([O-])=O)C=C1[N+]([O-])=O WGAXJEXVOSVLFY-UHFFFAOYSA-N 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
- ZPMHGGSUQMHBJM-UHFFFAOYSA-N 2-methoxysulfanyl-2-methylpropane Chemical compound COSC(C)(C)C ZPMHGGSUQMHBJM-UHFFFAOYSA-N 0.000 description 1
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 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
- JMTMSDXUXJISAY-UHFFFAOYSA-N 2H-benzotriazol-4-ol Chemical compound OC1=CC=CC2=C1N=NN2 JMTMSDXUXJISAY-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
- YKBCUDCQUOHPPT-UHFFFAOYSA-N 4-(2-chloroethoxy)benzoic acid Chemical compound OC(=O)C1=CC=C(OCCCl)C=C1 YKBCUDCQUOHPPT-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- PXACTUVBBMDKRW-UHFFFAOYSA-N 4-bromobenzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=C(Br)C=C1 PXACTUVBBMDKRW-UHFFFAOYSA-N 0.000 description 1
- 229940090248 4-hydroxybenzoic acid Drugs 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical class CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 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
- 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
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-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
- 238000005863 Friedel-Crafts acylation reaction Methods 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
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-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
- 241000124008 Mammalia Species 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
- 238000005481 NMR spectroscopy Methods 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
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 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
- VVMUYXVUPUHZSW-UHFFFAOYSA-N [4-(2-chloroethyl)phenyl]-[6-hydroxy-2-(4-hydroxyphenyl)-1-benzothiophen-3-yl]methanone Chemical compound C1=CC(O)=CC=C1C1=C(C(=O)C=2C=CC(CCCl)=CC=2)C2=CC=C(O)C=C2S1 VVMUYXVUPUHZSW-UHFFFAOYSA-N 0.000 description 1
- WFLRGOXPLOZUMC-UHFFFAOYSA-N [Li].O=C=O Chemical compound [Li].O=C=O WFLRGOXPLOZUMC-UHFFFAOYSA-N 0.000 description 1
- YIXYJZHPCDLFAW-UHFFFAOYSA-N [methoxy-[methoxy(phenyl)methoxy]methyl]benzene Chemical compound C=1C=CC=CC=1C(OC)OC(OC)C1=CC=CC=C1 YIXYJZHPCDLFAW-UHFFFAOYSA-N 0.000 description 1
- POIOOCHMXHKUHV-UHFFFAOYSA-N [nitro-[nitro(phenyl)methoxy]methyl]benzene Chemical group C=1C=CC=CC=1C([N+](=O)[O-])OC([N+]([O-])=O)C1=CC=CC=C1 POIOOCHMXHKUHV-UHFFFAOYSA-N 0.000 description 1
- GPWHDDKQSYOYBF-UHFFFAOYSA-N ac1l2u0q Chemical compound Br[Br-]Br GPWHDDKQSYOYBF-UHFFFAOYSA-N 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229910052786 argon Inorganic materials 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
- 239000012298 atmosphere Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 239000003637 basic solution Substances 0.000 description 1
- 229940077388 benzenesulfonate Drugs 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
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 125000001743 benzylic group Chemical group 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000001311 chemical methods and process Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- XTEGARKTQYYJKE-UHFFFAOYSA-N chloric acid Chemical compound OCl(=O)=O XTEGARKTQYYJKE-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
- 238000004587 chromatography analysis Methods 0.000 description 1
- 229940114081 cinnamate Drugs 0.000 description 1
- 229950002314 closilate Drugs 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000006184 cosolvent Substances 0.000 description 1
- 238000010908 decantation Methods 0.000 description 1
- MHDVGSVTJDSBDK-UHFFFAOYSA-N dibenzyl ether Chemical group C=1C=CC=CC=1COCC1=CC=CC=C1 MHDVGSVTJDSBDK-UHFFFAOYSA-N 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000003085 diluting agent Substances 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
- USIUVYZYUHIAEV-UHFFFAOYSA-N diphenyl ether Chemical compound C=1C=CC=CC=1OC1=CC=CC=C1 USIUVYZYUHIAEV-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
- GRWZHXKQBITJKP-UHFFFAOYSA-N dithionous acid Chemical compound OS(=O)S(O)=O GRWZHXKQBITJKP-UHFFFAOYSA-N 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 125000006575 electron-withdrawing group Chemical group 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 229950007655 esilate Drugs 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-N ethanesulfonic acid Chemical compound CCS(O)(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-N 0.000 description 1
- 125000005448 ethoxyethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- MNWFXJYAOYHMED-UHFFFAOYSA-M heptanoate Chemical compound CCCCCCC([O-])=O MNWFXJYAOYHMED-UHFFFAOYSA-M 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- YPGCWEMNNLXISK-UHFFFAOYSA-N hydratropic acid Chemical class OC(=O)C(C)C1=CC=CC=C1 YPGCWEMNNLXISK-UHFFFAOYSA-N 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 230000008676 import Effects 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 1
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 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
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical class CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910003002 lithium salt Inorganic materials 0.000 description 1
- 159000000002 lithium salts Chemical class 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-M mandelate Chemical compound [O-]C(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-M 0.000 description 1
- 125000005341 metaphosphate group Chemical group 0.000 description 1
- NSPJNIDYTSSIIY-UHFFFAOYSA-N methoxy(methoxymethoxy)methane Chemical compound COCOCOC NSPJNIDYTSSIIY-UHFFFAOYSA-N 0.000 description 1
- 150000005342 methoxybenzoic acids Chemical class 0.000 description 1
- KCZIYXFUZRAJMS-UHFFFAOYSA-N methoxymethoxy-dimethyl-phenylsilane Chemical compound COCO[Si](C)(C)C1=CC=CC=C1 KCZIYXFUZRAJMS-UHFFFAOYSA-N 0.000 description 1
- DYGOPFFOGFHOIB-UHFFFAOYSA-N methylperoxyethane Chemical compound CCOOC DYGOPFFOGFHOIB-UHFFFAOYSA-N 0.000 description 1
- CPZBTYRIGVOOMI-UHFFFAOYSA-N methylsulfanyl(methylsulfanylmethoxy)methane Chemical compound CSCOCSC CPZBTYRIGVOOMI-UHFFFAOYSA-N 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- 150000002762 monocarboxylic acid derivatives Chemical class 0.000 description 1
- HOGDNTQCSIKEEV-UHFFFAOYSA-N n'-hydroxybutanediamide Chemical compound NC(=O)CCC(=O)NO HOGDNTQCSIKEEV-UHFFFAOYSA-N 0.000 description 1
- 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 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical class C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- RBXVOQPAMPBADW-UHFFFAOYSA-N nitrous acid;phenol Chemical class ON=O.OC1=CC=CC=C1 RBXVOQPAMPBADW-UHFFFAOYSA-N 0.000 description 1
- 231100000956 nontoxicity Toxicity 0.000 description 1
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical class OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 1
- TYZYRCHEVXXLSJ-UHFFFAOYSA-N phenylmethoxymethoxymethoxymethylbenzene Chemical compound C=1C=CC=CC=1COCOCOCC1=CC=CC=C1 TYZYRCHEVXXLSJ-UHFFFAOYSA-N 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 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
- UORVCLMRJXCDCP-UHFFFAOYSA-M propynoate Chemical compound [O-]C(=O)C#C UORVCLMRJXCDCP-UHFFFAOYSA-M 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- 229940116351 sebacate Drugs 0.000 description 1
- CXMXRPHRNRROMY-UHFFFAOYSA-L sebacate(2-) Chemical compound [O-]C(=O)CCCCCCCCC([O-])=O CXMXRPHRNRROMY-UHFFFAOYSA-L 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 230000003381 solubilizing effect Effects 0.000 description 1
- 238000000935 solvent evaporation Methods 0.000 description 1
- TYFQFVWCELRYAO-UHFFFAOYSA-L suberate(2-) Chemical compound [O-]C(=O)CCCCCCC([O-])=O TYFQFVWCELRYAO-UHFFFAOYSA-L 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 229940086735 succinate Drugs 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-L sulfite Chemical compound [O-]S([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-L 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- KKEYFWRCBNTPAC-UHFFFAOYSA-L terephthalate(2-) Chemical compound [O-]C(=O)C1=CC=C(C([O-])=O)C=C1 KKEYFWRCBNTPAC-UHFFFAOYSA-L 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 229950004288 tosilate Drugs 0.000 description 1
- WBYWAXJHAXSJNI-VOTSOKGWSA-M trans-cinnamate Chemical compound [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- ZGYICYBLPGRURT-UHFFFAOYSA-N tri(propan-2-yl)silicon Chemical compound CC(C)[Si](C(C)C)C(C)C ZGYICYBLPGRURT-UHFFFAOYSA-N 0.000 description 1
- NPBFIVCLSIDQNN-UHFFFAOYSA-N triethyl(propyl)silane Chemical group CCC[Si](CC)(CC)CC NPBFIVCLSIDQNN-UHFFFAOYSA-N 0.000 description 1
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 1
- 229940071104 xylenesulfonate Drugs 0.000 description 1
Classifications
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
本发明涉及制备苯并噻吩的中间体和方法。
Description
本发明涉及药物化学领域并且涉及制备苯并噻吩的中间体和方法。
式I的化合物:其中R为-COR3或-SO2R3,X为氯、溴或SO2R3,R3为C1-C4烷基、三氟甲基、三氯甲基、苯基、对甲苯基、对甲氧苯基或一或二(卤代或硝基)苯基,可按照其公开内容通过引用并入本文的美国专利4358593所述的方法制备。该专利说明了一种酰化反应,其中式III的化合物:其中在两种情况下R均为一个羟基保护基团,在弗瑞德-克来福特酰化条件下与一种式IV的化合物:其中R4为氯、溴、碘或一个酰基活化基团,反应而提供式I的化合物。如果需要R为氢的式I化合物,该方法需要两个单独的反应和纯化,一个反应为上述的酰化反应,另一个反应为在4′和6位的去保护反应。
因此,更有效和低费用的制备化合物I的方法将是对本领域的一项重要贡献。
本发明涉及一种制备式VII化合物:其中Y为氯、溴、碘或SO2R9,R9为C1-C4烷基、三氟甲基、三氯甲基、苯基、对甲苯基、对甲氧苯基或一或二(卤或硝基)苯基的方法,它包括使式V的化合物:其中R5和R5′分别为羟基保护基团,与一种式VI的化合物:其中R8为一种酰基活化基团,在三卤化硼的存在下反应。
本发明还涉及制备下式IX化合物或者一种其药学上可接受的盐或溶剂化物的方法:其中R6和R7独立地为C1-C4烷基,或者与其相结合的氮结合在一起形成哌啶基、吡咯烷基、甲基吡咯烷基、二甲基吡咯烷基、吗啉代、二甲基氨基、二乙基氨基或1-六亚甲基亚氨基环;它包括使式VII的化合物与式VIII的化合物反应:其中R6和R7的定义和上面相同。
一般用于描述化学式的术语具有其常规的意义。例如术语“C1-C4烷基”是指1到4个碳原子的直链或支链烷基,包括甲基、乙基、丙基、异丙基、丁基、正丁基、异丁基和叔丁基;术语“烷基”除了包括诸如戊基、2-甲基丁基、异戊基、己基、2-甲基戊基、3-甲基戊基等外也包括“C1-C4烷基”定义中所包括的基团。术语“低级醇”是指C1-C4醇,包括甲醇、乙醇、丙醇、异丙醇、丁醇、正丁醇、异丁醇和叔丁醇。
术语“卤代”包括溴、氯、氟和碘。术语“三卤化物”是指三溴化物或三氯化物。
术语“羟基保护基团”是指在有机化学领域的技术人员理解为在T.H. Greene等人的“Protective Groups in Organic Synthesis”第二版(纽约的John Wiley&Sons出版公司1991年出版)(后文称为“Greene”)第二章中所述类型的基团。这种基团包括例如醚基团,包括甲基和取代甲基醚基团诸如甲醚、甲氧基甲基醚、甲基硫代甲基醚、叔丁基硫代甲基醚、(苯基二甲基硅烷基)甲氧基甲基醚、苄氧基甲基醚、对甲氧基苄氧基甲基醚和叔丁氧基甲基醚;取代乙基醚基团诸如乙氧基乙基醚、1-(2-氯乙氧基)乙基醚、2,2,2-三氯乙氧基甲基醚和2-(三甲基硅烷基)乙基醚;苯基和取代苯基醚基团诸如苯基醚、对氯苯基醚、对-甲氧基苯基醚和2,4-二硝基苯基醚;苄基和取代苄基醚基团诸如苄基醚、对甲氧基苄基醚、邻硝基苄基醚和2,6-二氯苄基醚;和烷基甲硅烷基醚基团诸如三甲基-、三乙基-和三异丙基硅烷基醚,混合的烷基甲硅烷基醚基团诸如二甲基异丙基硅烷基醚和二乙基异丙基硅烷基醚;和通式-CO-(C1-C6)烷基或-CO-Ar的酯保护基团,其中Ar为任选取代的苯基,或者特定的基团诸如甲酸酯、甲酸苄酯、一-、二-和三氯乙酸酯、苯氧乙酸酯和对氯苯氧乙酸酯等。只要所衍生的羟基基团在中间体分子的其它位置上的后续反应条件下稳定并且可在没有干扰包括任何其它羟基保护基团在内的所述分子的其余部分的情况下在适当时候被选择性去除,所用羟基保护基团的种类并不重要。在本发明中包括的优选的保护基团有甲基,例如R5或R5′总是为甲基。
术语“酰基活化基团”是指有助于羰基的亲核加成反应的羰基上的取代基。适用的活化取代基是在羰基上具有净吸电子作用的基团。典型的吸电子基团包括与碳基结合时形成酯或酰胺的基团。这种基团包括但不限于羟基苯并三唑、咪唑、硝基苯酚、五氯苯酚、N-羟基琥珀酰亚胺、二环己基碳化二亚胺、N-羟基-N-甲氧基胺等。术语酰基活化基团也包括与羰基结合时形成酸酐的基团。这种基团包括小(分子)羧酸诸如乙酸、甲酸、磺酸、甲磺酸、乙磺酸、苯磺酸或对甲苯磺酸等。此外,与羰基结合的卤素激活羧酸进行亲核加成。适用的卤素包括氯、溴或碘。
术语“适用的碱”是指具有足够影响所需反应的活性但不会显著影响非所需反应的碱。
术语“适用的溶剂”是指足以溶解反应剂来进行所需反应但对所进行的反应为惰性的溶剂。
术语“药学上可接受的盐”是指已知为无毒性且常在药学文献中使用的酸或碱的加成盐。与其衍生自的化合物相比,药学上可接受的盐一般具有增强的溶解性特征并因此经常更易于配制成液体或乳液。在本发明方法中使用的化合物主要与各种有机酸和无机酸形成药学上可接受的酸加成盐,并且包括经常在药物化学中使用的生理学上可接受的盐。这种盐也是本发明的一部分。
用于形成这种盐的典型的无机酸包括氢氯酸、氢溴酸、氢碘酸、硝酸、硫酸、磷酸、连二磷酸等。也可使用从有机酸衍生的盐诸如脂族单羧酸和二羧酸、苯基取代的链烷酸、羟基链烷酸和羟基链烷二酸、芳香酸、脂族和芳族磺酸衍生的盐。因此这种药学上可接受的盐包括乙酸盐、苯基乙酸盐、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、己酸盐、辛酸盐、氯化物、肉桂酸盐、柠檬酸盐、甲酸盐、富马酸盐、甘醇酸盐、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、对苯二甲酸盐、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、对溴苯磺酸盐、氯苯磺酸盐、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。优选的盐是氢氯酸盐。
所述药学上可接受的酸加成盐一般通过式IX的化合物与等摩尔或过量的酸反应来形成。反应剂一般在一种互溶剂诸如乙醚或乙酸乙酯中结合。所述盐通常可在约一小时到10天内沉淀出来并可通过过滤分离,或者溶剂可通过常规方法去除。本发明还提供给予需要治疗的哺乳动物(包括人)药学上可接受的制剂,所述制剂包括有效量的式IX化合物和药学上可接受的稀释剂或载体。
包括式V化合物的本发明方法的原料可通过多种途径获得,包括美国专利4380635、4133814和4418068中所公开的那些途径,所述美国专利的公开内容均通过引用并入本文。式VIII的化合物在本领域是已知的并且一般可购买到或通过本领域人员熟知的方法用易得的原料制备。
式IX的化合物可用式V的化合物制备。例如,式V的化合物可用式VI的化合物酰化成式VII的化合物。然后在式VII化合物中的Y基团用式VIII的仲胺取代而形成式IX的化合物。本发明的整个方法描述于图式1中,其中R5、R6、R7、R8和Y和上面的定义相同。
图式1
式IX的化合物可用式V的化合物制备。例如,可将式VI的化合物在三卤化硼的存在下加入到溶解或悬浮于适合的溶剂中的式V化合物中。适用的溶剂包括氯苯、四氯化碳、二氯甲烷、氯仿和其混合物等。1,2-二氯乙烷一般是优选的溶剂。优选的三卤化硼一般是三氯化硼。式V的化合物一般稍微摩尔过量作用。例如,一般相应于式VI的化合物来说,使用到1.05到1.25摩尔过量的程度。一般优选使用到1.1摩尔过量的程度。三氯化硼一般以较大的摩尔过量使用。例如相应于式VI化合物来说,一般使用4到8摩尔过量。一般优选6摩尔过量。反应一般通过将2等份三卤化硼加入到包含式V化合物和式VI化合物的溶液中来进行。第一份一般在0-5℃下加入并且让得到的混合物在0-5℃下搅拌约7小时。第二份三卤化硼一般伴随着将反应物加热到约30℃时加入并且搅拌约16小时。
式IX的化合物可用式VII的化合物和式VIII的化合物制备。例如式VIII的化合物可在一种催化量的碘化物或溴化物盐的存在下加入到溶解或悬浮于适合溶剂中的式VII的化合物中。适用的溶剂包括二氯甲烷、氯仿、乙腈、四氢呋喃、乙酸乙酯、低级醇和其混合物等。优选的溶剂是二甲基甲酰胺。适用的碘化物或溴化物盐包括钾盐、钠盐或锂盐。碘化钾为优选的盐。式VIII的化合物一般使用大的摩尔过量。例如一般相对于式VII化合物来说,使用20到30的摩尔过量。一般优选25摩尔过量。所述反应一般在约50℃进行约18小时。
式VI的化合物通过为本领域人员熟知的方法制备。例如,将4-羟基苯甲酸或式X的酯与式XI的化合物反应,接着当R8不是氢时将所述酯碱水解成式XIIa的酸。然后将在式XIIa的化合物中的酸基转变成Y基团而形成式VI的化合物。该化学过程说明于图式2中,其中R9为氢或C1-C4烷基,R8和Y的意义如上所述。
式XII的化合物可用为本领域人员熟知的方法制备。例如,溶解或悬浮于适合的溶剂中的式X的化合物可在一种适合的碱的存在下用式XI的化合物处理。适用的溶剂包括但不限于二氯甲烷、四氢呋喃、低级醇、二甲基亚砜、二甲基甲酰胺、乙腈和其混合物等。二甲基甲酰胺或二甲基亚砜是优选的溶剂。适用的碱包括钠、钾或铯的碳酸盐等。碳酸钾是优选的碱。优选的式XI的化合物为在两个位置上的Y均为氯。所述碱一般使用大的摩尔过量。例如,一般相对于式X的化合物来说,使用到1.5到2.5摩尔过量的程度。一般优选使用到2.0摩尔过量的程度。式XI的化合物一般也以较大的摩尔过量使用。例如,所述反应一般并优选用式XI的化合物作为共溶剂来进行。所述反应一般并优选在溶剂的回流温度下进行约12小时。
式XIIa的化合物通过本领域人们熟知的方法用式XII的化合物获得。例如,溶解于适合溶剂中的式XII的化合物可用一种适合的碱处理。适用的溶剂包括低级醇、四氢呋喃、二甲基甲酰胺、乙腈、乙醚及其混合物等。水和甲醇的混合物是优选的溶剂。适用的碱有碱土金属氢氧化物,包括氢氧化钾等。氢氧化钠为优选的碱。所述碱一般以稍微摩尔过量使用。例如相对于式XII的化合物来说,一般使用到1.1到1.4摩尔过量的程度。一般优选1.2摩尔过量。所述反应一般并优选在溶剂的回流温度下进行约1小时。
具有酰基活化基团(R8)的式VI的化合物通过本领域为人熟知的方法从式XIIa的化合物制备。例如,当R8为氯代时,可将溶解或悬浮于适合溶剂中的式XIIa化合物用亚硫酰氯处理。式VI的其余化合物可通过为本领域人员已知的类似方法制备。
一般来说,当图式1和2的反应在从约0℃到所给反应混合物的约回流温度下进行时,反应在约15分钟到72小时内完成。只要所用的溶剂对所进行的反应为惰性以及反应剂被充分溶解来进行所需反应,反应溶剂的选择并不重要。反应一旦完成,如果需要,可通过为本领域人员已知的方法将中间体化合物分离。例如,可将化合物结晶后通过过滤收集,或者可通过萃取、蒸发或滗析除去反应溶剂。如果需要,可将中间体通过常规方法诸如重结晶或通过固体载体诸如硅胶或氧化铝层析来进一步纯化。在后面的反应中式V-XIIa的化合物一般在使用前分离。
进行本发明反应的最佳时间可通过常规的色谱技术监测反应的进程来确定。此外,优选将本发明的反应在惰性气氛诸如像氩气或氮气气氛下进行。
下列实施例用于更好地说明本发明的实施,但是不能理解为对本发明范围的限定。本领域技术人员会理解在没有背离本发明的精神和范围下可做各种修改。所有在本专利说明书中提及的出版物和专利申请均指示了本发明涉及的本领域技术人员的现有水平。
实施例
制备1
4-(2-氯乙氧基)苯甲酸甲酯
混合4-羟基苯甲酸甲酯(1.52克,10毫摩尔)、无水碳酸钾(1.38克,10毫摩尔)、10毫升二甲基亚砜和20毫升1,2-二氯乙烷并加热至回流。高效液相色谱(HPLC)分析表明反应在约1小时内达到平衡。因此,加入另外一当量的碳酸钾。在碳酸钾第二次加入后,产物与二烷基化副产物的比率被极大地增加。将反应混合物冷却到室温并用30毫升水稀释。搅拌所述混合物,然后分层。将有机层用20毫升盐水反萃取后通过硫酸钠过滤。将滤液在约60℃真空浓缩成黄绿色油状物,其冷却后固化。将这种粗产物重新溶解于12毫升热甲醇中,滴加水(总共6毫升)直到出现结晶。伴随着冷却,让结晶过程持续一小时。将沉淀物过滤并用12毫升1∶1甲醇∶水洗涤。在约室温下将滤饼真空干燥而得到2.00克产物(93.5%)。HPLC。
制备2
4-(2-氯乙氧基)苯甲酸甲酯
混合4-羟基苯甲酸甲酯(1.52克,10毫摩尔)、无水碳酸锂(740毫克,10毫摩尔)、15毫升二甲基亚砜和15毫升1,2-二氯乙烷并加热至回流。HPLC分析表明反应在约2小时达到平衡,产物与原料比率为22.7∶68.7。
制备3
4-(2-氯乙氧基)苯甲酸甲酯
混合4-羟基苯甲酸甲酯(1.52克,10毫摩尔)、无水碳酸铯(3.26克,10毫摩尔)、5毫升经4A分子筛干燥的二甲基亚砜和15毫升1,2-二氯乙烷并在大致室温下搅拌。15小时后将混合物加热至回流并且再加入碳酸铯(约1当量以上)。HPLC分析表明产物与二烷基化副产物与原料的比率为93.1∶6.2:未检测到。将反应混合物冷却到室温并用30毫升水稀释。搅拌所述混合物,然后分层。将水层用15毫升二氯甲烷萃取后将合并的有机相通过硫酸钠过滤。将滤液在约60℃真空浓缩成黄绿色油状物,其冷却后固化而得到2.00克产物(94.8%)。HPLC。
制备4
4-(2-氯乙氧基)苯甲酸甲酯
混合4-羟基苯甲酸甲酯(30.4克,200毫摩尔)、无水碳酸铯(13.82克,100毫摩尔)、100毫升二甲基甲酰胺和400毫升1,2-二氯乙烷并加热至回流。通过HPLC监测进程并在1小时和5小时处加入另外1当量的碳酸钾。在24小时处,加入另外0.5当量的碳酸钾。HPLC分析表明产物与二烷基化副产物与原料的比率为93.7∶4.2:未检测到。将反应混合物冷却到室温并用500毫升水稀释。搅拌所述混合物,然后分层。将水层用50毫升1,2-二氯乙烷萃取后将合并的有机相通过硫酸钠过滤。将滤液在约60℃真空浓缩成黄绿色油状物。将残渣重新溶解于200毫升甲醇中,加入水直到达到恒定的浊点(约50毫升)。立即开始结晶,一旦混合物变稠就加入另外50毫升水。将这种混合物搅拌30分钟并且过滤。滤饼用100毫升1∶1甲醇∶水洗涤并在室温下真空干燥而得到38.6克产物。从滤液再获得2.48克产物,从而一共获得41.1克产物。(97.6%)。EA、UV、HPLC。
制备5
4-(2-氯代乙氧基)苯甲酸
混合4-(2-氯代乙氧基)苯甲酸甲酯(31.6克,150毫摩尔)、250毫升甲醇和36毫升5N氢氧化钠并加热至回流。在约50℃下溶液变成透明的淡黄色。在回流1.25小时后,(67℃)溶液仍然透明。通过HPLC监测反应进程。然后加入250毫升水并将温度升到77℃。滴加浓盐酸将pH调节到2.5,产生一种白色沉淀。将反应物冷却到19℃2小时并过滤。滤饼用100ml冷却的1∶1甲醇∶水洗涤并在50℃真空干燥而得到28.03克粗产物。残渣在350毫升沸腾的甲醇中搅拌并通过经预热的大的布氏漏斗过滤。滤液快速变得浑浊并且当混合物降到室温时再次过滤。滤饼用70毫升甲醇洗涤5次。往滤液中加入5N氢氧化钠直到pH调节到约为12。然后用乙酸将pH调节回到约4。加入400毫升水而得到大量沉淀物并将其过滤。滤饼用100毫升1∶1甲醇∶水洗涤并在50℃真空干燥而得到22.2克产物。滤液用300毫升水稀释并用盐酸将pH调节到1。通过吸滤收集得到的沉淀物并用100毫升1∶1甲醇∶水洗涤并在50℃下真空干燥而得到3.95克白色固体物。随着加入45%碳酸钾,将合并的产物在520毫升甲醇中搅拌。加入55毫升所述碱性溶液后,大多数溶解的混合物开始沉淀。加入120毫升水和120毫升甲醇得到一种浑浊溶液。分层并将上层过滤。将滤液的pH用乙酸调节到7,引起沉淀。将少量沉淀物滤除。将滤液用盐酸缓慢调节到pH4后过滤。滤饼用150毫升1∶1甲醇∶水洗涤而得到21.48克产物(71.4%)。1H NMR,HPLC。
制备6
4-(2-氯乙氧基)苯甲酰氯
在一个250毫升烧瓶中,混合4-(2-氯乙氧基)苯甲酸(2.58克,12.9毫摩尔)、二甲基甲酰胺(0.2毫升)和1,2-二氯乙烷(50毫升)。滴加草酰氯(1.35毫升)并在室温下将反应混合物搅拌过夜。在搅拌几小时后反应物变得均匀。搅拌一夜后,将溶剂蒸发至干,并将固体物重新溶解于1,2-二氯乙烷(2×50毫升)中并蒸发。产物在随后的反应中使用。
实施例1
2-(4-羟基苯基)-3-(4-[2-氯乙基]苯甲酰基)-6-羟基苯并[b]噻吩
在一个配有机械搅拌器和2个玻璃塞的100毫升的三颈烧瓶中,混合4-(2-氯乙氧基)苯甲酰氯、2-(4-甲氧基苯基)-6-甲氧基苯并[b]噻吩(3.17克,11.73毫摩尔)和50毫升1,2-二氯乙烷。将混合物冷却到0-5℃。将三氯化硼(3.0毫升,35.2毫摩尔)一次加入到混合物中。将混合物在0-5℃下搅拌7小时。再加入三氯化硼(3.0毫升,35.2毫摩尔)并将反应混合物加热到30℃并在该温度下搅拌过夜(约16小时)。通过缓慢加入50毫升甲醇将反应混合物骤冷。将混合物真空浓缩而得到粗残留物。通过快速层析(50%乙酸乙酯/己烷)纯化得到4.38克(88%)亮黄色粉末的343033。熔点:146-148℃;1H NMR(300.1MHz,DMSO-d6)δ3.91(m,2H),4.26(m,2H),6.68(d,J=8.7Hz,2H),6.86(dd,J=2.2和8.8Hz,1H),6.93(d,J=8.9Hz,2H),7.17(d,J=8.7Hz,2H),7.27(d,J=8.8Hz,1H),7.35(d,J=2.2Hz,1H),7.67(d,J=8.9Hz,2H),9.75(s,1H),9.80(s,1H);13C NMR(75.5MHz,DMSO-d6)δ42.8,68.2,107,1,114.5,115.2,115.7,123.3,123.8,129.6,129.7,130.1,131.8,132.3,139.3,140.6,155.4,157.8,162.2,192.5。
实施例2
2-(4-甲氧基苯基)-3-(4-(2-哌啶子基乙氧基)苯甲酰基)-6-羟基苯并[b]噻吩·氢氯化物
在一个配有N2清洗进口和温度计的50毫升三颈烧瓶中混合2-(4-羟基苯基)-3-(4-[2-氯乙基]苯甲酰基)-6-羟基苯并[b]噻吩(885毫克,2.0毫摩尔)、碘化钾(365毫克,2.2毫摩尔)、哌啶(5.0毫升,50毫摩尔)和二甲基甲酰胺(5毫升)。将溶液加热到50℃并搅拌18小时。HPLC分析指明反应已经完全。将混合物冷却并用乙酸乙酯(50毫升)稀释。将溶液用3%碳酸氢钠水溶液(3×50毫升)洗涤、经硫酸钠干燥并真空浓缩而得到1.3克橙色粗残渣。将残渣溶解于甲醇(5毫升)中并滴加浓盐酸(3滴)。往混合物中加入纯的2-(4-甲氧基苯基)-3-(4-(2-哌啶子基乙氧基)苯甲酰基)-6-羟基苯并[b]噻吩·氢氯化物作为晶种并在环境温度下搅拌66小时。将得到的淤浆过滤、用冷甲醇洗涤并在40℃真空干燥而得到798毫克(78%)淡黄色固体物状的产物:熔点254-256℃(文献258℃);1H NMR(300.1MHz,DMSO-d6)δ1.32(m,1H),1.65(m,1H),1.73(br s,4H),2.93(m,2H),3.40(m,4H),3.62(br s,1H),4.45(m,2H),6.68(d,2H),6.83(dd,1H),6.94(d,2H),7.13(d,2H),7.24(d,1H),7.37(d,1H),7.58(d,2H),9.88(br s,1H),10.46(br s,1H);13C NMR(75.5MHz,DMSO-d6)d 23.9,25.5,25.6,54.3,54.4,57.1,65.9,107.1,114.5,115.2,115.7,123.3,123.6,129.63,129.64,129.7,131.8,132.2,139.2,140.3,155.6,158.0,162.8,192.6。
Claims (11)
2.权利要求1的化合物,其中Y为-SO2R9。
3.按照权利要求1的化合物,其中Y为氯。
4.制备式VII化合物的方法其中Y为氯、溴、碘或-SO2R9,R9为C1-C4烷基、三氟甲基、三氯甲基、苯基、对甲苯基、对甲氧苯基或一或二(卤或硝基)苯基,它包括使式V的化合物:其中R5和R5’分别为羟基保护基团;与一种式VI的化合物:其中R8为一种酰基活化基团以及Y的定义和上面相同,在三卤化硼的存在下反应。
5.按照权利要求4的方法,其中所述三卤化硼是三氯化硼。
6.按照权利要求4的方法,其中R8和Y两者均为氯。
8.按照权利要求7的方法,其中所述三卤化硼是三氯化硼。
9.按照权利要求8的方法,其中R8和Y两者均为氯。
10.按照权利要求8的方法,其中所述式VIII的化合物是一种R6和R7与其相结合的氮结合在一起形成哌啶基环的化合物。
11.按照权利要求7的方法,其中所述盐是盐酸盐。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US4517797P | 1997-04-30 | 1997-04-30 | |
US60/045,177 | 1997-04-30 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN1253556A true CN1253556A (zh) | 2000-05-17 |
Family
ID=21936426
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN98804576A Pending CN1253556A (zh) | 1997-04-30 | 1998-04-28 | 制备苯并噻吩的方法 |
Country Status (11)
Country | Link |
---|---|
US (1) | US6090949A (zh) |
EP (1) | EP0875510A1 (zh) |
JP (1) | JP2001522372A (zh) |
KR (1) | KR20010020378A (zh) |
CN (1) | CN1253556A (zh) |
AU (1) | AU7261398A (zh) |
BR (1) | BR9809439A (zh) |
CA (1) | CA2287943A1 (zh) |
HU (1) | HUP0003187A3 (zh) |
IL (1) | IL132569A0 (zh) |
WO (1) | WO1998049156A1 (zh) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104031022A (zh) * | 2014-03-20 | 2014-09-10 | 浙江省医学科学院 | 盐酸雷洛昔芬的关键中间体及其中间产物的制备方法 |
CN105064445A (zh) * | 2015-07-27 | 2015-11-18 | 徐工集团工程机械股份有限公司科技分公司 | 一种装载机用多功能手柄操纵控制系统 |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ATE541840T1 (de) | 2002-09-30 | 2012-02-15 | Gea Farmaceutisk Fabrik As | Raloxifene-l-lactat oder ein hemihydrat davon, deren verwendungen, pharmazeutischen zusammensetzungen und herstellungsverfahren |
DE602005009208D1 (de) | 2004-07-30 | 2008-10-02 | Salvat Lab Sa | Tyrosinderivate als ppar-gamma-modulatoren |
GB2456096B (en) | 2006-10-17 | 2011-08-17 | Cipla Ltd | Crystalline form of benzothiophene compound and process for preparation thereof |
Family Cites Families (20)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1138163A (en) * | 1965-05-21 | 1968-12-27 | Bristol Myers Co | Benzothiophene derivatives having anti-fertility properties |
US3394125A (en) * | 1965-10-23 | 1968-07-23 | Bristol Myers Co | 2-phenyl-3-tertiary-aminoalkoxy phenyl-and corresponding tertiaryaminoalkyl thio benzfurans substituted in the benzo nucleus with an alkoxy or tertiaryamino alkoxy or alkylthio group |
US4133814A (en) * | 1975-10-28 | 1979-01-09 | Eli Lilly And Company | 2-Phenyl-3-aroylbenzothiophenes useful as antifertility agents |
US4358593A (en) * | 1981-04-03 | 1982-11-09 | Eli Lilly And Company | Process for preparing 3-(4-aminoethoxybenzoyl)benzo[b]thiophenes |
EP0062503A1 (en) * | 1981-04-03 | 1982-10-13 | Eli Lilly And Company | Benzothiophene compounds and process for preparing them |
IL65379A0 (en) * | 1981-04-03 | 1982-05-31 | Lilly Co Eli | Process for preparing acylated benzothiophenes |
US4418068A (en) * | 1981-04-03 | 1983-11-29 | Eli Lilly And Company | Antiestrogenic and antiandrugenic benzothiophenes |
US4380635A (en) * | 1981-04-03 | 1983-04-19 | Eli Lilly And Company | Synthesis of acylated benzothiophenes |
IL65378A (en) * | 1981-04-03 | 1986-02-28 | Lilly Co Eli | Process for preparing 3-(4-aminoethoxybenzoyl)benzo-(b)thiophenes |
US5175184A (en) * | 1982-10-19 | 1992-12-29 | Kotobuki Seiyaku Company Limited | Benzothiophene derivatives and antihyperuricemia thereof |
US5395842A (en) * | 1988-10-31 | 1995-03-07 | Endorecherche Inc. | Anti-estrogenic compounds and compositions |
FR2665444B1 (fr) * | 1990-08-06 | 1992-11-27 | Sanofi Sa | Derives d'amino-benzofuranne, benzothiophene ou indole, leur procede de preparation ainsi que les compositions les contenant. |
DE4117512A1 (de) * | 1991-05-25 | 1992-11-26 | Schering Ag | 2-phenylbenzo(b)furane und -thiophene, verfahren zu deren herstellung und diese enthaltende pharmazeutische praeparate |
JP3157882B2 (ja) * | 1991-11-15 | 2001-04-16 | 帝国臓器製薬株式会社 | 新規なベンゾチオフエン誘導体 |
TW383306B (en) * | 1992-12-22 | 2000-03-01 | Lilly Co Eli | New use of 2-phenyl-3-aroylbenzothiophenes in lowering serum cholesterol |
US5482949A (en) * | 1993-03-19 | 1996-01-09 | Eli Lilly And Company | Sulfonate derivatives of 3-aroylbenzo[b]thiophenes |
US6756388B1 (en) * | 1993-10-12 | 2004-06-29 | Pfizer Inc. | Benzothiophenes and related compounds as estrogen agonists |
US5523416A (en) * | 1994-07-22 | 1996-06-04 | Eli Lilly And Company | Process for preparing 3-(4-aminoethoxy-benzoyl) benzo (B)-thiophenes |
US5629425A (en) * | 1994-09-19 | 1997-05-13 | Eli Lilly And Company | Haloalkyl hemisolvates of 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-piperidinoethoxy)-benzoyl]benzo[b]thiophene |
US5552412A (en) * | 1995-01-09 | 1996-09-03 | Pfizer Inc | 5-substitued-6-cyclic-5,6,7,8-tetrahydronaphthalen2-ol compounds which are useful for treating osteoporosis |
-
1998
- 1998-04-28 IL IL13256998A patent/IL132569A0/xx unknown
- 1998-04-28 JP JP54727798A patent/JP2001522372A/ja active Pending
- 1998-04-28 BR BR9809439-4A patent/BR9809439A/pt not_active IP Right Cessation
- 1998-04-28 CN CN98804576A patent/CN1253556A/zh active Pending
- 1998-04-28 CA CA002287943A patent/CA2287943A1/en not_active Abandoned
- 1998-04-28 AU AU72613/98A patent/AU7261398A/en not_active Abandoned
- 1998-04-28 HU HU0003187A patent/HUP0003187A3/hu unknown
- 1998-04-28 KR KR1019997010000A patent/KR20010020378A/ko not_active Application Discontinuation
- 1998-04-28 WO PCT/US1998/008509 patent/WO1998049156A1/en not_active Application Discontinuation
- 1998-04-29 US US09/069,497 patent/US6090949A/en not_active Expired - Lifetime
- 1998-04-30 EP EP98303374A patent/EP0875510A1/en not_active Withdrawn
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104031022A (zh) * | 2014-03-20 | 2014-09-10 | 浙江省医学科学院 | 盐酸雷洛昔芬的关键中间体及其中间产物的制备方法 |
CN105064445A (zh) * | 2015-07-27 | 2015-11-18 | 徐工集团工程机械股份有限公司科技分公司 | 一种装载机用多功能手柄操纵控制系统 |
Also Published As
Publication number | Publication date |
---|---|
JP2001522372A (ja) | 2001-11-13 |
CA2287943A1 (en) | 1998-11-05 |
KR20010020378A (ko) | 2001-03-15 |
HUP0003187A3 (en) | 2002-04-29 |
HUP0003187A2 (hu) | 2001-05-28 |
IL132569A0 (en) | 2001-03-19 |
AU7261398A (en) | 1998-11-24 |
WO1998049156A1 (en) | 1998-11-05 |
EP0875510A1 (en) | 1998-11-04 |
US6090949A (en) | 2000-07-18 |
BR9809439A (pt) | 2000-06-13 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN1246295C (zh) | 用于制造抗叶酸剂的方法和中间体 | |
US6680386B2 (en) | Process for preparing 2-(4-chlorobenzoylamino)-3-[2 (1H)-quinolinon-4-yl] propionic acid | |
US11401235B2 (en) | Synthesis of terphenyl compounds | |
CN1253556A (zh) | 制备苯并噻吩的方法 | |
CN108358799B (zh) | 一种普瑞巴林的制备方法 | |
CN112154140B (zh) | 化合物及其在合成布瓦西坦(Brivaracetam)原料药中的用途 | |
JP4303792B2 (ja) | キノロン誘導体の製造方法 | |
JPWO2008093853A1 (ja) | マクロライド系化合物の固体およびその製造法並びにその医薬組成物 | |
JP7241682B2 (ja) | 重水素化イミダゾリジンジオン系化合物を調製する方法 | |
PT683165E (pt) | Processo para a preparacao de n-alquil-n-piridinil-1h-indol-1-aminas | |
JP2003286244A (ja) | N−フェニルビス(トリフルオロメタンスルホンイミド)の製造方法 | |
EP2027117A2 (en) | Process for preparing 7-(acryloyl)-indoles | |
WO2023020531A1 (zh) | 5,8-二氨基-3,4-二氢-2h-1-萘酮的合成方法以及其中采用的中间体化合物 | |
JP3511788B2 (ja) | 7−アミノ−2,3−ジヒドロ−2−オキソ−ピリド [2,3−d] ピリミジン及びその製造法 | |
CN112939848B (zh) | 一种布比卡因及其中间体(s)-2-哌啶甲酸的制备方法 | |
CN109824537B (zh) | 一种n-(3-乙酰基-2-羟基苯基)乙酰胺的制备方法 | |
CN112552200B (zh) | 一种光学纯4-(1-氨基)乙基苯甲酸酯及其盐的制备方法 | |
JP4829418B2 (ja) | 光学活性なハロヒドリン誘導体およびその使用方法 | |
JP4902247B2 (ja) | 2−(1−ベンゾチオフェン−5−イル)エタノールの新規製造法およびその中間体 | |
JP3020040B2 (ja) | 2−オキソ−5−ヒドロキシクロマンの製造方法 | |
JP2640622B2 (ja) | プログルメタシンの製造方法 | |
KR100372563B1 (ko) | 퀴놀론계항생제중간체인베타-케토에스테르유도체의제조방법 | |
JPH06279448A (ja) | 2種類のフタロジニトリル誘導体から対称性の低い新規なフタロシアニン錯体を製造する方法 | |
CN101391980A (zh) | 6-羟基-3,4二氢-2(1h)-喹啉酮的制备方法 | |
CN111848552A (zh) | 一种3-(取代苯基)氧杂环丁烷-3-羧酸及其中间体的制备方法及应用 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
WD01 | Invention patent application deemed withdrawn after publication |