WO2007049812A1 - 3-ヒドロキシメチルベンゾ[b]チオフェン誘導体およびその製造方法 - Google Patents
3-ヒドロキシメチルベンゾ[b]チオフェン誘導体およびその製造方法 Download PDFInfo
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- WO2007049812A1 WO2007049812A1 PCT/JP2006/322033 JP2006322033W WO2007049812A1 WO 2007049812 A1 WO2007049812 A1 WO 2007049812A1 JP 2006322033 W JP2006322033 W JP 2006322033W WO 2007049812 A1 WO2007049812 A1 WO 2007049812A1
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- 238000004519 manufacturing process Methods 0.000 title claims abstract description 58
- UYGMKSKKGSUAHB-UHFFFAOYSA-N 1-benzothiophen-3-ylmethanol Chemical class C1=CC=C2C(CO)=CSC2=C1 UYGMKSKKGSUAHB-UHFFFAOYSA-N 0.000 title abstract description 5
- 125000004432 carbon atom Chemical group C* 0.000 claims description 81
- 150000001875 compounds Chemical class 0.000 claims description 61
- 125000000217 alkyl group Chemical group 0.000 claims description 44
- -1 5 -oxo- 1, 2, 4—Oxadiazole — 3 —yl group Chemical group 0.000 claims description 35
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 27
- 238000000034 method Methods 0.000 claims description 24
- 125000003545 alkoxy group Chemical group 0.000 claims description 23
- 229910052799 carbon Inorganic materials 0.000 claims description 20
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- 125000005843 halogen group Chemical group 0.000 claims description 14
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 12
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 12
- 125000004414 alkyl thio group Chemical group 0.000 claims description 10
- 150000004802 benzothiophens Chemical class 0.000 claims description 10
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 10
- 230000007062 hydrolysis Effects 0.000 claims description 10
- 238000006460 hydrolysis reaction Methods 0.000 claims description 10
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 9
- 125000001424 substituent group Chemical group 0.000 claims description 9
- 125000004442 acylamino group Chemical group 0.000 claims description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 7
- 125000002947 alkylene group Chemical group 0.000 claims description 7
- 239000003054 catalyst Substances 0.000 claims description 7
- 229910052757 nitrogen Inorganic materials 0.000 claims description 7
- 229910052987 metal hydride Inorganic materials 0.000 claims description 6
- 150000004681 metal hydrides Chemical class 0.000 claims description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 6
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 claims description 5
- 125000002252 acyl group Chemical group 0.000 claims description 5
- 150000001721 carbon Chemical group 0.000 claims description 5
- 229910002091 carbon monoxide Inorganic materials 0.000 claims description 5
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 5
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 claims description 5
- 229910052708 sodium Inorganic materials 0.000 claims description 5
- 125000004953 trihalomethyl group Chemical group 0.000 claims description 5
- 125000004423 acyloxy group Chemical group 0.000 claims description 4
- 125000004450 alkenylene group Chemical group 0.000 claims description 4
- 125000003785 benzimidazolyl group Chemical class N1=C(NC2=C1C=CC=C2)* 0.000 claims description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 4
- 230000003301 hydrolyzing effect Effects 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 150000003577 thiophenes Chemical class 0.000 claims description 4
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 3
- 229910052783 alkali metal Inorganic materials 0.000 claims description 3
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 claims description 3
- 239000003638 chemical reducing agent Substances 0.000 claims description 3
- DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 claims description 3
- 125000004122 cyclic group Chemical group 0.000 claims description 3
- 229910052751 metal Inorganic materials 0.000 claims description 3
- 239000002184 metal Substances 0.000 claims description 3
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 3
- 125000004043 oxo group Chemical group O=* 0.000 claims description 3
- 229910052763 palladium Inorganic materials 0.000 claims description 3
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 3
- 238000007363 ring formation reaction Methods 0.000 claims description 3
- 125000004299 tetrazol-5-yl group Chemical group [H]N1N=NC(*)=N1 0.000 claims description 3
- GTLDTDOJJJZVBW-UHFFFAOYSA-N zinc cyanide Chemical compound [Zn+2].N#[C-].N#[C-] GTLDTDOJJJZVBW-UHFFFAOYSA-N 0.000 claims description 3
- DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical compound C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 claims description 2
- 150000001340 alkali metals Chemical class 0.000 claims description 2
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 2
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical compound [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 claims description 2
- 238000006114 decarboxylation reaction Methods 0.000 claims description 2
- YNPNZTXNASCQKK-UHFFFAOYSA-N Phenanthrene Natural products C1=CC=C2C3=CC=CC=C3C=CC2=C1 YNPNZTXNASCQKK-UHFFFAOYSA-N 0.000 claims 1
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 claims 1
- 125000004436 sodium atom Chemical group 0.000 claims 1
- 239000003601 chymase inhibitor Substances 0.000 abstract description 4
- 229940119334 Chymase inhibitor Drugs 0.000 abstract description 3
- 238000006243 chemical reaction Methods 0.000 description 40
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 26
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 18
- 229910052739 hydrogen Inorganic materials 0.000 description 17
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
- 125000004429 atom Chemical group 0.000 description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 13
- 238000003786 synthesis reaction Methods 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 150000001556 benzimidazoles Chemical class 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- 239000002904 solvent Substances 0.000 description 12
- 230000015572 biosynthetic process Effects 0.000 description 11
- 238000001308 synthesis method Methods 0.000 description 11
- 238000001914 filtration Methods 0.000 description 10
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 10
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 9
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 9
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 8
- 238000003756 stirring Methods 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000013078 crystal Substances 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- 150000003839 salts Chemical class 0.000 description 6
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 6
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 5
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 239000007810 chemical reaction solvent Substances 0.000 description 5
- 229910052802 copper Inorganic materials 0.000 description 5
- 239000010949 copper Substances 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- 230000002194 synthesizing effect Effects 0.000 description 5
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 4
- 150000003863 ammonium salts Chemical class 0.000 description 4
- 150000004820 halides Chemical class 0.000 description 4
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 4
- JWHOQZUREKYPBY-UHFFFAOYSA-N rubonic acid Natural products CC1(C)CCC2(CCC3(C)C(=CCC4C5(C)CCC(=O)C(C)(C)C5CC(=O)C34C)C2C1)C(=O)O JWHOQZUREKYPBY-UHFFFAOYSA-N 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- 229930192474 thiophene Natural products 0.000 description 4
- BWHDROKFUHTORW-UHFFFAOYSA-N tritert-butylphosphane Chemical compound CC(C)(C)P(C(C)(C)C)C(C)(C)C BWHDROKFUHTORW-UHFFFAOYSA-N 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- HQALDKFFRYFTKP-UHFFFAOYSA-N 2-[4-[4-(2-benzyl-1-benzothiophen-3-yl)phenyl]-2-bromo-6-(3-methoxyphenyl)phenoxy]acetic acid Chemical compound COC1=CC=CC(C=2C(=C(Br)C=C(C=2)C=2C=CC(=CC=2)C=2C3=CC=CC=C3SC=2CC=2C=CC=CC=2)OCC(O)=O)=C1 HQALDKFFRYFTKP-UHFFFAOYSA-N 0.000 description 3
- RXOQFQRGCOJXNC-UHFFFAOYSA-N 4-methyl-1-benzothiophene-3-carbonitrile Chemical compound CC1=CC=CC2=C1C(C#N)=CS2 RXOQFQRGCOJXNC-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 239000000654 additive Substances 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 210000000988 bone and bone Anatomy 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 230000002140 halogenating effect Effects 0.000 description 3
- 239000003446 ligand Substances 0.000 description 3
- 125000006239 protecting group Chemical group 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 229910052725 zinc Inorganic materials 0.000 description 3
- 239000011701 zinc Substances 0.000 description 3
- KDPGPPWJUPUFPB-UHFFFAOYSA-N (4-methyl-1-benzothiophen-3-yl)methanol Chemical compound CC1=CC=CC2=C1C(CO)=CS2 KDPGPPWJUPUFPB-UHFFFAOYSA-N 0.000 description 2
- GEYOCULIXLDCMW-UHFFFAOYSA-N 1,2-phenylenediamine Chemical compound NC1=CC=CC=C1N GEYOCULIXLDCMW-UHFFFAOYSA-N 0.000 description 2
- LVEYOSJUKRVCCF-UHFFFAOYSA-N 1,3-bis(diphenylphosphino)propane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCCP(C=1C=CC=CC=1)C1=CC=CC=C1 LVEYOSJUKRVCCF-UHFFFAOYSA-N 0.000 description 2
- IRIVQXLOJHCXIE-UHFFFAOYSA-N 2-cyclohexylpropan-1-ol Chemical compound OCC(C)C1CCCCC1 IRIVQXLOJHCXIE-UHFFFAOYSA-N 0.000 description 2
- BLZKSRBAQDZAIX-UHFFFAOYSA-N 2-methyl-1-benzothiophene Chemical compound C1=CC=C2SC(C)=CC2=C1 BLZKSRBAQDZAIX-UHFFFAOYSA-N 0.000 description 2
- JIRKNEAMPYVPTD-UHFFFAOYSA-N 3-(2-methylphenyl)propanoic acid Chemical compound CC1=CC=CC=C1CCC(O)=O JIRKNEAMPYVPTD-UHFFFAOYSA-N 0.000 description 2
- XLRUUTMTDMIIBH-UHFFFAOYSA-N 3-chloro-4-methyl-1-benzothiophene Chemical compound CC1=CC=CC2=C1C(Cl)=CS2 XLRUUTMTDMIIBH-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 102000003858 Chymases Human genes 0.000 description 2
- 108090000227 Chymases Proteins 0.000 description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 230000000996 additive effect Effects 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 208000026935 allergic disease Diseases 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 125000005605 benzo group Chemical group 0.000 description 2
- GZUXJHMPEANEGY-UHFFFAOYSA-N bromomethane Chemical compound BrC GZUXJHMPEANEGY-UHFFFAOYSA-N 0.000 description 2
- WXMZPPIDLJRXNK-UHFFFAOYSA-N butyl(diphenyl)phosphane Chemical compound C=1C=CC=CC=1P(CCCC)C1=CC=CC=C1 WXMZPPIDLJRXNK-UHFFFAOYSA-N 0.000 description 2
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 2
- 239000000920 calcium hydroxide Substances 0.000 description 2
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 2
- 150000007942 carboxylates Chemical class 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 150000001733 carboxylic acid esters Chemical group 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- AAXGWYDSLJUQLN-UHFFFAOYSA-N diphenyl(propyl)phosphane Chemical compound C=1C=CC=CC=1P(CCC)C1=CC=CC=C1 AAXGWYDSLJUQLN-UHFFFAOYSA-N 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 125000001153 fluoro group Chemical group F* 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- JUINSXZKUKVTMD-UHFFFAOYSA-N hydrogen azide Chemical compound N=[N+]=[N-] JUINSXZKUKVTMD-UHFFFAOYSA-N 0.000 description 2
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 2
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 2
- 208000027866 inflammatory disease Diseases 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- PFTXKXWAXWAZBP-UHFFFAOYSA-N octacene Chemical group C1=CC=CC2=CC3=CC4=CC5=CC6=CC7=CC8=CC=CC=C8C=C7C=C6C=C5C=C4C=C3C=C21 PFTXKXWAXWAZBP-UHFFFAOYSA-N 0.000 description 2
- JMANVNJQNLATNU-UHFFFAOYSA-N oxalonitrile Chemical compound N#CC#N JMANVNJQNLATNU-UHFFFAOYSA-N 0.000 description 2
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 2
- 150000003017 phosphorus Chemical class 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
- 238000006722 reduction reaction Methods 0.000 description 2
- 208000023504 respiratory system disease Diseases 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 description 2
- 235000009518 sodium iodide Nutrition 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- 125000004951 trihalomethoxy group Chemical group 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 description 1
- ZXSQEZNORDWBGZ-UHFFFAOYSA-N 1,3-dihydropyrrolo[2,3-b]pyridin-2-one Chemical compound C1=CN=C2NC(=O)CC2=C1 ZXSQEZNORDWBGZ-UHFFFAOYSA-N 0.000 description 1
- SUHKSQTXXZQEBH-UHFFFAOYSA-N 1-benzothiophen-2-ylmethanol Chemical class C1=CC=C2SC(CO)=CC2=C1 SUHKSQTXXZQEBH-UHFFFAOYSA-N 0.000 description 1
- XHQBIYCRFVVHFD-UHFFFAOYSA-N 1-benzothiophen-3-ol Chemical class C1=CC=C2C(O)=CSC2=C1 XHQBIYCRFVVHFD-UHFFFAOYSA-N 0.000 description 1
- WDJLPQCBTBZTRH-UHFFFAOYSA-N 1-benzothiophene-3-carbaldehyde Chemical compound C1=CC=C2C(C=O)=CSC2=C1 WDJLPQCBTBZTRH-UHFFFAOYSA-N 0.000 description 1
- 125000006218 1-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- KSAPYRIVHFAQGR-UHFFFAOYSA-N 1-sulfanylbenzimidazole Chemical compound C1=CC=C2N(S)C=NC2=C1 KSAPYRIVHFAQGR-UHFFFAOYSA-N 0.000 description 1
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical group C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 1
- UDHZFLBMZZVHRA-UHFFFAOYSA-N 2-(furan-2-yl)furan Chemical compound C1=COC(C=2OC=CC=2)=C1 UDHZFLBMZZVHRA-UHFFFAOYSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical class CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- ZRNSSRODJSSVEJ-UHFFFAOYSA-N 2-methylpentacosane Chemical compound CCCCCCCCCCCCCCCCCCCCCCCC(C)C ZRNSSRODJSSVEJ-UHFFFAOYSA-N 0.000 description 1
- 125000005916 2-methylpentyl group Chemical group 0.000 description 1
- YNJSNEKCXVFDKW-UHFFFAOYSA-N 3-(5-amino-1h-indol-3-yl)-2-azaniumylpropanoate Chemical compound C1=C(N)C=C2C(CC(N)C(O)=O)=CNC2=C1 YNJSNEKCXVFDKW-UHFFFAOYSA-N 0.000 description 1
- JIXGRXJTSCZWNB-UHFFFAOYSA-N 3-(chloromethyl)-1-benzothiophene Chemical compound C1=CC=C2C(CCl)=CSC2=C1 JIXGRXJTSCZWNB-UHFFFAOYSA-N 0.000 description 1
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 1
- FTYMOWXSFNYJSK-UHFFFAOYSA-N COCCO[AlH]OCCOC.[Li] Chemical class COCCO[AlH]OCCOC.[Li] FTYMOWXSFNYJSK-UHFFFAOYSA-N 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 241000277306 Esocidae Species 0.000 description 1
- 238000005727 Friedel-Crafts reaction Methods 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 1
- 238000007126 N-alkylation reaction Methods 0.000 description 1
- PHSPJQZRQAJPPF-UHFFFAOYSA-N N-alpha-Methylhistamine Chemical compound CNCCC1=CN=CN1 PHSPJQZRQAJPPF-UHFFFAOYSA-N 0.000 description 1
- 229910021585 Nickel(II) bromide Inorganic materials 0.000 description 1
- 229910021586 Nickel(II) chloride Inorganic materials 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- SZKKRCSOSQAJDE-UHFFFAOYSA-N Schradan Chemical group CN(C)P(=O)(N(C)C)OP(=O)(N(C)C)N(C)C SZKKRCSOSQAJDE-UHFFFAOYSA-N 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical group [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- AVRWEULSKHQETA-UHFFFAOYSA-N Thiophene-2 Chemical compound S1C=2CCCCCC=2C(C(=O)OC)=C1NC(=O)C1=C(F)C(F)=C(F)C(F)=C1F AVRWEULSKHQETA-UHFFFAOYSA-N 0.000 description 1
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- IXEVGHXRXDBAOB-GBIKHYSHSA-N [(1r,3s,4s)-4,7,7-trimethyl-3-bicyclo[2.2.1]heptanyl] 2-thiocyanatoacetate Chemical compound C1C[C@]2(C)[C@@H](OC(=O)CSC#N)C[C@@H]1C2(C)C IXEVGHXRXDBAOB-GBIKHYSHSA-N 0.000 description 1
- SUQHGDPPUZCCAF-UHFFFAOYSA-L [Ra+2].CC([O-])=O.CC([O-])=O Chemical compound [Ra+2].CC([O-])=O.CC([O-])=O SUQHGDPPUZCCAF-UHFFFAOYSA-L 0.000 description 1
- 239000005456 alcohol based solvent Substances 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 125000002521 alkyl halide group Chemical group 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- OSJRGDBEYARHLX-UHFFFAOYSA-N azido(trimethyl)stannane Chemical compound [N-]=[N+]=[N-].C[Sn+](C)C OSJRGDBEYARHLX-UHFFFAOYSA-N 0.000 description 1
- RQPZNWPYLFFXCP-UHFFFAOYSA-L barium dihydroxide Chemical compound [OH-].[OH-].[Ba+2] RQPZNWPYLFFXCP-UHFFFAOYSA-L 0.000 description 1
- 229910001863 barium hydroxide Inorganic materials 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
- 230000004097 bone metabolism Effects 0.000 description 1
- 229910052796 boron Inorganic materials 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 230000008414 cartilage metabolism Effects 0.000 description 1
- 238000010531 catalytic reduction reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000013058 crude material Substances 0.000 description 1
- 230000000911 decarboxylating effect Effects 0.000 description 1
- GPAYUJZHTULNBE-UHFFFAOYSA-N diphenylphosphine Chemical compound C=1C=CC=CC=1PC1=CC=CC=C1 GPAYUJZHTULNBE-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- RXPRRQLKFXBCSJ-UHFFFAOYSA-N dl-Vincamin Natural products C1=CC=C2C(CCN3CCC4)=C5C3C4(CC)CC(O)(C(=O)OC)N5C2=C1 RXPRRQLKFXBCSJ-UHFFFAOYSA-N 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- WUOIAOOSKMHJOV-UHFFFAOYSA-N ethyl(diphenyl)phosphane Chemical compound C=1C=CC=CC=1P(CC)C1=CC=CC=C1 WUOIAOOSKMHJOV-UHFFFAOYSA-N 0.000 description 1
- 125000004705 ethylthio group Chemical group C(C)S* 0.000 description 1
- UHCBBWUQDAVSMS-UHFFFAOYSA-N fluoroethane Chemical compound CCF UHCBBWUQDAVSMS-UHFFFAOYSA-N 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hcl hcl Chemical compound Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 238000010438 heat treatment Methods 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
- 150000004678 hydrides Chemical class 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 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
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 229940095060 magnesium tartrate Drugs 0.000 description 1
- MUZDLCBWNVUYIR-ZVGUSBNCSA-L magnesium;(2r,3r)-2,3-dihydroxybutanedioate Chemical compound [Mg+2].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O MUZDLCBWNVUYIR-ZVGUSBNCSA-L 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 229940102396 methyl bromide Drugs 0.000 description 1
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- NBVXSUQYWXRMNV-UHFFFAOYSA-N monofluoromethane Natural products FC NBVXSUQYWXRMNV-UHFFFAOYSA-N 0.000 description 1
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- QMMRZOWCJAIUJA-UHFFFAOYSA-L nickel dichloride Chemical compound Cl[Ni]Cl QMMRZOWCJAIUJA-UHFFFAOYSA-L 0.000 description 1
- IPLJNQFXJUCRNH-UHFFFAOYSA-L nickel(2+);dibromide Chemical compound [Ni+2].[Br-].[Br-] IPLJNQFXJUCRNH-UHFFFAOYSA-L 0.000 description 1
- UQPSGBZICXWIAG-UHFFFAOYSA-L nickel(2+);dibromide;trihydrate Chemical compound O.O.O.Br[Ni]Br UQPSGBZICXWIAG-UHFFFAOYSA-L 0.000 description 1
- QEKXARSPUFVXIX-UHFFFAOYSA-L nickel(2+);triphenylphosphane;dibromide Chemical compound [Ni+2].[Br-].[Br-].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 QEKXARSPUFVXIX-UHFFFAOYSA-L 0.000 description 1
- MUJIDPITZJWBSW-UHFFFAOYSA-N palladium(2+) Chemical compound [Pd+2] MUJIDPITZJWBSW-UHFFFAOYSA-N 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229910052705 radium Inorganic materials 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000004904 shortening Methods 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- LKZMBDSASOBTPN-UHFFFAOYSA-L silver carbonate Substances [Ag].[O-]C([O-])=O LKZMBDSASOBTPN-UHFFFAOYSA-L 0.000 description 1
- 229910001958 silver carbonate Inorganic materials 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- ZNCPFRVNHGOPAG-UHFFFAOYSA-L sodium oxalate Chemical compound [Na+].[Na+].[O-]C(=O)C([O-])=O ZNCPFRVNHGOPAG-UHFFFAOYSA-L 0.000 description 1
- 229940039790 sodium oxalate Drugs 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 1
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 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
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- 125000004149 thio group Chemical group *S* 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000008096 xylene Substances 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
-
- 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
- C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
- C07D333/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Definitions
- the present invention relates to a method for producing a 3-hydroxymethylbenzoic [b] thiophene derivative, which is important as an intermediate for producing a compound useful as a pharmaceutical product.
- it has chymase inhibitory activity in the body
- the present invention relates to a method for producing a production intermediate useful for the synthesis of a compound that can be used as a prophylactic / therapeutic agent for inflammatory diseases, allergic diseases, respiratory diseases, circulatory diseases, or bone and soft bone metabolic diseases.
- R 1 is an alkyl group having 1 to 6 carbon atoms, a halogenated alkyl group having 1 to 6 carbon atoms, a halogen atom, a cyano group, an alkoxy group having 1 to 6 carbon atoms, or an alkyl group having 1 to 6 carbon atoms. It represents an alkylthio group, an acyl group having 1 to 6 carbon atoms, an acylamino group having 1 to 6 carbon atoms, or a halogenated alkoxy group having 1 to 6 carbon atoms.
- R 2 , R 3 , and R 4 are the same or independently, a hydrogen atom, an alkyl group having 1 to 6 carbon atoms. The number of carbons! ⁇ 6 halogenated alkyl groups, groups, mouth atoms, cyan groups
- alkoxy group having 1 to 6 carbon atoms an alkylthio group having 1 to 6 carbon atoms, an acyloxy group having 1 to 6 carbon atoms, an acylamino group having 1 to 6 carbon atoms, or a halogenated alkoxy group having 1 to 6 carbon atoms.
- the 3-hydroxy benzo [b] thiophene derivative represented by the above formula (I I) is extremely important as an intermediate in the production of a pharmacologically active compound.
- a compound represented by _h PL.A (II) in which the hydride F-xyl group is substituted with an odor atom is shown in the National Publication No. 0 1 5 3 2 9 1 Non-Fresh Therefore, it is a synthetic intermediate for the Irubenzimidazole derivative and is extremely important as an intermediate in the production of pharmacologically active compounds.
- the benzimidazole derivative has chymase inhibitory activity in the living body, and is associated with inflammatory diseases and allergic diseases.
- the object of the present invention is to provide 3-hydroxymethyl-4-methylbenzo [b] which is useful as an intermediate for the production of a compound that is a chymase inhibitor described in WO 0 1 Z 5 3 2 9 1 pamphlet. It is possible to provide a method suitable for producing thiophene in a regioselective manner with a high yield and in a short time.
- the inventors of the present invention have a short process, a high yield, and a regioselective 3-hydroxymethylbenzo [b] A method for producing a phen derivative was found. That is, the present invention
- R 1 is an alkyl group having 16 carbon atoms, a halogenated alkyl group having 16 ash atoms, a hydrogen atom, a rogen atom, a cyan group, an alkoxy group having 16 carbon atoms, an alkyl group having 16 carbon atoms.
- Lucio group, Ashyl group having 16 ash, C16 alkyl group, or carbon number Represents ⁇ 6 halogenated alkoxy groups.
- R 2 R 3 and R 4 may be simultaneously or independently selected from a hydrogen atom, an alkyl group having 16 ash atoms, a halogenated alkyl group having 16 carbon atoms, an octacene atom, a cyan group, and carbon.
- alkoxy group having 16 carbon atoms an alkylthio group having 16 carbon atoms, an acyloxy group having 16 carbon atoms, an acylamino group having 1 D carbon atoms, or a halogenated alkoxy group having 16 carbon atoms.
- R 5 represents a hydrogen atom or an alkyl group having 16 carbon atoms.
- R 1 , R 2 , R 3 , and R 4 are the same as defined in the formula (I). ]
- a benzo [b] thiophene derivative represented by the formula (I) is produced by converting the chloro group of the compound represented by the formula (IV,) to a carboxyl group, (1) to (3) The production method according to any one of
- R 1 , R 2 , R 3 , and R 4 are the same as defined in the above formula (I).
- R 6 represents a hydrogen atom or a metal.
- R 1 , R 2 , R 3 , and R 4 are the same as defined in the formula (I).
- a compound represented by '-' is reacted with thionyl chloride to cyclize to produce a benzo [b] thiophene derivative represented by the formula (V), according to (1 3) ' Production method ;
- a method for producing a benzimidazole derivative represented by the formula (XX) including the production of (i) and (ii):
- R 2 3 and R 2 4 may be simultaneously or independently hydrogen atom, halogen atom, hydrogen methyl group, cyan group, hydroxyl group, alkyl having 1 to 4 carbon atoms.
- Group, Chishigu is an alkoxy group having 1 to 4 carbon atoms, or R 2 3 and R 2 4 are joined together.
- A represents a substituted or unsubstituted straight-chain, cyclic or branched alkylene group having 1 to 7 carbon atoms, or an alkylene group, with _ ⁇ —, — S—, — S 0. 2 -, - NR 2 5 - (. in here ⁇ 2 5 represents a hydrogen atom or a straight-chain is also properly is branched Arukiru group having 1 to 6 carbon atoms) one also properly not contain multiple May be.
- Substituents that these groups can have include halogen atoms, hydroxyl groups, two-necked groups, cyanosyl groups, straight-chain or branched alkyl groups having 1 to 6 carbon atoms, straight-chain or branched carbons.
- a 1 to 6 prime alkoxy group (including the case where two adjacent groups form a cetal bond) ', a straight chain if ⁇ is a branched carbon atom having 1 to 6 carbon atoms
- One or more of these substituents may be independently substituted at any position of the alkylene group or alkeneylene group.
- the formula (X X) the case where a hydroxyl group and a phenyl group are simultaneously substituted on the carbon of A in which M is a single bond and is bonded to M is excluded.
- E is 1 COO R 2 5 ,-SO 3 R 5, 1 C ⁇ ⁇ ⁇ R 2 5,-O, NHR 2 5 , Tetrazol-5-Il 5-Oxo _ 1, 2 , 4 1 oxadiazo 1 lu 3 —yl group, or 5 —oxo _ 1, 2
- ⁇ represents a single bond or —S (O) m_, where m is an integer of 0-2. .
- G and J represent the above formula (I I).
- G represents the 3rd-position methylene of the benzothiophene of the said formula (II), and the hydroxyl group of the said formula (II) 'replaces the nitrogen atom on a benzimidazole ring.
- R 1 , R 2 , R 3 , R 4 and R 5 are the same as defined above.
- the product of the production method of the present invention can form a salt
- the product is a salt. Is obtained, or when it is led to a salt, it is also included in the scope of the present invention.
- a 3-hydr ⁇ xymethyl benzo [b] thiophene derivative useful as a production intermediate of a compound that is a chymase inhibitor can be produced in a short process and in a regioselective manner. Therefore, its industrial value is great.
- reaction conditions can be appropriately selected by those skilled in the art depending on the nature of the substrate used, and are not limited to the following conditions.
- R 1 is an alkyl group having 1 to 6 carbon atoms, a halogenated alkyl group having 1 to 6 carbon atoms, a halogen atom, a cyano group, an alkoxy group having 1 to 6 carbon atoms, or an alkyl group having 1 to 6 carbon atoms. It represents an alkylthio group, an acyloxy group having 1 to 6 carbon atoms, an acylamino group having 1 to 6 carbon atoms, or a halogenated alkoxy group having 1 to 6 carbon atoms.
- R 2 , R 3 , and R Sometimes or independently, a hydrogen atom, an alkyl group having 16 carbon atoms, an alkyl halide group having 16 carbon atoms, a halogen atom, a cyan group, an alkoxy group having 16 carbon atoms, an alkylthio group having 16 carbon atoms, A 16-carbon acyloxy group, a 16-carbon acylamino group, or a 16-carbon halogenated alkoxy group.
- R 5 represents a hydrogen atom or an alkyl group having 16 carbon atoms.
- R 6 represents a hydrogen atom or a metal.
- R 1 mentioned above is a alkyl Le group 1 4 carbon atoms Konomajiku, JP Sico.
- R 1 may be ⁇ or arbitrary methyl.
- the R 2 R 3, and are all correct even the is preferred is hydrogen atom or, R 5 is also correct preferred that a hydrogen atom or a Echiru group 'R 6 is a hydrogen atom or Na Application Benefits um atoms It is preferable
- an alkyl group having 16 carbon atoms means 1 carbon atom.
- octacene atom J means a fluorine atom, a chlorine atom, a bromine atom, a silicon atom, etc., and preferred specific examples thereof include a fluorine atom, a chlorine atom, and a bromine atom. It is done.
- an alkyl atom having 16 carbon atoms means eight
- 16-carbon alkoxy group means “consisting of the 16-prime alkyl group” and an oxy group. Examples include a methoxy group, an oxy group, an isopropoxy group, a t ter t-butoxy group, and the like.
- alkylthio group having 16 carbon atoms in the present invention means a group consisting of HU eci “alkyl group having 16 ash atoms” and thio group. Examples include a methylthio group and an ethylthio group.
- the “16-carbon acyloxy group” means a combination of 16-carbon C 1 and Xi. "Number of ash atoms 1
- “Acyl group of 6” means a combination of the word “alkyl group having 16 carbon atoms” and a force group, for example, acetyl, propionyl, petityl, isoptyryl, valeryl, isovaleryl, And piva mouth.
- “Asiloxy group having 16 ash atoms” means, for example, aceoxy, pioxyloxy, butyryloxy, isobutyryloxy
- acylamino group having 16 ash atoms refers to the number of ash atoms.
- acyl This means a combination of 1-6 acyl and amino group.
- This step is a reaction for constructing a benzo [b] thiophene ring using thionyl chloride, which is a reaction for synthesizing compound (V) from compound (VI).
- the reaction of this step the method described in J. Org. Chem., 4 1, 3 3 9 9 (1 9 7 6) is helpful.
- the optimum conditions are 5 equivalents of thionyl chloride and 0.1 equivalent of pyridine.
- the reaction temperature is usually from 130 to 170 ° C, preferably from 150 to 160 ° C. When the reaction is carried out at 150 ° C, it is usually completed in 3 to 6 hours.
- the product since it has a strong lpoxyl group, it can form a salt.
- salts include alkali metal salts or alkaline earth metal salts such as sodium salts.
- the solvent is preferably a solvent-free from the viewpoint of shortening the reaction time, but chlorobenzene, toluene, N, N-dimethylformamide may be used.
- This step is a decarboxylation step of the carboxyl group of the cyclized product obtained in the above step, and is a reaction for synthesizing the compound (IV) from the compound (V). Copper is usually used in an amount of 0.1 to 1.0 equivalent.
- the reaction solvent quinoline, N, N-dimethylformamide, N, N_dimethylacetamide, or dimethylaniline is used.
- the preferred solvent is quinolin.
- N, N-dimethylformamide is preferred when a cyclized free carboxylate is used as a starting material.
- the reaction temperature is usually from 130 to 180 ° C, preferably from 1550 to: 1600 ° C. When the reaction is carried out at 150 ° C, it is usually completed in 3 to 6 hours.
- This step converts the black end group on the aromatic ring to a carboxylic ester group.
- This is a reaction for synthesizing compound (I) from compound (IV).
- the catalyst used in the present invention is paradium acetate, dibromobis (triphenylphosphine) palladium ( ⁇ ), dichlorobis (triphenylphosphine) no-radium (II), dicyclo [1, 1 ' — Bis (diphenylphosphino) phenocene] Palladium (II) or Tetrakis (triphenylphosphine) Palladium (0).
- the ligand may be diphenylphosphinoethane, diphenylphosphinopronozone, diphenylphosphinobutane, triphenylphosphine; or tri-t-butylphosphine.
- Base is triethylamine, sodium acetate
- the additive sodium iodide, sodium chloride, or sodium bromide is used.
- the reaction solvent ethanol or an alcohol solvent such as methanol is used.
- the carbon monoxide pressure is 0.1 to 1.0 MPa. Particularly preferred conditions are: palladium acetate for the catalyst, diphenylphosphinopropane as the ligand, 1,8-diazabicyclo [5.4.0] undecaker 7-en, and sodium iodide as the additive.
- the reaction solvent is ethanol and the carbon monoxide pressure is 0.6 MPa.
- the reaction temperature is 50 ° C. to 1550 ° C., and 1 20 ° C. to 140 ° C. is particularly preferable. More preferably, it is around 1300 ° C.
- This step is a reaction for substituting the cyano group on the aromatic ring with a cyano group, and is a reaction for synthesizing compound (III) from compound (IV).
- nickel bromide, nickel chloride, dibromobis (triphenylphosphine) nickel (II), or the like is used as the catalyst used in the present invention.
- the ligand is triphenylphosphine or diphenylphosphine. Sufinotan, diphenylphosphinopropane, diphenylphosphinobutane, or tri-t-butylphosphine are used.
- the catalyst is usually used in an amount of 0.03 to 0.50 equivalent, but preferably 0.05 equivalent or more.
- the reaction solvents are ethanol, methanol, tetrahydrofuran, acetonitrile, N, N-dimethylformamide, N, N_dimethylacetamide, dimethyl sulfoxide, hexamethyl phosphate
- the ability to use amide, 1,1,3,3-tetramethyl'urea, sulfolane, etc. Tetrahydrofuran and ether are particularly preferred.
- As the cyanogen agent potassium cyanide, sodium cyanide, copper cyanide, zinc cyanide, or the like is used, and potassium cyanide is particularly preferable.
- the reaction temperature is 50 ° C to 150 ° C, particularly preferably 0 ° C to 100 ° C. More preferably, it is around 90 ° C.
- This step is a hydrolysis step of the cyan group, and is a reaction for synthesizing compound (I) from compound (I I I).
- This step is preferably basic hydrolysis.
- basic hydrolysis sodium hydroxide, calcium hydroxide, calcium hydroxide, barium hydroxide, etc. are used, and sodium hydroxide is preferred.
- the amount of alkali is preferably from 3.0 to 10 equivalents, particularly preferably from 3.0 to 5.0 equivalents.
- the reaction temperature is usually 80 to 200 ° C., preferably 160 ° C. or higher and 20 ° C. or lower. When the reaction is carried out at 190 ° C, it is usually completed in 2 to 3 hours.
- Alcohol solvents such as methanol, ethanol and ethylene glycol are used as the reaction solvent. Ethylene glycol is preferred for carrying out the reaction at a high temperature.
- This step is a reduction step of carboxylic acid or carboxylic acid ester
- compound (II) is synthesized from compound (I).
- metal hydride complex compounds are preferred.
- hydrated bifuran complex (2-methoxetoxy) is preferred to hydrated bis (2-methoxetoxy) armorumumuna lyeum.
- solvents include tetrohydrofuranfuran and ⁇ ruen.
- alcohol such as methanol or ethanol may be added.
- sodium borohydride and additives such as chloride chloride.
- the reaction temperature is 0. C to 100 ° C, preferably 0 ° C to 30 ° C
- the number of processes in the two routes h in the equation (V I I) is 4 or.
- the total yield was 49.7% for the first half through the third step, and 4 o% when the fourth and fifth steps were passed. If the third pass is passed, the number is less and the yield is high. On the other hand, if the 4th and 5th steps are efficient, the use of a relatively inexpensive nickel catalyst can reduce industrial costs.
- One or a plurality of alkyl groups having 1 to 4 carbon atoms may be substituted.
- A represents a substituted or unsubstituted straight-chain, cyclic, or branched alkylene group or alkenylene group having 1 to 7 carbon atoms, and one O—, one S—, — S 0 2 — in the middle. , — NR 25 , — (wherein R 25 represents a hydrogen atom or a straight-chain or branched alkyl group having 1 to 6 carbon atoms). Good. Substituents that these groups may have are halogen atoms, hydroxyl groups, nitro groups, cyan groups, straight chain or branched alkyl groups having 1 to 6 carbon atoms, straight chain or branched carbons.
- 1 to 6 alkoxy groups (including the case where two adjacent groups form an alkyl bond), straight chain or branched C 1-6 alkylthio groups, straight chain Or a branched alkylsulfonyl group having 1 to 6 carbon atoms, a straight chain or branched alkyl group having 1 to 6 carbon atoms, a straight chain or branched chain alkyl group having 1 to 6 carbon atoms.
- substituents may be independently substituted at any position of the alkylene group or alkenylene group.
- substituents may be independently substituted at any position of the alkylene group or alkenylene group.
- the case where a hydroxyl group and a phenyl group are simultaneously substituted on the carbon of A in which M is a single bond to M is excluded.
- E is C0 OR 25 , -S 0 3 R 2 5> — CONHR 25 , -SO 2 NHR 25 , Tetrazol 5 —yl group, 5 —Oxo— 1, 2, 4 —Oxazodiazole 3 —yl group, or 5 —oxo— 1, 2, 4 Diazo-Lu 3 —yl group (where is the same as above)
- M represents a single bond or one S ( ⁇ ) m —, and m is an integer of 0-2.
- G and J represent the above formula (I I). However, G represents methylene at the 3-position of benzothiophene in the Hij sti formula (I I), and FJi) the hydroxyl group in the self formula (I I) is replaced with a nitrogen atom on the benzimidazol ring.
- benzimidazole derivative (XX) when E is C 000 k 2 and M is S, it can be produced by the synthesis method (A) or the synthesis method (B) shown below.
- Z represents a halogen, a sulfonyloxy, or an ammonium salt
- R 23 , R 2 R 25 , A, G, J, and X are as defined above.
- nitro group of the 2-2-nitroaniline derivative (al) is reduced to obtain orthophenylenediamine (a2).
- a compound (a 7) can be obtained by reacting a halide derivative (a 6) obtained by halogenating a group.
- a benzimidazole derivative (a 8) in which R 25 is a hydrogen atom can be obtained by hydrolyzing it as necessary.
- the reduction of the nitro group is carried out according to the conditions of a normal catalytic reduction reaction, for example, in the presence of a catalyst such as P d -C, under acidic conditions, neutral and alkaline conditions, and at a temperature of room temperature to 100 ° C. This can be done by reacting with a gas.
- a catalyst such as P d -C
- ortho-phenylenediamine derivatives (a 2) and CS 2 can be treated by treatment with zinc or tin under acidic conditions, or with zinc powder under neutral or alkaline conditions.
- Chiobenzui imidazole compound (a 3) - the reaction of the payment Doesuteru (a 4) is in accordance with the conditions of normal S- alkylation, for example N a H, E t 3 N , N A_ ⁇ H, K 2 C_ ⁇ It can be carried out by stirring at a temperature of 0 ° C. to 200 ° C. in the presence of a base such as 3 .
- Halogenating reagents that convert hydroxymethyl-benzothiophene derivatives (II) to (a6) include hydrogen halides, halogenated phosphorus, sulfonic acid chloride, and thionyl halides. Among them, preferred are a halogenated phosphorus, a halogenated thionyl, and particularly preferably a phosphorus tribromide.
- the solvent include hydrocarbons such as cyclohexane and hexane, and aromatic hydrocarbons such as benzene, toluene, and xylene. Preferably, cyclohexane is used. Xan and toluene can be mentioned.
- the reaction may be from room temperature to reflux temperature for several tens of minutes to several hours.
- the reaction of thiobenzimidazole (a 5) with halide derivatives or ammonium salts (a 6) depends on the conditions of normal N-alkylation or N monosylation reaction, for example, N a HE t 3 in the presence of NN a OHK 2 C 0 3 C s 2 C_ ⁇ 3 such bases 0: can be carried out by stirring at a temperature of ⁇ 2 0 0 ° C.
- the elimination reaction of the carboxyl protecting group R 25 it is preferable to use a method of hydrolysis using an alkali such as lithium hydroxide, or an acid such as hydrochloric acid or 'phosphoroacetic acid.
- an alkali such as lithium hydroxide
- an acid such as hydrochloric acid or 'phosphoroacetic acid.
- the compound (b 3) directly by reacting the halide derivative ( a 6) with the unprotected nitrotroline derivative (al).
- the protecting group L include a trifluoroacetyl group, a acetyl group, a t-butoxycarbonyl group, and a benzyl group.
- the reaction of ol-phenylenediamine derivative (b 4) and CS 2 can be carried out in the same manner as in the synthesis method (A).
- Synthesis (OS) 1 9 6 3 4th volume 5 6 9-5 70 The method described on page 0 can be used. Other reactions can be carried out in the same manner as in the synthesis method (A).
- the Cyan isomer ( e 1) is reacted with various azide compounds to convert it to the tetrazole isomer (e 2).
- the azide compound include trialkyltin azide compounds such as trimethyltin azide, hydrazoic acid or ammonium salts thereof.
- organotin azide compound When an organotin azide compound is used, it is preferably used in an amount of about 1 to 4 moles relative to the compound (el).
- hydrazoic acid or its ammonium salt It is preferable to use sodium and a tertiary amine such as ammonium chloride or triethylamine in an amount of about 1 to 5 times the molar amount of the compound (e 1).
- Each reaction is performed at a temperature of 0 ° C. to 200 ° C. by using a solvent such as toluene, benzene, N, N-dimethylformamide or the like.
- R ′ 23 , R 2 ⁇ , R 25 , ⁇ , G,. J and X are as defined above.
- sulfoxide derivative (f 1) and Z or sulfone derivative (f 2) can be obtained by reacting benzimidazole compound (a 7) with a peroxide compound in an appropriate solvent.
- the peroxide compound used include perbenzoic acid, m-chloroperbenzoic acid, peracetic acid, hydrogen peroxide, and the like.
- the solvent used include chloroform, Examples include dichloromethane.
- the ratio of the compound (a 7) and the peroxide compound used is not particularly limited and may be appropriately selected within a wide range. In general, the amount used is about 1.2 to 5 times the molar amount. preferable.
- Each reaction is usually carried out at about 0 to 50 ° C, preferably 0 ° C to room temperature, and is generally completed in about 4 to 20 hours.
- the benzimidazole derivative (g 2) can be obtained by reacting the diamine compound (b 4) with a known acid chloride derivative (g 1).
- the benzimidazole derivative (g 3) in which R 25 is a hydrogen atom can be obtained by hydrolyzing _COO R 25 in (g 2) as necessary.
- Nickel bromide (2 5 1 '. 1 mg, 1.15 mmol), triphenylphosphine (1.21 g, 4.59 mmo1), zinc (2300 mg, 3.4) 5 mmo 1) and ethanol (12 mL) were stirred at 88 ° C. for 1.5 hours. .1. 5 hours later, 3_-chloro-4-methylbenzo [b] dissolved in potassium cyanide (1.28 g, 19.69 mm o 1) and ethanol (30 mL). Thiophene (3.0 g, 16.4 2 mm o 1) was sequentially added, and the mixture was further stirred for 3 hours.
- 3-Hydroxymethyl-4-methylbenzo [b] thiophene obtained by the production method of the present invention is used as an intermediate for producing pharmaceuticals such as chymase inhibitors.
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- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
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Abstract
Description
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US12/091,704 US20090264663A1 (en) | 2005-10-27 | 2006-10-27 | 3-HYDROXYMETHYLBENZO[b]THIOPHENE DERIVATIVES AND PROCESS FOR THEIR PRODUCTION |
CA002627325A CA2627325A1 (en) | 2005-10-27 | 2006-10-27 | 3-hydroxymethylbenzo[b]thiophene derivative and method for producing same |
JP2007542820A JPWO2007049812A1 (ja) | 2005-10-27 | 2006-10-27 | 3−ヒドロキシメチルベンゾ[b]チオフェン誘導体およびその製造方法 |
BRPI0617924A BRPI0617924A2 (pt) | 2005-10-27 | 2006-10-27 | processo de produção, e, composto |
AU2006306983A AU2006306983A1 (en) | 2005-10-27 | 2006-10-27 | 3-hydroxymethylbenzo[b]thiophene derivative and method for producing same |
EP06822951A EP1947096A1 (en) | 2005-10-27 | 2006-10-27 | 3-HYDROXYMETHYLBENZO[b]THIOPHENE DERIVATIVE AND METHOD FOR PRODUCING SAME |
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WO2001053291A1 (fr) | 2000-01-17 | 2001-07-26 | Teijin Limited | Derives benzimidazoles |
WO2002066457A1 (fr) | 2001-02-22 | 2002-08-29 | Teijin Limited | Derive benzo[b]thiophene et procede de production correspondant |
WO2002090345A1 (en) | 2001-05-07 | 2002-11-14 | Teijin Limited | 3-hydroxymethylbenzo[b]thiophene derivatives and process for their preparation |
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US20040010004A1 (en) * | 2000-01-17 | 2004-01-15 | Naoki Tsuchiya | Benzimidazole derivatives |
EP1243361A1 (en) * | 2001-03-19 | 2002-09-25 | Vesuvius Crucible Company | Apparatus for injecting gas into molten metal |
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WO2001053291A1 (fr) | 2000-01-17 | 2001-07-26 | Teijin Limited | Derives benzimidazoles |
WO2002066457A1 (fr) | 2001-02-22 | 2002-08-29 | Teijin Limited | Derive benzo[b]thiophene et procede de production correspondant |
WO2002090345A1 (en) | 2001-05-07 | 2002-11-14 | Teijin Limited | 3-hydroxymethylbenzo[b]thiophene derivatives and process for their preparation |
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CAMPAIGNE E. ET AL.: "Benzo[b]thiophene derivatives. XIX. Sulfur isosteres of psilocine and related isomers", JOURNAL OF HETEROCYCLIC CHEMISTRY, vol. 10, no. 3, 1973, pages 297 - 305, XP002082811 * |
HIGA T. ET AL.: "Oxidations by thionyl chloride. 8. A convenient synthesis of benzo[b]thiophenes from carboxylic acids and ketones", JOURNAL OF ORGANIC CHEMISTRY, vol. 41, no. 21, 1976, pages 3399 - 3403, XP003012427 * |
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US20090264663A1 (en) | 2009-10-22 |
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JPWO2007049812A1 (ja) | 2009-04-30 |
BRPI0617924A2 (pt) | 2016-08-23 |
RU2008121223A (ru) | 2009-12-10 |
AU2006306983A1 (en) | 2007-05-03 |
CA2627325A1 (en) | 2007-05-03 |
EP1947096A1 (en) | 2008-07-23 |
CN101300247A (zh) | 2008-11-05 |
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