KR870000471B1 - Process for preparing benzylalcohol derivatives - Google Patents
Process for preparing benzylalcohol derivatives Download PDFInfo
- Publication number
- KR870000471B1 KR870000471B1 KR828205098A KR820005098A KR870000471B1 KR 870000471 B1 KR870000471 B1 KR 870000471B1 KR 828205098 A KR828205098 A KR 828205098A KR 820005098 A KR820005098 A KR 820005098A KR 870000471 B1 KR870000471 B1 KR 870000471B1
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- South Korea
- Prior art keywords
- compound
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- carried out
- derivative
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- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical class OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 title claims description 18
- 238000004519 manufacturing process Methods 0.000 title claims description 5
- 150000001875 compounds Chemical class 0.000 claims description 41
- -1 thionyl halide Chemical class 0.000 claims description 40
- ANOUKFYBOAKOIR-UHFFFAOYSA-N 3,4-dimethoxyphenylethylamine Chemical compound COC1=CC=C(CCN)C=C1OC ANOUKFYBOAKOIR-UHFFFAOYSA-N 0.000 claims description 22
- 239000002904 solvent Substances 0.000 claims description 14
- 239000002253 acid Substances 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 12
- 238000005978 reductive desulfurization reaction Methods 0.000 claims description 12
- 150000003839 salts Chemical class 0.000 claims description 11
- 125000000217 alkyl group Chemical group 0.000 claims description 10
- 150000008062 acetophenones Chemical class 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- 239000001257 hydrogen Substances 0.000 claims description 9
- 230000002829 reductive effect Effects 0.000 claims description 9
- 239000002168 alkylating agent Substances 0.000 claims description 8
- 230000029936 alkylation Effects 0.000 claims description 8
- 238000005804 alkylation reaction Methods 0.000 claims description 8
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 8
- 125000001589 carboacyl group Chemical group 0.000 claims description 8
- 239000003638 chemical reducing agent Substances 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 229910052783 alkali metal Inorganic materials 0.000 claims description 5
- 150000001340 alkali metals Chemical class 0.000 claims description 5
- YUKQRDCYNOVPGJ-UHFFFAOYSA-N thioacetamide Chemical class CC(N)=S YUKQRDCYNOVPGJ-UHFFFAOYSA-N 0.000 claims description 5
- 229940100198 alkylating agent Drugs 0.000 claims description 4
- 230000003009 desulfurizing effect Effects 0.000 claims description 4
- 150000002431 hydrogen Chemical class 0.000 claims description 4
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 4
- 229910001507 metal halide Inorganic materials 0.000 claims description 3
- 150000005309 metal halides Chemical class 0.000 claims description 3
- 229910021586 Nickel(II) chloride Inorganic materials 0.000 claims description 2
- 150000001350 alkyl halides Chemical class 0.000 claims description 2
- 229960002089 ferrous chloride Drugs 0.000 claims description 2
- NMCUIPGRVMDVDB-UHFFFAOYSA-L iron dichloride Chemical compound Cl[Fe]Cl NMCUIPGRVMDVDB-UHFFFAOYSA-L 0.000 claims description 2
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 2
- QMMRZOWCJAIUJA-UHFFFAOYSA-L nickel dichloride Chemical compound Cl[Ni]Cl QMMRZOWCJAIUJA-UHFFFAOYSA-L 0.000 claims description 2
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 claims description 2
- 239000011592 zinc chloride Substances 0.000 claims description 2
- 235000005074 zinc chloride Nutrition 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims 1
- JFBZPFYRPYOZCQ-UHFFFAOYSA-N [Li].[Al] Chemical compound [Li].[Al] JFBZPFYRPYOZCQ-UHFFFAOYSA-N 0.000 claims 1
- 150000008051 alkyl sulfates Chemical class 0.000 claims 1
- GVPFVAHMJGGAJG-UHFFFAOYSA-L cobalt dichloride Chemical compound [Cl-].[Cl-].[Co+2] GVPFVAHMJGGAJG-UHFFFAOYSA-L 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 18
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 15
- 239000000047 product Substances 0.000 description 15
- 239000012279 sodium borohydride Substances 0.000 description 15
- 229910000033 sodium borohydride Inorganic materials 0.000 description 15
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 12
- 239000000203 mixture Substances 0.000 description 11
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 9
- 238000002844 melting Methods 0.000 description 8
- 230000008018 melting Effects 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 239000000370 acceptor Substances 0.000 description 4
- 150000007530 organic bases Chemical class 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 239000012448 Lithium borohydride Substances 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000012458 free base Substances 0.000 description 3
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 3
- LAIZPRYFQUWUBN-UHFFFAOYSA-L nickel chloride hexahydrate Chemical compound O.O.O.O.O.O.[Cl-].[Cl-].[Ni+2] LAIZPRYFQUWUBN-UHFFFAOYSA-L 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- TXFPEBPIARQUIG-UHFFFAOYSA-N 4'-hydroxyacetophenone Chemical compound CC(=O)C1=CC=C(O)C=C1 TXFPEBPIARQUIG-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 2
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 125000004043 oxo group Chemical group O=* 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 150000003467 sulfuric acid derivatives Chemical class 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
- ZJABPUSDYOXUKS-UHFFFAOYSA-N 1-(2-phenylmethoxyphenyl)ethanone Chemical compound CC(=O)C1=CC=CC=C1OCC1=CC=CC=C1 ZJABPUSDYOXUKS-UHFFFAOYSA-N 0.000 description 1
- MKYMYZJJFMPDOA-UHFFFAOYSA-N 1-(4-phenylmethoxyphenyl)ethanone Chemical compound C1=CC(C(=O)C)=CC=C1OCC1=CC=CC=C1 MKYMYZJJFMPDOA-UHFFFAOYSA-N 0.000 description 1
- AVFZOVWCLRSYKC-UHFFFAOYSA-N 1-methylpyrrolidine Chemical compound CN1CCCC1 AVFZOVWCLRSYKC-UHFFFAOYSA-N 0.000 description 1
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 1
- YTDXZPMDCNOWDQ-UHFFFAOYSA-N 2-[2-(3,4-dimethoxyphenyl)ethylamino]-1-(2-phenylmethoxyphenyl)ethanol;hydrochloride Chemical compound Cl.C1=C(OC)C(OC)=CC=C1CCNCC(O)C1=CC=CC=C1OCC1=CC=CC=C1 YTDXZPMDCNOWDQ-UHFFFAOYSA-N 0.000 description 1
- JYOLSOCMLLSKIS-UHFFFAOYSA-N 2-[2-(3,4-dimethoxyphenyl)ethylamino]-1-(4-phenylmethoxyphenyl)ethanol;hydrochloride Chemical compound Cl.C1=C(OC)C(OC)=CC=C1CCNCC(O)C(C=C1)=CC=C1OCC1=CC=CC=C1 JYOLSOCMLLSKIS-UHFFFAOYSA-N 0.000 description 1
- ZWVHTXAYIKBMEE-UHFFFAOYSA-N 2-hydroxyacetophenone Chemical compound OCC(=O)C1=CC=CC=C1 ZWVHTXAYIKBMEE-UHFFFAOYSA-N 0.000 description 1
- SMIOEQSLJNNKQF-UHFFFAOYSA-N 4-acetoxy acetophenone Chemical compound CC(=O)OC1=CC=C(C(C)=O)C=C1 SMIOEQSLJNNKQF-UHFFFAOYSA-N 0.000 description 1
- ALYNCZNDIQEVRV-UHFFFAOYSA-N 4-aminobenzoic acid Chemical compound NC1=CC=C(C(O)=O)C=C1 ALYNCZNDIQEVRV-UHFFFAOYSA-N 0.000 description 1
- 229940073735 4-hydroxy acetophenone Drugs 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 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
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 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
- AEMRFAOFKBGASW-UHFFFAOYSA-M Glycolate Chemical compound OCC([O-])=O AEMRFAOFKBGASW-UHFFFAOYSA-M 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- AHVYPIQETPWLSZ-UHFFFAOYSA-N N-methyl-pyrrolidine Natural products CN1CC=CC1 AHVYPIQETPWLSZ-UHFFFAOYSA-N 0.000 description 1
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 229940064734 aminobenzoate Drugs 0.000 description 1
- 229940072107 ascorbate Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229940009098 aspartate 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
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000006477 desulfuration reaction Methods 0.000 description 1
- 230000023556 desulfurization Effects 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- DENRZWYUOJLTMF-UHFFFAOYSA-N diethyl sulfate Chemical compound CCOS(=O)(=O)OCC DENRZWYUOJLTMF-UHFFFAOYSA-N 0.000 description 1
- 229940008406 diethyl sulfate Drugs 0.000 description 1
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 1
- DZGCGKFAPXFTNM-UHFFFAOYSA-N ethanol;hydron;chloride Chemical compound Cl.CCO DZGCGKFAPXFTNM-UHFFFAOYSA-N 0.000 description 1
- 239000002024 ethyl acetate extract Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- FIMAYKDZLLQUDW-UHFFFAOYSA-N fluoro(dioxido)borane;trimethyloxidanium Chemical compound C[O+](C)C.C[O+](C)C.[O-]B([O-])F FIMAYKDZLLQUDW-UHFFFAOYSA-N 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical group 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000010410 layer Substances 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
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 150000002823 nitrates Chemical class 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical class OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 1
- BGAXCPSNMHVHJC-UHFFFAOYSA-N phenacyl acetate Chemical compound CC(=O)OCC(=O)C1=CC=CC=C1 BGAXCPSNMHVHJC-UHFFFAOYSA-N 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 238000005554 pickling Methods 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- IIACRCGMVDHOTQ-UHFFFAOYSA-M sulfamate Chemical compound NS([O-])(=O)=O IIACRCGMVDHOTQ-UHFFFAOYSA-M 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
- C07C215/46—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
- C07C215/56—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by hydroxy groups
- C07C215/58—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by hydroxy groups with hydroxy groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain
- C07C215/60—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by hydroxy groups with hydroxy groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain the chain having two carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/075—Ethers or acetals
- A61K31/085—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C1/00—Preparation of hydrocarbons from one or more compounds, none of them being a hydrocarbon
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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Abstract
내용 없음.No content.
Description
본 발명은 하기구조식(Ⅰ)의 벤질알콜 유도체 및 약리적으로 허용되는 그의 산부가염을 제조하는 방법에 관한 것이다 :The present invention relates to a process for preparing benzyl alcohol derivatives of formula (I) and pharmacologically acceptable acid addition salts thereof:
상기식에서, R1은 수소 또는 아릴킬이다.Wherein R 1 is hydrogen or arylalkyl.
벤질알콜 유도체(Ⅰ) 또는 약리적으로 허용되는 그의 산부가염은 강심제 또는 당뇨병 치료제로서 유용한 것으로 알려져 있다(미국특허 제4032575호 참조).Benzyl alcohol derivative (I), or pharmacologically acceptable acid addition salts thereof, are known to be useful as cardiac or diabetic agents (see US4032575).
미국특허 제4032575호에서는 α-할로-모노벤질옥시아세토페논(A)를 3,4-디메톡시펜에틸아민(B)과 축합하여 α-(3,4-디메톡시페네틸아미노) 모노벤질옥시 아세트페논(C)를 얻은 다음, 화합물(C)를 선택적으로 환원하여 α-(3,4-디메톡시펜에틸아미모메틸) 모노벤질옥시벤질알콜(D)을 얻은 다음, 화합물(C) 또는 (D)를 촉매적으로 수소첨가하므로써 구조식(Ⅰ)의 화합물을 제조할 수 있다는 것을 설명하고 있다.U.S. Pat. Acetphenone (C) was obtained, followed by selective reduction of compound (C) to obtain α- (3,4-dimethoxyphenethylamimomethyl) monobenzyloxybenzyl alcohol (D), followed by compound (C) or It is explained that the compound of formula (I) can be prepared by catalytically hydrogenating (D).
그러나, 더 연구한 결과, 본 발명자들은 벤질알콜 유도체(Ⅰ)를 제조하는 신However, as a result of further studies, the inventors have found that the preparation of benzyl alcohol derivative (I)
본 발명에 따르면, 벤질알콜 유도체(Ⅰ)은 하기 단계에 따라 제조된다 :According to the invention, benzyl alcohol derivative (I) is prepared according to the following steps:
(a) 하기구조식(Ⅱ)의 아써토페논 유도체를 할로겐화티오닐과 반응시키고 :(a) reacting an atotophenone derivative of formula (II) with thionyl halide:
(상기식에서 R2는 수소, 알카노일 또는 아랄킬임) ; (b) 그결과 형성된 생성물을 3,4-디메톡시펜에틸아민과 반응시켜 하기 구조식(Ⅲ)의 티오아세트아마이드 유도체를 얻고 :(Wherein R 2 is hydrogen, alkanoyl or aralkyl); (b) the resulting product is reacted with 3,4-dimethoxyphenethylamine to give thioacetamide derivatives of the following formula (III):
(상기식에서 R2는 상기에서 규정한 바와 같음) ; (C-1) 화합물(Ⅲ)을 환원적으로 탈황시키거나 ; (C-2) 화합물(Ⅲ)을 알킬화하여 하기 구조식(Ⅳ)의 아세토페논 유도체를 얻은 다음, 화합물(Ⅳ)을 환원적으로 탈황시키거나 :(Wherein R 2 is as defined above); (C-1) reductively desulfurize compound (III); (C-2) alkylation of compound (III) to give an acetophenone derivative of formula (IV), followed by reductive desulfurization of compound (IV):
(상기식에서, R3는 알킬이고, R2는 상기에서 규정한 바와 같음) ; 또는 (C-(Wherein R 3 is alkyl and R 2 is as defined above); Or (C-
(상기식에서, R1및 R3는 상기에서 규정한 바와 같다.)(Wherein R 1 and R 3 are as defined above)
본 발명의 방법에서 출발물질로 사용되는 아세토페논 유도체(Ⅱ)에서 R2의 양호한 예로는 수소 ; 아세틸,프로피오닐같은 저급알카노일 ; 그리고 벤질같은 페닐-저급알킬이 있다. 한편, 염화티오닐은 상기한 할로겐화 티오닐로서 양호하게 사용된다. R3의 양호한 예로는 메틸 또는 에틸같은 저급알킬이 있다.Preferred examples of R 2 in the acetophenone derivative (II) used as starting materials in the process of the present invention include hydrogen; Lower alkanoyls such as acetyl and propionyl; And phenyl-loweralkyl, such as benzyl. On the other hand, thionyl chloride is preferably used as the aforementioned thionyl halide. Preferred examples of R 3 include lower alkyl such as methyl or ethyl.
아세토페논 유도체(Ⅱ)와 할로겐화 티오닐의 반응은 화합물(Ⅱ)를 할로겐화 티오닐에 용해한 다음 그용액을 교반하므로써 달성된다. 이 반응은 유기염기의 촉매량 존재하에서 양호하게 실시된다. 이러한 유기염기의 적당한 예로는 피리딘, 트리에틸아민, 디메틸아닐린 등이 있다. 사용될 할로겐화 티오닐의 적당량은 아세토페논 유도체(Ⅱ) 1몰당 약 3-10몰이다. 10°- 50℃에서 반응을 실시하는 것이 양호The reaction of the acetophenone derivative (II) with thionyl halide is accomplished by dissolving compound (II) in thionyl halide and then stirring the solution. This reaction is preferably carried out in the presence of a catalytic amount of organic base. Suitable examples of such organic bases include pyridine, triethylamine, dimethylaniline and the like. Suitable amounts of thionyl halide to be used are about 3-10 moles per mole of acetophenone derivative (II). It is preferable to carry out the reaction at 10 ° -50 ° C.
상기식에서, X는 할로겐이고 R2는 상기에서 규정한 바와 같다.Wherein X is halogen and R 2 is as defined above.
상기 생성물과 3,4-디메톡시펜에틸아민과의 반응은 적당한 용매중 산수용체의 존재여부에 관계없이 달성될 수 있다. 산수용체의 적당한 예로는 유기염기(예, 피리딘, 트리에틸아민, 디메틸아닐린 또는 N-메틸피롤리딘)와 무기염기(예, 탄산칼륨, 탄산나트륨, 중탄산나트륨 또는 수산화나트륨)가 있다. 유기용매(예, 벤젠, 클로로포름, 염화메틸렌, 에틸아세테이트, 디메틸포름아마이드) 또는 상기 유기용매와 물의 혼합물이 용매로서 적당하다. 반응은 0°내지 30℃에서 실시되는 것이 양호하다.The reaction of the product with 3,4-dimethoxyphenethylamine can be achieved regardless of the presence of an acid acceptor in a suitable solvent. Suitable examples of acid acceptors are organic bases (eg pyridine, triethylamine, dimethylaniline or N-methylpyrrolidine) and inorganic bases (eg potassium carbonate, sodium carbonate, sodium bicarbonate or sodium hydroxide). Organic solvents (eg benzene, chloroform, methylene chloride, ethyl acetate, dimethylformamide) or mixtures of the organic solvents with water are suitable as solvents. The reaction is preferably carried out at 0 ° to 30 ° C.
벤질 유도체(Ⅰ)은 상기 방법(C-1), (C-2) 및 (C-3)중 하나에 따라 상기 티오아세트아마이드 유도체로부터 제조될 수 있다.Benzyl derivative (I) may be prepared from the thioacetamide derivative according to one of the methods (C-1), (C-2) and (C-3) above.
즉, 방법(C-1)에 따라, 벤질알콜 유도체(Ⅰ)은 화합물(Ⅲ)을 환원적으로 탈황하므로서 제조된다. 화합물(Ⅲ)의 환원적 탈황반응은 화합물(Ⅲ)을 적당한 용매중 금속 할로겐화물 존재하에서 환원제로 처리하므로써 실시될 수 있다. 금속 할로겐화물의 적당한 예로는 염화니켈, 염화제일철, 염화제일주석, 염화아연염, 화코발트 등이 있다. 환원제의 적당한 예로는 나트륨 보로하이드라이드, 리튬보로하이드2 1 That is, according to the method (C-1), benzyl alcohol derivative (I) is prepared by reductively desulfurizing compound (III). Reductive desulfurization of compound (III) can be carried out by treating compound (III) with a reducing agent in the presence of a metal halide in a suitable solvent. Suitable examples of metal halides include nickel chloride, ferrous chloride, tin chloride, zinc chloride, cobalt hydride, and the like. Suitable examples of reducing agents include sodium borohydride, lithium borohydride 2 1
방법(C-2)에 따라, 벤질알콜 유도체(Ⅳ)는 화합물(Ⅲ)을 알킬화한다음, 생성된 화합물(Ⅳ)을 환원적 탈황반응에 도입시킴으로써 제조된다. 화합물(Ⅲ)의 알킬화반응은 적당한 용매중 산수용체의 존재여부에 관계없이 화합물(Ⅲ)을 알킬화제로 처리하므로써 실시될 수 있다. 알킬화제로서 적당한 것은 요오드화메틸 또는 브롬화 에틸같은 저급알킬할로겐화물 ; 트리메틸옥소늄플루오로보레이트 또는 트리에틸옥소늄플루오로보레이트 같은 트리(저급알킬)옥소늄플루오로보레이트 ; 및 황산 디메틸 또는 황산디에틸같은 디(저급알킬) 황산염이 있다. 산수용체의 적당한 예로는 탄산칼륨, 탄산나트륨 또는 중탄산나트륨 같은 무기염기와 피리딘, 트리에틸아민 또는 1,5-디아자비시클로 [5.4.0]-5-운데센같은 유기염기가 있다. 염화메틸렌, 아세톤, 클로로포름, 메탄올, 에탄올, 에테르, 디메틸포름아마이드, 테트라하이드로푸란등은 용매로서 적당하다. 반응은 0°내지 30℃에서 실시하는 것이 양호하다.이 반응에 의해 아세토페논 유도체(Ⅳ)가 제조된다. 이와같이 해서 얻어진 화합물(Ⅳ)According to method (C-2), benzyl alcohol derivative (IV) is prepared by alkylating compound (III) and then introducing the resulting compound (IV) into a reductive desulfurization reaction. The alkylation of compound (III) can be carried out by treating compound (III) with an alkylating agent, regardless of the presence of an acid acceptor in a suitable solvent. Suitable alkylating agents include lower alkyl halides such as methyl iodide or ethyl bromide; Tri (lower alkyl) oxonium fluoroborate such as trimethyloxonium fluoroborate or triethyloxonium fluoroborate; And di (lower alkyl) sulfates such as dimethyl sulfate or diethyl sulfate. Suitable examples of acid acceptors include inorganic bases such as potassium carbonate, sodium carbonate or sodium bicarbonate and organic bases such as pyridine, triethylamine or 1,5-diazabicyclo [5.4.0] -5-undecene. Methylene chloride, acetone, chloroform, methanol, ethanol, ether, dimethylformamide, tetrahydrofuran and the like are suitable as a solvent. The reaction is preferably carried out at 0 ° to 30 ° C. This reaction produces an acetophenone derivative (IV). Compound (IV) obtained in this manner
화합물(Ⅳ)의 환원적 탈황반응은 적당한 용매존재하에 화합물(Ⅳ)를 환원제로 처리하므로써 실시될 수 있다. 환원제의 적당한 예로는 알카리 금속 보로하이드라이드(예, 나트륨 보로하이드라이드, 리튬보로하이드라이드), 리튬 알루미늄 하이드라이드등이 있다. 알칸올(예, 메탄올, 에탄올, 프로판올), 테트라하이드로푸란, 디옥산 및 디메톡시에탄이 용매로서 적당하다. 반응은 0°내지 30℃에서 실시하는 것이 양호하다. 이 반응단계에서, 화합물(Ⅳ)의 알킬기는 옥소기의 환원과 동시에 제거된다. R2가 알카노일인 화합물(Ⅳ)가 이 단계에서 사용될 때, 상기 알카노일기는 또한 상기 반응과 동시에 가수분해된다.Reductive desulfurization of compound (IV) can be carried out by treating compound (IV) with a reducing agent in the presence of a suitable solvent. Suitable examples of reducing agents include alkali metal borohydrides (eg sodium borohydride, lithium borohydride), lithium aluminum hydride and the like. Alkanols (eg methanol, ethanol, propanol), tetrahydrofuran, dioxane and dimethoxyethane are suitable as solvents. The reaction is preferably carried out at 0 ° to 30 ° C. In this reaction step, the alkyl group of compound (IV) is removed simultaneously with the reduction of the oxo group. When compound (IV) in which R 2 is alkanoyl is used in this step, the alkanoyl group is also hydrolyzed simultaneously with the reaction.
한편, 벤질알콜 유도체(Ⅰ)는 방법(C-3), 즉 화합물(Ⅲ)을 환원하여 벤질알콜 유도체(Ⅴ)를 얻은후, 화합물(Ⅴ)를 알킬화하여 얻은 벤질알콜 유도체(Ⅵ)를 환원적 탈황시키는 단계에 의해 제조될 수 있다.On the other hand, benzyl alcohol derivative (I) is obtained by reducing the method (C-3), that is, compound (III) to obtain benzyl alcohol derivative (V), and then reducing the benzyl alcohol derivative (VI) obtained by alkylating compound (V). It may be prepared by the step of desulfurization.
화합물(Ⅲ)의 환원반응은 화합물(Ⅲ)을 적당한 용매중에서 환원제로 처리하므로써 실시될 수 있다. 환원제의 적당한 예로는 나트륨 보로하이드라이드, 리튬 보로하이드라이드등 같은 알카리금속 보로하이드라이드가 있다. 알칸올(예, 메탄올, 에탄올, 프로판올), 테트라하이드로푸란과 디옥산이 용매로서 적당하다. 반응은 0°- 30℃에서 실시하는 것이 양호하다. R2가 알카노일인 화합물(Ⅲ)이 본 반응 단계에서 사용될 때, 화합물(Ⅲ)중 옥소기의 환원은 상기 알카노일기의 가수분해와Reduction of compound (III) can be carried out by treating compound (III) with a reducing agent in a suitable solvent. Suitable examples of reducing agents include alkali metal borohydrides such as sodium borohydride, lithium borohydride and the like. Alkanols (eg methanol, ethanol, propanol), tetrahydrofuran and dioxane are suitable as solvents. The reaction is preferably carried out at 0 ° -30 ° C. When compound (III) in which R 2 is alkanoyl is used in this reaction step, the reduction of the oxo group in compound (III) is characterized by the hydrolysis of
그다음, 화합물(Ⅴ)의 알킬화 반응과 화합물(Ⅵ)의 환원적 탈황반응은 각각 화합물(Ⅲ)의 알킬화 또는 방법(C-2)에서 화합물(Ⅳ)의 환원적 탈황 반응에서와 똑같은 조건하에서 실시될 수 있다.The alkylation of compound (V) and the reductive desulfurization of compound (VI) are then carried out under the same conditions as in the alkylation of compound (III) or the reductive desulfurization of compound (IV) in method (C-2), respectively. Can be.
본 발명에 따라 제조된 벤질알콜 유도체(Ⅰ)는 필요한 경우, 약리학적으로 허용되는 그의 산부가염으로 전환될 수 있다. 염의 적당한 예로는 염화수소 부가염, 브롬화수소 부가염, 과염소산염, 질산염, 황산염 또는 인산염과 같은 무기산 부가염 ; 그리고 초산염, 프로피온산염, 글리콜산염, 락트산염, 아스코르빈산염, 말레산염, 푸마르산염, 말론산염, 호박산염, 옥살산염, 구연산염, 메탄설포네이트, 벤젠설포네이트, 아미노벤조에이트, 설파민산염, 아스파르산염, 글루타민산염 또는 니코틴산염같은 유기산 부가염이 있다.Benzyl alcohol derivatives (I) prepared according to the invention can be converted, if necessary, to their pharmacologically acceptable acid addition salts. Suitable examples of salts include inorganic acid addition salts such as hydrogen chloride addition salts, hydrogen bromide addition salts, perchlorates, nitrates, sulfates or phosphates; And acetate, propionate, glycolate, lactate, ascorbate, maleate, fumarate, malonate, succinate, oxalate, citrate, methanesulfonate, benzenesulfonate, aminobenzoate, sulfamate, There are organic acid addition salts such as aspartate, glutamate or nicotinate.
본 발명의 방법은 바람직하지 못한 부반응을 일으키지 않고 높은 수율로 벤질알콜 유도체(Ⅰ)를 제조할 수 있어 공업적인 규모로 상기 유도체(Ⅰ)을 제조하는데 유용하다. 더우기, 본 발명의 중간생성물(Ⅲ)이 매우 안정하고 종래방법대로 쉽게 분리 및 정제되기 때문에, 본 발명은 또한, 벤질 알콜 유도체(Ⅰ)가 불필요한 부산물로 오염되지 않는 높은 순도로 얻어지는 장점이 있다.The process of the present invention can produce benzyl alcohol derivative (I) in high yield without causing undesirable side reactions and is useful for preparing the derivative (I) on an industrial scale. Furthermore, because the intermediate (III) of the present invention is very stable and easily separated and purified according to the conventional method, the present invention also has the advantage that the benzyl alcohol derivative (I) is obtained in high purity so as not to be contaminated with unnecessary by-products.
본 명세서 및 청구범위에서, "저급알킬" 및 "저급 알카노일"라는 것은 탄소수 1-4를 갖는 직쇄 또는 측쇄알킬 및 알카노일기를 뜻한다.In the present specification and claims, "lower alkyl" and "lower alkanoyl" refer to straight or branched chain alkyl and alkanoyl groups having 1 to 4 carbon atoms.
본 발명의 양호한 실시예는 다음에 예증된다.Preferred embodiments of the invention are illustrated next.
[실시예 1]Example 1
(1) 4-벤질옥시아세토페논 4.97g을 염화티오닐 15mll에 용해한후 피리딘 0.02ml를 다시 첨가한다. 혼합물을 실온에서 5시간동안 교반한다. 혼합물을 감압하에서 농축하여 과잉의 염화티오일을 제거한다. 잔류물을 벤젠 30ml에 용해한다. 용액을 3,4-디메톡시펜에틸아민 4.78g, 10% 탄산나트륨 수용액 90ml와 벤젠 50ml로 구성된 혼합물에 첨가한 후 실온에서 4시간 동안 교반한다. 벤젠 용액은 반응혼합물로부터 수집되고 수용성층은 초산에틸로 추출된다. 벤젠용액과 초산에틸 추출물을 혼합한후 물, 10% 염산 및 물로 각각 세척한다. 유기층을 건조한후 감압하에서 증발한다. 잔류물은 에탄올로부터 재결정화된다. 2-(4-벤질옥시페닐)-2-옥소-N-(3,4-디메톡시펜에틸)티오아세트아마이드 7.67g은 엷은 황색의 침산으로 얻어진다. 수율 80.1%, 융점 132°- 133℃(1) 4.97 g of 4-benzyloxyacetophenone is dissolved in 15 mmol of thionyl chloride, and then 0.02 ml of pyridine is added again. The mixture is stirred at room temperature for 5 hours. The mixture is concentrated under reduced pressure to remove excess thioyl chloride. The residue is dissolved in 30 ml of benzene. The solution was added to a mixture consisting of 4.78 g of 3,4-dimethoxyphenethylamine, 90 ml of 10% aqueous 10% sodium carbonate solution and 50 ml of benzene, followed by stirring at room temperature for 4 hours. The benzene solution is collected from the reaction mixture and the aqueous layer is extracted with ethyl acetate. Benzene solution and ethyl acetate extract were mixed and washed with water, 10% hydrochloric acid and water, respectively. The organic layer is dried and evaporated under reduced pressure. The residue is recrystallized from ethanol. 7.67 g of 2- (4-benzyloxyphenyl) -2-oxo-N- (3,4-dimethoxyphenethyl) thioacetamide is obtained by pale yellow pickling. Yield 80.1%, Melting Point 132 ° -133 ° C
(2) 2-(4-벤질옥시페닐)-2-옥시-N-(3,4-디메톡시펜에틸) 티오아세트 아마이드 500mg과 염화니켈 6수화물을 메탄올 30ml에 용해하고, 나트륨 보로하이드라이드 700mg을 실온에서 다시 첨가된다. 혼합물을 똑같은 온도에서 1.5시간동안 같은 온도에서 교반한다. 불용성 물질은 여과해내고, 여액은 감압하에서 농축된다. 잔류물을 클로로포름에 용해하여 물로 처리하고 건조한 다음 감압하에서 건조 및 증발한다. 잔류물은 에탄올성 염화수소로 처리되며, 결정 침전물은 여과에 의해 수집된다. α-(3,4-디메톡시펜에틸 아미노메틸)-4-벤질옥시벤질알콜 하이드로클로라이드가 얻어진다. 수율 70%, 융점 168-170℃(2) 500 mg of 2- (4-benzyloxyphenyl) -2-oxy-N- (3,4-dimethoxyphenethyl) thioacetamide and nickel chloride hexahydrate were dissolved in 30 ml of methanol, and 700 mg of sodium borohydride. Is added again at room temperature. The mixture is stirred at the same temperature for 1.5 hours at the same temperature. Insoluble matter is filtered off and the filtrate is concentrated under reduced pressure. The residue is dissolved in chloroform, treated with water, dried, dried and evaporated under reduced pressure. The residue is treated with ethanol hydrogen chloride and the crystalline precipitate is collected by filtration. α- (3,4-dimethoxyphenethyl aminomethyl) -4-benzyloxybenzyl alcohol hydrochloride is obtained. Yield 70%, Melting Point 168-170 ° C
[실시예 2]Example 2
2-(4-벤질옥시페닐)-2-옥시-N-(3,4-디메톡시펜에틸) 티오아세트아마이드2- (4-benzyloxyphenyl) -2-oxy-N- (3,4-dimethoxyphenethyl) thioacetamide
[실시예 3]Example 3
2-(4-벤질옥시페닐)-2-옥소-N-(3,4-디메톡시펜에틸)티오아세트아마이드 2.2g을 아세톤 30ml에 첨가한후 탄산칼륨 850mg과 요오드화메틸 1.0g을 다시 첨가한다. 혼합물을 실온에서 철야 교반한다. 불용성 물질을 여과분리하고, 여액은 감압하에 농축한다. 잔류물을 메탄올 50ml에 용해한후 나트륨 보로하이드라이드 300mg을 첨가한다.-(3,4-디메톡시펜에틸아미노메틸)-4-벤질옥시벤질알콜(유리염기) 1.65g이 무색 침상물질로 얻어진다. 수율 80%2.2 g of 2- (4-benzyloxyphenyl) -2-oxo-N- (3,4-dimethoxyphenethyl) thioacetamide is added to 30 ml of acetone, followed by 850 mg of potassium carbonate and 1.0 g of methyl iodide. . The mixture is stirred overnight at room temperature. Insoluble matter is filtered off and the filtrate is concentrated under reduced pressure. The residue is dissolved in 50 ml of methanol and then 300 mg of sodium borohydride is added. 1.65 g of-(3,4-dimethoxyphenethylaminomethyl) -4-benzyloxybenzyl alcohol (free base) is obtained as a colorless needle. Yield 80%
상기 생성물의 물리-화학적 성질은 실시예 2에서 얻어진 생성물과 똑같다.The physical-chemical properties of the product are the same as the product obtained in Example 2.
[실시예 4]Example 4
(1) 2-(4-벤질옥시페닐)-2-옥소-N-(3,4-디메톡시펜에틸) 티오아세트 아마이드 8.0g을 메탄올 150ml에 용해한후, 나트륨 보로하이드라이드 500mg을 다시 첨가한다. 혼합물을 실온에서 1시간동안 교반한다. 혼합물을 감압하에서 농축한다. 잔류물을 클로로포름에 용해한후, 물로 세척한 다음 감압하에서 건조 및 증발한다.(1) Dissolve 8.0 g of 2- (4-benzyloxyphenyl) -2-oxo-N- (3,4-dimethoxyphenethyl) thioacetamide in 150 ml of methanol, and then add 500 mg of sodium borohydride again. . The mixture is stirred at rt for 1 h. The mixture is concentrated under reduced pressure. The residue is dissolved in chloroform, washed with water, then dried and evaporated under reduced pressure.
(2) 2-(4-벤질옥시페닐)-2-하이드록시-N-(3,4-디메톡시펜에틸)티오아세트 아마이드 1.0g을 염화메틸렌 20ml에 용해한 후 트리에틸옥소늄플루오로보레이트 460ml을 첨가한다. 혼합물을 실온에서 30분동안 교반한후 감압하에서 농축한다. 잔류물을 메탄올 20ml와 클로로포름 20ml의 혼합액에 첨가한다음, 나트륨 보로하이드라이드 440mg을 다시 첨가한다. 혼합물을 실온에서 1시간동안 교반한다. 그다음, 반응 혼합물을 실시예 2에서와 똑같이 처리한다. 무색 침상물질로서 α-(3,4-디메톡시펜에틸아미노메틸)-4-벤질옥시벤질알콜(유리염기)를 얻는다. 수율 84%.(2) 1.0 g of 2- (4-benzyloxyphenyl) -2-hydroxy-N- (3,4-dimethoxyphenethyl) thioacetamide was dissolved in 20 ml of methylene chloride, and then 460 ml of triethyloxonium fluoroborate. Add. The mixture is stirred at room temperature for 30 minutes and then concentrated under reduced pressure. The residue is added to a mixture of 20 ml of methanol and 20 ml of chloroform and then 440 mg of sodium borohydride is added again. The mixture is stirred at rt for 1 h. The reaction mixture is then treated in the same manner as in Example 2. Α- (3,4-dimethoxyphenethylaminomethyl) -4-benzyloxybenzyl alcohol (free base) is obtained as a colorless needle. Yield 84%.
이 생성물의 물리-화학적 성질은 실시예 2에서 얻어진 생성물의 성질과 같다.The physical-chemical properties of this product are the same as those of the product obtained in Example 2.
[실시예 5]Example 5
(1) 4-아세톡시아세토페논 5.34g, 염화티오닐 20ml, 피리딘 0.03ml와 3,4-디메톡시펜에틸아민 6.51g을 실시예 1-(1)에서와 똑같은 방법으로 처리한다. 2-(4-아세톡시페닐)-2-옥소-N-(3,4-디메톡시펜에틸) 티오아세트 아마이드 8.5g을 엷은 황색기름 형태로 얻는다.(1) 5.34 g of 4-acetoxyacetophenone, 20 ml of thionyl chloride, 0.03 ml of pyridine and 6.51 g of 3,4-dimethoxyphenethylamine were treated in the same manner as in Example 1- (1). 8.5 g of 2- (4-acetoxyphenyl) -2-oxo-N- (3,4-dimethoxyphenethyl) thioacetamide are obtained in the form of pale yellow oil.
수율 73%Yield 73%
IRVliq max(cm-1) : 1755,1665IRV liq max (cm -1 ): 1755,1665
Mass m/e : 387(M+)Mass m / e: 387 (M + )
NMR(CDCl3)δ : 2.30(S,3H,),3.00 (t,2H, J=7.5Hz,), 3.84(S,6H, )NMR (CDCl 3 ) δ: 2.30 (S, 3H, ), 3.00 (t, 2H, J = 7.5 Hz, ), 3.84 (S, 6H, )
(2) 2-(4-아세토페닐)-2-옥소-N-(3,4-디메톡시펜에틸)티오아세트아마이드 1.94g, 트리에틸옥소늄플루오로보레이트 1.14g과 나트륨 보로하이드라이드 1.0g을 실시예 2에서와 똑같은 방법으로 처리한다. 무색프리즘 형태로서 α-(3,4-디메톡시펜에틸아미노메틸)-4-하이드록시벤질알콜 1.47g을 얻는다. 수율 92%. 융점 151°- 153℃(2) 1.94 g of 2- (4-acetophenyl) -2-oxo-N- (3,4-dimethoxyphenethyl) thioacetamide, 1.14 g of triethyloxonium fluoroborate and 1.0 g of sodium borohydride Is treated in the same manner as in Example 2. 1.47 g of α- (3,4-dimethoxyphenethylaminomethyl) -4-hydroxybenzyl alcohol is obtained as a colorless prism form. Yield 92%. Melting Point 151 °-153 ℃
[실시예 6]Example 6
(1) 4-하이드록시아세토페논 4.08g, 염화티오닐 12ml, 피리딘 0.06ml와 3,4-디메톡시펜에틸아민 6.51g을 실시예 1-(1)에서와 똑같은 방법으로 처리한다. 엷은 황색 침상물질로서 2-(4-하이드록시페닐)-2-옥소-N-(3,4-디메톡시펜에틸)티오아세트아마이드 3.1g을 얻는다. 수율 30%. 융점 179°- 180℃ (에탄올로 재결정됨).(1) 4.08 g of 4-hydroxyacetophenone, 12 ml of thionyl chloride, 0.06 ml of pyridine and 6.51 g of 3,4-dimethoxyphenethylamine were treated in the same manner as in Example 1- (1). 3.1 g of 2- (4-hydroxyphenyl) -2-oxo-N- (3,4-dimethoxyphenethyl) thioacetamide is obtained as a pale yellow needle. Yield 30%. Melting point 179 ° -180 ° C. (recrystallized from ethanol).
(2) 2-(4-하이드록시페닐)-2-옥소-N-(3,4-디메톡시펜에틸)티오아세트 아마이드 1.0g, 염화니켈 6수화물 1.37g과 나트륨보로하이드라이드 1.1g을 실시예 1-(2)에서와 똑같은 방법으로 처리한다. α-(3,4-디메톡시펜에틸아미노메틸)-4-하이드록시벤질알콜 230mg을 무색 프리즘 형태로 얻는다. 수율 25%.(2) 1.0 g of 2- (4-hydroxyphenyl) -2-oxo-N- (3,4-dimethoxyphenethyl) thioacetamide, 1.37 g of nickel chloride hexahydrate and 1.1 g of sodium borohydride Treatment is carried out in the same manner as in Example 1- (2). 230 mg of α- (3,4-dimethoxyphenethylaminomethyl) -4-hydroxybenzyl alcohol are obtained in the form of a colorless prism. Yield 25%.
이 생성물의 물리-화학적 성질은 실시예 5-(2)에서 얻어진 생성물의 성질과 똑같다.The physico-chemical properties of this product are the same as those of the product obtained in Example 5- (2).
[실시예 7]Example 7
2-(4-하이드록시페닐)-2-옥소-N-(3,4-디메톡시펜에틸) 티오아세트아마이드 1.58, 트리에틸옥소늄플루오로보레이트 1.13g과 나트륨 보로하이드라이드 870mg을 실시예 2에서와 똑같은 방법으로 처리한다. 무색프리즘 형태로서 α-(3,4-디메톡시펜에틸아미노메틸)-4-하이드록시벤질알콜 940mg을 얻는다. 수율 65%Example 2 of 1.58 g of 2- (4-hydroxyphenyl) -2-oxo-N- (3,4-dimethoxyphenethyl) thioacetamide, 1.13 g of triethyloxonium fluoroborate and 870 mg of sodium borohydride Do the same as in. 940 mg of α- (3,4-dimethoxyphenethylaminomethyl) -4-hydroxybenzyl alcohol is obtained as a colorless prism form. Yield 65%
이 생성물의 물리-화학적 성질은 실시예 5-(2)에서 얻어진 생성물의 성질과 똑같다.The physico-chemical properties of this product are the same as those of the product obtained in Example 5- (2).
[실시예 8]Example 8
(1) 2-벤질옥시아세토페논 6.78g, 염화티오닐 21ml, 피리딘 0.05ml와 3,4-디메톡시펜에틸아민 6.54g을 실시예 1-(1)에서와 똑같은 방법으로 처리한다. 엷은 황색 프리즘 형태로서 2-(2-벤질옥시페닐)-2-옥소-N-(3,4-디메톡시펜에틸)티오아세트아마이드 10.3g을 얻는다. 수율 79%, 융점 112-114℃(1) 6.78 g of 2-benzyloxyacetophenone, 21 ml of thionyl chloride, 0.05 ml of pyridine and 6.54 g of 3,4-dimethoxyphenethylamine were treated in the same manner as in Example 1- (1). 10.3 g of 2- (2-benzyloxyphenyl) -2-oxo-N- (3,4-dimethoxyphenethyl) thioacetamide is obtained in the form of a pale yellow prism. Yield 79%, melting point 112-114 ° C
(2) 2-(2-벤질옥시페닐)-2-옥소-N-(3,4-디메톡시펜에틸)티오아세트 아마이드 500mg, 염화니켈 6수화물 900mg과 나트륨 보로하이드라이드 700mg을 실시예 1-(2)에서와 똑같은 방법으로 처리한다. 무색침상물질로서 α-(3,4-디메톡시펜에틸 아미노메틸)-2-벤질옥시벤질알콜 하이드로클로라이드 165mg을 얻는다 : 수율 32%. 융점159-160℃(2) Example 1-, 500 mg of 2- (2-benzyloxyphenyl) -2-oxo-N- (3,4-dimethoxyphenethyl) thioacetamide, 900 mg of nickel chloride hexahydrate and 700 mg of sodium borohydride Process in the same way as in (2). As a colorless needle, 165 mg of α- (3,4-dimethoxyphenethyl aminomethyl) -2-benzyloxybenzyl alcohol hydrochloride is obtained: yield 32%. Melting Point159-160 ℃
[실시예 9]Example 9
2-(2-벤질옥시페닐)-2-옥소-N-(3,4-디메톡시펜에틸) 티오아세트아마이드 2.0g, 트리에틸옥소늄플루오로보레이트 1.13g과 나트륨 보로하이드라이드 870mg을2.0 g of 2- (2-benzyloxyphenyl) -2-oxo-N- (3,4-dimethoxyphenethyl) thioacetamide, 1.13 g of triethyloxonium fluoroborate and 870 mg of sodium borohydride
[실시예 10]Example 10
2-(2-벤질옥시페닐)-2-옥소-N-(3,4-디메톡시펜에틸) 티오아세트아마이드 2.2g, 탄산칼륨 850mg, 요오드화메틸 1.0g과 나트륨 보로하이드라이드 300mg을 실시예 3에서와 똑같은 방법으로 처리한다. 무색침상 물질로서 α-(3,4-디메톡시펜에틸아미노메틸)-2-벤질옥시벤질알콜(유리염기) 1.1g을 얻는다. 수율 53%.Example 3 of 2.2 g of 2- (2-benzyloxyphenyl) -2-oxo-N- (3,4-dimethoxyphenethyl) thioacetamide, 850 mg of potassium carbonate, 1.0 g of methyl iodide and 300 mg of sodium borohydride Do the same as in. 1.1 g of alpha-(3,4-dimethoxyphenethylaminomethyl) -2-benzyloxybenzyl alcohol (free base) is obtained as a colorless needle. Yield 53%.
이 생성물의 물리-화학적 성질은 실시예 9에서 얻어진 생성물의 성질과 똑같다.The physico-chemical properties of this product are the same as those of the product obtained in Example 9.
[실시예 11]Example 11
(1) 2-하이드록시아세토페논 2.73g, 염화티오닐 8ml, 피리딘 0.03ml와 3,4-디메톡시펜에틸아민 2.53g을 실시예 1-(1)에서와 똑같은 방법으로 처리한다. 2-(2-하이드록시페닐)-2-옥소-N-(3,4-디메톡시펜에틸)티오아세트아마이드 4.0g을 엷은 적갈색 침상 형태로 얻는다.수율 58%, 융점 166°-168℃(에탄올로 재결정됨).(1) 2.73 g of 2-hydroxyacetophenone, 8 ml of thionyl chloride, 0.03 ml of pyridine and 2.53 g of 3,4-dimethoxyphenethylamine were treated in the same manner as in Example 1- (1). 4.0 g of 2- (2-hydroxyphenyl) -2-oxo-N- (3,4-dimethoxyphenethyl) thioacetamide is obtained in the form of pale reddish brown needles. Yield 58%, Melting point 166 ° -168 ° C ( Recrystallized from ethanol).
(2) 2-(2-하이드록시페닐)-2-옥소-N-(3,4-디메톡시펜에틸) 티오아마이드 1.58g, 트리에틸옥소늄플루오로보레이트 1.13g과 나트륨 보로하이드라이드 1.4g을 실시예 2에서와 똑같은 방법으로 처리한다. 무색 기름형태로서 α-(3,4-디메톡시펜에틸아미노메틸)-2-하이드록시벤질알콜 850mg을 얻는다. 수율58%, 이 생성물의 옥살산염 융점 175°-176℃(2) 1.58 g of 2- (2-hydroxyphenyl) -2-oxo-N- (3,4-dimethoxyphenethyl) thioamide, 1.13 g of triethyloxonium fluoroborate and 1.4 g of sodium borohydride Is treated in the same manner as in Example 2. 850 mg of α- (3,4-dimethoxyphenethylaminomethyl) -2-hydroxybenzyl alcohol is obtained as a colorless oil. Yield 58%, the oxalate melting point of this product: 175 ° -176 ° C
[실시예 12]Example 12
(1) 2-아세톡시아세토페논 1.78g, 염화티오닐 6ml, 피리딘 0.02ml와 3,4-디메톡시펜에틸아민 1.27g을 실시예 1-(1)에서와 똑같은 방법으로 처리한다. 엷은 황색기름 형태로서 2-(2-아세톡시페닐)-2-옥소-N-(3,4-디메톡시펜에틸)티오아세트 아마이드 1.37g을 얻는다. 수율 35.4%(1) 1.78 g of 2-acetoxyacetophenone, 6 ml of thionyl chloride, 0.02 ml of pyridine and 1.27 g of 3,4-dimethoxyphenethylamine were treated in the same manner as in Example 1- (1). 1.37 g of 2- (2-acetoxyphenyl) -2-oxo-N- (3,4-dimethoxyphenethyl) thioacetamide is obtained as a pale yellow oil form. Yield 35.4%
:1760, 1670 1760, 1670
Mass m/e : 387(M+)Mass m / e: 387 (M + )
NMR(CDCl3)δ:2.20(S(3H,, 2.94(e, 2H, J=7.5Hz,), 3.85(S,6H,- NMR (CDCl 3 ) δ: 2.20 (S (3H, , 2.94 (e, 2H, J = 7.5 Hz, ), 3.85 (S, 6H,-
(2) 2-(2-아세톡시페닐)-2-옥소-N-(3,4-디메톡시펜에틸)티오아세트아마이드, 트리에틸옥소늄플루오로보레이트와 나트륨 보로하이드라이드를 실시예 2에서와 똑같은 방법으로 처리한다. α-(3,4-디메톡시펜에틸아미노메틸)-2-하이드록시벤질알콜을 얻는다.(2) 2- (2-acetoxyphenyl) -2-oxo-N- (3,4-dimethoxyphenethyl) thioacetamide, triethyloxonium fluoroborate and sodium borohydride in Example 2 Handle it the same way. α- (3,4-dimethoxyphenethylaminomethyl) -2-hydroxybenzyl alcohol is obtained.
이 생성물의 물리-화학적 성질은 실시예 11-(2)에서 얻어진 생성물의 성질과 똑같다.The physical-chemical properties of this product are the same as those of the product obtained in Example 11- (2).
Claims (9)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP181951 | 1981-11-12 | ||
JP56181951A JPS5883661A (en) | 1981-11-12 | 1981-11-12 | Preparation of benzyl alcohol derivative |
Publications (2)
Publication Number | Publication Date |
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KR840002343A KR840002343A (en) | 1984-06-25 |
KR870000471B1 true KR870000471B1 (en) | 1987-03-11 |
Family
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Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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KR828205098A KR870000471B1 (en) | 1981-11-12 | 1982-11-11 | Process for preparing benzylalcohol derivatives |
Country Status (10)
Country | Link |
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JP (1) | JPS5883661A (en) |
KR (1) | KR870000471B1 (en) |
AT (1) | AT382866B (en) |
CA (1) | CA1196342A (en) |
CH (1) | CH650247A5 (en) |
DK (1) | DK163660C (en) |
ES (1) | ES8401013A1 (en) |
HU (1) | HU189190B (en) |
IT (1) | IT1191227B (en) |
SE (1) | SE454775B (en) |
Cited By (1)
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US7985168B2 (en) | 2009-03-25 | 2011-07-26 | Graa Innovations, Llc | Power stride apparatus and method of training therefor |
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US4579972A (en) * | 1983-04-28 | 1986-04-01 | Smithkline Beckman Corporation | Intermediates for preparing secondary amines |
JPH0735693U (en) * | 1993-12-14 | 1995-07-04 | 協和電機化学株式会社 | Seal for sealing the butt of glass doors |
Family Cites Families (2)
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JPS5310974B2 (en) * | 1974-06-10 | 1978-04-18 | ||
JPS6241829Y2 (en) * | 1980-03-28 | 1987-10-26 |
-
1981
- 1981-11-12 JP JP56181951A patent/JPS5883661A/en active Granted
-
1982
- 1982-11-05 CA CA000415011A patent/CA1196342A/en not_active Expired
- 1982-11-08 CH CH6482/82A patent/CH650247A5/en not_active IP Right Cessation
- 1982-11-09 SE SE8206352A patent/SE454775B/en not_active IP Right Cessation
- 1982-11-11 DK DK502682A patent/DK163660C/en not_active IP Right Cessation
- 1982-11-11 ES ES517297A patent/ES8401013A1/en not_active Expired
- 1982-11-11 AT AT0409882A patent/AT382866B/en not_active IP Right Cessation
- 1982-11-11 KR KR828205098A patent/KR870000471B1/en active
- 1982-11-11 HU HU823632A patent/HU189190B/en not_active IP Right Cessation
- 1982-11-11 IT IT68332/82A patent/IT1191227B/en active
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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US7985168B2 (en) | 2009-03-25 | 2011-07-26 | Graa Innovations, Llc | Power stride apparatus and method of training therefor |
Also Published As
Publication number | Publication date |
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ATA409882A (en) | 1986-09-15 |
DK163660B (en) | 1992-03-23 |
SE454775B (en) | 1988-05-30 |
HU189190B (en) | 1986-06-30 |
CA1196342A (en) | 1985-11-05 |
ES517297A0 (en) | 1983-12-01 |
IT8268332A0 (en) | 1982-11-11 |
KR840002343A (en) | 1984-06-25 |
JPS6121620B2 (en) | 1986-05-28 |
SE8206352L (en) | 1983-05-13 |
SE8206352D0 (en) | 1982-11-09 |
JPS5883661A (en) | 1983-05-19 |
IT1191227B (en) | 1988-02-24 |
CH650247A5 (en) | 1985-07-15 |
DK163660C (en) | 1992-08-17 |
AT382866B (en) | 1987-04-27 |
ES8401013A1 (en) | 1983-12-01 |
DK502682A (en) | 1983-05-13 |
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