JPS632258B2 - - Google Patents
Info
- Publication number
- JPS632258B2 JPS632258B2 JP55081340A JP8134080A JPS632258B2 JP S632258 B2 JPS632258 B2 JP S632258B2 JP 55081340 A JP55081340 A JP 55081340A JP 8134080 A JP8134080 A JP 8134080A JP S632258 B2 JPS632258 B2 JP S632258B2
- Authority
- JP
- Japan
- Prior art keywords
- formula
- reaction
- group
- acid
- alkyl group
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
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- 150000001875 compounds Chemical class 0.000 claims description 13
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 5
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical group O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 claims description 4
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 3
- 125000003118 aryl group Chemical group 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 3
- 230000007062 hydrolysis Effects 0.000 claims description 3
- 238000006460 hydrolysis reaction Methods 0.000 claims description 3
- 230000007017 scission Effects 0.000 claims description 3
- 150000002475 indoles Chemical class 0.000 claims description 2
- 238000003385 ring cleavage reaction Methods 0.000 claims description 2
- 238000006798 ring closing metathesis reaction Methods 0.000 claims description 2
- 238000006243 chemical reaction Methods 0.000 description 20
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- 238000000034 method Methods 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 239000002904 solvent Substances 0.000 description 7
- NLMQHXUGJIAKTH-UHFFFAOYSA-N 4-hydroxyindole Chemical compound OC1=CC=CC2=C1C=CN2 NLMQHXUGJIAKTH-UHFFFAOYSA-N 0.000 description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 6
- -1 alkali metal salt Chemical class 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- 229910052739 hydrogen Inorganic materials 0.000 description 5
- 239000001257 hydrogen Substances 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 238000006722 reduction reaction Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- BRLQWZUYTZBJKN-UHFFFAOYSA-N Epichlorohydrin Chemical compound ClCC1CO1 BRLQWZUYTZBJKN-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 238000000862 absorption spectrum Methods 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 150000003973 alkyl amines Chemical class 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- QQVDYSUDFZZPSU-UHFFFAOYSA-M chloromethylidene(dimethyl)azanium;chloride Chemical compound [Cl-].C[N+](C)=CCl QQVDYSUDFZZPSU-UHFFFAOYSA-M 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 238000000921 elemental analysis Methods 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 125000001041 indolyl group Chemical group 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- JZQKKSLKJUAGIC-UHFFFAOYSA-N pindolol Chemical compound CC(C)NCC(O)COC1=CC=CC2=C1C=CN2 JZQKKSLKJUAGIC-UHFFFAOYSA-N 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- YIUIPTVCXWPNJM-UHFFFAOYSA-N 1-(butan-2-ylamino)-3-(1H-indol-4-yloxy)propan-2-ol Chemical compound CCC(C)NCC(COC1=CC=CC2=C1C=CN2)O YIUIPTVCXWPNJM-UHFFFAOYSA-N 0.000 description 1
- ZQQSYPZAPHRXRY-UHFFFAOYSA-N 1-hydroxyazetidine Chemical compound ON1CCC1 ZQQSYPZAPHRXRY-UHFFFAOYSA-N 0.000 description 1
- GAKLFAZBKQGUBO-UHFFFAOYSA-N 2-methyl-3-nitrophenol Chemical compound CC1=C(O)C=CC=C1[N+]([O-])=O GAKLFAZBKQGUBO-UHFFFAOYSA-N 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- FNZTVUHCYCHOFH-UHFFFAOYSA-N 3-(1h-indol-4-yloxy)propane-1,2-diol Chemical compound OCC(O)COC1=CC=CC2=C1C=CN2 FNZTVUHCYCHOFH-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- MCSXGCZMEPXKIW-UHFFFAOYSA-N 3-hydroxy-4-[(4-methyl-2-nitrophenyl)diazenyl]-N-(3-nitrophenyl)naphthalene-2-carboxamide Chemical compound Cc1ccc(N=Nc2c(O)c(cc3ccccc23)C(=O)Nc2cccc(c2)[N+]([O-])=O)c(c1)[N+]([O-])=O MCSXGCZMEPXKIW-UHFFFAOYSA-N 0.000 description 1
- BGNGWHSBYQYVRX-UHFFFAOYSA-N 4-(dimethylamino)benzaldehyde Chemical compound CN(C)C1=CC=C(C=O)C=C1 BGNGWHSBYQYVRX-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 206010003658 Atrial Fibrillation Diseases 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- OIFBSDVPJOWBCH-UHFFFAOYSA-N Diethyl carbonate Chemical compound CCOC(=O)OCC OIFBSDVPJOWBCH-UHFFFAOYSA-N 0.000 description 1
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-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
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- JLCHNBRGUPQWKF-UHFFFAOYSA-J [OH-].[C+4].[OH-].[OH-].[OH-] Chemical compound [OH-].[C+4].[OH-].[OH-].[OH-] JLCHNBRGUPQWKF-UHFFFAOYSA-J 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000008052 alkyl sulfonates Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001414 amino alcohols Chemical group 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 230000006793 arrhythmia Effects 0.000 description 1
- GMWFCJXSQQHBPI-UHFFFAOYSA-N azetidin-3-ol Chemical class OC1CNC1 GMWFCJXSQQHBPI-UHFFFAOYSA-N 0.000 description 1
- 239000002585 base Substances 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
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 230000008033 biological extinction Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 238000010531 catalytic reduction reaction Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 229910017052 cobalt Inorganic materials 0.000 description 1
- 239000010941 cobalt Substances 0.000 description 1
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000006326 desulfonation Effects 0.000 description 1
- 238000005869 desulfonation reaction Methods 0.000 description 1
- SPWVRYZQLGQKGK-UHFFFAOYSA-N dichloromethane;hexane Chemical compound ClCCl.CCCCCC SPWVRYZQLGQKGK-UHFFFAOYSA-N 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N ethylene glycol Natural products OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- ZHNUHDYFZUAESO-UHFFFAOYSA-N formamide Substances NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 1
- 150000003948 formamides Chemical class 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 230000002140 halogenating effect Effects 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
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 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
- 238000002955 isolation Methods 0.000 description 1
- 239000007788 liquid 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
- 239000011976 maleic acid Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 125000004108 n-butyl group Chemical group [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
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 230000000701 neuroleptic effect Effects 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 229960002508 pindolol Drugs 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- OVYTZAASVAZITK-UHFFFAOYSA-M sodium;ethanol;hydroxide Chemical compound [OH-].[Na+].CCO OVYTZAASVAZITK-UHFFFAOYSA-M 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000013077 target material Substances 0.000 description 1
- 239000013076 target substance Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
Landscapes
- Indole Compounds (AREA)
Description
【発明の詳細な説明】
本発明は、一般式
(式中Rはアルキル基を示す)で表わされるイン
ドール誘導体の新規な製法に関する。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to the general formula The present invention relates to a novel method for producing an indole derivative represented by the formula (wherein R represents an alkyl group).
式の化合物及びその酸付加塩はβ−アドレナ
リン作動神経遮断作用を有し、不整脈、心房細動
又は冠状動脈疾患の治療ならびに予防に有用であ
り、特にRがイソプロピル基の化合物はピンドロ
ールの名で広く使用されている。 The compounds of the formula and their acid addition salts have β-adrenergic neuroleptic action and are useful in the treatment and prevention of arrhythmia, atrial fibrillation or coronary artery disease, and in particular, the compound in which R is isopropyl is known as pindolol. Widely used.
従来この種の化合物の製法としては、例えば下
記の方法が知られている。 Conventionally, as a method for producing this type of compound, for example, the following method is known.
(1) 4−ヒドロキシインドールをアルカリ金属塩
の形で酸素不含の系内でエピクロルヒドリンと
反応させ、次いで粗生成物をアルキルアミンと
反応させる方法又は前記生成物をベンジルアル
キルアミンと反応させたのち、反応生成物から
ベンジル基を水素分解的に脱離する方法(特公
昭42−9954号公報参照)、
(2) 4−ヒドロキシインドールをアルカリ性媒質
中でかつ酸素不含の系内でエピクロルヒドリン
と反応させ、次いで粗生成物をベンジルアミン
と反応させたのち、触媒の存在下に水素還元的
にベンジル基を脱離する方法(特公昭43−
26621号公報参照)、
(3) 4−ヒドロキシインドールを3−アゼチジノ
ール誘導体と反応させてアゼチジノールを開環
することにより、4−インドリルオキシ誘導体
を製造する方法(特公昭47−19259号公報参
照)、
(4) 4−ヒドロキシインドールのアルカリ金属塩
を1−ハロゲノ−2・3−プロパンジオールと
反応させ、得られた4−(2・3−ジヒドロキ
シプロポキシ)−インドールをフエニルスルホ
ン化又はアルキルスルホン化したのち、アルキ
ルアミンを作用させて脱スルホン化する方法
(特開昭48−54058号公報参照)など。(1) A process in which 4-hydroxyindole is reacted in the form of an alkali metal salt with epichlorohydrin in an oxygen-free system and the crude product is then reacted with an alkylamine, or after reacting said product with a benzylalkylamine. , a method of hydrogenolytically removing a benzyl group from a reaction product (see Japanese Patent Publication No. 42-9954), (2) Reacting 4-hydroxyindole with epichlorohydrin in an alkaline medium in an oxygen-free system. The crude product is then reacted with benzylamine, and then the benzyl group is eliminated by hydrogen reduction in the presence of a catalyst (Japanese Patent Publication No. 43-1999).
26621), (3) A method for producing 4-indolyloxy derivatives by reacting 4-hydroxyindole with a 3-azetidinol derivative to open the ring of azetidinol (see Japanese Patent Publication No. 47-19259). , (4) Reacting an alkali metal salt of 4-hydroxyindole with 1-halogeno-2,3-propanediol, and converting the resulting 4-(2,3-dihydroxypropoxy)-indole into phenylsulfonate or alkylsulfonate. and then desulfonation by the action of an alkylamine (see JP-A-48-54058).
しかしこれらの方法では、原料物質として用い
られる4−ヒドロキシインドールが、大気中及び
光線下で極めて不安定なため取扱いが困難で、特
に工業的規模でこれらの方法を実施する場合に
は、原料の自己分解及び副反応により不純物が混
入し、精製が煩雑であると共に収率が低下し、さ
らに保護基の導入及び脱離のため反応工程が複雑
になるなどの欠点があつた。 However, in these methods, the 4-hydroxyindole used as the raw material is extremely unstable in the air and under light, making it difficult to handle.Especially when implementing these methods on an industrial scale, the raw material There were drawbacks such as contamination of impurities due to self-decomposition and side reactions, complicating purification and lower yields, and further complicating the reaction process due to the introduction and removal of protecting groups.
このため4−ヒドロキシインドールを経由しな
い製法の開発が望まれ、アミノアルコール側鎖を
導入したのち、インドール環を形成する方法も報
告されている(特開昭52−89668号及び同55−
11559号各公報参照)。しかし、この方法はインド
ール環の形成に多くの工程を要し、かつ反応に長
時間を要するなどの欠点がある。 For this reason, it is desired to develop a production method that does not involve 4-hydroxyindole, and a method has also been reported in which an indole ring is formed after introducing an amino alcohol side chain (JP-A-52-89668 and JP-A No. 55-52).
(Refer to each publication No. 11559). However, this method has drawbacks such as requiring many steps to form an indole ring and requiring a long time for the reaction.
本発明者はこれら従来法の欠点を解決するため
種々研究した結果、一般式
(式中Rはアルキル基を示す)で表わされる化合
物を、一般式
(式中X及びYはハロゲン原子、個々のR1は同
一でも異なつてもよく、それぞれアルキル基、ア
リール基又はアルアルキル基を示す)で表わされ
る化合物と反応させ、生成物を塩基の存在下に還
元及び加水分解することにより、閉環及びオキサ
ゾリジノン環の開裂を行うことにより、式の化
合物が簡単かつ経済的な手段で高収率で得られる
ことを見出した。 As a result of various researches to solve the drawbacks of these conventional methods, the present inventor found that the general formula (wherein R represents an alkyl group), a compound represented by the general formula (In the formula, X and Y are halogen atoms, and each R 1 may be the same or different and each represents an alkyl group, an aryl group, or an aralkyl group.) It has been found that by reduction and hydrolysis to , by ring closure and cleavage of the oxazolidinone ring, compounds of the formula can be obtained in high yields by simple and economical means.
式の出発物質及びこれに対応する式の目的
物質の置換基Rのためのアルキル基としては低級
アルキル基が好ましく、例えばメチル基、エチル
基、n−プロピル基、n−ブチル基、イソブチル
基、三級ブチル基、特にイソプロピル基又は二級
ブチル基があげられる。 The alkyl group for the substituent R in the starting material of the formula and the corresponding target material of the formula is preferably a lower alkyl group, such as a methyl group, ethyl group, n-propyl group, n-butyl group, isobutyl group, Mention may be made of tertiary butyl groups, especially isopropyl groups or secondary butyl groups.
式における置換基X及びYのハロゲン原子と
しては通常は塩素原子又は臭素原子が用いられ、
R1のアルキル基としては、例えばメチル基、エ
チル基、プロピル基、ブチル基、アリール基とし
てはフエニル基、ナフチル基、アルアルキル基と
してはベンジル基又はフエネチル基が好ましい。 As the halogen atom of the substituents X and Y in the formula, a chlorine atom or a bromine atom is usually used,
The alkyl group for R 1 is preferably a methyl group, ethyl group, propyl group, or butyl group, the aryl group is preferably a phenyl group or naphthyl group, and the aralkyl group is preferably a benzyl group or a phenethyl group.
式のオキサゾリジノン誘導体は、例えば6−
(2−ヒドロキシ−3−アルキルアミノプロポキ
シ)−2−ニトロトルエンを炭酸エステル類もし
くはホスゲンと反応させるか又は6−ヒドロキシ
−2−ニトロトルエンを5−ハロゲンメチル−3
−アルキシオキサゾリジン−2−オンと反応させ
ることにより得られる。 Oxazolidinone derivatives of the formula include, for example, 6-
(2-Hydroxy-3-alkylaminopropoxy)-2-nitrotoluene is reacted with carbonate esters or phosgene, or 6-hydroxy-2-nitrotoluene is reacted with 5-halogenmethyl-3
-obtained by reaction with alkoxyoxazolidin-2-one.
式の化合物は、置換ホルムアミドにハロゲン
化剤を作用させることにより得られる。ジメチル
ホルムアミドにオキシ塩化燐又は塩化チオニルを
作用させることにより得られるいわゆるビルスマ
イヤー試薬を、単離せずにそのまま用いることが
好ましい。 A compound of the formula can be obtained by reacting a substituted formamide with a halogenating agent. It is preferable to use the so-called Vilsmeier reagent obtained by reacting dimethylformamide with phosphorus oxychloride or thionyl chloride without isolation.
本発明を実施するに際しては、好ましくは溶媒
の存在下に、式の化合物と式の化合物を反応
させる。溶媒としては例えば炭化水素、ハロゲン
化炭化水素、エーテル類、グルコールエーテル
類、ジメチルスルホキシド、ジメチルホルムアミ
ド等の非プロトン性溶媒が用いられる。 In carrying out the invention, compounds of the formula and compounds of the formula are reacted, preferably in the presence of a solvent. As the solvent, aprotic solvents such as hydrocarbons, halogenated hydrocarbons, ethers, glycol ethers, dimethyl sulfoxide, and dimethylformamide are used.
本反応は常圧、減圧又は加圧下に行うことがで
きる。反応温度は通常は反応混合物の沸騰温度以
下、好ましく50〜150℃であり、一般に数時間で
反応が終了する。反応を促進するため、有機塩基
例えばトリエチルアミンを添加することが好まし
い。 This reaction can be carried out under normal pressure, reduced pressure or increased pressure. The reaction temperature is usually below the boiling temperature of the reaction mixture, preferably 50 to 150°C, and the reaction is generally completed in several hours. In order to accelerate the reaction, it is preferred to add an organic base such as triethylamine.
式の化合物と式の化合物の反応生成物の還
元は常法により、触媒の存在下に水素を用いる接
触還元法を使用することが好ましい。この場合に
必要な塩基としては、例えば水酸化ナトリウム、
水酸化カリウム等の無機強塩基が好ましい。触媒
としては、例えば白金、パラジウム、ニツケル、
コバルト等の金属又はその酸化物もしくは水酸化
物が用いられる。 The reaction product of the compound of the formula and the compound of the formula is reduced by a conventional method, preferably a catalytic reduction method using hydrogen in the presence of a catalyst. The base required in this case includes, for example, sodium hydroxide,
A strong inorganic base such as potassium hydroxide is preferred. Examples of catalysts include platinum, palladium, nickel,
A metal such as cobalt or its oxide or hydroxide is used.
還元反応は好ましくは溶媒中で行われ、特に含
水溶媒中では加水分解によるオキサゾリジノン環
の開裂も同時に行うことができる。溶媒として
は、例えばアルコール類、グリコール類、ジメチ
ルホルムアミドなどが好ましい。還元は時間をか
けてゆつくり行うことが好ましく、通常は3〜20
時間で終了するように、反応温度、水素ガス導入
量等を調整する。 The reduction reaction is preferably carried out in a solvent, and in particular in a water-containing solvent, cleavage of the oxazolidinone ring by hydrolysis can also be carried out at the same time. As the solvent, for example, alcohols, glycols, dimethylformamide, etc. are preferable. It is preferable to reduce the amount slowly over time, usually 3 to 20
Adjust the reaction temperature, amount of hydrogen gas introduced, etc. so that the reaction can be completed within a certain time.
目的物質は常法により単離、精製することがで
き、その操作条件により遊離塩基又は酸付加塩の
形の式の化合物が得られる。酸付加塩を形成す
るための酸としては、例えば塩酸、臭化水素酸、
硫酸、燐酸等の無機酸ならびに例えば酢酸、プロ
ピオン酸、修酸、マレイン酸、こはく酸、酒石
酸、くえん酸、安息香酸、メタンスルホン酸、エ
タンスルホン酸、p−トルエンスルホン酸等の有
機酸が用いられる。 The target substance can be isolated and purified by conventional methods, and depending on the operating conditions, a compound of the formula can be obtained in the form of a free base or an acid addition salt. Examples of acids for forming acid addition salts include hydrochloric acid, hydrobromic acid,
Inorganic acids such as sulfuric acid and phosphoric acid as well as organic acids such as acetic acid, propionic acid, oxalic acid, maleic acid, succinic acid, tartaric acid, citric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, and p-toluenesulfonic acid are used. It will be done.
式の化合物の製造例
−(2−ヒドロキシ−3−イソプロピルアミノ
プロポキシ)−2−ニトロトルエン13.4gをジメ
チルホルムアミド350mlに溶解し、炭酸ジエチル
30.7g及び炭酸カリウム25gを加えて約7時間撹
拌下に還流する。反応終了後、炭酸カリウムを
去し、液から減圧下に溶媒を留去する。得られ
た褐色の残査を大量の氷水に分散させ、クロロホ
ルム200mlで数回に分けて抽出する。抽出液を硫
酸ナトリウム23gにより乾燥し、過したのち、
真空蒸留によりクロロホルムを留去し、得られた
黄色結晶をジクロルメタン−n−ヘキサンから再
結晶すると、融点108〜110℃の次式
で表わされる5−(2−メチル−3−ニトロフエ
ノキシメチル)−3−イソプロピル−オキサゾリ
ジン−2−オンの淡黄色結晶13.46g(収率91.56
%)が得られる。Example of preparing a compound of the formula -(2-hydroxy-3-isopropylaminopropoxy)-2-nitrotoluene (13.4 g) was dissolved in 350 ml of dimethylformamide, diethyl carbonate
Add 30.7 g and 25 g of potassium carbonate, and reflux with stirring for about 7 hours. After the reaction is completed, potassium carbonate is removed and the solvent is distilled off from the liquid under reduced pressure. The resulting brown residue is dispersed in a large amount of ice water and extracted in several portions with 200 ml of chloroform. After drying the extract with 23 g of sodium sulfate and filtering it,
When chloroform is removed by vacuum distillation and the obtained yellow crystals are recrystallized from dichloromethane-n-hexane, the following formula with a melting point of 108-110℃ is obtained. 13.46 g of pale yellow crystals of 5-(2-methyl-3-nitrophenoxymethyl)-3-isopropyl-oxazolidin-2-one (yield: 91.56)
%) is obtained.
元素分析値C14H18N2O5として
C H N
計算値(%) 57.14 6.12 9.52
実測値(%) 57.03 6.07 9.49
赤外線吸収スペクトル
νKBr naxcm-1:
3440、2965、2915、2865、1720、1604、
1528、1450、1438、1355、1265、1205、
1052、831、795、770、748
実施例 1
無水ジメチルホルムアミド8.0gを冷却しなが
ら、塩化チオニル13gを約20分で滴下する。その
間反応液の温度を10〜20℃に保持する。滴加終了
後、同温度で約15分間撹拌したのち、5−(2−
メチル−3−ニトロフエニル)−オキシメチル−
3−イソプロピルオキサゾリジン−2−オン29.4
gをジクロルエタン250mlに溶解して滴下する。
20℃付近の温度で約1時間撹拌し、次いで6時間
還流加熱する。反応が進行すると、反応液は赤色
ないし深紅色に変化する。反応終了後、ジクロル
エタンを真空下で留去し、残留した濃赤色油状物
に3N−水酸化ナトリウム−エタノール水溶液
(エタノール2:水1)500mlを加えて溶解し、20
%水酸化パラジウム−炭素9.0gを加え、水素を
徐々に導入しながら約60℃まで加温する。水素の
消費とともに反応液は赤褐色から黄色を経て淡黄
色となり、次第に無色へと変化する。無色になる
と水素の消費が止まり、約10時間で還元が終了す
る。反応の終了は、反応液を薄層シリカゲル板に
プロツトし、イソプロピルアルコール−10%アン
モニア水(10:1)を展開溶媒として展開したの
ち、エーリツヒ試薬で発色する紫色スポットの位
置により確認する。Elemental analysis value C 14 H 18 N 2 O 5 as C H N Calculated value (%) 57.14 6.12 9.52 Actual value (%) 57.03 6.07 9.49 Infrared absorption spectrum ν KBr nax cm -1 : 3440, 2965, 2915, 2865, 1720 , 1604,
1528, 1450, 1438, 1355, 1265, 1205,
1052, 831, 795, 770, 748 Example 1 While cooling 8.0 g of anhydrous dimethylformamide, 13 g of thionyl chloride is added dropwise over about 20 minutes. During this time, the temperature of the reaction solution is maintained at 10-20°C. After the dropwise addition, stir at the same temperature for about 15 minutes, then add 5-(2-
Methyl-3-nitrophenyl)-oxymethyl-
3-isopropyloxazolidin-2-one 29.4
Dissolve g in 250 ml of dichloroethane and add dropwise.
Stir for about 1 hour at a temperature around 20°C and then heat under reflux for 6 hours. As the reaction progresses, the reaction solution turns red to deep red. After the reaction, dichloroethane was distilled off under vacuum, and the remaining dark red oil was dissolved in 500 ml of a 3N sodium hydroxide-ethanol aqueous solution (2 ethanol: 1 water).
Add 9.0 g of % palladium hydroxide-carbon and heat to about 60°C while gradually introducing hydrogen. As hydrogen is consumed, the reaction solution changes from reddish brown to yellow to pale yellow, and then gradually becomes colorless. When it becomes colorless, hydrogen consumption stops and the reduction ends in about 10 hours. The completion of the reaction is confirmed by plotting the reaction solution on a thin silica gel plate and developing it using isopropyl alcohol-10% aqueous ammonia (10:1) as a developing solvent, and then checking the position of a purple spot developed with Ehrlich's reagent.
反応液を過し、液より真空下でエタノール
を留去し、適量の水を加えて一夜放置し、析出し
た結晶をエタノールから再結晶すると、融点169
〜171℃の次式で表わされる4−(2−ヒドロキシ
−3−イソプロピルアミノプロポキシ)−インド
ール15.6g(収率約62.9%)が無色針状結晶とし
て得られる。 The reaction solution was filtered, ethanol was distilled off from the solution under vacuum, an appropriate amount of water was added, the mixture was left overnight, and the precipitated crystals were recrystallized from ethanol, resulting in a melting point of 169.
15.6 g (yield: about 62.9%) of 4-(2-hydroxy-3-isopropylaminopropoxy)-indole represented by the following formula are obtained as colorless needle crystals at a temperature of -171 DEG C.
元素分析値C14H20N2O2として
C H N
計算値(%) 67.74 8.06 11.29
実測値(%) 67.63 8.02 11.31
紫外部吸収スペトル(メタノール16ppm溶液)
264〜266nm、276〜278.5nm及び288nmに極大
吸収。 Elemental analysis value C 14 H 20 N 2 O 2 as C H N Calculated value (%) 67.74 8.06 11.29 Actual value (%) 67.63 8.02 11.31 Ultraviolet absorption spectrum (methanol 16 ppm solution) 264-266 nm, 276-278.5 nm and 288 nm maximum absorption.
236〜238nm及び284.5〜286.5nmに極小吸収。Minimal absorption at 236-238nm and 284.5-286.5nm.
紫外部吸光係数値(C=6.5×10-5mol/スペク
トル用エタノール)
λnax:265nm(ε=7.37×103)
278nm(Shoulder ε=5.08×103)
288nm(ε=4.30×103)
λnio:237nm(ε=2.61×103)
285.3nm(ε=3.07×103)
実施例 2
無水ジメチルホルムアミド168mlを冷却し、塩
化チオニル13gを滴下し、実施例1と同様に反応
させる。ビルスマイヤー試薬生成後の前記反応液
に、5−(2−メチル−3−ニトロフエニル)−オ
キシメチル−3−二級ブチルオキサゾリジン−2
−オン31gをジクロルメタン300mlに溶解して滴
加する。以下実施例1と同様に処理すると、融点
153〜155℃の次式で表わされる、4−(2−ヒド
ロキシ−3−第二ブチルアミノプロポキシ)−イ
ンドール15.6g(収率約59.5%)が得られる。Ultraviolet extinction coefficient value (C = 6.5 × 10 -5 mol / ethanol for spectrum) λ nax : 265 nm (ε = 7.37 × 10 3 ) 278 nm (Shoulder ε = 5.08 × 10 3 ) 288 nm (ε = 4.30 × 10 3 ) λ nio : 237 nm (ε=2.61×10 3 ) 285.3 nm (ε=3.07×10 3 ) Example 2 168 ml of anhydrous dimethylformamide is cooled, 13 g of thionyl chloride is added dropwise, and the reaction is carried out in the same manner as in Example 1. 5-(2-Methyl-3-nitrophenyl)-oxymethyl-3-sec-butyloxazolidine-2 was added to the reaction solution after the Vilsmeier reagent was produced.
Dissolve 31 g of -one in 300 ml of dichloromethane and add dropwise. Following treatment in the same manner as in Example 1, the melting point
15.6 g (yield: about 59.5%) of 4-(2-hydroxy-3-sec-butylaminopropoxy)-indole of the following formula is obtained at 153 DEG -155 DEG C.
Claims (1)
物を、一般式 (式中X及びYはハロゲン原子、個々のR1 は同
一でも異なつてもよく、それぞれアルキル基、ア
リール基又はアルアルキル基を示す)で表わされ
る化合物と反応させ、生成物を塩基の存在下に還
元及び加水分解することにより、閉環及びオキサ
ゾリジノン環の開裂を行うことを特徴とする、一
般式 (式中Rは前記の意味を有する)で表わされるイ
ンドール誘導体の製法。[Claims] 1. General formula (wherein R represents an alkyl group), a compound represented by the general formula (In the formula, X and Y are halogen atoms, and each R 1 may be the same or different and each represents an alkyl group, an aryl group, or an aralkyl group.) A general formula characterized by ring closure and cleavage of the oxazolidinone ring by reduction and hydrolysis to A method for producing an indole derivative represented by the formula (wherein R has the above-mentioned meaning).
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP8134080A JPS577466A (en) | 1980-06-18 | 1980-06-18 | Preparation of indole derivative |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP8134080A JPS577466A (en) | 1980-06-18 | 1980-06-18 | Preparation of indole derivative |
Publications (2)
Publication Number | Publication Date |
---|---|
JPS577466A JPS577466A (en) | 1982-01-14 |
JPS632258B2 true JPS632258B2 (en) | 1988-01-18 |
Family
ID=13743634
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP8134080A Granted JPS577466A (en) | 1980-06-18 | 1980-06-18 | Preparation of indole derivative |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPS577466A (en) |
-
1980
- 1980-06-18 JP JP8134080A patent/JPS577466A/en active Granted
Also Published As
Publication number | Publication date |
---|---|
JPS577466A (en) | 1982-01-14 |
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