CH526537A - (I) A=CO2A1, CONA2A3, CONA4, C(=NOH)OH, or C(OR9)3 A1-A3=H, (1-12C) alkyl or cycloalkyl opt. contng. OH, NH2 and/or 1-2 multiple bonds, and opt. broken by - Google Patents
(I) A=CO2A1, CONA2A3, CONA4, C(=NOH)OH, or C(OR9)3 A1-A3=H, (1-12C) alkyl or cycloalkyl opt. contng. OH, NH2 and/or 1-2 multiple bonds, and opt. broken byInfo
- Publication number
- CH526537A CH526537A CH1732270A CH1732270A CH526537A CH 526537 A CH526537 A CH 526537A CH 1732270 A CH1732270 A CH 1732270A CH 1732270 A CH1732270 A CH 1732270A CH 526537 A CH526537 A CH 526537A
- Authority
- CH
- Switzerland
- Prior art keywords
- piperidino
- acid
- methyl
- formula
- opt
- Prior art date
Links
- 125000000217 alkyl group Chemical group 0.000 title claims abstract description 9
- 125000000753 cycloalkyl group Chemical group 0.000 title abstract 2
- 239000002253 acid Substances 0.000 claims abstract description 21
- 125000002947 alkylene group Chemical group 0.000 claims abstract 3
- 150000003839 salts Chemical class 0.000 claims description 19
- 150000001875 compounds Chemical class 0.000 claims description 17
- ZGUNAGUHMKGQNY-UHFFFAOYSA-N alpha-phenylglycine Chemical class OC(=O)C(N)C1=CC=CC=C1 ZGUNAGUHMKGQNY-UHFFFAOYSA-N 0.000 claims description 16
- 238000000034 method Methods 0.000 claims description 12
- 239000000203 mixture Substances 0.000 claims description 12
- 150000007513 acids Chemical class 0.000 claims description 11
- 125000004432 carbon atom Chemical group C* 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- 238000006243 chemical reaction Methods 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 230000003287 optical effect Effects 0.000 claims description 3
- 150000003242 quaternary ammonium salts Chemical class 0.000 claims description 3
- 150000003254 radicals Chemical class 0.000 claims 2
- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 claims 1
- 150000003863 ammonium salts Chemical class 0.000 abstract description 5
- 150000008064 anhydrides Chemical class 0.000 abstract description 5
- 229910052760 oxygen Inorganic materials 0.000 abstract description 3
- 229910052717 sulfur Inorganic materials 0.000 abstract description 2
- 125000004430 oxygen atom Chemical group O* 0.000 abstract 2
- PUAQLLVFLMYYJJ-UHFFFAOYSA-N 2-aminopropiophenone Chemical compound CC(N)C(=O)C1=CC=CC=C1 PUAQLLVFLMYYJJ-UHFFFAOYSA-N 0.000 abstract 1
- 150000008043 acidic salts Chemical class 0.000 abstract 1
- 150000001447 alkali salts Chemical class 0.000 abstract 1
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 abstract 1
- 125000003710 aryl alkyl group Chemical group 0.000 abstract 1
- 125000004434 sulfur atom Chemical group 0.000 abstract 1
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 abstract 1
- -1 araliphatic Chemical group 0.000 description 40
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 36
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 33
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 20
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 16
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 15
- 229960000583 acetic acid Drugs 0.000 description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 9
- 239000000243 solution Substances 0.000 description 8
- ROEXAHPGEQNLCG-UHFFFAOYSA-N 2-(3-chloro-4-piperidin-1-ylphenyl)propanoic acid Chemical compound ClC1=CC(C(C(O)=O)C)=CC=C1N1CCCCC1 ROEXAHPGEQNLCG-UHFFFAOYSA-N 0.000 description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 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 5
- 230000002378 acidificating effect Effects 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- KWGRBVOPPLSCSI-WPRPVWTQSA-N (-)-ephedrine Chemical compound CN[C@@H](C)[C@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WPRPVWTQSA-N 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- WGLPBDUCMAPZCE-UHFFFAOYSA-N Trioxochromium Chemical compound O=[Cr](=O)=O WGLPBDUCMAPZCE-UHFFFAOYSA-N 0.000 description 4
- 150000001735 carboxylic acids Chemical class 0.000 description 4
- 150000001768 cations Chemical class 0.000 description 4
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 4
- PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical compound NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 description 4
- 239000012442 inert solvent Substances 0.000 description 4
- 238000007254 oxidation reaction Methods 0.000 description 4
- NDVLTYZPCACLMA-UHFFFAOYSA-N silver oxide Chemical compound [O-2].[Ag+].[Ag+] NDVLTYZPCACLMA-UHFFFAOYSA-N 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-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
- 235000011054 acetic acid Nutrition 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical class OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 150000003946 cyclohexylamines Chemical class 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- MWUXSHHQAYIFBG-UHFFFAOYSA-N nitrogen oxide Inorganic materials O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical class OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical class OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-REOHCLBHSA-N L-lactic acid Chemical compound C[C@H](O)C(O)=O JVTAAEKCZFNVCJ-REOHCLBHSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical class CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical class OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 2
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- LOUPRKONTZGTKE-WZBLMQSHSA-N Quinine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-WZBLMQSHSA-N 0.000 description 2
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 2
- 239000012346 acetyl chloride Substances 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical class OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- GZUXJHMPEANEGY-UHFFFAOYSA-N bromomethane Chemical compound BrC GZUXJHMPEANEGY-UHFFFAOYSA-N 0.000 description 2
- 150000001244 carboxylic acid anhydrides Chemical class 0.000 description 2
- 235000012000 cholesterol Nutrition 0.000 description 2
- KMPWYEUPVWOPIM-KODHJQJWSA-N cinchonidine Chemical compound C1=CC=C2C([C@H]([C@H]3[N@]4CC[C@H]([C@H](C4)C=C)C3)O)=CC=NC2=C1 KMPWYEUPVWOPIM-KODHJQJWSA-N 0.000 description 2
- KMPWYEUPVWOPIM-UHFFFAOYSA-N cinchonidine Natural products C1=CC=C2C(C(C3N4CCC(C(C4)C=C)C3)O)=CC=NC2=C1 KMPWYEUPVWOPIM-UHFFFAOYSA-N 0.000 description 2
- KWGRBVOPPLSCSI-UHFFFAOYSA-N d-ephedrine Natural products CNC(C)C(O)C1=CC=CC=C1 KWGRBVOPPLSCSI-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- GNTDGMZSJNCJKK-UHFFFAOYSA-N divanadium pentaoxide Chemical compound O=[V](=O)O[V](=O)=O GNTDGMZSJNCJKK-UHFFFAOYSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 239000012362 glacial acetic acid Substances 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical class OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 2
- TWBYWOBDOCUKOW-UHFFFAOYSA-N isonicotinic acid Chemical class OC(=O)C1=CC=NC=C1 TWBYWOBDOCUKOW-UHFFFAOYSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 2
- SJWFXCIHNDVPSH-UHFFFAOYSA-N octan-2-ol Chemical compound CCCCCCC(C)O SJWFXCIHNDVPSH-UHFFFAOYSA-N 0.000 description 2
- 235000011007 phosphoric acid Nutrition 0.000 description 2
- WLJVNTCWHIRURA-UHFFFAOYSA-N pimelic acid Chemical compound OC(=O)CCCCCC(O)=O WLJVNTCWHIRURA-UHFFFAOYSA-N 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 238000005956 quaternization reaction Methods 0.000 description 2
- LOUPRKONTZGTKE-LHHVKLHASA-N quinidine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@H]2[C@@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-LHHVKLHASA-N 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical class OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 229910052709 silver Inorganic materials 0.000 description 2
- 229910001923 silver oxide Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical class CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 230000000699 topical effect Effects 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
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- 238000010626 work up procedure Methods 0.000 description 2
- NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 0.000 description 1
- DTGKSKDOIYIVQL-WEDXCCLWSA-N (+)-borneol Chemical compound C1C[C@@]2(C)[C@@H](O)C[C@@H]1C2(C)C DTGKSKDOIYIVQL-WEDXCCLWSA-N 0.000 description 1
- REPVLJRCJUVQFA-UHFFFAOYSA-N (-)-isopinocampheol Natural products C1C(O)C(C)C2C(C)(C)C1C2 REPVLJRCJUVQFA-UHFFFAOYSA-N 0.000 description 1
- IWYDHOAUDWTVEP-ZETCQYMHSA-N (S)-mandelic acid Chemical compound OC(=O)[C@@H](O)C1=CC=CC=C1 IWYDHOAUDWTVEP-ZETCQYMHSA-N 0.000 description 1
- OCJBOOLMMGQPQU-UHFFFAOYSA-N 1,4-dichlorobenzene Chemical compound ClC1=CC=C(Cl)C=C1 OCJBOOLMMGQPQU-UHFFFAOYSA-N 0.000 description 1
- IBODDUNKEPPBKW-UHFFFAOYSA-N 1,5-dibromopentane Chemical compound BrCCCCCBr IBODDUNKEPPBKW-UHFFFAOYSA-N 0.000 description 1
- LIUSHSVUMMYGRB-UHFFFAOYSA-N 1-naphthalen-1-yl-n-phenoxymethanamine Chemical compound C=1C=CC2=CC=CC=C2C=1CNOC1=CC=CC=C1 LIUSHSVUMMYGRB-UHFFFAOYSA-N 0.000 description 1
- LNETULKMXZVUST-UHFFFAOYSA-N 1-naphthoic acid Chemical class C1=CC=C2C(C(=O)O)=CC=CC2=C1 LNETULKMXZVUST-UHFFFAOYSA-N 0.000 description 1
- RQEUFEKYXDPUSK-UHFFFAOYSA-N 1-phenylethylamine Chemical compound CC(N)C1=CC=CC=C1 RQEUFEKYXDPUSK-UHFFFAOYSA-N 0.000 description 1
- WUIKSLFJHIMTMQ-UHFFFAOYSA-N 2-(3-bromo-4-piperidin-1-ylphenyl)butanoic acid Chemical compound BrC=1C=C(C=CC=1N1CCCCC1)C(C(=O)O)CC WUIKSLFJHIMTMQ-UHFFFAOYSA-N 0.000 description 1
- XXIINSHWYFXOSI-UHFFFAOYSA-N 2-(3-chloro-4-piperidin-1-ylphenyl)acetic acid Chemical compound ClC1=CC(CC(=O)O)=CC=C1N1CCCCC1 XXIINSHWYFXOSI-UHFFFAOYSA-N 0.000 description 1
- FVOUSYOQOQZXMK-UHFFFAOYSA-N 2-(3-chloro-4-piperidin-1-ylphenyl)propanal Chemical compound ClC1=CC(C(C=O)C)=CC=C1N1CCCCC1 FVOUSYOQOQZXMK-UHFFFAOYSA-N 0.000 description 1
- MNFRWZKZZWTJMO-UHFFFAOYSA-N 2-(3-methyl-4-piperidin-1-ylphenyl)acetic acid Chemical compound CC1=CC(CC(O)=O)=CC=C1N1CCCCC1 MNFRWZKZZWTJMO-UHFFFAOYSA-N 0.000 description 1
- AMJNJAWMIDLNCF-UHFFFAOYSA-N 2-(3-methylsulfanyl-4-piperidin-1-ylphenyl)propanoic acid Chemical compound CSC=1C=C(C=CC=1N1CCCCC1)C(C(=O)O)C AMJNJAWMIDLNCF-UHFFFAOYSA-N 0.000 description 1
- PVEZJAJMCCZIIY-UHFFFAOYSA-N 2-(3-nitro-4-piperidin-1-ylphenyl)acetic acid Chemical compound [N+](=O)([O-])C=1C=C(C=CC1N1CCCCC1)CC(=O)O PVEZJAJMCCZIIY-UHFFFAOYSA-N 0.000 description 1
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- GLVYLTSKTCWWJR-UHFFFAOYSA-N 2-carbonoperoxoylbenzoic acid Chemical compound OOC(=O)C1=CC=CC=C1C(O)=O GLVYLTSKTCWWJR-UHFFFAOYSA-N 0.000 description 1
- JHWIEAWILPSRMU-UHFFFAOYSA-N 2-methyl-3-pyrimidin-4-ylpropanoic acid Chemical compound OC(=O)C(C)CC1=CC=NC=N1 JHWIEAWILPSRMU-UHFFFAOYSA-N 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
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical class OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 239000005711 Benzoic acid Chemical class 0.000 description 1
- HXBRMPPBOODCMP-UHFFFAOYSA-N BrC=1C=C(C=CC1N1CCCC1)CC(=O)O Chemical compound BrC=1C=C(C=CC1N1CCCC1)CC(=O)O HXBRMPPBOODCMP-UHFFFAOYSA-N 0.000 description 1
- WPCDAFBUOGBFGY-UHFFFAOYSA-N BrC=1C=C(C=CC1N1CCCCC1)CC(=O)O Chemical compound BrC=1C=C(C=CC1N1CCCCC1)CC(=O)O WPCDAFBUOGBFGY-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D295/155—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
Abstract
(I) A=CO2A1, CONA2A3, CONA4, C(=NOH)OH, or C(OR9)3 - A1-A3=H, (1-12C) alkyl or cycloalkyl opt. contng. OH, NH2 and/or 1-2 multiple bonds, and opt. broken by Y or by 1-3 O atoms, A5NA4, Ph, or (6-14C) aralkyl - A4=(1-6C) alkyl, opt. broken by O or Y; A5=(1-6C) alkylene - Y=S, NH, (1-6C) Nalkyl opt. subst. by OH, N-Ph, or (7-10C) Nphenylalkyl - R1 and R2=same or different H or (1-4C) alkyl - R3=F, Hal, CF3, OH, NO2, CN, R9, OR9, SH, SR9, NR1COR9, NR1R2, SO2NR1R2, SOR9, or SO2R9; R4, R5, R6 = H, one may be F, Hal, R9, OR9 or SR9 and R4 + R5 together, may form an unsatd. tetramethylene (and if so, R3 may be H, and R6 may be H, F, Hal, CF3, OH, NO2, CN, R9, OR9, SR9, NR1COR9, NR1R2, SO2NR1R2, SOR9, or SO2R9). - R7 and R8=(1-7C) alkyl or a (2-14C) alkylene residue opt. broken by an O or S atom - R9=(1-4C) alkyl - (II) Acid and basic salts of (I) - (III) Quat. ammonium salts of (I) - (IV) Anhydrides of (I).
Description
Verfahren zur Herstellung von Aminophenylessigsäuren Es wurde gefunden, dass Aminophenylessigsäure-De- rivate der Formel I
EMI0001.0002
worin gleich oder verschieden sind und H oder AI Rl und R kyl mit 1 - 4 C-Atomen, R3 F, Cl, Br, J, CF3, N02, R3, ORB, SR9, NR1-COR9 oder NR1R2, R, und RE H, einer dieser Reste auch F, Cl, Br, J 1t die Reste R4 und R, zusammen auch oder R -CH=CH-CH=CH-, zusammen eine lineare oder verzweigte Al R7 und R kylenkette mit 2 - 14 C-Atomen, R3 Alkyl mit 1 - 4 C-Atomen, zusammen bedeuten, worin ferner, falls R4 und R -CH=CH-CH=CH- bedeuten, R3 = H ist oder die angegebene Bedeutung hat, sowie ihre Salze mit Säuren oder gegebenenfalls Basen,
ihre quartären Ammonium salze und gegebenenfalls ihre Anhydride bei guter Ver träglichkeit eine hervorragende antiphlogistische Wir kung besitzen, die von einer guten analgetischen und anti- pyretischen Wirkung begleitet ist. Ferner treten bakterio- statische, bakterizide, antiprotozoäre, diuretische, blut zuckersenkende, choleretische, cholesterinspiegelsenken de und Strahlenschutz-Wirkungen auf. Gegenstand der Erfindung ist ein Verfahren zur Her stellung von Aminophenylessigsäuren der Formel I so wie ihrer Salze mit Säure oder Basen, das dadurch ge kennzeichnet ist, dass man eine Verbindung der For mel II <B>2</B> 2 <B>,</B>
EMI0001.0010
OH bedeutet, oxydiert. worin L CHO oder CH.
Die so erhaltene Verbindung der Formel I kann zur Herstellung von quartären Ammoniumsalzen verwendet werden. Diese Herstellung erfolgt durch Behandlung der Verbindung I mit quaternierenden Mitteln.
Die Oxydation von Verbindungen der Formel II zu den Amino-phenylessigsäuren der Formel I kann, wie in der Literatur beschrieben, mit verschiedenen Oxyda tionsmitteln durchgeführt werden, insbesondere mit Luft oder Sauerstoff, bevorzugt unter Zusatz von Katalysa toren, wie Mn, Co, Fe, Ag, V2O5; mit Silberoxid, bevor O2, bevorzugt in zugt zusammen mit Kupferoxid; mit H Gegenwart von Alkalien; mit organischen Persäuren, wie Peressigsäure, Perbenzoesäure oder Perphthalsäure;
mit Kaliumpermanganat in wässeriger oder acetonischer Lö sung und/oder saurem, neutralem oder alkalischem Mi- ; mit Chrom- lieu, gegebenenfalls unter Zusatz von MgSO säure oder Cr03, bevorzugt in Eisessig, gegebenenfalls unter Zusatz von Benzol, oder Schwefelsäure; mit sal petriger Säure; mit bevorzugt 2-68 oiger Salpetersäure, gegebenenfalls unter Druck (bis zu 100 at); mit Stick- oxiden oder mit Natrium- oder Kaliumhydroxid / 02 in der Schmelze; oder mit Hypohalogeniden.
Bei diesen Oxy dationen arbeitet man bevorzugt in inerten Lösungsmit teln, wie Wasser, Eisessig, Dioxan, Benzol, Aceton, Te- trahydrofuran, Dimethylformamid, Äthanol, Methanol, oder in Gemischen dieser Lösungsmittel, und bei Tem peraturen zwischen -30 und 300 , zweckmässig bei Raumtemperatur.
Eine Verbindung der Formel I kann mit einer Säure in üblicher Weise in das zugehörige Säureadditionssalz übergeführt werden. Für diese Umsetzung kommen sol che Säuren in Frage, die physiologisch unbedenkliche Salze liefern. So können organische und anorganische Säuren, wie z.B.
aliphatische, alicyclische, araliphatische, aromatische oder heterocyclische ein- oder mehrbasige Carbon- oder Sulfonsäuren, wie Ameisensäure, Essig säure, Propionsäure, Pivalinsäure, Diäthylessigsäure, Oxalsäure, Malonsäure, Bernsteinsäure, Pimelinsäure, Fumarsäure, Maleinsäure, Milchsäure, Weinsäure, Äpfel säure, Aminocarbonsäuren, Sulfaminsäure, Benzoesäure, Salicylsäure, Phenylpropionsäure, Citronensäure, Glu- consäure, Ascorbinsäure, Nicotinsäure, Isonicotinsäure, Methansulfonsäure, Äthandisulfonsäure, ss-Hydroxy- äthansulfonsäure, p-Toluolsulfonsäure, Naphthalinmono- und -disulfonsäuren, Schwefelsäure, Salpetersäure,
Halo genwasserstoffsäuren, wie Chlorwasserstoffsäure oder Bromwasserstoffsäure, oder Phosphorsäuren, wie Ortho phosphorsäure, usw. verwendet werden.
Andererseits können Carbonsäuren der Formel 1 durch Umsetzung mit einer Base in eines ihrer physiolo gisch unbedenklichen Metall- bzw. Ammoniumsalze übergeführt werden. Als Salze kommen insbesondere die Natrium-, Kalium-, Magnesium-, Calcium- und Ammo niumsalze in Betracht, ferner substituierte Ammonium salze, wie z.B. die Dimethyl- und Diäthylammonium-, Monoäthanol-, Diäthanol- und Triäthanolammonium-, Cyclohexylammonium- und Dibenzyl-Äthylendiammo- nium-Salze.
Umgekehrt können Verbindungen der Formel I aus ihren Säureadditionssalzen durch Behandlung mit starken Basen, wie Natrium- oder Kaliumhydroxid, Natrium- oder Kaliumcarbonat, bzw. gegebenenfalls aus ihren Me tall- und Ammoniumsalzen durch Behandlung mit Säu ren, vor allem Mineralsäuren wie Salz- oder Schwefel säure, in Freiheit gesetzt werden.
Für diese Quaternierung sind beispielsweise Alkylha logenide, wie Methylbromid oder Äthylchlorid oder auch Dialkylsulfate, wie z.B. Diäthyl- oder Dimethylsulfat, geeignet. Die Quaternierungsbedingungen sind die übli chen, wie sie in der Literatur beschrieben bzw. zitiert sind.
Carbonsäureanhydride von Carbonsäuren der For mel I kann man nach den in der Literatur angegebenen Methoden gewinnen. So kann man beispielsweise Salze der Aminophenylessigsäuren, wie Natrium-, Kalium- oder Magnesiumsalze, durch Umsetzung mit Aminophenyles- sigsäurehalogeniden, wie -chloriden, -bromiden oder -jo- diden in die symmetrischen Anhydride umwandeln, wo bei man bevorzugt bei 60 - 160 und in inerten Lösungs mitteln, wie Dioxan, Benzol, Tetrahydrofuran oder Di- chlorbenzol, arbeitet. Zur Gewinnung gemischter Anhy dride setzt man die aminophenylessigsauren Salze bzw.
die Aminophenylessigsäurehalogenide mit anderen Car- bonsäurehalogeniden, wie Acetylchlorid, oder Carbon- säureanhydriden, wie Acetanhydrid, vorzugsweise unter Zusatz katalytischer Mengen an Mineralsäuren wie kon- zentrierter Schwefelsäure, bzw. mit anderen carbonsauren Salzen, wie Na-Propionat, um. Besonders leicht lassen sich die freien Aminophenylessigsäuren der Formel I durch Behandlung mit Acetanhydrid oder Acetylchlorid in der Wärme, gegebenenfalls unter Zusatz inerter Lö sungsmittel, wie Dioxan, Benzol, Tetrachlormethan oder Xylol, in die gemischten Anhydride umwandeln.
Die An hydridbildung gelingt auch dann ausgezeichnet, wenn man z.B. ein kalt bereitetes Aminophenylessigsäurechlo rid-Pyridin-Gemisch, gegebenenfalls unter Zusatz eines inerten Lösungsmittels, wie Äther, Tetrahydrofuran oder Dioxan, mit der freien Aminophenylessigsäure versetzt. Anstelle von Pyridin lässt sich auch Trimethylamin ver wenden.
Falls die Verbindungen der Formel I ein Asymme triezentrum enthalten, liegen sie gewöhnlich in racemi- scher Form vor. Weisen sie zwei oder mehrere Asymme triezentren auf, dann fallen diese Verbindungen bei der Synthese im allgemeinen als Gemische von Racematen, an, aus denen man in an sich bekannter Weise die ein zelnen Racemate beispielsweise durch mehrmaliges Um kristallisieren aus geeigneten Lösungsmitteln isolieren und in reiner Form gewinnen kann.
Solche Racemate können nach einer Vielzahl be kannter Methoden, wie sie in der Literatur angegeben sind, in ihre optischen Antipoden getrennt werden.
So kann man einige racemische Gemische als Eutek- tika anstatt in Form von Mischkristallen fällen und auf diese Weise rasch trennen, wobei in diesen Fällen auch eine selektive Ausfällung möglich sein kann. Die Metho de der chemischen Trennung ist jedoch zu bevorzugen. Danach werden aus dem racemischen Gemisch durch Umsetzung mit einem optisch aktiven Trennmittel Dia- stereomere gebildet. So kann man gegebenenfalls eine optisch aktive Base mit der Carböxylgruppe oder eine optisch aktive Säure mit der Aminogruppe einer substi tuierten Aminophenylessigsäure der Formel I umsetzen.
Zum Beispiel kann man Salz-Diastereomere der substi tuierten Aminophenylessigsäuren der Formel 1 gegebe nenfalls mit optisch aktiven Aminen, wie Chinin, Cin- chonidin, Brucin, Cinchonin, Hydroxyhydrindiamin, Mor phin, 1-Phenyläthylamin, Phenyloxynaphthylmethylamin, Chinidin, 1-Fenchylamin, Strychnin, basischen Amino säuren, wie Lysin, Arginin, Aminosäureestern oder mit optisch aktiven Säuren, wie D- und L-Weinsäure, Di- benzoyl-D- und -L-Weinsäure, Diacetyl-D- und -L-Wein- säure, ss-Camphersulfonsäure, D- und L-Mandelsäure, D- und L-Äpfelsäure oder D- und L-Milchsäure bilden.
In ähnlicher Weise lassen sich Ester-Diastereomere der Aminophenylessigsäuren der Formel I mit optisch akti ven Alkoholen, wie Borneol, Menthol, Octanol-2, her stellen. Der Unterschied in der Löslichkeit der anfallen den Diastereomeren erlaubt die selektive Kristallisation der einen Form und die Regeneration der jeweiligen op tisch aktiven substituierten Aminophenylessigsäuren aus dem Gemisch. Die optischen Antipoden können auch biochemisch unter Anwendung selektiver, enzymatischer Reaktionen getrennt werden.
So kann man die racemi- schen substituierten Aminophenylessigsäuren einer asym metrischen Oxydase oder gegebenenfalls Decarboxylase aussetzen, die durch Oxydation oder Decarboxylierung eine Form zerstört, während die andere Form unverän dert bleibt.
Möglich ist die Verwendung einer Hydrolase bei einem Derivat des racemischen Gemischs zur bevor zugten Bildung einer Form der substituierten Aminophe- nylessigsäuren. So kann man Ester oder Amide der Ami- nophenylessigsäuren der Formel I der Einwirkung einer Hydrolase aussetzen, welche das eine Enantiomorph se lektiv verseift und das andere unverändert lässt.
Weiterhin ist es natürlich möglich, optisch aktive Ver bindungen nach den oben beschriebenen Methoden zu er halten, indem man Ausgangsstoffe verwendet, die bereits optisch aktiv sind.
Die Verbindungen der Formel 1 und/oder gegebenen falls ihre physiologisch unbedenklichen Metall- und Am monium- sowie Säureadditionssalze können im Gemisch mit üblichen Arzneimittelträgern in der Human- oder Veterinärmedizin eingesetzt werden. Als Trägersubstan zen kommen solche organischen oder anorganischen Stoffe in Frage, die für die parenterale, enterale oder topikale Applikation geeignet sind und die mit den neuen Verbindungen nicht in Reaktion treten, wie beispiels weise Wasser, pflänzliche Öle, Polyäthylenglykole, Ge latine, Milchzucker, Stärke, Magnesiumstearat, Talk, Vaseline, Cholesterin. Zur parenteralen Applikation die nen insbesondere Lösungen, vorzugsweise ölige oder wässrige Lösungen, sowie Suspensionen, oder Emulsio nen.
Für die enterale Applikation eignen sich ferner Ta bletten oder Dragees, für die topikale Anwendung Sal ben oder Cremes, die gegebenenfalls sterilisiert oder mit Hilfsstoffen, wie Konservierungs-, Stabilisierungs- oder Netzmitteln oder Salzen zur Beeinflussung des osmoti schen Druckes oder mit Puffersubstanzen versetzt sind.
Die erfindungsgemässen Substanzen werden vorzugs weise in einer Dosierung von 1 bis 2000 mg pro Dosie rungseinheit appliziert.
In den nachfolgenden Beispielen sind die Tempera turen in Grad Celsius angegeben. Übliche Aufarbei tung bedeutet: man stellt das Reaktionsgemisch gege benenfalls durch Zugabe von Salzsäure oder Natron lauge auf den angegebenen pH-Wert ein, extrahiert mit Äthylacetat oder Chloroform, trocknet über Natrium sulfat, filtriert, destilliert das Lösungsmittel ab und de stilliert den Rückstand oder kristallisiert ihn aus dem angegebenen Lösungsmittel.
(a) = spezifische Drehung [α]D20, gemessen bei einer Konzentration von 1 g in 100 ml Methanol. <I>Beispiel 1</I> Aus 6,4 g AgNO3 und 1,6g NaOH in 50 ml Wasser frisch bereitetes Silberoxid wird zu einem Gemisch von 5 g 2-(3-Chlor-4-piperidino-phenyl)-1-propanol und 4 g NaOH in 40 ml Wasser gegeben. Man kocht 2 Stunden und filtriert das ausgefällte Silber ab. Das Filtrat wird wie üblich aufgearbeitet (pH 5,2-5,4). Man erhält 3-Chlor- -4-piperidino-α-methyl-phenylessigsäure, F. 106 - 107 .
Analog erhält man durch Oxydation der nachstehen den Phenylacetaldehyde: 3-Brom-4-piperidino 3-Brom-4-pyrrolidino 3-Brom-4-piperidino-α-methyl 3-Chlor-4-piperidino 3-Methyl-4-piperidino 3-Brom-4-pyrrolidino-α-methyl 3-Nitro-4-piperidino 3,α-Dimethyl-4-piperidino 3-Nitro-4-piperidino,α-methyl 3-Acetamido-4-piperidino-α-methyl 3-Chlor-4-pyrrolidino,α-methyl 3-Jod-4-piperidino-α-methyl 3-Nitro-4-pyrrolidino,α-methyl 3-Brom-4-piperidino-α-äthyl 3-Chlor-4-piperidino-α,α-dimethyl- 3-Nitro-4-homopiperidino-α-methyl 3-Fluor-4-piperidino-α-methyl 3,5,α-Trimethyl-4-piperidino 3-Trifluormethyl-4-piperidino 3-Trifluormethyl-4-piperidino-α-methyl 3-Chlor-4-(4,4-dimethyl-piperidino)-α-methyl 3-Methylmercapto-4-piperidino-α
-methyl 3-Nitro-4-(3-methylpiperidino)-α-methyl 3-Chlor-4-(3-methyl-piperidino)-α-methyl 2-Chlor-3,α-dimethyl-4-piperidino 2,3,α-Trimethyl-4-piperidino 2,α-Dimethyl-3-chlor-4-piperidino 2,5-Dichlor-4-piperidino-α-methyl 2,3-Dichlor-4-piperidino-α-methyl- 2,5,α-Trimethyl-4-piperidino- bzw. aus 4-Piperidino-naphthyl-1-acetaldehyd 4-Piperidino-α-methyl-naphthyl-1-acetaldehyd 4-Pyrrolidino-naphthyl-1-acetaldehyd 4-Piperidino-α-äthyl-naphthyl-1-acetaldehyd 3-Chlor-4-piperidino-naphthyl-1-acetaldehyd 2-Methyl-4-piperidino-naphthyl-1-acetaldehyd 2,α-Dimethyl-4-piperidino-naphthyl-1-acetaldehyd mit Ag2O die nachstehenden Verbindungen:
3-Brom-4-piperidino-phenylessigsäure, F. 129 - 130 3-Brom-4-pyrrolidino-phenylessigsäure, F. 92 -<B>930</B> 3-Brom-4-piperidino-α-methyl-phenylessigsäure, F. 115 -116 3-Chlor-4-piperidino-phenylessigsäure, F. 105 - 106 3-Methyl-4-piperidino-phenylessigsäure, F. 72 3-Brom-4-pyrrolidino-α-methyl-phenylessigsäure, F. 112- 113 3-Nitro-4-piperidino-phenylessigsäure, F. 108 - 110 3,α-Dimethyl-4-piperidino-phenylessigsäure, F.99 3-Nitro-4-piperidino-α-methyl-phenylessigsäure, F. 87 - 88 3-Acetamido-4-piperidino-α-methyl-phenylessigsäure, F. 162 - 163 3-Chlor-4-pyrrolidino-α-methyl-phenylessigsäure, F. 95 - 96 3-Jod-4-piperidino-α-methyl-phenylessigsäure, F.126-127 3-Nitro-4-pyrrolidino-α-methyl-phenylessigsäure, F. 129 3-Brom-4-piperidino-α
-äthyl-phenylessigsäure, F. 96 3-Chlor-4-piperidino-α,α-dimethyl-phenylessigsäure, F. 115 3-Nitro-4-homopiperidino-α-methyl-phenylessigsäure, Cyclohexylamin-Salz, F. 153 - 155 3-Fluor-4-piperidino-α-methyl-phenylessigsäure, F. 97 - 98 3,5,α-Trimethyl-4-piperidino-phenylessigsäure, F. 113 - 114 3-Trifluormethyl-4-piperidino-phenylessigsäure, F.89-91 3-Trifluormethyl-4-piperidino-α-methyl-phenylessigsäure, F. 88 - 90 3-Chlor-4-(4,4-dimethyl-piperidino)-a-methyl-phenyl- essigsäure, F.145 3-Methylmercapto-4-piperidino-α-methyl-phenylessig- säure, F. 104 - 105 3-Nitro-4-(3-methyl-piperidino)-α
-methyl-phenylessig- säure, Cyclohexylamin-Salz, F. 135 - 136 3-Chlor-4-(3-methyl-piperidino)-α-methyl-phenylessig- säure, Cyclohexylamin-Salz, F. 170 -172 2-Chlor-3,α-dimethyl-4-piperidino-phenylessigsäure, F. 137 2,3,α-Trimethyl-4-piperidino-phenylessigsäure, F. 189 -<B>1920</B> 2,α-Dimethyl-3-chlor-4-piperidino-phenylessigsäure, F. 156 - 157 2,5-Dichlor-4-piperidino-α-methyl-phenylessigsäure, F. 119 - l21 2,3-Dichlor-4-piperidino-α-methyl-phenylessigsäure, F.115 -116 2,5,α-Trimethyl-4-piperidino-phenylessigsäure, F. 189 -190 4-Piperidino-naphthyl-1-essigsäure, F. 142 - 143 4-Piperidino-α
-methyl-naphthyl-1-essigsäure, F. 181 - l83 4-Pyrrolidino-naphthyl-1-essigsäure, F. 110 - 114 4-Piperidino-α-äthyl-naphthyl-1-essigsäure, F. 145 - 146 3-Chlor-4-piperidino-naphthyl-1-essigsäure, F. 166 -167 2-Methyl-4-piperidino-naphthyl-1-essigsäure, F. 167 -169 2,α-Dimethyl-4-piperidino-naphthyl-1-essigsäure, F. 163 - 164 .
<I>Beispiel 2</I> 1 g 3-Chlor-4-piperidino-α-methyl-phenylacetaldehyd werden in einem Gemisch von 20 ml Essigsäure und 20 ml Benzol auf 0 - 4 abgekühlt und unter Rühren mit einer Lösung von 0,25 g CrO3 in 1 ml Wasser und 20 ml Essigsäure innerhalb von 10 Minuten versetzt. Nach ein stündigem Stehen bei Raumtemperatur werden 10 ml Methanol zugegeben. Anschliessend wird mit Wasser ver dünnt. Die Lösung wird mit Äther ausgeschüttelt und die Ätherphase mit 4%iger NaOH extrahiert. Die alkali schen Auszüge werden wie üblich aufgearbeitet (pH 5,2- 5,4). Man erhält 3-Chlor-4-piperidino-α-methyl-phenyl- essigsäure, F. 106 - 107 .
<I>Beispiel 3</I> a) 15,2 g 2-(3-Chlor-4-piperidino-phenyl)-propanol-1, [herstellbar durch Umsetzung von 2-(3-Chlor-4-amino- -phenyl)-propylacetat mit 1,5-Dibrompentan und an- schliessende Verseifung des Reaktionsgemisches] werden in 100 ml 10%iger Schwefelsäure gelöst.
Man fügt 6 g Na2Cr2O7 - 2H0 hinzu, rührt bei 50 - 60 mehrere Stunden, kühlt das Reaktionsgemisch ab und erhält nach üblicher Aufarbeitung und chromato- graphischer Reinigung an Kieselgel 2-(3-Chlor-4-piperi- dino-phenyl)-propionsäure vom F. 106 - 107 .
Analog erhält man aus 2-(3-Brom-4-piperidino-phenyl)-äthanol 2-(3-Brom-4-pyrrolidino-phenyl)-äthanol 2-(3-Brom-4-piperidino-phenyl)-propanol-1 2-(3-Chlor-4-piperidino-phenyl)-äthanol 2-(3-Methyl-4-piperidino-phenyl)-äthanol 2-(3-Brom-4-pyrrolidino-phenyl)-propanol-1 2-(3-Nitro-4-piperidino-phenyl)-äthanol 2-(3-Methyl-4-piperidino-phenyl)-propanol-1 2-(3-Nitro-4-piperidino-phenyl)-propanol-1 2-(3-Chlor-4-pyrrolidino-phenyl)-propanol-1 2-(3-Jod-4-piperidino-phenyl)-propanol-1 2-(3-Nitro-4-pyrrolidino-phenyl)-propanol-1 2-(3-Brom-4-piperidino-phenyl)-butanol-1 2-(3-Chlor-4-piperidino-phenyl)-2-methyl-propanol-1 2-(3-Nitro-4-homopiperidino-phenyl)-propanol-1 2-(3-Fluor-4-piperidino-phenyl)-propanol-1 2-(3,5-Dimethyl-4-piperidino-phenyl)-propanol-1 2-(3-Trifluormethyl-4-piperidino-phenyl)-äthanol 2-(3-Trifluormethyl-4-piperidino-phenyl)
-propanol-1 2-[3-Chlor-4-(4,4-dimethyl-piperidino)-phenyl]-propanol-1 2-[3-Nitro-4-(3-methyl-piperidino)-phenyl]-propanol-1 2-[3-Chlor-4-(3-methyl-piperidino)-phenyl]-propanol-1 2-(2-Chlor-3-methyl-4-piperidino-phenyl)-propanol-1 2-(2,3-Dimethyl-4-piperidino-phenyl)-propanol-1 2-(2-Methyl-3-chlor-4-piperidino-phenyl)-propanol-1 2-(2,5-Dichlor-4-piperidino-phenyl)-propanol-1 2-(2,3-Dichlor-4-piperidino-phenyl)-propanol-1 2-(2,5-Dimethyl-4-piperidino-phenyl)-propanol-1 2-(4-Piperidino-naphthyl-1)-äthanol 2-(4-Piperidino-naphthyl-1)-propanol-1 2-(4-Pyrrolidino-naphthyl-1)-äthanol 2-(4-Piperidino-naphthyl-1)-butanol-1 2-(3-Chlor-4-piperidino-naphthyl-1)-äthanol 2-(2-Methyl-4-piperidino-naphthyl-1)-äthanol 2-(2-Methyl-4-piperidino-naphthyl-1)-propanol-1 durch Oxydation mit Natriumdichromat die entspre chenden Carbonsäuren.
b) 53,5 g 3-Chlor-4-piperidino-α-methyl-phenylessig- säure und 18,2 g L-Ephedrin werden in 200 ml Äther 2 Tage bei Raumtemperatur stehen gelassen. Das ausge fallene Salz wird abgesaugt, dreimal aus Äthylacetat und danach zweimal aus Aceton umkristallisiert. F. 125 -126 ; -26,8 .
6 g dieses Salzes werden in einem Gemisch von 150 ml Methanol und 150 ml Äthanol gelöst. Die Lösung wird über einen schwach sauren Kationenaustauscher geleitet und mit Methanol/Äthanol (1 : 1) eluiert. Die Eluate werden bei 40 eingedampft. Der ölige Rückstand (3,12 g; (x) -I-35,5 ) wird in 50 ml Äther gelöst, über Kohle fil triert und mit einer Lösung von 1,15 g Cyclohexylamin in 10 ml Äther versetzt. Das ausfallende Cyclohexylam- monium-3-chlor-4-piperidino-α-methyl-phenylacetat wird abgesaugt. F.<B>197</B> - 198 (Methanol); (a) -7,2 .
2 g dieses Salzes werden in 100 ml Methanol/Ätha- nol (1 : 1) unter Erwärmen gelöst, über einen schwach sauren Kationenaustauscher geleitet und mit Methanol/ Äthanol (1 : 1) eluiert. Die Eluate werden eingedampft. Man erhält 1,2 g (+)-3-Chlor-4-piperidino-α-methyl-phe- nylessigsäure mit (x) r37,4 .
c) 26,7 g 3-Chlor-4-piperidino-α-methyl-phenylessig- säure werden in 100 ml Acetonitril mit 9,1g L-Ephedrin 48 Stunden bei 0 - 6 stehen gelassen. Das ausgefallene Salz wird zweimal aus Äthylacetat umkristallisiert. F. 124 - 126 ; (a) -15,6. 5 g dieses Salzes werden in 250 ml Methanol/Äthanol (1 : 1) gelöst, über einen schwach sau ren Kationenaustauscher geleitet und mit Methanol/Ätha- nol (1 : 1) eluiert. Die Eluate werden eingedampft. Der Rückstand (2 g öl, (;z) -37,2 ) wird in 40 ml Äther ge löst und mit einer Lösung von 0,73g Cyclohexylamin in 10 ml Äther versetzt.
Das ausgefallene Cyclohexyl- aminsalz (F. 197-198 ; (a) -I- 8,1 ) wird abgesaugt, in 100 ml Methanol/Äthanol (1 : 1 gelöst, über einen schwach sauren Kationenaustauscher geleitet und mit Methanol/Äthanol (1 : 1) eluiert. Die Eluate werden ein gedampft. Man erhält 1,1 g (-)-3-Chlor-4-piperidino-α- -methyl-phenylessigsäure, (x) =41,1 .
Process for the preparation of aminophenylacetic acids It has been found that aminophenylacetic acid derivatives of the formula I
EMI0001.0002
in which are identical or different and H or AI Rl and R kyl with 1-4 C atoms, R3 F, Cl, Br, J, CF3, NO2, R3, ORB, SR9, NR1-COR9 or NR1R2, R, and RE H, one of these radicals also F, Cl, Br, J 1t the radicals R4 and R, together also or R -CH = CH-CH = CH-, together a linear or branched Al R7 and R kylene chain with 2-14 C- Atoms, R3 denote alkyl with 1-4 carbon atoms, in which furthermore, if R4 and R denote -CH = CH-CH = CH-, R3 = H or has the meaning given, as well as their salts with acids or optionally Bases,
Their quaternary ammonium salts and possibly their anhydrides, if tolerated well, have an excellent antiphlogistic effect, which is accompanied by a good analgesic and antipyretic effect. Furthermore, bacteriostatic, bactericidal, antiprotozoal, diuretic, blood sugar lowering, choleretic, cholesterol lowering and radiation protection effects occur. The invention relates to a process for the preparation of aminophenylacetic acids of the formula I and their salts with acids or bases, which is characterized in that a compound of the formula II <B> 2 </B> 2 <B>, </B>
EMI0001.0010
OH means oxidized. wherein L is CHO or CH.
The compound of formula I thus obtained can be used for the preparation of quaternary ammonium salts. This preparation takes place by treating the compound I with quaternizing agents.
The oxidation of compounds of the formula II to the aminophenylacetic acids of the formula I can, as described in the literature, be carried out with various oxidizing agents, in particular with air or oxygen, preferably with the addition of catalysts such as Mn, Co, Fe, Ag, V2O5; with silver oxide, before O2, preferably in combination with copper oxide; with H presence of alkalis; with organic peracids such as peracetic acid, perbenzoic acid or perphthalic acid;
with potassium permanganate in aqueous or acetone solution and / or acidic, neutral or alkaline mi; with chromium, optionally with the addition of MgSO acid or CrO3, preferably in glacial acetic acid, optionally with the addition of benzene, or sulfuric acid; with sal petroleum acid; with preferably 2-68% nitric acid, optionally under pressure (up to 100 at); with nitrogen oxides or with sodium or potassium hydroxide / 02 in the melt; or with hypohalides.
These oxydations are preferably carried out in inert solvents, such as water, glacial acetic acid, dioxane, benzene, acetone, tetrahydrofuran, dimethylformamide, ethanol, methanol, or in mixtures of these solvents, and at temperatures between -30 and 300, expediently at room temperature.
A compound of the formula I can be converted into the associated acid addition salt using an acid in the customary manner. For this implementation, such acids come into question, which provide physiologically harmless salts. Organic and inorganic acids, such as e.g.
aliphatic, alicyclic, araliphatic, aromatic or heterocyclic monobasic or polybasic carboxylic or sulfonic acids, such as formic acid, acetic acid, propionic acid, pivalic acid, diethylacetic acid, oxalic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, , Sulfamic acid, benzoic acid, salicylic acid, phenylpropionic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methanesulfonic acid, ethanedisulfonic acid, ß-hydroxyethanesulfonic acid, p-toluenesulfonic acid, naphthalenic acid, sulfuric acid, sulfuric acid,
Hydrogen halide acids such as hydrochloric acid or hydrobromic acid, or phosphoric acids such as orthophosphoric acid, etc. can be used.
On the other hand, carboxylic acids of formula 1 can be converted into one of their physiologically harmless metal or ammonium salts by reaction with a base. Particularly suitable salts are the sodium, potassium, magnesium, calcium and ammonium salts, and also substituted ammonium salts, e.g. the dimethyl and diethylammonium, monoethanol, diethanol and triethanolammonium, cyclohexylammonium and dibenzyl-ethylenediammonium salts.
Conversely, compounds of the formula I can be obtained from their acid addition salts by treatment with strong bases such as sodium or potassium hydroxide, sodium or potassium carbonate, or optionally from their metal and ammonium salts by treatment with acids, especially mineral acids such as hydrochloric or sulfur acid, set free.
For this quaternization, for example, alkyl halides, such as methyl bromide or ethyl chloride or dialkyl sulfates, such as e.g. Diethyl or dimethyl sulfate, suitable. The quaternization conditions are the customary ones as described or cited in the literature.
Carboxylic acid anhydrides of carboxylic acids of the formula I can be obtained by the methods given in the literature. For example, salts of aminophenylacetic acids, such as sodium, potassium or magnesium salts, can be converted into symmetrical anhydrides by reaction with aminophenylacetic acid halides, such as chlorides, bromides or iodides, where preference is given to 60-160 and in inert solvents such as dioxane, benzene, tetrahydrofuran or dichlorobenzene works. To obtain mixed anhydrides, the aminophenylacetic acid salts or
the aminophenylacetic acid halides with other carboxylic acid halides, such as acetyl chloride, or carboxylic acid anhydrides, such as acetic anhydride, preferably with the addition of catalytic amounts of mineral acids such as concentrated sulfuric acid, or with other carboxylic acid salts such as sodium propionate. The free aminophenylacetic acids of the formula I can be converted into the mixed anhydrides particularly easily by treatment with acetic anhydride or acetyl chloride under heat, optionally with the addition of inert solvents such as dioxane, benzene, carbon tetrachloride or xylene.
The formation of hydrides is also excellent if, for example, a cold-prepared aminophenylacetic acid chloride-pyridine mixture, optionally with the addition of an inert solvent such as ether, tetrahydrofuran or dioxane, with the free aminophenylacetic acid added. Trimethylamine can also be used instead of pyridine.
If the compounds of the formula I contain a center of asymmetry, they are usually in racemic form. If they have two or more asymmetric centers, then these compounds are generally obtained in the synthesis as mixtures of racemates, from which the individual racemates can be isolated in a manner known per se, for example by repeated recrystallization from suitable solvents, and in pure form can win.
Such racemates can be separated into their optical antipodes by a large number of known methods, as are given in the literature.
For example, some racemic mixtures can be precipitated as eutectics instead of in the form of mixed crystals and in this way separated quickly, and selective precipitation may also be possible in these cases. However, the method of chemical separation is preferable. Thereafter, diastereomers are formed from the racemic mixture by reaction with an optically active resolving agent. For example, an optically active base with the carboxyl group or an optically active acid with the amino group of a substituted aminophenylacetic acid of the formula I can optionally be reacted.
For example, salt diastereomers of the substituted aminophenylacetic acids of the formula 1 can be mixed with optically active amines, such as quinine, cinchonidine, brucine, cinchonine, hydroxyhydrin, morphine, 1-phenylethylamine, phenyloxynaphthylmethylamine, quinidine, 1-fenchylamine, Basic amino acids such as lysine, arginine, amino acid esters or with optically active acids such as D- and L-tartaric acid, dibenzoyl-D- and -L-tartaric acid, diacetyl-D- and -L-tartaric acid, ss -Camphorsulfonic acid, D- and L-mandelic acid, D- and L-malic acid or D- and L-lactic acid.
In a similar way, ester diastereomers of aminophenylacetic acids of the formula I can be produced with optically active alcohols, such as borneol, menthol, 2-octanol. The difference in the solubility of the resulting diastereomers allows the selective crystallization of one form and the regeneration of the respective optically active substituted aminophenylacetic acids from the mixture. The optical antipodes can also be separated biochemically using selective enzymatic reactions.
For example, the racemic substituted aminophenylacetic acids can be exposed to an asymmetric oxidase or, if appropriate, decarboxylase, which destroys one form by oxidation or decarboxylation, while the other form remains unchanged.
It is possible to use a hydrolase with a derivative of the racemic mixture for the preferred formation of a form of the substituted aminophenyl acetic acids. For example, esters or amides of aminophenylacetic acids of the formula I can be exposed to the action of a hydrolase which selectively saponifies one enantiomorph and leaves the other unchanged.
Furthermore, it is of course possible to obtain optically active compounds by the methods described above, by using starting materials that are already optically active.
The compounds of the formula 1 and / or, if appropriate, their physiologically harmless metal and ammonium and acid addition salts can be used in admixture with conventional medicament carriers in human or veterinary medicine. Suitable carrier substances are organic or inorganic substances that are suitable for parenteral, enteral or topical application and that do not react with the new compounds, such as water, vegetable oils, polyethylene glycols, gelatin, lactose, starch , Magnesium stearate, talc, petroleum jelly, cholesterol. For parenteral administration, in particular solutions, preferably oily or aqueous solutions, and suspensions, or emulsions are used.
Tablets or coated tablets are also suitable for enteral application, ointments or creams for topical application, which may be sterilized or mixed with auxiliaries such as preservatives, stabilizers or wetting agents or salts to influence the osmotic pressure or with buffer substances.
The substances according to the invention are preferably administered in a dosage of 1 to 2000 mg per dosage unit.
In the following examples, the temperatures are given in degrees Celsius. Customary work-up means: the reaction mixture is adjusted to the specified pH by adding hydrochloric acid or sodium hydroxide solution, extracted with ethyl acetate or chloroform, dried over sodium sulfate, filtered, the solvent is distilled off and the residue is distilled or crystallized him from the specified solvent.
(a) = specific rotation [α] D20 measured at a concentration of 1 g in 100 ml of methanol. <I> Example 1 </I> Silver oxide freshly prepared from 6.4 g AgNO3 and 1.6 g NaOH in 50 ml water is converted into a mixture of 5 g 2- (3-chloro-4-piperidino-phenyl) -1- propanol and 4 g of NaOH in 40 ml of water. It is boiled for 2 hours and the precipitated silver is filtered off. The filtrate is worked up as usual (pH 5.2-5.4). 3-chloro--4-piperidino-α-methyl-phenylacetic acid is obtained, mp 106-107.
Analogously, the following phenylacetaldehydes are oxidized: 3-Bromo-4-piperidino 3-Bromo-4-pyrrolidino 3-Bromo-4-piperidino-α-methyl 3-chloro-4-piperidino 3-Methyl-4-piperidino 3-Bromo-4-pyrrolidino-α-methyl 3-nitro-4-piperidino 3, α-dimethyl-4-piperidino 3-nitro-4-piperidino, α-methyl 3-acetamido-4-piperidino-α ; -methyl 3-chloro-4-pyrrolidino, α-methyl 3-iodo-4-piperidino-α-methyl 3-nitro-4-pyrrolidino, α-methyl 3-bromo-4-piperidino-α- ethyl 3-chloro-4-piperidino-α, α-dimethyl-3-nitro-4-homopiperidino-α-methyl 3-fluoro-4-piperidino-α-methyl 3,5, α-trimethyl- 4-piperidino 3-trifluoromethyl-4-piperidino 3-trifluoromethyl-4-piperidino-α-methyl 3-chloro-4- (4,4-dimethyl-piperidino) -α-methyl 3-methylmercapto-4-piperidino- α
-methyl 3-nitro-4- (3-methylpiperidino) -α-methyl 3-chloro-4- (3-methyl-piperidino) -α-methyl 2-chloro-3, α-dimethyl-4-piperidino 2,3, α-trimethyl-4-piperidino 2, α-dimethyl-3-chloro-4-piperidino 2,5-dichloro-4-piperidino-α-methyl 2,3-dichloro-4-piperidino- α-methyl-2,5, α-trimethyl-4-piperidino- or 4-piperidino-α-methyl-naphthyl-1-acetaldehyde 4-pyrrolidino-naphthyl from 4-piperidino-naphthyl-1-acetaldehyde 1-acetaldehyde 4-piperidino-α-ethyl-naphthyl-1-acetaldehyde 3-chloro-4-piperidino-naphthyl-1-acetaldehyde 2-methyl-4-piperidino-naphthyl-1-acetaldehyde 2, α-dimethyl- 4-piperidino-naphthyl-1-acetaldehyde with Ag2O the following compounds:
3-Bromo-4-piperidino-phenylacetic acid, m.p. 129 - 130 3-Bromo-4-pyrrolidino-phenylacetic acid, m.p. 92 - 930 3-Bromo-4-piperidino-α-methyl- phenylacetic acid, m.p. 115-116 3-chloro-4-piperidino-phenylacetic acid, m.p. 105-106 3-methyl-4-piperidino-phenylacetic acid, m.p. 72 3-bromo-4-pyrrolidino-α-methyl-phenylacetic acid, F. 112-113 3-Nitro-4-piperidino-phenylacetic acid, F. 108-110 3, α-dimethyl-4-piperidino-phenylacetic acid, F.99 3-nitro-4-piperidino-α-methyl-phenylacetic acid , F. 87-88 3-Acetamido-4-piperidino-α-methyl-phenylacetic acid, F. 162-163 3-Chloro-4-pyrrolidino-α-methyl-phenylacetic acid, F. 95-96 3-iodine- 4-piperidino-α-methyl-phenylacetic acid, F. 126-127 3-nitro-4-pyrrolidino-α-methyl-phenylacetic acid, F. 129 3-Bromo-4-piperidino-α
-ethyl-phenylacetic acid, F. 96 3-Chloro-4-piperidino-α, α-dimethyl-phenylacetic acid, F. 115 3-Nitro-4-homopiperidino-α-methyl-phenylacetic acid, cyclohexylamine salt, F. 153-155 3-Fluoro-4-piperidino-α-methyl-phenylacetic acid, m.p. 97-98 3.5, α-trimethyl-4-piperidino-phenylacetic acid, m.p. 113-114 3-trifluoromethyl-4-piperidino -phenylacetic acid, F.89-91 3-trifluoromethyl-4-piperidino-α-methyl-phenylacetic acid, F. 88-90 3-chloro-4- (4,4-dimethyl-piperidino) -a-methyl-phenyl- acetic acid, M.p. 145 3-methylmercapto-4-piperidino-α-methyl-phenylacetic acid, M.p. 104-105 3-nitro-4- (3-methyl-piperidino) -α;
-methyl-phenylacetic acid, cyclohexylamine salt, F. 135-136 3-chloro-4- (3-methyl-piperidino) -α-methyl-phenylacetic acid, cyclohexylamine salt, F. 170-172 2- Chloro-3, α-dimethyl-4-piperidino-phenylacetic acid, m.p. 137 2,3, α-trimethyl-4-piperidino-phenylacetic acid, m.p. 189 - <B> 1920 </B> 2, α- Dimethyl-3-chloro-4-piperidino-phenylacetic acid, m.p. 156-157 2,5-dichloro-4-piperidino-α-methyl-phenylacetic acid, m.p. 119-121 2,3-dichloro-4-piperidino-α ; -methyl-phenylacetic acid, m. 115-116 2.5, α-trimethyl-4-piperidino-phenylacetic acid, m.p. 189-190 4-piperidino-naphthyl-1-acetic acid, m.p. 142-143 4-piperidino- α
-methyl-naphthyl-1-acetic acid, mp 181-183 4-pyrrolidino-naphthyl-1-acetic acid, mp 110-114 4-piperidino-α-ethyl-naphthyl-1-acetic acid, mp 145-146 3 -Chlor-4-piperidino-naphthyl-1-acetic acid, F. 166-167 2-Methyl-4-piperidino-naphthyl-1-acetic acid, F. 167-169 2,? -Dimethyl-4-piperidino-naphthyl- 1-acetic acid, F. 163-164.
<I> Example 2 </I> 1 g of 3-chloro-4-piperidino-α-methyl-phenylacetaldehyde is cooled to 0-4 in a mixture of 20 ml of acetic acid and 20 ml of benzene and, while stirring, with a solution of 0 , 25 g of CrO3 in 1 ml of water and 20 ml of acetic acid are added within 10 minutes. After standing for an hour at room temperature, 10 ml of methanol are added. It is then diluted with water. The solution is extracted with ether and the ether phase extracted with 4% NaOH. The alkaline extracts are worked up as usual (pH 5.2-5.4). 3-Chloro-4-piperidino-α-methyl-phenylacetic acid is obtained, mp 106-107.
<I> Example 3 </I> a) 15.2 g of 2- (3-chloro-4-piperidino-phenyl) -propanol-1, [can be prepared by reacting 2- (3-chloro-4-amino- - phenyl) propyl acetate with 1,5-dibromopentane and subsequent saponification of the reaction mixture] are dissolved in 100 ml of 10% strength sulfuric acid.
6 g of Na2Cr2O7-2H0 are added, the mixture is stirred at 50-60 for several hours, the reaction mixture is cooled and, after conventional work-up and chromatographic purification on silica gel, 2- (3-chloro-4-piperidino-phenyl) propionic acid is obtained from F. 106 - 107.
Similarly, 2- (3-bromo-4-piperidino-phenyl) -ethanol gives 2- (3-bromo-4-pyrrolidino-phenyl) -ethanol 2- (3-bromo-4-piperidino-phenyl) -propanol- 1 2- (3-chloro-4-piperidino-phenyl) -ethanol 2- (3-methyl-4-piperidino-phenyl) -ethanol 2- (3-bromo-4-pyrrolidino-phenyl) -propanol-1 2- (3-Nitro-4-piperidino-phenyl) -ethanol 2- (3-methyl-4-piperidino-phenyl) -propanol-1 2- (3-nitro-4-piperidino-phenyl) -propanol-1 2- ( 3-chloro-4-pyrrolidino-phenyl) -propanol-1 2- (3-iodo-4-piperidino-phenyl) -propanol-1 2- (3-nitro-4-pyrrolidino-phenyl) -propanol-1 2- (3-Bromo-4-piperidino-phenyl) -butanol-1 2- (3-chloro-4-piperidino-phenyl) -2-methyl-propanol-1 2- (3-nitro-4-homopiperidino-phenyl) - propanol-1 2- (3-fluoro-4-piperidino-phenyl) -propanol-1 2- (3,5-dimethyl-4-piperidino-phenyl) -propanol-1 2- (3-trifluoromethyl-4-piperidino- phenyl) ethanol 2- (3-trifluoromethyl-4-piperidino-phenyl)
-propanol-1 2- [3-Chloro-4- (4,4-dimethyl-piperidino) -phenyl] -propanol-1 2- [3-nitro-4- (3-methyl-piperidino) -phenyl] -propanol -1 2- [3-Chloro-4- (3-methyl-piperidino) -phenyl] -propanol-1 2- (2-chloro-3-methyl-4-piperidino-phenyl) -propanol-1 2- (2 , 3-Dimethyl-4-piperidino-phenyl) -propanol-1 2- (2-methyl-3-chloro-4-piperidino-phenyl) -propanol-1 2- (2,5-dichloro-4-piperidino-phenyl ) -propanol-1 2- (2,3-dichloro-4-piperidino-phenyl) -propanol-1 2- (2,5-dimethyl-4-piperidino-phenyl) -propanol-1 2- (4-piperidino- naphthyl-1) ethanol 2- (4-piperidino-naphthyl-1) -propanol-1 2- (4-pyrrolidino-naphthyl-1) -ethanol 2- (4-piperidino-naphthyl-1) -butanol-1 2 - (3-Chloro-4-piperidino-naphthyl-1) -ethanol 2- (2-methyl-4-piperidino-naphthyl-1) -ethanol 2- (2-methyl-4-piperidino-naphthyl-1) -propanol -1 the corresponding carboxylic acids by oxidation with sodium dichromate.
b) 53.5 g of 3-chloro-4-piperidino-α-methyl-phenylacetic acid and 18.2 g of L-ephedrine are left to stand in 200 ml of ether for 2 days at room temperature. The precipitated salt is filtered off with suction, recrystallized three times from ethyl acetate and then twice from acetone. F. 125-126; -26.8.
6 g of this salt are dissolved in a mixture of 150 ml of methanol and 150 ml of ethanol. The solution is passed over a weakly acidic cation exchanger and eluted with methanol / ethanol (1: 1). The eluates are evaporated at 40. The oily residue (3.12 g; (x) -I-35.5) is dissolved in 50 ml of ether, filtered over charcoal and treated with a solution of 1.15 g of cyclohexylamine in 10 ml of ether. The precipitated cyclohexylammonium-3-chloro-4-piperidino-α-methyl-phenyl acetate is filtered off with suction. F. 197-198 (methanol); (a) -7.2.
2 g of this salt are dissolved in 100 ml of methanol / ethanol (1: 1) with warming, passed through a weakly acidic cation exchanger and eluted with methanol / ethanol (1: 1). The eluates are evaporated. 1.2 g of (+) - 3-chloro-4-piperidino-α-methylphenylacetic acid with (x) r 37.4 are obtained.
c) 26.7 g of 3-chloro-4-piperidino-α-methyl-phenylacetic acid are left to stand in 100 ml of acetonitrile with 9.1 g of L-ephedrine at 0-6 for 48 hours. The precipitated salt is recrystallized twice from ethyl acetate. F. 124-126; (a) -15.6. 5 g of this salt are dissolved in 250 ml of methanol / ethanol (1: 1), passed through a weakly acidic cation exchanger and eluted with methanol / ethanol (1: 1). The eluates are evaporated. The residue (2 g of oil, (z) -37.2) is dissolved in 40 ml of ether and treated with a solution of 0.73 g of cyclohexylamine in 10 ml of ether.
The precipitated cyclohexylamine salt (F. 197-198; (a) -I- 8.1) is filtered off with suction, dissolved in 100 ml of methanol / ethanol (1: 1, passed through a weakly acidic cation exchanger and treated with methanol / ethanol (1 : 1) eluted The eluates are evaporated to give 1.1 g of (-) - 3-chloro-4-piperidino-α-methyl-phenylacetic acid, (x) = 41.1.
Claims (1)
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEM0074881 | 1967-07-22 | ||
| DEM0077363 | 1968-02-23 | ||
| DEM0077429 | 1968-03-01 | ||
| CH1059768A CH520667A (en) | 1967-07-22 | 1968-07-15 | Process for the preparation of aminophenylacetic acids |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH526537A true CH526537A (en) | 1972-08-15 |
Family
ID=27429303
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH1732270A CH526537A (en) | 1967-07-22 | 1968-07-15 | (I) A=CO2A1, CONA2A3, CONA4, C(=NOH)OH, or C(OR9)3 A1-A3=H, (1-12C) alkyl or cycloalkyl opt. contng. OH, NH2 and/or 1-2 multiple bonds, and opt. broken by |
Country Status (1)
| Country | Link |
|---|---|
| CH (1) | CH526537A (en) |
-
1968
- 1968-07-15 CH CH1732270A patent/CH526537A/en not_active IP Right Cessation
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