FI61481C - Foerfarande foer framstaellning av nya terapeutiskt anvaendbara piperidinderivat - Google Patents
Foerfarande foer framstaellning av nya terapeutiskt anvaendbara piperidinderivat Download PDFInfo
- Publication number
- FI61481C FI61481C FI760646A FI760646A FI61481C FI 61481 C FI61481 C FI 61481C FI 760646 A FI760646 A FI 760646A FI 760646 A FI760646 A FI 760646A FI 61481 C FI61481 C FI 61481C
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- FI
- Finland
- Prior art keywords
- parts
- formula
- methyl
- phenylethyl
- filtered
- Prior art date
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- 238000002360 preparation method Methods 0.000 title claims description 76
- 230000001225 therapeutic effect Effects 0.000 title 2
- 238000000034 method Methods 0.000 claims abstract description 63
- 150000003839 salts Chemical class 0.000 claims description 89
- 150000001875 compounds Chemical class 0.000 claims description 88
- -1 4-phenylcyclohexyl Chemical group 0.000 claims description 83
- 239000002253 acid Substances 0.000 claims description 61
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 48
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 48
- 238000006243 chemical reaction Methods 0.000 claims description 44
- 125000000217 alkyl group Chemical group 0.000 claims description 31
- 239000003054 catalyst Substances 0.000 claims description 30
- 239000002904 solvent Substances 0.000 claims description 24
- 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 claims description 23
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 23
- 239000001257 hydrogen Substances 0.000 claims description 22
- 229910052739 hydrogen Inorganic materials 0.000 claims description 22
- UFUASNAHBMBJIX-UHFFFAOYSA-N propan-1-one Chemical group CC[C]=O UFUASNAHBMBJIX-UHFFFAOYSA-N 0.000 claims description 18
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 15
- WYVAMUWZEOHJOQ-UHFFFAOYSA-N propionic anhydride Chemical compound CCC(=O)OC(=O)CC WYVAMUWZEOHJOQ-UHFFFAOYSA-N 0.000 claims description 14
- 125000003342 alkenyl group Chemical group 0.000 claims description 11
- 150000002148 esters Chemical group 0.000 claims description 10
- WMPPDTMATNBGJN-UHFFFAOYSA-N 2-phenylethylbromide Chemical compound BrCCC1=CC=CC=C1 WMPPDTMATNBGJN-UHFFFAOYSA-N 0.000 claims description 7
- ZOOSILUVXHVRJE-UHFFFAOYSA-N cyclopropanecarbonyl chloride Chemical compound ClC(=O)C1CC1 ZOOSILUVXHVRJE-UHFFFAOYSA-N 0.000 claims description 7
- 229910052736 halogen Inorganic materials 0.000 claims description 7
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 6
- 238000005917 acylation reaction Methods 0.000 claims description 6
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 6
- 230000003287 optical effect Effects 0.000 claims description 6
- 230000010933 acylation Effects 0.000 claims description 5
- 125000003118 aryl group Chemical group 0.000 claims description 5
- 150000007942 carboxylates Chemical group 0.000 claims description 5
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims description 5
- 150000003254 radicals Chemical class 0.000 claims description 5
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 4
- 125000005129 aryl carbonyl group Chemical group 0.000 claims description 4
- 125000001475 halogen functional group Chemical group 0.000 claims description 4
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 3
- VEDLHCQCGPNHOL-UHFFFAOYSA-N 1-[4-anilino-1-(2-phenylethyl)piperidin-4-yl]ethanone Chemical compound C1CC(C(=O)C)(NC=2C=CC=CC=2)CCN1CCC1=CC=CC=C1 VEDLHCQCGPNHOL-UHFFFAOYSA-N 0.000 claims description 3
- PHLAURNEKNFKNH-UHFFFAOYSA-N 4-(methoxymethyl)-n-phenyl-1-(2-phenylethyl)piperidin-4-amine Chemical compound C1CC(COC)(NC=2C=CC=CC=2)CCN1CCC1=CC=CC=C1 PHLAURNEKNFKNH-UHFFFAOYSA-N 0.000 claims description 3
- 125000002252 acyl group Chemical group 0.000 claims description 3
- 125000005196 alkyl carbonyloxy group Chemical group 0.000 claims description 3
- 125000003277 amino group Chemical group 0.000 claims description 3
- 150000008064 anhydrides Chemical class 0.000 claims description 3
- 125000001769 aryl amino group Chemical group 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- 125000006501 nitrophenyl group Chemical group 0.000 claims description 3
- 150000003053 piperidines Chemical class 0.000 claims description 3
- 150000001266 acyl halides Chemical class 0.000 claims description 2
- 125000005037 alkyl phenyl group Chemical group 0.000 claims description 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
- 125000004981 cycloalkylmethyl group Chemical group 0.000 claims description 2
- 125000006255 cyclopropyl carbonyl group Chemical group [H]C1([H])C([H])([H])C1([H])C(*)=O 0.000 claims description 2
- 150000004820 halides Chemical class 0.000 claims description 2
- 125000001624 naphthyl group Chemical group 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000004076 pyridyl group Chemical group 0.000 claims description 2
- MLWPHHMHVICYGG-UHFFFAOYSA-N 2-anilino-1-(2-phenylethyl)piperidine-4-carboxylic acid Chemical compound C=1C=CC=CC=1NC1CC(C(=O)O)CCN1CCC1=CC=CC=C1 MLWPHHMHVICYGG-UHFFFAOYSA-N 0.000 claims 2
- 150000008065 acid anhydrides Chemical class 0.000 claims 2
- JEXXKCWIDSBELU-UHFFFAOYSA-N C1(=CC=CC=C1)CCOC(=O)C1CCNCC1 Chemical compound C1(=CC=CC=C1)CCOC(=O)C1CCNCC1 JEXXKCWIDSBELU-UHFFFAOYSA-N 0.000 claims 1
- 101100080278 Caenorhabditis elegans ncr-2 gene Proteins 0.000 claims 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims 1
- 239000012442 inert solvent Substances 0.000 claims 1
- NFENKNXOMHOGEC-UHFFFAOYSA-N n-[4-acetyl-1-(2-phenylethyl)piperidin-4-yl]-n-phenylcyclopropanecarboxamide Chemical compound C1CC(C(=O)C)(N(C(=O)C2CC2)C=2C=CC=CC=2)CCN1CCC1=CC=CC=C1 NFENKNXOMHOGEC-UHFFFAOYSA-N 0.000 claims 1
- 229910052760 oxygen Inorganic materials 0.000 claims 1
- 239000001301 oxygen Substances 0.000 claims 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims 1
- 239000000543 intermediate Substances 0.000 abstract description 44
- 230000000202 analgesic effect Effects 0.000 abstract description 3
- LKRMTUUCKBQGFO-UHFFFAOYSA-N n-phenylpiperidin-4-amine Chemical class C1CNCCC1NC1=CC=CC=C1 LKRMTUUCKBQGFO-UHFFFAOYSA-N 0.000 abstract description 2
- 230000003389 potentiating effect Effects 0.000 abstract description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 210
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 201
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 175
- 239000000203 mixture Substances 0.000 description 149
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 118
- 239000000243 solution Substances 0.000 description 112
- 239000003480 eluent Substances 0.000 description 102
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 99
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 95
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 90
- 239000000047 product Substances 0.000 description 89
- 229960001701 chloroform Drugs 0.000 description 87
- 239000011541 reaction mixture Substances 0.000 description 79
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 57
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 53
- 239000000706 filtrate Substances 0.000 description 53
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 52
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 52
- 239000000741 silica gel Substances 0.000 description 52
- 229910002027 silica gel Inorganic materials 0.000 description 52
- 238000004440 column chromatography Methods 0.000 description 49
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 48
- 239000000284 extract Substances 0.000 description 45
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 43
- 238000003756 stirring Methods 0.000 description 41
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 37
- MUBZPKHOEPUJKR-UHFFFAOYSA-L Oxalate Chemical compound [O-]C(=O)C([O-])=O MUBZPKHOEPUJKR-UHFFFAOYSA-L 0.000 description 37
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 36
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 36
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 33
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 31
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 29
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 27
- 239000000908 ammonium hydroxide Substances 0.000 description 27
- 229910052799 carbon Inorganic materials 0.000 description 27
- 238000001816 cooling Methods 0.000 description 27
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 27
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 26
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 24
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 23
- 238000010992 reflux Methods 0.000 description 22
- 239000002244 precipitate Substances 0.000 description 21
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 19
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 19
- 239000012074 organic phase Substances 0.000 description 19
- 239000007858 starting material Substances 0.000 description 18
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- 229960000583 acetic acid Drugs 0.000 description 15
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 15
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 14
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical class OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 14
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 13
- 239000005457 ice water Substances 0.000 description 13
- 229910052757 nitrogen Inorganic materials 0.000 description 13
- 229910000029 sodium carbonate Inorganic materials 0.000 description 13
- 239000008346 aqueous phase Substances 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 11
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 11
- 239000002585 base Substances 0.000 description 11
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 11
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 11
- 239000012044 organic layer Substances 0.000 description 11
- 239000007787 solid Substances 0.000 description 11
- 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 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 239000011734 sodium Substances 0.000 description 10
- 150000001408 amides Chemical class 0.000 description 9
- 239000003208 petroleum Substances 0.000 description 9
- 229910052708 sodium Inorganic materials 0.000 description 9
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 8
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 8
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 8
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 8
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 8
- 239000003960 organic solvent Substances 0.000 description 8
- 229920006395 saturated elastomer Polymers 0.000 description 8
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 7
- 150000001335 aliphatic alkanes Chemical class 0.000 description 7
- 239000010410 layer Substances 0.000 description 7
- 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 description 6
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 6
- ULOZGJWEIWAWML-UHFFFAOYSA-N Noralfentanil Chemical compound C1CNCCC1(COC)N(C(=O)CC)C1=CC=CC=C1 ULOZGJWEIWAWML-UHFFFAOYSA-N 0.000 description 6
- 239000012043 crude product Substances 0.000 description 6
- 239000012458 free base Substances 0.000 description 6
- SRJOCJYGOFTFLH-UHFFFAOYSA-N isonipecotic acid Chemical compound OC(=O)C1CCNCC1 SRJOCJYGOFTFLH-UHFFFAOYSA-N 0.000 description 6
- HFNFODVRYCEIQL-UHFFFAOYSA-N methyl 4-(n-propanoylanilino)piperidine-4-carboxylate Chemical compound C1CNCCC1(C(=O)OC)N(C(=O)CC)C1=CC=CC=C1 HFNFODVRYCEIQL-UHFFFAOYSA-N 0.000 description 6
- 229910000104 sodium hydride Inorganic materials 0.000 description 6
- 239000012258 stirred mixture Substances 0.000 description 6
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 5
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 5
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 5
- 150000007513 acids Chemical class 0.000 description 5
- HTZCNXWZYVXIMZ-UHFFFAOYSA-M benzyl(triethyl)azanium;chloride Chemical compound [Cl-].CC[N+](CC)(CC)CC1=CC=CC=C1 HTZCNXWZYVXIMZ-UHFFFAOYSA-M 0.000 description 5
- 125000004432 carbon atom Chemical group C* 0.000 description 5
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 5
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 150000002825 nitriles Chemical group 0.000 description 5
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 5
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 5
- 239000012312 sodium hydride Substances 0.000 description 5
- 159000000000 sodium salts Chemical class 0.000 description 5
- 239000006228 supernatant Substances 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- DJVCIHFRPVAFAU-UHFFFAOYSA-N 4-anilino-1-(2-phenylethyl)piperidine-4-carboxylic acid Chemical compound C1CC(C(=O)O)(NC=2C=CC=CC=2)CCN1CCC1=CC=CC=C1 DJVCIHFRPVAFAU-UHFFFAOYSA-N 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 4
- 238000010934 O-alkylation reaction Methods 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 description 4
- VVJWPSNDGLSAMC-UHFFFAOYSA-N [4-anilino-1-(2-phenylethyl)piperidin-4-yl]methanol Chemical compound C1CC(CO)(NC=2C=CC=CC=2)CCN1CCC1=CC=CC=C1 VVJWPSNDGLSAMC-UHFFFAOYSA-N 0.000 description 4
- 239000003513 alkali Substances 0.000 description 4
- 229910052783 alkali metal Inorganic materials 0.000 description 4
- 150000004645 aluminates Chemical class 0.000 description 4
- 229910021529 ammonia Inorganic materials 0.000 description 4
- 230000008878 coupling Effects 0.000 description 4
- 238000010168 coupling process Methods 0.000 description 4
- 238000005859 coupling reaction Methods 0.000 description 4
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 4
- 239000006185 dispersion Substances 0.000 description 4
- IZIAEPZQNMQAGS-UHFFFAOYSA-N ethyl 4-anilino-1-(2-phenylethyl)piperidine-4-carboxylate Chemical compound C1CC(C(=O)OCC)(NC=2C=CC=CC=2)CCN1CCC1=CC=CC=C1 IZIAEPZQNMQAGS-UHFFFAOYSA-N 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 238000005984 hydrogenation reaction Methods 0.000 description 4
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 4
- 235000019341 magnesium sulphate Nutrition 0.000 description 4
- 229910052751 metal Inorganic materials 0.000 description 4
- 239000002184 metal Substances 0.000 description 4
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 4
- 125000003386 piperidinyl group Chemical group 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
- NAMYKGVDVNBCFQ-UHFFFAOYSA-N 2-bromopropane Chemical compound CC(C)Br NAMYKGVDVNBCFQ-UHFFFAOYSA-N 0.000 description 3
- MWJKXKBVWIHKOB-UHFFFAOYSA-N 4-(methoxymethyl)-n-phenylpiperidin-4-amine Chemical compound C=1C=CC=CC=1NC1(COC)CCNCC1 MWJKXKBVWIHKOB-UHFFFAOYSA-N 0.000 description 3
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 3
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 238000005904 alkaline hydrolysis reaction Methods 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- 239000003638 chemical reducing agent Substances 0.000 description 3
- 239000003795 chemical substances by application 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
- 125000005745 ethoxymethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])* 0.000 description 3
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 238000003818 flash chromatography Methods 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 125000004970 halomethyl group Chemical group 0.000 description 3
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 3
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- RCCCDDCOWBHPMR-UHFFFAOYSA-N ethyl 4-(4-methylanilino)-1-(2-phenylethyl)piperidine-4-carboxylate Chemical compound C1CC(C(=O)OCC)(NC=2C=CC(C)=CC=2)CCN1CCC1=CC=CC=C1 RCCCDDCOWBHPMR-UHFFFAOYSA-N 0.000 description 1
- HDPKHACYNVLNLF-UHFFFAOYSA-N ethyl 4-(N-propanoylanilino)piperidine-4-carboxylate oxalic acid Chemical compound C(C(=O)O)(=O)O.O=C(CC)N(C1=CC=CC=C1)C1(CCNCC1)C(=O)OCC HDPKHACYNVLNLF-UHFFFAOYSA-N 0.000 description 1
- RPVMTHSREUIZIT-UHFFFAOYSA-N ethyl 4-(n-butanoylanilino)-1-(2-phenylethyl)piperidine-4-carboxylate;hydrochloride Chemical compound Cl.C1CN(CCC=2C=CC=CC=2)CCC1(C(=O)OCC)N(C(=O)CCC)C1=CC=CC=C1 RPVMTHSREUIZIT-UHFFFAOYSA-N 0.000 description 1
- PERLDSWWCVDWDL-UHFFFAOYSA-N ethyl 4-[n-(cyclopropanecarbonyl)anilino]-1-(2-phenylethyl)piperidine-4-carboxylate;hydrochloride Chemical compound Cl.C1CC(C(=O)OCC)(N(C(=O)C2CC2)C=2C=CC=CC=2)CCN1CCC1=CC=CC=C1 PERLDSWWCVDWDL-UHFFFAOYSA-N 0.000 description 1
- HKSPFTABYQTLQV-UHFFFAOYSA-N ethyl 4-carbamoyl-4-(4-methylanilino)piperidine-1-carboxylate Chemical compound C(C)OC(=O)N1CCC(CC1)(NC1=CC=C(C=C1)C)C(N)=O HKSPFTABYQTLQV-UHFFFAOYSA-N 0.000 description 1
- VRZVPALEJCLXPR-UHFFFAOYSA-N ethyl 4-methylbenzenesulfonate Chemical compound CCOS(=O)(=O)C1=CC=C(C)C=C1 VRZVPALEJCLXPR-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 229940052308 general anesthetics halogenated hydrocarbons Drugs 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 230000002140 halogenating effect Effects 0.000 description 1
- QMEZUZOCLYUADC-UHFFFAOYSA-N hydrate;dihydrochloride Chemical compound O.Cl.Cl QMEZUZOCLYUADC-UHFFFAOYSA-N 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-M iodide Chemical compound [I-] XMBWDFGMSWQBCA-UHFFFAOYSA-M 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 239000011630 iodine Substances 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
- ODBLHEXUDAPZAU-UHFFFAOYSA-N isocitric acid Chemical compound OC(=O)C(O)C(C(O)=O)CC(O)=O ODBLHEXUDAPZAU-UHFFFAOYSA-N 0.000 description 1
- 238000005304 joining Methods 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 229910003002 lithium salt Inorganic materials 0.000 description 1
- 159000000002 lithium salts Chemical class 0.000 description 1
- 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- MEUHMLFRTOSTFF-UHFFFAOYSA-N methyl 1-(2,3-dihydro-1h-inden-2-yl)-4-(n-propanoylanilino)piperidine-4-carboxylate Chemical compound C1CN(C2CC3=CC=CC=C3C2)CCC1(C(=O)OC)N(C(=O)CC)C1=CC=CC=C1 MEUHMLFRTOSTFF-UHFFFAOYSA-N 0.000 description 1
- VKFQFGRAFZXPHL-UHFFFAOYSA-N methyl 1-(2-phenylethyl)-4-[N-propanoyl-3-(trifluoromethyl)anilino]piperidine-4-carboxylate oxalic acid Chemical compound OC(=O)C(O)=O.C1CN(CCC=2C=CC=CC=2)CCC1(C(=O)OC)N(C(=O)CC)C1=CC=CC(C(F)(F)F)=C1 VKFQFGRAFZXPHL-UHFFFAOYSA-N 0.000 description 1
- XSDGHDRUTYCYHL-UHFFFAOYSA-N methyl 1-(cyclopropylmethyl)-4-(N-propanoylanilino)piperidine-4-carboxylate Chemical compound C1CN(CC2CC2)CCC1(C(=O)OC)N(C(=O)CC)C1=CC=CC=C1 XSDGHDRUTYCYHL-UHFFFAOYSA-N 0.000 description 1
- CXLSUTOBXXFOEV-UHFFFAOYSA-N methyl 1-[2-(4-methylphenyl)ethyl]-4-(n-propanoylanilino)piperidine-4-carboxylate;hydrochloride Chemical compound Cl.C1CN(CCC=2C=CC(C)=CC=2)CCC1(C(=O)OC)N(C(=O)CC)C1=CC=CC=C1 CXLSUTOBXXFOEV-UHFFFAOYSA-N 0.000 description 1
- QKRGHVDSVANHAD-UHFFFAOYSA-N methyl 1-benzyl-4-(n-propanoylanilino)piperidine-4-carboxylate Chemical compound C1CN(CC=2C=CC=CC=2)CCC1(C(=O)OC)N(C(=O)CC)C1=CC=CC=C1 QKRGHVDSVANHAD-UHFFFAOYSA-N 0.000 description 1
- NYXYAZZWWCNTOT-UHFFFAOYSA-N methyl 1-pentyl-4-(N-propanoylanilino)piperidine-4-carboxylate oxalic acid Chemical compound OC(=O)C(O)=O.C1CN(CCCCC)CCC1(C(=O)OC)N(C(=O)CC)C1=CC=CC=C1 NYXYAZZWWCNTOT-UHFFFAOYSA-N 0.000 description 1
- JWXGBLNGCIGLBH-UHFFFAOYSA-N methyl 3-methyl-4-oxopiperidine-1-carboxylate Chemical compound COC(=O)N1CCC(=O)C(C)C1 JWXGBLNGCIGLBH-UHFFFAOYSA-N 0.000 description 1
- NPOMYZMTQSCHSC-UHFFFAOYSA-N methyl 4-(3-methoxyanilino)-1-(2-phenylethyl)piperidine-4-carboxylate;oxalic acid Chemical compound OC(=O)C(O)=O.C1CC(C(=O)OC)(NC=2C=C(OC)C=CC=2)CCN1CCC1=CC=CC=C1 NPOMYZMTQSCHSC-UHFFFAOYSA-N 0.000 description 1
- XHGLLTITHKUDDE-UHFFFAOYSA-N methyl 4-(N-propanoylanilino)-1-propylpiperidine-4-carboxylate oxalic acid Chemical compound OC(=O)C(O)=O.C1CN(CCC)CCC1(C(=O)OC)N(C(=O)CC)C1=CC=CC=C1 XHGLLTITHKUDDE-UHFFFAOYSA-N 0.000 description 1
- DWBZNLFRHNAWPW-UHFFFAOYSA-N methyl 4-[3-(trifluoromethyl)anilino]piperidine-4-carboxylate Chemical compound C=1C=CC(C(F)(F)F)=CC=1NC1(C(=O)OC)CCNCC1 DWBZNLFRHNAWPW-UHFFFAOYSA-N 0.000 description 1
- IFQWTLUCYHGSSI-UHFFFAOYSA-N methyl 4-anilino-1-(2-phenylethyl)piperidine-4-carboxylate Chemical compound C1CC(C(=O)OC)(NC=2C=CC=CC=2)CCN1CCC1=CC=CC=C1 IFQWTLUCYHGSSI-UHFFFAOYSA-N 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- MXNALQRSXHOIEA-UHFFFAOYSA-N n-(2-bromoethyl)aniline;hydrobromide Chemical compound [Br-].BrCC[NH2+]C1=CC=CC=C1 MXNALQRSXHOIEA-UHFFFAOYSA-N 0.000 description 1
- BDLHEYOIAQYADD-UHFFFAOYSA-N n-[1-(2-hydroxy-2-phenylethyl)-4-(methoxymethyl)piperidin-4-yl]-n-phenylpropanamide Chemical compound C1CN(CC(O)C=2C=CC=CC=2)CCC1(COC)N(C(=O)CC)C1=CC=CC=C1 BDLHEYOIAQYADD-UHFFFAOYSA-N 0.000 description 1
- CKGXIGKMYMSTRC-UHFFFAOYSA-N n-[1-(2-hydroxy-2-phenylethyl)-4-(methoxymethyl)piperidin-4-yl]-n-phenylpropanamide;hydrochloride Chemical compound Cl.C1CN(CC(O)C=2C=CC=CC=2)CCC1(COC)N(C(=O)CC)C1=CC=CC=C1 CKGXIGKMYMSTRC-UHFFFAOYSA-N 0.000 description 1
- FYAGIJMJHIDNBX-UHFFFAOYSA-N n-[1-[2-(4-aminophenyl)ethyl]-4-(methoxymethyl)piperidin-4-yl]-n-phenylpropanamide Chemical compound C1CN(CCC=2C=CC(N)=CC=2)CCC1(COC)N(C(=O)CC)C1=CC=CC=C1 FYAGIJMJHIDNBX-UHFFFAOYSA-N 0.000 description 1
- UEHITAZETWNUOP-UHFFFAOYSA-N n-[1-benzyl-4-(ethoxymethyl)piperidin-4-yl]-n-phenylpropanamide;oxalic acid Chemical compound OC(=O)C(O)=O.C1CC(COCC)(N(C(=O)CC)C=2C=CC=CC=2)CCN1CC1=CC=CC=C1 UEHITAZETWNUOP-UHFFFAOYSA-N 0.000 description 1
- RIGNIZMZYKGGHY-UHFFFAOYSA-N n-[1-benzyl-4-(methoxymethyl)piperidin-4-yl]-n-phenylpropanamide Chemical compound C1CN(CC=2C=CC=CC=2)CCC1(COC)N(C(=O)CC)C1=CC=CC=C1 RIGNIZMZYKGGHY-UHFFFAOYSA-N 0.000 description 1
- YOSUJPFYHBEKAM-UHFFFAOYSA-N n-[1-benzyl-4-(propoxymethyl)piperidin-4-yl]-n-phenylpropanamide;oxalic acid Chemical compound OC(=O)C(O)=O.C1CC(COCCC)(N(C(=O)CC)C=2C=CC=CC=2)CCN1CC1=CC=CC=C1 YOSUJPFYHBEKAM-UHFFFAOYSA-N 0.000 description 1
- IUFFNKZCZVDKAA-UHFFFAOYSA-N n-[1-butyl-4-(methoxymethyl)piperidin-4-yl]-n-phenylpropanamide;hydrochloride Chemical compound Cl.C1CN(CCCC)CCC1(COC)N(C(=O)CC)C1=CC=CC=C1 IUFFNKZCZVDKAA-UHFFFAOYSA-N 0.000 description 1
- SMJQGAOLVOHPAQ-UHFFFAOYSA-N n-[4-(methoxymethyl)-1-(1-oxo-1-phenylpropan-2-yl)piperidin-4-yl]-n-phenylpropanamide Chemical compound C1CN(C(C)C(=O)C=2C=CC=CC=2)CCC1(COC)N(C(=O)CC)C1=CC=CC=C1 SMJQGAOLVOHPAQ-UHFFFAOYSA-N 0.000 description 1
- KYRGRXWWBNRGKR-UHFFFAOYSA-N n-[4-(methoxymethyl)-1-(2-pyridin-2-ylethyl)piperidin-4-yl]-n-phenylpropanamide Chemical compound C1CN(CCC=2N=CC=CC=2)CCC1(COC)N(C(=O)CC)C1=CC=CC=C1 KYRGRXWWBNRGKR-UHFFFAOYSA-N 0.000 description 1
- PKCVQFDFGMSBMV-UHFFFAOYSA-N n-[4-(methoxymethyl)-1-[2-(4-nitrophenyl)ethyl]piperidin-4-yl]-n-phenylpropanamide Chemical compound C1CN(CCC=2C=CC(=CC=2)[N+]([O-])=O)CCC1(COC)N(C(=O)CC)C1=CC=CC=C1 PKCVQFDFGMSBMV-UHFFFAOYSA-N 0.000 description 1
- QJUKOQOYOORXMO-UHFFFAOYSA-N n-[4-(methoxymethyl)-1-propan-2-ylpiperidin-4-yl]-n-phenylpropanamide;hydrochloride Chemical compound Cl.C1CN(C(C)C)CCC1(COC)N(C(=O)CC)C1=CC=CC=C1 QJUKOQOYOORXMO-UHFFFAOYSA-N 0.000 description 1
- ICCKRZDLWUZYPR-UHFFFAOYSA-N n-[4-(methoxymethyl)-1-propylpiperidin-4-yl]-n-phenylpropanamide;hydrochloride Chemical compound Cl.C1CN(CCC)CCC1(COC)N(C(=O)CC)C1=CC=CC=C1 ICCKRZDLWUZYPR-UHFFFAOYSA-N 0.000 description 1
- YDJXNYNKKXZBMP-UHFFFAOYSA-N n-phenethyl-4-piperidinone Chemical compound C1CC(=O)CCN1CCC1=CC=CC=C1 YDJXNYNKKXZBMP-UHFFFAOYSA-N 0.000 description 1
- PJTTUONVSVGXRW-UHFFFAOYSA-N n-phenyl-1-(2-phenylethyl)-4-(phenylmethoxymethyl)piperidin-4-amine Chemical compound C1CC(COCC=2C=CC=CC=2)(NC=2C=CC=CC=2)CCN1CCC1=CC=CC=C1 PJTTUONVSVGXRW-UHFFFAOYSA-N 0.000 description 1
- HGVNXVUBCPMFHB-UHFFFAOYSA-N n-phenylcyclopropanecarboxamide;hydrochloride Chemical compound Cl.C1CC1C(=O)NC1=CC=CC=C1 HGVNXVUBCPMFHB-UHFFFAOYSA-N 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 210000000056 organ Anatomy 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
- HWOCNWRPIUYVDF-UHFFFAOYSA-N oxalic acid N-phenyl-1-(2-phenylethyl)-4-(phenylmethoxymethyl)piperidin-4-amine Chemical compound OC(=O)C(O)=O.C1CC(COCC=2C=CC=CC=2)(NC=2C=CC=CC=2)CCN1CCC1=CC=CC=C1 HWOCNWRPIUYVDF-UHFFFAOYSA-N 0.000 description 1
- GEVPUGOOGXGPIO-UHFFFAOYSA-N oxalic acid;dihydrate Chemical compound O.O.OC(=O)C(O)=O GEVPUGOOGXGPIO-UHFFFAOYSA-N 0.000 description 1
- ROCHZUNCIZLTRQ-UHFFFAOYSA-N oxalic acid;propan-2-ol Chemical compound CC(C)O.OC(=O)C(O)=O ROCHZUNCIZLTRQ-UHFFFAOYSA-N 0.000 description 1
- OZHOHTGAQOJLCS-UHFFFAOYSA-N oxalic acid;propanoic acid Chemical compound CCC(O)=O.OC(=O)C(O)=O OZHOHTGAQOJLCS-UHFFFAOYSA-N 0.000 description 1
- 150000002924 oxiranes Chemical class 0.000 description 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 1
- 229960002296 paroxetine Drugs 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 229960003742 phenol Drugs 0.000 description 1
- BSCCSDNZEIHXOK-UHFFFAOYSA-N phenyl carbamate Chemical compound NC(=O)OC1=CC=CC=C1 BSCCSDNZEIHXOK-UHFFFAOYSA-N 0.000 description 1
- RJUAEBLXGFKZMS-UHFFFAOYSA-N piperidin-1-ylmethanol Chemical compound OCN1CCCCC1 RJUAEBLXGFKZMS-UHFFFAOYSA-N 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- UQPGCLOZEWKMBO-UHFFFAOYSA-N prop-2-enyl 4-anilino-1-(2-phenylethyl)piperidine-4-carboxylate Chemical compound C1CC(C(=O)OCC=C)(NC=2C=CC=CC=2)CCN1CCC1=CC=CC=C1 UQPGCLOZEWKMBO-UHFFFAOYSA-N 0.000 description 1
- VTOVDQCZYVGCIR-UHFFFAOYSA-N propan-2-yl 4-anilino-1-(2-phenylethyl)piperidine-4-carboxylate Chemical compound C1CC(C(=O)OC(C)C)(NC=2C=CC=CC=2)CCN1CCC1=CC=CC=C1 VTOVDQCZYVGCIR-UHFFFAOYSA-N 0.000 description 1
- RZWZRACFZGVKFM-UHFFFAOYSA-N propanoyl chloride Chemical compound CCC(Cl)=O RZWZRACFZGVKFM-UHFFFAOYSA-N 0.000 description 1
- BQCWHLMBFROKFM-UHFFFAOYSA-N propyl 1-(2-hydroxy-2-phenylethyl)-4-(N-propanoylanilino)piperidine-4-carboxylate hydrochloride Chemical compound Cl.C1CC(C(=O)OCCC)(N(C(=O)CC)C=2C=CC=CC=2)CCN1CC(O)C1=CC=CC=C1 BQCWHLMBFROKFM-UHFFFAOYSA-N 0.000 description 1
- SBOHVYYTKVYCTA-UHFFFAOYSA-N propyl 4-anilino-1-benzylpiperidine-4-carboxylate Chemical compound C1CC(C(=O)OCCC)(NC=2C=CC=CC=2)CCN1CC1=CC=CC=C1 SBOHVYYTKVYCTA-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000005624 silicic acid group Chemical class 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- HJHVQCXHVMGZNC-JCJNLNMISA-M sodium;(2z)-2-[(3r,4s,5s,8s,9s,10s,11r,13r,14s,16s)-16-acetyloxy-3,11-dihydroxy-4,8,10,14-tetramethyl-2,3,4,5,6,7,9,11,12,13,15,16-dodecahydro-1h-cyclopenta[a]phenanthren-17-ylidene]-6-methylhept-5-enoate Chemical compound [Na+].O[C@@H]([C@@H]12)C[C@H]3\C(=C(/CCC=C(C)C)C([O-])=O)[C@@H](OC(C)=O)C[C@]3(C)[C@@]2(C)CC[C@@H]2[C@]1(C)CC[C@@H](O)[C@H]2C HJHVQCXHVMGZNC-JCJNLNMISA-M 0.000 description 1
- HLUKWPFQFJTUCB-UHFFFAOYSA-M sodium;4-anilino-1-(2-phenylethyl)piperidine-4-carboxylate Chemical compound [Na+].C1CC(C(=O)[O-])(NC=2C=CC=CC=2)CCN1CCC1=CC=CC=C1 HLUKWPFQFJTUCB-UHFFFAOYSA-M 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- GGCSSNBKKAUURC-UHFFFAOYSA-N sufentanil Chemical compound C1CN(CCC=2SC=CC=2)CCC1(COC)N(C(=O)CC)C1=CC=CC=C1 GGCSSNBKKAUURC-UHFFFAOYSA-N 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 238000003786 synthesis reaction Methods 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
- NRTLTGGGUQIRRT-UHFFFAOYSA-N triethylazanium;bromide Chemical compound [Br-].CC[NH+](CC)CC NRTLTGGGUQIRRT-UHFFFAOYSA-N 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/333—Radicals substituted by oxygen or sulfur atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/56—Nitrogen atoms
- C07D211/58—Nitrogen atoms attached in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
- C07D211/66—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4 having a hetero atom as the second substituent in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
- C07D333/16—Radicals substituted by singly bound hetero atoms other than halogen by oxygen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Pain & Pain Management (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Hydrogenated Pyridines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Heterocyclic Compounds Containing Sulfur Atoms (AREA)
- Pyrrole Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US55851175A | 1975-03-14 | 1975-03-14 | |
US55851175 | 1975-03-14 | ||
US05/648,685 US3998834A (en) | 1975-03-14 | 1976-01-13 | N-(4-piperidinyl)-n-phenylamides and -carbamates |
US64868576 | 1976-01-13 |
Publications (3)
Publication Number | Publication Date |
---|---|
FI760646A7 FI760646A7 (en, 2012) | 1976-09-15 |
FI61481B FI61481B (fi) | 1982-04-30 |
FI61481C true FI61481C (fi) | 1982-08-10 |
Family
ID=27071767
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
FI760646A FI61481C (fi) | 1975-03-14 | 1976-03-12 | Foerfarande foer framstaellning av nya terapeutiskt anvaendbara piperidinderivat |
Country Status (28)
Country | Link |
---|---|
US (1) | US3998834A (en, 2012) |
JP (1) | JPS5946217B2 (en, 2012) |
AT (1) | AT359493B (en, 2012) |
AU (1) | AU503632B2 (en, 2012) |
BG (1) | BG28259A3 (en, 2012) |
CA (1) | CA1080232A (en, 2012) |
CH (1) | CH629486A5 (en, 2012) |
CZ (1) | CZ278060B6 (en, 2012) |
DE (1) | DE2610228A1 (en, 2012) |
DK (1) | DK148960C (en, 2012) |
ES (1) | ES446034A1 (en, 2012) |
FI (1) | FI61481C (en, 2012) |
FR (1) | FR2303546A1 (en, 2012) |
GB (1) | GB1538938A (en, 2012) |
HU (1) | HU172963B (en, 2012) |
IE (1) | IE42512B1 (en, 2012) |
IL (1) | IL49204A (en, 2012) |
IT (1) | IT1057988B (en, 2012) |
LU (1) | LU74511A1 (en, 2012) |
NL (1) | NL185279C (en, 2012) |
NO (1) | NO146162C (en, 2012) |
NZ (1) | NZ180096A (en, 2012) |
PH (1) | PH12746A (en, 2012) |
PL (1) | PL102474B1 (en, 2012) |
PT (1) | PT64898B (en, 2012) |
SE (1) | SE426486B (en, 2012) |
SU (1) | SU1227109A3 (en, 2012) |
YU (1) | YU39960B (en, 2012) |
Families Citing this family (61)
Publication number | Priority date | Publication date | Assignee | Title |
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US4179569A (en) * | 1975-03-14 | 1979-12-18 | Janssen Pharmaceutica N.V. | N-(4-piperidinyl)-N-phenylamides |
US4208418A (en) * | 1975-09-23 | 1980-06-17 | Janssen Pharmaceutica N.V. | N-Aryl-N-(1-alkyl-4-piperidinyl)arylacetamides |
US4225606A (en) * | 1975-09-23 | 1980-09-30 | Janssen Pharmaceutica N.V. | N-Aryl-N-(1-L-4-piperidinyl)arylacetamides |
FR2389622B1 (en, 2012) * | 1977-05-05 | 1982-05-21 | Janssen Pharmaceutica Nv | |
US4167574A (en) * | 1978-03-13 | 1979-09-11 | Janssen Pharmaceutica, N.V. | N-phenyl-N-(4-piperidinyl)amides |
US4584303A (en) * | 1984-04-09 | 1986-04-22 | The Boc Group, Inc. | N-aryl-N-(4-piperidinyl)amides and pharmaceutical compositions and method employing such compounds |
FR2608602A1 (fr) * | 1986-12-23 | 1988-06-24 | Cerm Cent Europ Rech Mauvernay | Nouvelles 3-piperidineamines ou 3-azepineamines substituees, leur preparation et leurs applications en therapeutique |
US5013742A (en) * | 1987-11-02 | 1991-05-07 | Boc, Inc. | 4-phenyl-4-N-(phenyl) amido piperidine derivatives and pharmaceutical compositions and method employing such compounds |
US4957929A (en) * | 1987-11-02 | 1990-09-18 | Boc, Inc. | 4-phenyl-4-[N-(phenyl)amido]piperidine compounds and pharmaceutical compositions employing such compounds |
US4791121A (en) * | 1987-11-02 | 1988-12-13 | The Boc Group, Inc. | 4-phenyl-4-(N-(phenyl)amido) piperidine derivatives and pharmaceutical compositions and method employing such compounds |
US4921864A (en) * | 1987-11-02 | 1990-05-01 | Boc, Inc. | 4-Phenyl-4-(N-(phenyl)amido) piperidine derivatives and pharmaceutical compositions and method employing such compounds |
US4849521A (en) * | 1987-11-02 | 1989-07-18 | Boc, Inc. | Stereoselective preparation of 3-substituted-4-piperidine compounds and derivatives |
USRE33495E (en) * | 1987-11-02 | 1990-12-18 | Boc, Inc. | Stereoselective preparation of 3-substituted-4-anilino-piperidine compounds and derivatives |
US4791120A (en) * | 1987-12-31 | 1988-12-13 | The Boc Group, Inc. | 4-heteropentacyclic-4-[N-(phenyl)amino] piperidine derivatives and pharmaceutical compositions and method employing such compounds |
US4801615A (en) * | 1987-12-31 | 1989-01-31 | The Boc Group, Inc. | 4-heterohexacyclic-4-(N-(phenyl)amido) piperidine derivatives and pharmaceutical compositions and method employing such compounds |
US5019583A (en) * | 1989-02-15 | 1991-05-28 | Glaxo Inc. | N-phenyl-N-(4-piperidinyl)amides useful as analgesics |
USRE34201E (en) * | 1989-04-20 | 1993-03-23 | Anaquest, Inc. | N-aryl-N-[4-(1-heterocyclicalkyl)piperidinyl]amides and pharmaceutical compositions and methods employing such compounds |
US5053411A (en) * | 1989-04-20 | 1991-10-01 | Anaquest, Inc. | N-aryl-N-[4-(1-heterocyclicalkyl)piperidinyl]amides and pharmaceutical compositions and methods employing such compounds |
US5145967A (en) * | 1989-04-20 | 1992-09-08 | Anaquest, Inc. | Method for preparing 4-alkoxyalkyl-4-phenylaminopiperdines and derivatives thereof |
US4939161A (en) * | 1989-05-12 | 1990-07-03 | Boc, Inc. | Analgesic N-aryl-N-[1-substituted-3,5-dimethyl-4-piperidinyl]amides |
US4994471A (en) * | 1989-05-12 | 1991-02-19 | Boc, Inc. | N-aryl-N-(1-substituted-3-alkoxy-4-piperidinyl)amides and pharmaceutical compositions and methods employing such compounds |
US5100903A (en) * | 1989-05-12 | 1992-03-31 | Anaquest, Inc. | N-aryl-n-(1-substituted-3-alkoxy-4-piperidinyl)amides and pharmaceutical compositions and methods employing such compounds |
US5039804A (en) * | 1989-12-13 | 1991-08-13 | Glaxo Inc. | Preparation of substituted alkali metal piperidine-4-carboxylates |
US5126455A (en) * | 1989-12-13 | 1992-06-30 | Glaxo Inc. | Preparation of substituted alkali metal piperidine-4-carboxylates |
US5130321A (en) * | 1990-12-18 | 1992-07-14 | Glaxo Inc. | Analgesic n-phenyl-n-(3-or 1-3-me-4-piperidinyl)amides |
US5214148A (en) * | 1990-12-18 | 1993-05-25 | Glaxo Inc. | Analgesic N-phenyl-N-(3-OR1 -3-ME-4-piperidinyl)amides |
FR2676054B1 (fr) * | 1991-05-03 | 1993-09-03 | Sanofi Elf | Nouveaux composes n-alkylenepiperidino et leurs enantiomeres, procede pour leur preparation et compositions pharmaceutiques les contenant. |
GB9316863D0 (en) * | 1993-08-13 | 1993-09-29 | Glaxo Group Ltd | Chemical process |
US5489689A (en) * | 1993-09-30 | 1996-02-06 | Mallinckrodt Chemical, Inc. | Preparation of piperidine derivatives |
US6541021B1 (en) | 1999-03-18 | 2003-04-01 | Durect Corporation | Devices and methods for pain management |
US6835194B2 (en) * | 1999-03-18 | 2004-12-28 | Durect Corporation | Implantable devices and methods for treatment of pain by delivery of fentanyl and fentanyl congeners |
EP1182192A4 (en) * | 1999-04-09 | 2002-06-05 | Mochida Pharm Co Ltd | 4-HYDROXYPIPERIDINE DERIVATIVES WITH ANTI-ARRHYTHMIC EFFECT |
US6635661B2 (en) | 2000-05-25 | 2003-10-21 | Sepracor Inc. | Heterocyclic analgesic compounds and methods of use thereof |
US6677332B1 (en) | 1999-05-25 | 2004-01-13 | Sepracor, Inc. | Heterocyclic analgesic compounds and methods of use thereof |
US7361666B2 (en) * | 1999-05-25 | 2008-04-22 | Sepracor, Inc. | Heterocyclic analgesic compounds and methods of use thereof |
CA2393559C (en) * | 1999-12-06 | 2009-05-26 | Mallinckrodt Inc. | Methods for the syntheses of alfentanil, sufentanil and remifentanil |
US7074803B2 (en) * | 2001-03-02 | 2006-07-11 | Durect Corporation | Opioid formulations |
US20040102476A1 (en) * | 2002-11-25 | 2004-05-27 | Chan Tai Wah | High concentration formulations of opioids and opioid derivatives |
US20090030041A1 (en) * | 2004-09-14 | 2009-01-29 | Toshihiro Takahashi | N-substituted N-(4-piperidinyl) Amide Derivative |
JP2008088057A (ja) * | 2005-03-23 | 2008-04-17 | Nippon Chemiphar Co Ltd | N−置換−n−(4−ピペリジニル)アミド誘導体 |
EP1966140A1 (en) * | 2005-11-17 | 2008-09-10 | Mallinckrodt, Inc. | Process for synthesizing remifentanil |
CN101374812A (zh) * | 2006-01-24 | 2009-02-25 | 马林克罗特公司 | 合成瑞芬太尼的方法 |
EP1867635A1 (en) * | 2006-06-15 | 2007-12-19 | Kern Pharma, S.L. | Process for preparing remifentanil, intermediates thereof, use of said intermediates and processes for their preparation |
US20080009782A1 (en) * | 2006-06-28 | 2008-01-10 | Alza Corporation | Methods and Devices for Transdermal Electrotransport Delivery of Lofentanil and Carfentanil |
WO2008005423A1 (en) * | 2006-07-03 | 2008-01-10 | Cambrex Charles City, Inc. | Improved method of making sufentanil |
EP2125730A2 (en) * | 2006-11-29 | 2009-12-02 | Mallinckrodt Inc. | New process for remifentanil synthesis |
US20100056574A1 (en) * | 2008-09-04 | 2010-03-04 | Mallinckrodt Inc. | Crystalline Forms of Sufentanil |
US8299258B2 (en) * | 2008-11-04 | 2012-10-30 | Cambrex Charles City | Method of making piperidine derivatives |
ES2664801T3 (es) | 2010-09-17 | 2018-04-23 | Mallinckrodt Llc | Proceso mejorado para la preparación de un precursor de sufentanilo base |
EP2455377B1 (de) | 2010-11-11 | 2014-07-09 | hameln rds gmbh | Synthese von Fentanyl Analoga |
CN103328038A (zh) | 2010-12-01 | 2013-09-25 | 史拜诺莫度雷森公司 | 向神经解剖结构直接递送药剂 |
SG10201700952XA (en) * | 2013-03-13 | 2017-04-27 | Harvard College | Stapled and stitched polypeptides and uses thereof |
EP3233077A4 (en) | 2014-12-19 | 2018-08-08 | The Broad Institute Inc. | Dopamine d2 receptor ligands |
US10752588B2 (en) | 2014-12-19 | 2020-08-25 | The Broad Institute, Inc. | Dopamine D2 receptor ligands |
ES2806631T3 (es) | 2015-05-27 | 2021-02-18 | SpecGx LLC | Preparación de citrato de sufentanilo y base de sufentanilo |
CN106854203B (zh) * | 2015-12-08 | 2020-12-01 | 江苏恩华药业股份有限公司 | 枸橼酸舒芬太尼的新晶型及其制备方法 |
EP3199523B1 (en) | 2016-01-29 | 2018-08-15 | Bioka s. r.o. | The new process for producing n-phenyl-n-(4-piperidinyl) amide derivatives such as remifentanil and carfentanil |
CN108503579B (zh) * | 2018-03-28 | 2021-03-26 | 南京医科大学 | 芬太尼类似物及其应用 |
CN113214139B (zh) * | 2020-02-03 | 2022-03-04 | 江苏谛奇医药科技有限公司 | 哌啶酰胺类衍生物及其制备方法、其药物组合物、其单晶培养方法及其应用 |
IL299091A (en) | 2020-08-14 | 2023-02-01 | Novartis Ag | Heteroaryl substituted spiropiperidinyl derivatives and pharmaceutical uses thereof |
CN114262320A (zh) * | 2021-12-28 | 2022-04-01 | 宜昌人福药业有限责任公司 | 一种利用连续流微通道反应器制备苯胺基哌啶类药物的合成方法 |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
BE623427A (en, 2012) * | 1961-10-10 | |||
US3171838A (en) * | 1961-10-10 | 1965-03-02 | Res Lab Dr C Janssen N V | Aroylalkyl and hydroxyaralkyl derivatives of 4-(n-arylalkanamido)-piperidines and related compounds |
-
1976
- 1976-01-13 US US05/648,685 patent/US3998834A/en not_active Expired - Lifetime
- 1976-02-23 NO NO760591A patent/NO146162C/no unknown
- 1976-02-24 NZ NZ180096A patent/NZ180096A/xx unknown
- 1976-02-27 SE SE7602740A patent/SE426486B/xx active Protection Beyond IP Right Term
- 1976-02-27 CA CA246,697A patent/CA1080232A/en not_active Expired
- 1976-03-09 LU LU74511A patent/LU74511A1/xx unknown
- 1976-03-10 FR FR7606870A patent/FR2303546A1/fr active Granted
- 1976-03-10 GB GB9593/76A patent/GB1538938A/en not_active Expired
- 1976-03-11 HU HU76JA00000751A patent/HU172963B/hu unknown
- 1976-03-11 DE DE19762610228 patent/DE2610228A1/de active Granted
- 1976-03-12 JP JP51026226A patent/JPS5946217B2/ja not_active Expired
- 1976-03-12 PL PL1976187910A patent/PL102474B1/pl unknown
- 1976-03-12 AT AT184676A patent/AT359493B/de not_active IP Right Cessation
- 1976-03-12 NL NLAANVRAGE7602612,A patent/NL185279C/xx not_active IP Right Cessation
- 1976-03-12 ES ES446034A patent/ES446034A1/es not_active Expired
- 1976-03-12 SU SU762332950A patent/SU1227109A3/ru active
- 1976-03-12 DK DK110376A patent/DK148960C/da not_active IP Right Cessation
- 1976-03-12 IT IT48556/76A patent/IT1057988B/it active
- 1976-03-12 CH CH310476A patent/CH629486A5/de not_active IP Right Cessation
- 1976-03-12 PT PT64898A patent/PT64898B/pt unknown
- 1976-03-12 IL IL49204A patent/IL49204A/xx unknown
- 1976-03-12 IE IE527/76A patent/IE42512B1/en not_active IP Right Cessation
- 1976-03-12 CZ CS761632A patent/CZ278060B6/cs unknown
- 1976-03-12 BG BG032601A patent/BG28259A3/xx unknown
- 1976-03-12 PH PH18204A patent/PH12746A/en unknown
- 1976-03-12 YU YU652/76A patent/YU39960B/xx unknown
- 1976-03-12 FI FI760646A patent/FI61481C/fi not_active IP Right Cessation
- 1976-03-15 AU AU12006/76A patent/AU503632B2/en not_active Expired
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Legal Events
Date | Code | Title | Description |
---|---|---|---|
MA | Patent expired | ||
MA | Patent expired |
Owner name: JANSSEN PHARMACEUTICA N.V. |