DK157919B - Analogifremgangsmaade til fremstilling af hidtil ukendte racemiske eller optisk aktive 2-pyrrolidonderivater - Google Patents
Analogifremgangsmaade til fremstilling af hidtil ukendte racemiske eller optisk aktive 2-pyrrolidonderivater Download PDFInfo
- Publication number
- DK157919B DK157919B DK408676A DK408676A DK157919B DK 157919 B DK157919 B DK 157919B DK 408676 A DK408676 A DK 408676A DK 408676 A DK408676 A DK 408676A DK 157919 B DK157919 B DK 157919B
- Authority
- DK
- Denmark
- Prior art keywords
- alkyl
- general formula
- compounds
- benzyl
- phenyl
- Prior art date
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- 238000000034 method Methods 0.000 title claims description 13
- 150000003953 γ-lactams Chemical class 0.000 title claims description 4
- 238000002360 preparation method Methods 0.000 title description 5
- 150000001875 compounds Chemical class 0.000 claims description 31
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 239000000126 substance Substances 0.000 claims description 6
- 150000001266 acyl halides Chemical class 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 2
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 2
- 238000003776 cleavage reaction Methods 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 230000007017 scission Effects 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 23
- -1 m-monosubstituted phenyl-2-pyrrolidones Chemical class 0.000 description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 13
- 238000009835 boiling Methods 0.000 description 13
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 150000002148 esters Chemical class 0.000 description 8
- 230000008018 melting Effects 0.000 description 8
- 238000002844 melting Methods 0.000 description 8
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- 230000000694 effects Effects 0.000 description 7
- 238000001953 recrystallisation Methods 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 229910052739 hydrogen Inorganic materials 0.000 description 6
- 150000003839 salts Chemical class 0.000 description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 5
- 239000002585 base Substances 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 239000001257 hydrogen Substances 0.000 description 5
- 239000003208 petroleum Substances 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- JNRKFSJWVCILHE-UHFFFAOYSA-N 4-(3,4-dimethoxyphenyl)pyrrolidin-2-one Chemical compound C1=C(OC)C(OC)=CC=C1C1CC(=O)NC1 JNRKFSJWVCILHE-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 4
- 229960000583 acetic acid Drugs 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 239000003513 alkali Substances 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 238000000354 decomposition reaction Methods 0.000 description 4
- 239000012362 glacial acetic acid Substances 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 239000002798 polar solvent Substances 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 150000001298 alcohols Chemical class 0.000 description 3
- 150000003935 benzaldehydes Chemical class 0.000 description 3
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzenecarboxaldehyde Natural products O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 239000012948 isocyanate Substances 0.000 description 3
- 150000002513 isocyanates Chemical class 0.000 description 3
- 230000020477 pH reduction Effects 0.000 description 3
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 3
- 229910052698 phosphorus Inorganic materials 0.000 description 3
- 239000011574 phosphorus Substances 0.000 description 3
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 3
- 239000012312 sodium hydride Substances 0.000 description 3
- 229910000104 sodium hydride Inorganic materials 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- KYVBNYUBXIEUFW-UHFFFAOYSA-N 1,1,3,3-tetramethylguanidine Chemical compound CN(C)C(=N)N(C)C KYVBNYUBXIEUFW-UHFFFAOYSA-N 0.000 description 2
- KXTAOXNYQGASTA-UHFFFAOYSA-N 2-benzylidenepropanedioic acid Chemical compound OC(=O)C(C(O)=O)=CC1=CC=CC=C1 KXTAOXNYQGASTA-UHFFFAOYSA-N 0.000 description 2
- KJEYEDTXTAUVBL-UHFFFAOYSA-N 4-(3,4-dimethoxyphenyl)-2-oxopyrrolidine-1-carboxamide Chemical compound C1=C(OC)C(OC)=CC=C1C1CC(=O)N(C(N)=O)C1 KJEYEDTXTAUVBL-UHFFFAOYSA-N 0.000 description 2
- VUGWJDGEPZNBKZ-UHFFFAOYSA-N 4-methoxy-3-(2-methylpropoxy)benzaldehyde Chemical compound COC1=CC=C(C=O)C=C1OCC(C)C VUGWJDGEPZNBKZ-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- IVOMOUWHDPKRLL-KQYNXXCUSA-N Cyclic adenosine monophosphate Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=CN=C2N)=C2N=C1 IVOMOUWHDPKRLL-KQYNXXCUSA-N 0.000 description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 2
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 2
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- 239000007868 Raney catalyst Substances 0.000 description 2
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 2
- 229910000564 Raney nickel Inorganic materials 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- YKIOKAURTKXMSB-UHFFFAOYSA-N adams's catalyst Chemical compound O=[Pt]=O YKIOKAURTKXMSB-UHFFFAOYSA-N 0.000 description 2
- 230000029936 alkylation Effects 0.000 description 2
- 238000005804 alkylation reaction Methods 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 150000001768 cations Chemical class 0.000 description 2
- ZPEIMTDSQAKGNT-UHFFFAOYSA-N chlorpromazine Chemical compound C1=C(Cl)C=C2N(CCCN(C)C)C3=CC=CC=C3SC2=C1 ZPEIMTDSQAKGNT-UHFFFAOYSA-N 0.000 description 2
- 229960001076 chlorpromazine Drugs 0.000 description 2
- VUWPIBNKJSEYIN-UHFFFAOYSA-N diethyl 2-benzylidenepropanedioate Chemical compound CCOC(=O)C(C(=O)OCC)=CC1=CC=CC=C1 VUWPIBNKJSEYIN-UHFFFAOYSA-N 0.000 description 2
- USIUVYZYUHIAEV-UHFFFAOYSA-N diphenyl ether Chemical compound C=1C=CC=CC=1OC1=CC=CC=C1 USIUVYZYUHIAEV-UHFFFAOYSA-N 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 229960003692 gamma aminobutyric acid Drugs 0.000 description 2
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 2
- 150000004820 halides Chemical class 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 239000012442 inert solvent Substances 0.000 description 2
- 238000002329 infrared spectrum Methods 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- JVTZFYYHCGSXJV-UHFFFAOYSA-N isovanillin Chemical compound COC1=CC=C(C=O)C=C1O JVTZFYYHCGSXJV-UHFFFAOYSA-N 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 229940043265 methyl isobutyl ketone Drugs 0.000 description 2
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 2
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
- HLVFKOKELQSXIQ-UHFFFAOYSA-N 1-bromo-2-methylpropane Chemical compound CC(C)CBr HLVFKOKELQSXIQ-UHFFFAOYSA-N 0.000 description 1
- JMVIVASFFKKFQK-UHFFFAOYSA-N 1-phenylpyrrolidin-2-one Chemical class O=C1CCCN1C1=CC=CC=C1 JMVIVASFFKKFQK-UHFFFAOYSA-N 0.000 description 1
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 1
- 125000003762 3,4-dimethoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 description 1
- GMPNSKPTQXVWAF-UHFFFAOYSA-N 3-cyano-3-phenylpropanoic acid Chemical compound OC(=O)CC(C#N)C1=CC=CC=C1 GMPNSKPTQXVWAF-UHFFFAOYSA-N 0.000 description 1
- CAZFGBJTGWIPGG-UHFFFAOYSA-N 4-(3,4-dimethoxyphenyl)-n-methyl-2-oxopyrrolidine-1-carboxamide Chemical compound C1C(=O)N(C(=O)NC)CC1C1=CC=C(OC)C(OC)=C1 CAZFGBJTGWIPGG-UHFFFAOYSA-N 0.000 description 1
- OVRPDYOZYMCTAK-UHFFFAOYSA-N 4-(4-chlorophenyl)pyrrolidin-2-one Chemical compound C1=CC(Cl)=CC=C1C1CC(=O)NC1 OVRPDYOZYMCTAK-UHFFFAOYSA-N 0.000 description 1
- YDVYLFOSWUPISL-UHFFFAOYSA-N 4-(4-methoxyphenyl)pyrrolidin-2-one Chemical class C1=CC(OC)=CC=C1C1CC(=O)NC1 YDVYLFOSWUPISL-UHFFFAOYSA-N 0.000 description 1
- AGQGSLHQIUKIEO-UHFFFAOYSA-N 4-[4-methoxy-3-(2-methylpropoxy)phenyl]pyrrolidin-2-one Chemical compound C1=C(OCC(C)C)C(OC)=CC=C1C1CC(=O)NC1 AGQGSLHQIUKIEO-UHFFFAOYSA-N 0.000 description 1
- BMTAFVWTTFSTOG-UHFFFAOYSA-N Butylate Chemical compound CCSC(=O)N(CC(C)C)CC(C)C BMTAFVWTTFSTOG-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- IYXGSMUGOJNHAZ-UHFFFAOYSA-N Ethyl malonate Chemical compound CCOC(=O)CC(=O)OCC IYXGSMUGOJNHAZ-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 238000010934 O-alkylation reaction Methods 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 238000001720 action spectrum Methods 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229940095564 anhydrous calcium sulfate Drugs 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 230000001773 anti-convulsant effect Effects 0.000 description 1
- 230000003502 anti-nociceptive effect Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 150000007860 aryl ester derivatives Chemical class 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 1
- 229940073608 benzyl chloride Drugs 0.000 description 1
- 230000000035 biogenic effect Effects 0.000 description 1
- 150000001649 bromium compounds Chemical class 0.000 description 1
- 150000004657 carbamic acid derivatives Chemical class 0.000 description 1
- 125000002915 carbonyl group Chemical class [*:2]C([*:1])=O 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 210000001638 cerebellum Anatomy 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- WRJWRGBVPUUDLA-UHFFFAOYSA-N chlorosulfonyl isocyanate Chemical compound ClS(=O)(=O)N=C=O WRJWRGBVPUUDLA-UHFFFAOYSA-N 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 238000006114 decarboxylation reaction Methods 0.000 description 1
- 230000003001 depressive effect Effects 0.000 description 1
- VQKSJEVJSPWVIE-UHFFFAOYSA-N diethyl 2-(2-nitro-1-phenylethyl)propanedioate Chemical compound CCOC(=O)C(C(=O)OCC)C(C[N+]([O-])=O)C1=CC=CC=C1 VQKSJEVJSPWVIE-UHFFFAOYSA-N 0.000 description 1
- UXGNZZKBCMGWAZ-UHFFFAOYSA-N dimethylformamide dmf Chemical compound CN(C)C=O.CN(C)C=O UXGNZZKBCMGWAZ-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- HJKJXWMIISKYGB-UHFFFAOYSA-N ethyl 3-cyano-3-phenylpropanoate Chemical compound CCOC(=O)CC(C#N)C1=CC=CC=C1 HJKJXWMIISKYGB-UHFFFAOYSA-N 0.000 description 1
- DOAKZQUNXQKUPM-UHFFFAOYSA-N ethyl 4-(3,4-dimethoxyphenyl)-2-oxopyrrolidine-1-carboxylate Chemical compound C(C)OC(=O)N1C(CC(C1)C1=CC(=C(C=C1)OC)OC)=O DOAKZQUNXQKUPM-UHFFFAOYSA-N 0.000 description 1
- 238000004817 gas chromatography Methods 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 150000002440 hydroxy compounds Chemical class 0.000 description 1
- 125000001841 imino group Chemical group [H]N=* 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 150000004694 iodide salts Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 1
- CIXSDMKDSYXUMJ-UHFFFAOYSA-N n,n-diethylcyclohexanamine Chemical compound CCN(CC)C1CCCCC1 CIXSDMKDSYXUMJ-UHFFFAOYSA-N 0.000 description 1
- IOMFXMPKQPMLND-UHFFFAOYSA-N n-benzyl-4-(3,4-dimethoxyphenyl)-n-methyl-2-oxopyrrolidine-1-carboxamide Chemical compound C1=C(OC)C(OC)=CC=C1C1CC(=O)N(C(=O)N(C)CC=2C=CC=CC=2)C1 IOMFXMPKQPMLND-UHFFFAOYSA-N 0.000 description 1
- 230000003533 narcotic effect Effects 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229910003446 platinum oxide Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000011514 reflex Effects 0.000 description 1
- 238000012958 reprocessing Methods 0.000 description 1
- 238000007127 saponification reaction Methods 0.000 description 1
- 239000000932 sedative agent Substances 0.000 description 1
- 230000001624 sedative effect Effects 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 125000005346 substituted cycloalkyl group Chemical group 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 125000005270 trialkylamine group Chemical group 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 238000002211 ultraviolet spectrum Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
- 239000008096 xylene Substances 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
- C07D207/18—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 one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—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 one double bond between ring members or between a ring member and a non-ring member 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
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
-
- 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
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
- C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
- C07C45/70—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form
- C07C45/71—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form being hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C47/00—Compounds having —CHO groups
- C07C47/52—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings
- C07C47/575—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings containing ether groups, groups, groups, or groups
-
- 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
- C07D207/18—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 one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—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 one double bond between ring members or between a ring member and a non-ring member 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
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/273—2-Pyrrolidones 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 other ring carbon atoms
- C07D207/277—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
- C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
- C07D317/60—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
- C07D319/14—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems
- C07D319/16—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D319/18—Ethylenedioxybenzenes, not substituted on the hetero ring
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Neurology (AREA)
- General Chemical & Material Sciences (AREA)
- Biomedical Technology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Psychiatry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Neurosurgery (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Hydrogenated Pyridines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyrrole Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
X
DK 157919B
Den foreliggende opfindelse angår en analogifremsgangsmSde til fremstilling af hidtil ukendte racemiske eller optisk aktive
2-pyrrolidonderivater med den almene formel I
- OR1 "Ah 1° .
CO
E5 hvor Ri er Cj-Cs-alkyl eller en eventuelt med Cj_4-alkyl sub-15 stitueret C3_7-cykloalkylgruppe, R5 er O-alkyl, 0-phe-nyl, 0-benzyl, NH2-, NH-alkyl{_4), NH-phenyl, NH-benzyl, benzyl / N , N(alkyl(Cj_4)>2 eller N(phenyl)2 \ 20 alkyl(C1_4), I DK patent nr. 139.965 er beskrevet racemiske og optisk aktive 4-(4-methoxy-phenyl)-2-pyrrolidoner med den almene formel
25 OR
'Ah 30 Nr ^0
H
hvor R er alkyl med indtil 5 C-atomer, en eventuelt med C1-C4-alkyl substitueret cykloalkylgruppe med 3-7 C-atomer eller 3-35 tetrahydrofurylgruppen samt en fremgangsmåde til deres frem stilling. Disse forbindelser har værdifuld neuropsykotrop virkning.
2
DK 157919 B
Det har nu vist sig, at 2-pyrrolidonder ivaterne med formlen I med samme farmakologiske virkningsspektrum udviser en udpræget protraheret virkning.
5 Analogifremgangsmåden ifølge opfindelsen til fremstilling af
forbindelserne med den almene formel I er ejendommelig ved, at man acylerer 2-pyrrolidonderivater med den almene formel II
OR1 10 CH,0
Tyk-.
kNA0
H
15 hvor Ri har den ovennævnte betydning, med et acylhalogenid HalCO-R5, hvor R5 har den ovennævnte betydning og Hal betyder halogen, hvorpå man, såfremt R5 i den således fremstillede 20 forbindelse med den almene formel I betyder NH-alkyl(C1-C4), eventuelt aralkylerer til dannelse af en forbindelse med den almene formel I, hvori R*> betyder benzyl /
25 M
\ alkyl {(^.4), og hvis der opstår racemater af optisk aktive forbindelser, eventuelt underkaster disse en racematspaltning.
30
Forbindelserne med den almene formel I har et asymmetrisk car-bonatom og kan derfor eksistere både som racemater og som optiske antipoder.
35 Hvis Ri i forbindelserne med den almene formel I er cykloal-kyl med 3-7 carbonatomer, foretrækkes cyklopropyl-, cyklopen-tyl- og cyklohexylgruppen.
3
DK 157919B
De racemiske og optisk aktive forbindelser med den almene formel I er værdifulde neuropsykotrope lægemidler. De hidtil ukendte forbindelser udviser centraldepressive, apomorfinan-tagonistiske og antinociceptive virkninger og udviser derfor 5 en vis lighed med chlorpromazin (litteratur: Modern Problems of Pharmacopsychiatry, bind 5, side 33-44; P.A.Y. Janssen, "Chemical and Pharmalogical Classification og Neuroleptics", redigeret af D.P. Bobon m.fl., S. Karger Verlag, Basel, Mun-chen, Paris, New York (1970)). På den anden side adskiller 10 forbindelserne fremstillet ifølge opfindelsen sig fra chlorpromazin ved mindre udpræget refleksbeskadigelse, mindre udpræget sederende og narkotiske egenskaber og en anden påvirkning af de biogene aminer.
15 Forbindelserne fremstillet ifølge opfindelsen udmærker sig ved en hurtig indtræden af virkningen og en ringe akut toksicitet.
Især udmærker forbindelserne fremstillet ifølge opfindelsen, der er substitueret ved ringnitrogenet med en 0- eller N-sub-20 stitueret carbonylgruppe, sig ved en udpræget protraheret virkning.
De gunstige egenskaber af de hidtil ukendte forbindelser med formlen I kunne ikke forventes, da det ved forsøg har vist 25 sig, at de tilsvarende p- eller m-monosubstituerede phenyl-2-pyrrolidoner har et andet virkningsspektrum eller kun en ringe virkning.
Den i japansk patent nr. 70 16 692 beskrevne 4-(4-chlorphe-30 nyl)-2-pyrrolidon har f.eks. antikonvulsiv virkning. De usub-stituerede phenyl-2-pyrrolidoner er kun svagt virksomme.
Udgangsforbindelserne til fremgangsmåden ifølge opfindelsen kan fremstilles ved, at man på i og for sig kendt måde
a) forsæber og decarboxylerer tilsvarende 4-(substitueret phenyl )-2-pyrrolidon-3-carbonsyrealkylestere med den almene formel III
35 4
DK 157919 B
1* ΟΈΓ
COOR* (HD
H
10 hvor R1' betyder enten R1 eller hydrogen, og R' er en fortrinsvis lavere alkylgruppe, eller
b) under, alkoholfraspaltning cykliserer 3-(substitueret phe-15 nyl)-4-aminosmørsyrealkylestere med den almene formel IV
ORl' CH30.
20 |C3T {IV) CH-CH2-C00R' ch2-nh2 25 hvor Ri* og R' har den ovennævnte betydning, eTler et syreadditionssalt deraf, eller
c) under vandfraspaltning cykliserer 3-(substitueret phenyl)-30 4-aminosmørsyre med den almene formel V
35
. DK 157919B
5 orI' ch3°Vn/A\ lOl
^\CH-CH2-COOH
ch2-nh2 10 hvor Ri' har den ovennævnte betydning, eller et syreadditionssalt deraf,
Forsæbningen ifølge fremgangsmåde a) udføres med vandig alkali hensigtsmæssigt i et med vand blandbart opløsningsmiddel, 15 f.eks. i en alkohol såsom ethanol, i tetrahydrofuran eller dioxan ved temperaturer mellem ca. 60 og 150*C, fortrinsvis ved kogetemperatur. Decarboxyleringen ifølge a) sker ved opvarmning af carbonsyren til ca. 160 til 280*C. Fortrinsvis opvarmes stoffet i vakuum. Man kan eventuelt også foretage 20 C02-fraspaltningen i nærværelse af et højtkogende, indifferent opløsningsmiddel, f.eks. i diphenylether eller quinolin.
Cykliseringen ifølge fremgangsmåde b) foretages under alkohol-fraspaltning i et organisk opløsningsmiddel som f.eks. dimeth-25 ylformamid, dimethylacetamid, tetrahydrofuran, dioxan, benzen, toluen, xylen, osv. under opvarmning til ca. 50 til 150eC. Hvis man går ud fra et salt, f.eks. hydrochloridet, af amino-syreesteren med den almene formel III, opvarmes i nærværelse af en tertiær base. Som tertiære baser egner sig trialkylami-30 ner, f.eks. triethylamin og tributylamin, men f.eks. også N-methylmorpholin, diethylcyklohexylamin, pyridin, osv.
Ifølge fremgangsmåde c) foretages cykliseringen under vandfra-spaltning ved temperaturer mellem ca. 160 og 280eC. Det er 35 gunstigt at arbejde i vakuum, således at det fraspaltede vand lettere kan fjernes og tilgang af luftens oxygen er forhindret. Hvis man går ud fra de tilsvarende syreadditionssalte, opvarmes som under b) i nærvrelse af en tertiær base.
DK 157919B
6
De ifølge a), b) eller c) fremstillede forbindelser, hvori Ri' betyder et hydrogenatom, må bagefter omdannes til udgangsforbindelserne med den almene formel II ved O-alkylering. Alky-leringen udføres fortrinsvis med det tilsvarende Rl-halogenid 5 eller -tosylat på i og for sig kendt måde. Som halogenider egner sig chloriderne, bromiderne og jodiderne. Med henblik på alkylering opløses hydroxyforbindelsen f.eks. i et polært opløsningsmiddel og opvarmes i nærværelse af en base med alky-leringsmidlet til temperaturer mellem 30 og 150°C. Som baser 10 egner sig f.eks. natriumhydrid, kaliumcarbonat, alkalialkoho-later, såsom natriumethylat, kaliumbutylat og kalium-tert.-bu-tylat. Som..polære opløsningsmidler kan der være tale om di-methylformamid, dimethylacetamid, tetrahydrofuran, dioxan, ketoner såsom acetone og methylisobutylketon, samt alkoholer 15 såsom ethanol, butanol og tert.-butanol.
Acylering af iminogruppen ved fremgangsmåden ifølge opfindelsen sker ligeledes på kendte måder. F.eks. opløses iminofor-bindelsen i et polært opløsningsmiddel og opvarmes i nærværel-20 se af en saltdanner med et acylhalogenid til ca. 40-150*C. Som polære opløsningsmidler kan der anvendes dimethylformamid, dimethylacetamid, tetrahydrofuran, dioxan, ketoner såsom acetone og methylisobutylketon, samt alkoholer såsom ethanol og butanol. Egnede saltdannere er f.eks. natriumhydrid, kaliumcarbo-25 nat, alkalialkoholater såsom natriumethylat, kalium-tert.-bu-tylat osv.
Ved omsætningen med en halogenkulsyreester, f.eks. chlorkulsy-realkyl- eller arylester, kan man undvære opløsningsmidlet og 30 lade reaktionen forløbe i længere tid ved forhøjet temperatur i nærværelse af et alkalicarbonat såsom natriumcarbonat.
Hvis man omsætter iminoforbindelsen med et isocyanat til car-baminsyrederivater, kan der anvendes indifferente opløsnings-35 midler, såsom halogenerede kulbrinter, f.eks. methylenchlorid eller chloroform.
Udgangsforbindelserne med formlerne III, IV og V kan ligeledes fremstilles på kendte måder, f.eks. på følgende måde.
DK 157919 B
7
Idet der gås ud fra det med. R1' substituerede benzaldehyd fremstilles med malonsyredialkylester den tilsvarende benzal-malonsyredialkylester. Den substituerede benzalmalonsyredial-kylester kan omdannes til 4-(substitueret phenyl)-2-pyrroli-5 don-3-carbonsyrealkylester med den almene formel III med ni-tromethan i nærværelse af tetramethylguanidin via l-(substitu-eret phenyl)-2-nitroethylmalonsyredialkylester og påfølgende trykhydrogenering under anvendelse af Raney-nikkel.
10 Til fremstilling af 3-(substitueret phenyl)-4-aminosmørsyreal-kylester med den almene formel IV tillejres der HCN til dobbeltbindingen i benzalmalonsyrediesteren med kaliumcyanid i vandig alkohol under opvarmning til 60°C under samtidig fra-spaltning af en carbalkoxygruppe, og cyanoforbindelsen hydro-15 generes under tryk i nærværelse af platindioxid. Hvis HCN til-lejringen udføres ved kogevarme, opstår den tilsvarende smørsyre med den almene formel V.
Omsætningerne af substitueret benzaldehyd til forbindelserne 2o ni, IV og V belyses af følgende reaktionsskema: OH-jI j®l CB3° CB3° \/\ f JI , * TO] /C00E1 ^όοοη' 30 35 8
DK 157919 B
^ HCN
5 φΊ/ i .
ογ. · CH3° \ JL CH3° ( ) >COOH' KJ! , ^Vi^CH-CH^ s^Y\cH-CH2C00a' 15 ^ 20 I ψ ivB» All$rl
III
V R1 = H 25 I det følgende beskrives fremgangsmåden nærmere.
Ved sædvanlig oparbejdning forstås ekstraktion med det anførte 30 opløsningsmiddel, vask af den organiske fase med mættet kogsaltopløsning, tørring over vandfri calciumsulfat og inddamp-ning i vakuum ved en badtemperatur på 40-45°C. Yderligere behandling af den organiske fase, såsom vask med syre eller lud, omtales specielt.
De angivne udbytter er ikke optimale værdier. Der er ikke foretaget nogen optimeringsforsøg.
35
DK 157919B
9
Temperaturerne angives i alle tilfalde i °C.
De som råprodukt nævnte stoffer blev undersøgt for tilstrækkelig renhed ved tyndtlagskromatografi i mindst to systemer og 5 ved hjælp af IR-spektre. Alle andre stoffer er analyserene (C-, H-, N-bestemmelser, IR-, UV- og NMR-spektre, tyndlagskromatografi, til dels titreringer og gaskromatografi).
Efter det på Koflerbænk bestemte smeltepunkt er anført i pa-10 rentes det til omkrystallisationen benyttede opløsningsmiddel.
For opløsningsmidler anvendes følgende forkortelser: DMF dimethylformamid EE eddikesyreethylester 15 DIP diisopropylether ACOH iseddike
Forbindelserne med den almene formel III kan f.eks. fremstilles som følger: 20 A) Benzalmalonsvrediethvlester 1 mol af det substituerede benzaldehyd opvarmes med vandud-skiller med 160 g malonsyrediethylester (1 mol), 30 ml ised-25 dike og 3 ml piperidin i 1 liter benzen, indtil der er fraspaltet 1 mol vand. Den benzeniske opløsning oparbejdes på sædvanlig måde.
Det i litteraturen endnu ikke beskrevne 3-isobutoxy-4-methoxy-30 benzaldehyd fremstilles som følger: 108 g 3-hydroxy-4-methoxybenzaldehyd (710 mmol) opvarmes til kogning med 40,5 g kaliumhydroxid (723 mmol) og 120 g isobut-ylbromid (875 mmol) i 250 ml ethanol under omrøring i 26 ti-35 mer. Efter afdestillering af alkoholen i vakuum oparbejdes remanensen på sædvanlig måde med EE, men vaskes desuden med 2n natronlud. Af den alkaliske ekstrakt genvindes 35 g udgangsmateriale ved syrning. Udbyttet af 3-isobutoxy-4-methoxybenzal-dehyd er 80 g. Smp. 70eC (heptan).
10
DK 157919 B
I følgende tabel er anført udbytterne og koge- eller smeltepunkterne af nogle forbindelser.
OR1' 5 \_ COOC2H5
A) CH30-(0VCH=CX
N J C00C2H5 20 Udbytte Kogepunkt, smelte- (% af punkt (omkrystalli- _r! '__teoretisk!__sationsmiddel 1_ a -CH3 70 K0,6 185-189° d -CH2CH{CH3)2 95 K0,1 190-192° 15 e -H 78 Kj 213-215°
Smp. 86° (DIP) B) l-(substitueret phenvl)-2-nitroethvlmalonsvrediethvlester 20 500 mmol af den tilsvarende benzalmalonsyrediethylester (se A) opløses i 250 ml nitromethan, og under omrøring ved 0°C tilsættes 12,7 ml tetramethylguanidin. Efter hendøen af den ekso-terme reaktion lader man omrøre ved stuetemperatur i endnu 18 25 timer. Reaktionsblandingen oparbejdes på sædvanlig måde med EE, den vaskes desuden med 2n saltsyre.
30 35 11
DK 157919B
ORl‘ \ cooc2h5
B) CH3O · ^ (3/—CH-CH
5 I C00C2H5 CH2 ( no2
Udbytte Kogepunkt, smelte- {% af punkt (omkrystalli- __rIJ__teoretisk)__sationsmiddel)_ a “CH3 59 75° (methylen- chlorid-DIP) 15 C) 4-(substitueret phenyl)-2-pyrrol i don-3-carbonsvreethylester (III) 300 mmol af den tilsvarende 1-phenyl-2-nitro-ethyl-malonsyre-diethylester opløses i 700 ml methanol og hydrogeneres med ca.
2 0 10 g Raney-nikkel ved 60eC og 95 atmosfæres tryk indtil optagelse af 3 mol hydrogen. Derefter filtreres fra katalysatoren, inddampes i vakuum, og den olieagtige remanens krystalliseres.
25 30 35
Olt
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12
1 T
. /^coocæ c) CH3°—(Cj)—-S 2 5
5 I
Π
Udbytte Kogepunkt, smelte- (% af punkt (omkrystalli- __Ri'__teoretisk)__sationsmiddel)_ 10 a -CH3 84 106° (EE) b -H 70 125° (EE-DIP) (fraspaltning af acetylgruppen ved hydrering og oparbejdning) 15
Forbindelserne med den almene formel III kan f.eks. fremstilles på følgende måde: D) 3-(substitueret phenyl)-3-cyano-propionsyreethvlester
Til 100 mmol af en tilsvarende benzalmalonester (se A) sættes i 180 ml ethanol en opløsning af 6,3 g kaliumcyanid (100 mmol) i 25 ml vand, og der opvarmes i 7 timer til 60eC. Efter 18 ti-25 mers henstand ved stuetemperatur aftrækkes opløsningsmidlet i vakuum, og remanensen oparbejdes på sædvanlig måde med EE, herunder ekstraktion med ln natronlud. Af natronludekstrakten kan eventuelt ved syrning fås den tilsvarende 3-phenyl-3-cya-nopropionsyre.
30 35
DK 157919 B
13
ORl* S
D) CH30 CH-CH2-COOC2H5
CN
5
Udbytte Kogepunkt, smelte- (¾ af punkt (omkrystalli- __Rl_!__teoretisk)__sationsmiddel)_ a -CH3 85 K0/i 177-182° 10 d -CH2CH(CH3)2 83 Råprodukt (DC,IR) E) 3-(substitueret phenyl)-4-amino-smørsvreethvlesterhvdro-chlorid (III) 15 50 mmol af en 3-phenyl-3-cyanopropionsyreethylester hydrogeneres i 60 ml iseddike over 1 g platinoxid ved stuetemperatur og 100 atmosfærer indtil optagelse af 2 mol hydrogen, der frasu-ges fra katalysatoren, og efter tilsætning af 25 ml 2n metha-2Q nolisk saltsyre inddampes i vakuum til et lille rumfang.
ORl' E) CH30 ——-CH-CH2-COOC2H5 25 CH2-NH2.HC1
Udbytte Kogepunkt, smelte- (% af punkt (omkrystalli- __RlJ_;__teoretisk)__sat i onsmiddel)_ 3Q a -CH3 90 Smp. 185° (AC0H) d -CH2CH(CH3)2 63 Smp. 124° (EE)
Forbindelserne med den almene formel IV kan fremstilles som 35 følger: 14
DK 157919 B
F) 3-(substitueret phenvl)-3-cvanopropionsvre
Ved omsætning af en tilsvarende substitueret benzalmolonester (se under A) med kaliumcyanid i samme mængdeforhold og samme 5 reaktionstider som beskrevet under D, men i kogevarme, fås 3-(substitueret phenyl)-3-cyanopropionsyrer. De isoleres efter afdampning af opløsningsmidlet, optagning af remanensen i vand, vask med EE og syrning af den vandige fase og renses ved krystal 1 isation.
10 ORl'
F) CH30 -\C)/— CH-CHZ-C00H
'-' CN
15
Udbytte Kogepunkt, smelte- (% af punkt (omkrystalli- ____teoretisk)__sationsmiddel)_ a -CH3 54 Smp. 133-135 (ethanol) 20 ---- G) 3-(substitueret phenvl)-4-amino-smørsvrehvdrochlorid (IV) 100 mmol 3-(substitueret phenyl)-3-cyanopropionsyre (se F) hy-25 drogeneres i 200 ml iseddike under tilsætning af 9,5 ml koncentreret saltsyre over 3 g platindioxid ved stuetemperatur og 100 atmosfærer indtil optagelse af 2 mol hydrogen. Der filtreres fra katalysatoren og inddampes i vakuum. Ved krystallisation af den for det meste olieagtige remanens fås 3-(substitu-30 eret phenyl)-4-amino-smørsyrehydrochlorider.
35
DK 157919B
IS i»
R O
C
g) ch3o-\Cy)— ch~ch2-cooh ch2-nh2.hci 5
Udbytte Kogepunkt, smelte- {% af punkt (omkrystalli- __R*_]__teoretisk)__sationsmiddel)_ a -CH3 50 Snip. 220* (Z.) (ACOH) 10 -----— Følgende eksempler illustrerer fremgangsmåden ifølge opfindelsen .
15 Eksempel 1 2,21 g 4-(3,4-dimethoxyphenyl)-2-pyrrolidon (10 mmol) omrøres med 1 g vandfrit natriumcarbonat og 30 ml chlorkulsyreethyles-ter i 16 timer ved 100°C, og derefter filtreres og inddampes i 20 vakuum. Man får 1,09 g 4-(3,4-dimethoxypheny1)-2-pyrrolidon-1-carbonsyreethylester, smp. 88-90°C. (EE/petroleumsether).
Eksempel 2 25 2,21 g 4-(3,4-dimethoxyphenyl)-2-pyrrolidon omsættes analogt med eksempel 1 med chlorkulsyrebenzylester og renses ved kromatografi på kiselgel med benzen/EE (1:1). Man får 1,24 g 4-(3,4-dimethoxyphenyl)-2-pyrroli don-1-carbonsyrebenzylester, smp. B6-87°C (EE/petroleumsether).
30
Analogt fremstilles 4-(3-isobutyloxy-4-methoxyphenyl)-2-pyrro-1idon-l-carbonsyrebenzylester af 4-(3-isobutyloxy-4-methoxy-phenyl)-2-pyrrolidon (smp. 76-78°C af EE/petroleumsether).
35 DK 157919 Β 16 ί
Eksempel 3
Til 0,221 g 4-(3,4-dimethoxyphenyl)-2-pyrrolidon i 10 ml me-thylenchlorid sættes 3 ml chlorsulfonylisocyanat, og der omrø-5 res i 1 1/2 time ved stuetemperatur. Materialet oparbejdes på sædvanlig måde med methylenchlorid og renses ved søjlekromatografi på kiselgel med chloroforra/acetone (1:1). Man får 0,026 g 4-{3,4-dimethoxyphenyl)-2-pyrrolidon-l-carbonsyreamid, smp.
125-127°C (methanol).
10
Eksempel 4 4-(3,4-dimethoxvphenvl)-2-pvrrolidon-l-carbonsvreamid 15 2,21 g 4-(3,4-dimethoxyphenyl)-2-pyrrolidon opvarmes til kogning i 2 1/2 time med et isocyanat med den almene formel RM-NC0 i overskud (ca. tidobbelt mængde) og derefter inddampes i vakuum.
20 Afhængende af det anvendte isocyanat fås følgende 1-carbonsy-reamider:
Smeltepunkt R” Udbytte (omkrvsta11 i sat i onsmiddel 1 25 -CH3 1,47 g 95-98° (EE-DIP) CH3 / 30 -CH 1,53 g 105-107° (EE-petroleumsether) \ CH3 —υ \ 2,62 g 110-112° (EE-petroleumsether) 35 \=/
DK 157919B
17
Eksempel 5
Til 2,78 g 4-(3,4-dimethoxypheny 1)-2-pyrrolidon-l-carbonsyre-methylamid (10 mmol) i 20 ml dimethyl formamid sættes ved 0*C 5 under omrøring 0,5 g 50% natriumhydrid. Efter endt hydrogenudvikling tildryppes 1,27 g benzylchlorid, og der omrøres i 16 timer ved stuetemperatur. Man afdamper opløsningsmidlet i vakuum og oparbejder på sædvanlig måde med EE. Man får 1,58 g 4-(3,4-dimethoxyphenyl)-2-pyrrolidon-l-carbonsyre-N-benzyl -10 methylamid, smp. 76-78°C (EE-DIP).
Virkningen af de ifølge opfindelsen fremstillede forbindelser blev undersøgt og sammenlignet med de kendte forbindelser ved måling af phosphordiesterase-hæmningen (PDE) på følgende måde: 15
Hjernen uden cerebellum fra Wistar-rotter med en vægt på 180-220 g blev samlet og i forholdet 1:100 homogeniseret i trisstødpude (20 mM tris-HCl, 2 mM MgCl2, pH 7,5). Homogenatet blev centrifugeret i 30 min. ved 50.000 g. Den ovenstående 20 væske tjener som råt phosphordiesterase - enzympræparat. Lige store dele af hjerneekstrakten inkuberes i 5 min. ved 30°C i nærværelse af prøvestofferne i en koncentration på 62,5-250 μ mol og af radioaktivt mærket cyklisk adenosinmonophosphat (cAMP) i 3 parallelforsøg. Efter standsning af inkubationen 25 ved opvarmning til 100°C fraskilles reaktionsproduktet 5ΆΜΡ, og den procentiske hæmning af phosphordiesterase måles.
I tabellen er indeholdt resultaterne for den kendte forbindelse, hvor R^CHø og for forbindelserne fremstillet ifølge dansk 30 patent nr. 139.965,
Me hvor Ri = -CH2-CH og —^ , og R* = H, samt for forbin- 35 Me delser fremstillet ifølge opfindelsen. Det fremgår heraf, at forbindelserne fremstillet ifølge opfindelsen er de kendte forbindelser overlegne.
Claims (2)
15 H 14 10 <10 25 10 23 10 <10 COCH3 10 S c02Et 37 21 Γ5 C02Bz 40 30 30 35 CONHCH3 27 13 <10 ✓ Me 2Q C0NH-CH^ 55 40 30 25 45 Me C0NH-C6H5 30 20 20 20 Gennemsnit af forbindelserne fremsti 1 let ifølge opfindelsen 39,7 28,8 20 25 33,3 25 ____ De mere højmolekulære substituenters indflydelse på de undersøgte forbindelsers opløselighed er så stor, at der ved koncentrationer større end 62,5 μ mol ikke kan opnås en fuldstæn-30 dig opløsning af prøvestoffet. Patentkrav. Analogifremsgangsmåde til fremstilling af hidtil ukendte race-miske eller optisk aktive 2-pyrrolidonderivater med den almene formel I 3 5 DK 157919 B "ti 5 sA, CO i R5 10 hvor R1 er Cj-Cs-alkyl eller en eventuelt med Ci-4-alkyl substitueret C3_7-cykloalkylgruppe, R5 er O-alkyl(Cj_4), 0-phe-nyl, 0-benzyl, NH2-, NH-alkyl(C1-4)f NH-phenyl, NH-benzyl, benzyl / N , N(alkyl(C1-4))2 eller N(phenyl)2 15 \ alkyl(C1-4) kendetegnet ved, at man acylerer 2-pyrrolidinderi-vater med den almene formel II 20 OR1 194-1
25 A « O S hvor Ri har den ovennævnte betydning, med et acylhalogenid 30 HalCO-R®, hvor R5 har den ovennævnte betydning og Hal betyder halogen, hvorpå man, såfremt R^ i den således fremstillede forbindelse med den almene formel I betyder NH-alkyl(-C4), eventuelt aralkylerer til dannelse af en forbindelse med den almene formel I, hvori R5 betyder 35 ^benzyl N , og hvis der opstår racemater af optisk aktive Nsalkyl(C1-4) DK 157919B forbindelser, eventuelt underkaster disse racematspaltning. 5 10 15 25 30 35
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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DE2541855 | 1975-09-18 | ||
DE19752541855 DE2541855A1 (de) | 1975-09-18 | 1975-09-18 | 4-(polyalkoxy-phenyl)-2-pyrrolidone ii |
Publications (3)
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DK408676A DK408676A (da) | 1977-03-19 |
DK157919B true DK157919B (da) | 1990-03-05 |
DK157919C DK157919C (da) | 1990-08-06 |
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DK408676A DK157919C (da) | 1975-09-18 | 1976-09-10 | Analogifremgangsmaade til fremstilling af hidtil ukendte racemiske eller optisk aktive 2-pyrrolidonderivater |
Country Status (18)
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US (1) | US4153713A (da) |
JP (1) | JPS5236659A (da) |
AT (1) | AT349459B (da) |
BE (1) | BE846335R (da) |
CA (1) | CA1077496A (da) |
CH (1) | CH623571A5 (da) |
CS (1) | CS225802B2 (da) |
DD (1) | DD126894A6 (da) |
DE (1) | DE2541855A1 (da) |
DK (1) | DK157919C (da) |
ES (1) | ES451518A2 (da) |
FR (1) | FR2324299A2 (da) |
GB (1) | GB1563398A (da) |
HU (1) | HU173117B (da) |
IE (1) | IE43723B1 (da) |
NL (1) | NL7610300A (da) |
SE (1) | SE407799B (da) |
SU (1) | SU795465A3 (da) |
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Publication number | Priority date | Publication date | Assignee | Title |
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IT1131959B (it) * | 1979-08-09 | 1986-06-25 | Hoffmann La Roche | Derivati pirrolidinici |
HU215433B (hu) * | 1986-04-29 | 2000-05-28 | Pfizer Inc. | Eljárás új 2-oxo-5-fenil-pirimidin-származékok előállítására |
US5459145A (en) * | 1988-01-19 | 1995-10-17 | Pfizer Inc. | Calcium independent camp phosphodiesterase inhibitor antidepressant |
YU162789A (en) * | 1988-09-01 | 1990-12-31 | Lonza Ag | 2-aza-4-(alcoxycarbonyl) spiro/4,5/decan-3-ones |
JP2578001B2 (ja) * | 1989-12-11 | 1997-02-05 | 明治製菓株式会社 | 抗痴呆薬 |
WO1992002220A1 (en) * | 1990-08-03 | 1992-02-20 | Smithkline Beecham Corporation | Tnf inhibitors |
DE4032055A1 (de) * | 1990-10-05 | 1992-04-09 | Schering Ag | Verfahren zur herstellung von optisch aktiven 4-aryl-2-pyrrolidinonen |
US5319099A (en) * | 1991-01-21 | 1994-06-07 | Shionogi Seiyaku Kabushiki Kaisha | 3-benzylidene-1-carbamoyl-2-pyrrolidone compounds useful as antiinflammatory agents |
US5514678A (en) * | 1992-03-26 | 1996-05-07 | E. I. Du Pont De Nemours And Company | Arthropodicidal 1,2,4-triazinyl amides |
US5547979A (en) * | 1992-03-30 | 1996-08-20 | Smithkline Beecham | TNF inhibition |
US5395935A (en) * | 1992-05-08 | 1995-03-07 | Pfizer Inc. | Endo-bicyclo[2.2.1]heptan-2-ol and derived pharmaceutical agents |
GB9212673D0 (en) * | 1992-06-15 | 1992-07-29 | Celltech Ltd | Chemical compounds |
GB9222253D0 (en) * | 1992-10-23 | 1992-12-09 | Celltech Ltd | Chemical compounds |
GB9226830D0 (en) * | 1992-12-23 | 1993-02-17 | Celltech Ltd | Chemical compounds |
US5622977A (en) * | 1992-12-23 | 1997-04-22 | Celltech Therapeutics Limited | Tri-substituted (aryl or heteroaryl) derivatives and pharmaceutical compositions containing the same |
GB9304919D0 (en) * | 1993-03-10 | 1993-04-28 | Celltech Ltd | Chemical compounds |
GB9304920D0 (en) * | 1993-03-10 | 1993-04-28 | Celltech Ltd | Chemical compounds |
US5665754A (en) * | 1993-09-20 | 1997-09-09 | Glaxo Wellcome Inc. | Substituted pyrrolidines |
GB9326173D0 (en) * | 1993-12-22 | 1994-02-23 | Celltech Ltd | Chemical compounds and process |
EP0738268B1 (en) * | 1993-12-22 | 2004-03-03 | Celltech R&D Limited | Trisubstituted phenyl derivatives, processes for their preparation and their use as phosphodiesterase (type iv) inhibitors |
US5672622A (en) * | 1994-04-21 | 1997-09-30 | Berlex Laboratories, Inc. | Treatment of multiple sclerosis |
US6060501A (en) * | 1994-06-02 | 2000-05-09 | Schering Aktiengesellschaft | Combined treatment of multiple sclerosis |
US6245774B1 (en) | 1994-06-21 | 2001-06-12 | Celltech Therapeutics Limited | Tri-substituted phenyl or pyridine derivatives |
US5786354A (en) * | 1994-06-21 | 1998-07-28 | Celltech Therapeutics, Limited | Tri-substituted phenyl derivatives and processes for their preparation |
GB9412571D0 (en) * | 1994-06-22 | 1994-08-10 | Celltech Ltd | Chemical compounds |
GB9412573D0 (en) * | 1994-06-22 | 1994-08-10 | Celltech Ltd | Chemical compounds |
GB9412672D0 (en) * | 1994-06-23 | 1994-08-10 | Celltech Ltd | Chemical compounds |
WO1996024350A1 (de) * | 1995-02-10 | 1996-08-15 | Schering Aktiengesellschaft | Pharmazeutische präparate zur tnf-inhibition |
DE19540475A1 (de) * | 1995-10-20 | 1997-04-24 | Schering Ag | Chirale Methylphenyloxazolidinone |
GB9523675D0 (en) | 1995-11-20 | 1996-01-24 | Celltech Therapeutics Ltd | Chemical compounds |
GB9526246D0 (en) * | 1995-12-21 | 1996-02-21 | Celltech Therapeutics Ltd | Chemical compounds |
GB9526245D0 (en) * | 1995-12-21 | 1996-02-21 | Celltech Therapeutics Ltd | Chemical compounds |
GB9526243D0 (en) * | 1995-12-21 | 1996-02-21 | Celltech Therapeutics Ltd | Chemical compounds |
GB9608435D0 (en) * | 1996-04-24 | 1996-06-26 | Celltech Therapeutics Ltd | Chemical compounds |
GB9619284D0 (en) * | 1996-09-16 | 1996-10-30 | Celltech Therapeutics Ltd | Chemical compounds |
GB9622363D0 (en) * | 1996-10-28 | 1997-01-08 | Celltech Therapeutics Ltd | Chemical compounds |
GB9625184D0 (en) * | 1996-12-04 | 1997-01-22 | Celltech Therapeutics Ltd | Chemical compounds |
AU5330698A (en) | 1996-12-23 | 1998-07-17 | Celltech Therapeutics Limited | Fused polycyclic 2-aminopyrimidine derivatives, their preparation and their use as protein tyrosine kinase inhibitors |
GB9705361D0 (en) | 1997-03-14 | 1997-04-30 | Celltech Therapeutics Ltd | Chemical compounds |
GB9713087D0 (en) * | 1997-06-20 | 1997-08-27 | Celltech Therapeutics Ltd | Chemical compounds |
GB9914258D0 (en) | 1999-06-18 | 1999-08-18 | Celltech Therapeutics Ltd | Chemical compounds |
GB9924862D0 (en) * | 1999-10-20 | 1999-12-22 | Celltech Therapeutics Ltd | Chemical compounds |
WO2002096888A1 (de) * | 2001-05-29 | 2002-12-05 | Schering Aktiengesellschaft | Cdk inhibitorische pyrimidine, deren herstellung und verwendung als arzneimittel |
Family Cites Families (9)
Publication number | Priority date | Publication date | Assignee | Title |
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CA709405A (en) * | 1965-05-11 | Parke, Davis And Company | Methods for producing pyrrolidine compounds | |
US2975193A (en) * | 1959-06-18 | 1961-03-14 | Parke Davis & Co | Organic amine compounds and method of obtaining the same |
FR1516776A (fr) * | 1966-07-21 | 1968-03-15 | Rhone Poulenc Sa | Nouveaux dérivés du pyrrole et leur préparation |
US3647790A (en) * | 1969-04-08 | 1972-03-07 | American Home Prod | Ouinoxalinyl-oxazolidines and -oxazines |
US3644398A (en) * | 1969-04-11 | 1972-02-22 | Robins Co Inc A H | 1-carbamoyl-3-phenylpyrrolidines |
US3956314A (en) * | 1970-07-24 | 1976-05-11 | U.C.B., Societe Anonyme | Derivatives of 2-pyrrolidinone |
GB1350582A (en) * | 1970-07-24 | 1974-04-18 | Ucb Sa | Cerivatives of 2-pyrrolidinone |
JPS5232064B2 (da) * | 1972-06-14 | 1977-08-19 | ||
DE2413935A1 (de) * | 1974-03-20 | 1975-10-16 | Schering Ag | 4-(polyalkoxy-phenyl)-2-pyrrolidone |
-
1975
- 1975-09-18 DE DE19752541855 patent/DE2541855A1/de not_active Withdrawn
-
1976
- 1976-07-05 CH CH857676A patent/CH623571A5/de not_active IP Right Cessation
- 1976-07-28 SU SU762385904A patent/SU795465A3/ru active
- 1976-09-10 DK DK408676A patent/DK157919C/da not_active IP Right Cessation
- 1976-09-14 ES ES451518A patent/ES451518A2/es not_active Expired
- 1976-09-15 IE IE2052/76A patent/IE43723B1/en unknown
- 1976-09-16 SE SE7610275A patent/SE407799B/xx not_active IP Right Cessation
- 1976-09-16 DD DD194827A patent/DD126894A6/xx not_active IP Right Cessation
- 1976-09-16 NL NL7610300A patent/NL7610300A/xx not_active Application Discontinuation
- 1976-09-17 CA CA261,454A patent/CA1077496A/en not_active Expired
- 1976-09-17 JP JP51111693A patent/JPS5236659A/ja active Granted
- 1976-09-17 HU HU76SC578A patent/HU173117B/hu unknown
- 1976-09-17 CS CS766054A patent/CS225802B2/cs unknown
- 1976-09-17 FR FR7627961A patent/FR2324299A2/fr active Granted
- 1976-09-17 BE BE170731A patent/BE846335R/xx not_active IP Right Cessation
- 1976-09-17 US US05/724,213 patent/US4153713A/en not_active Expired - Lifetime
- 1976-09-17 AT AT690776A patent/AT349459B/de not_active IP Right Cessation
- 1976-09-20 GB GB38887/76A patent/GB1563398A/en not_active Expired
Also Published As
Publication number | Publication date |
---|---|
SE407799B (sv) | 1979-04-23 |
SE7610275L (sv) | 1977-03-19 |
CA1077496A (en) | 1980-05-13 |
FR2324299A2 (fr) | 1977-04-15 |
ATA690776A (de) | 1978-09-15 |
NL7610300A (nl) | 1977-03-22 |
FR2324299B2 (da) | 1980-02-01 |
BE846335R (fr) | 1977-03-17 |
JPS612660B2 (da) | 1986-01-27 |
AT349459B (de) | 1979-04-10 |
GB1563398A (en) | 1980-03-26 |
CH623571A5 (da) | 1981-06-15 |
IE43723B1 (en) | 1981-05-06 |
IE43723L (en) | 1977-03-18 |
DK157919C (da) | 1990-08-06 |
ES451518A2 (es) | 1977-10-01 |
DK408676A (da) | 1977-03-19 |
US4153713A (en) | 1979-05-08 |
DD126894A6 (da) | 1977-08-17 |
DE2541855A1 (de) | 1977-03-31 |
CS225802B2 (en) | 1984-02-13 |
HU173117B (hu) | 1979-02-28 |
JPS5236659A (en) | 1977-03-22 |
SU795465A3 (ru) | 1981-01-07 |
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