NO121212B - - Google Patents
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- Publication number
- NO121212B NO121212B NO164109A NO16410966A NO121212B NO 121212 B NO121212 B NO 121212B NO 164109 A NO164109 A NO 164109A NO 16410966 A NO16410966 A NO 16410966A NO 121212 B NO121212 B NO 121212B
- Authority
- NO
- Norway
- Prior art keywords
- phenyl
- benzophenone
- propoxy
- hydroxy
- group
- Prior art date
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- -1 cyano, carboxy, nitro, amino Chemical group 0.000 claims description 95
- 150000001875 compounds Chemical class 0.000 claims description 56
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 23
- 239000002253 acid Substances 0.000 claims description 20
- NPFYZDNDJHZQKY-UHFFFAOYSA-N 4-Hydroxybenzophenone Chemical compound C1=CC(O)=CC=C1C(=O)C1=CC=CC=C1 NPFYZDNDJHZQKY-UHFFFAOYSA-N 0.000 claims description 16
- 229910052736 halogen Inorganic materials 0.000 claims description 15
- 150000002367 halogens Chemical group 0.000 claims description 13
- 150000003839 salts Chemical class 0.000 claims description 13
- LJRIZGQRKVWXSI-UHFFFAOYSA-N [4-(oxiran-2-ylmethoxy)phenyl]-phenylmethanone Chemical compound C=1C=C(OCC2OC2)C=CC=1C(=O)C1=CC=CC=C1 LJRIZGQRKVWXSI-UHFFFAOYSA-N 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 12
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 11
- OMPXTQYWYRWWPH-UHFFFAOYSA-N 4-phenyl-1,2,3,6-tetrahydropyridine Chemical compound C1NCCC(C=2C=CC=CC=2)=C1 OMPXTQYWYRWWPH-UHFFFAOYSA-N 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 9
- 125000005905 mesyloxy group Chemical group 0.000 claims description 7
- 125000005279 aryl sulfonyloxy group Chemical group 0.000 claims description 6
- 125000005424 tosyloxy group Chemical group S(=O)(=O)(C1=CC=C(C)C=C1)O* 0.000 claims description 6
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
- 230000003287 optical effect Effects 0.000 claims description 5
- WMNGQDWXSCKKEC-UHFFFAOYSA-N (4-fluorophenyl)-[4-(oxiran-2-ylmethoxy)phenyl]methanone Chemical compound O1C(COC2=CC=C(C(=O)C3=CC=C(C=C3)F)C=C2)C1 WMNGQDWXSCKKEC-UHFFFAOYSA-N 0.000 claims description 4
- JBGSIKDLUVVKOV-UHFFFAOYSA-N 1-(oxiran-2-ylmethyl)-4-phenyl-3,6-dihydro-2H-pyridine Chemical compound C1(=CC=CC=C1)C=1CCN(CC1)CC1CO1 JBGSIKDLUVVKOV-UHFFFAOYSA-N 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- 150000008378 aryl ethers Chemical class 0.000 claims description 3
- 125000003118 aryl group Chemical group 0.000 claims description 3
- 239000012965 benzophenone Substances 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 150000002923 oximes Chemical class 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 150000004677 hydrates Chemical class 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 125000003386 piperidinyl group Chemical group 0.000 claims description 2
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims 3
- 229960005141 piperazine Drugs 0.000 claims 3
- 125000001475 halogen functional group Chemical group 0.000 claims 2
- WDJKAQCAPHSOIO-UHFFFAOYSA-N 1-phenyl-3,6-dihydro-2h-pyridine Chemical compound C1C=CCCN1C1=CC=CC=C1 WDJKAQCAPHSOIO-UHFFFAOYSA-N 0.000 claims 1
- HLRVUOFDBXRZBI-UHFFFAOYSA-N 4-fluoro-4'-hydroxybenzophenone Chemical compound C1=CC(O)=CC=C1C(=O)C1=CC=C(F)C=C1 HLRVUOFDBXRZBI-UHFFFAOYSA-N 0.000 claims 1
- 125000003055 glycidyl group Chemical group C(C1CO1)* 0.000 claims 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 56
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 43
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 28
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 27
- 239000000243 solution Substances 0.000 description 24
- 239000000155 melt Substances 0.000 description 23
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 22
- 235000019441 ethanol Nutrition 0.000 description 20
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 17
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 16
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 15
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 13
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- 238000001953 recrystallisation Methods 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- KQIGOYIOGJKOIU-UHFFFAOYSA-N [4-[2-hydroxy-3-(4-phenyl-3,6-dihydro-2H-pyridin-1-yl)propoxy]phenyl]-phenylmethanone Chemical compound C1(=CC=CC=C1)C=1CCN(CC1)CC(COC1=CC=C(C(=O)C2=CC=CC=C2)C=C1)O KQIGOYIOGJKOIU-UHFFFAOYSA-N 0.000 description 11
- 239000003921 oil Substances 0.000 description 10
- 235000019198 oils Nutrition 0.000 description 10
- BRLQWZUYTZBJKN-UHFFFAOYSA-N Epichlorohydrin Chemical compound ClCC1CO1 BRLQWZUYTZBJKN-UHFFFAOYSA-N 0.000 description 9
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- 239000011541 reaction mixture Substances 0.000 description 9
- 238000010992 reflux Methods 0.000 description 9
- 235000011121 sodium hydroxide Nutrition 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 7
- 239000002585 base Substances 0.000 description 7
- 238000000354 decomposition reaction Methods 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 238000001704 evaporation Methods 0.000 description 6
- 239000007858 starting material Substances 0.000 description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
- 125000004432 carbon atom Chemical group C* 0.000 description 5
- 230000008020 evaporation Effects 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- OWNIIQNYQOWRGD-UHFFFAOYSA-N [4-[2-hydroxy-3-(4-phenyl-3,6-dihydro-2H-pyridin-1-yl)propoxy]phenyl]-phenylmethanone hydrochloride Chemical compound Cl.C1(=CC=CC=C1)C=1CCN(CC1)CC(COC1=CC=C(C(=O)C2=CC=CC=C2)C=C1)O OWNIIQNYQOWRGD-UHFFFAOYSA-N 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- 235000011152 sodium sulphate Nutrition 0.000 description 4
- ZFDLKXODHDEZEC-UHFFFAOYSA-N (4-chlorophenyl)-[4-(oxiran-2-ylmethoxy)phenyl]methanone Chemical compound C1=CC(Cl)=CC=C1C(=O)C(C=C1)=CC=C1OCC1OC1 ZFDLKXODHDEZEC-UHFFFAOYSA-N 0.000 description 3
- NSYCSTBOFKKYLO-UHFFFAOYSA-N 4-[4-(oxiran-2-ylmethoxy)benzoyl]benzonitrile Chemical compound C=1C=C(C#N)C=CC=1C(=O)C(C=C1)=CC=C1OCC1CO1 NSYCSTBOFKKYLO-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- ARVNLGNHEHPUNY-UHFFFAOYSA-N O1C(COC2=CC=C(C(=O)C3=CC=C(C=C3)Br)C=C2)C1 Chemical compound O1C(COC2=CC=C(C(=O)C3=CC=C(C=C3)Br)C=C2)C1 ARVNLGNHEHPUNY-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 125000005278 alkyl sulfonyloxy group Chemical group 0.000 description 3
- 238000009835 boiling Methods 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
- 239000012458 free base Substances 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 125000004076 pyridyl group Chemical group 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- YIHPAACELCNVRB-UHFFFAOYSA-N (4-methoxyphenyl)-[4-(oxiran-2-ylmethoxy)phenyl]methanone Chemical compound O1C(COC2=CC=C(C(=O)C3=CC=C(C=C3)OC)C=C2)C1 YIHPAACELCNVRB-UHFFFAOYSA-N 0.000 description 2
- NXPWJGOQPHUZFF-UHFFFAOYSA-N 1-chloro-3-(4-phenyl-3,6-dihydro-2H-pyridin-1-yl)propan-2-ol Chemical compound C1(=CC=CC=C1)C=1CCN(CC1)CC(CCl)O NXPWJGOQPHUZFF-UHFFFAOYSA-N 0.000 description 2
- CZYTUQCWOMSDFL-UHFFFAOYSA-N 4-(4-hydroxybenzoyl)benzonitrile Chemical compound C1=CC(O)=CC=C1C(=O)C1=CC=C(C#N)C=C1 CZYTUQCWOMSDFL-UHFFFAOYSA-N 0.000 description 2
- LJZVSJCLGALFPA-UHFFFAOYSA-N 4-(4-methoxybenzoyl)benzonitrile Chemical compound C1=CC(OC)=CC=C1C(=O)C1=CC=C(C#N)C=C1 LJZVSJCLGALFPA-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 2
- 208000001953 Hypotension Diseases 0.000 description 2
- 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 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Chemical compound OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 2
- ORUWJGFIPMNEOZ-UHFFFAOYSA-N [3-methyl-4-(oxiran-2-ylmethoxy)phenyl]-phenylmethanone Chemical compound CC1=CC(C(=O)C=2C=CC=CC=2)=CC=C1OCC1CO1 ORUWJGFIPMNEOZ-UHFFFAOYSA-N 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 230000001476 alcoholic effect Effects 0.000 description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 2
- 150000001555 benzenes Chemical class 0.000 description 2
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Substances N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 2
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 2
- 239000001110 calcium chloride Substances 0.000 description 2
- 229910001628 calcium chloride Inorganic materials 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 239000002026 chloroform extract Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 150000002334 glycols Chemical class 0.000 description 2
- 229940093915 gynecological organic acid Drugs 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 208000021822 hypotensive Diseases 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- UNEIHNMKASENIG-UHFFFAOYSA-N para-chlorophenylpiperazine Chemical compound C1=CC(Cl)=CC=C1N1CCNCC1 UNEIHNMKASENIG-UHFFFAOYSA-N 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridin-1-ium;chloride Chemical compound [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 235000002906 tartaric acid Nutrition 0.000 description 2
- 239000011975 tartaric acid Substances 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 2
- GRDGBWVSVMLKBV-UHFFFAOYSA-N (2-amino-5-nitrophenyl)-(2-chlorophenyl)methanone Chemical compound NC1=CC=C([N+]([O-])=O)C=C1C(=O)C1=CC=CC=C1Cl GRDGBWVSVMLKBV-UHFFFAOYSA-N 0.000 description 1
- XUJHKPSBHDQIOD-UHFFFAOYSA-N (2-bromo-7,7-dimethyl-3-oxo-4-bicyclo[2.2.1]heptanyl)methanesulfonic acid Chemical compound C1CC2(CS(O)(=O)=O)C(=O)C(Br)C1C2(C)C XUJHKPSBHDQIOD-UHFFFAOYSA-N 0.000 description 1
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- VEGIRNXPRBDNEU-UHFFFAOYSA-N (3-chlorophenyl)-[4-(oxiran-2-ylmethoxy)phenyl]methanone Chemical compound O1C(COC2=CC=C(C(=O)C3=CC(=CC=C3)Cl)C=C2)C1 VEGIRNXPRBDNEU-UHFFFAOYSA-N 0.000 description 1
- VFMPCNWWYIQPCN-UHFFFAOYSA-N (4-bromophenyl)-(4-methoxyphenyl)methanone Chemical compound C1=CC(OC)=CC=C1C(=O)C1=CC=C(Br)C=C1 VFMPCNWWYIQPCN-UHFFFAOYSA-N 0.000 description 1
- UDGHTNPEJPFNIP-UHFFFAOYSA-N (4-hydroxy-3-methylphenyl)-phenylmethanone Chemical compound C1=C(O)C(C)=CC(C(=O)C=2C=CC=CC=2)=C1 UDGHTNPEJPFNIP-UHFFFAOYSA-N 0.000 description 1
- LGJXZWFPIDESNQ-UHFFFAOYSA-N (4-hydroxyphenyl)-(4-methoxyphenyl)methanone Chemical compound C1=CC(OC)=CC=C1C(=O)C1=CC=C(O)C=C1 LGJXZWFPIDESNQ-UHFFFAOYSA-N 0.000 description 1
- XEPLMYDKEVCRES-UHFFFAOYSA-N (4-nitrophenyl)-[4-(oxiran-2-ylmethoxy)phenyl]methanone Chemical compound C1=CC([N+](=O)[O-])=CC=C1C(=O)C(C=C1)=CC=C1OCC1OC1 XEPLMYDKEVCRES-UHFFFAOYSA-N 0.000 description 1
- VNZLQLYBRIOLFZ-UHFFFAOYSA-N 1-(2-methoxyphenyl)piperazine Chemical compound COC1=CC=CC=C1N1CCNCC1 VNZLQLYBRIOLFZ-UHFFFAOYSA-N 0.000 description 1
- FTHTWSFXCUMECK-UHFFFAOYSA-N 1-[4-(N-hydroxy-C-phenylcarbonimidoyl)phenoxy]-3-(4-phenyl-3,6-dihydro-2H-pyridin-1-yl)propan-2-ol Chemical compound C1(=CC=CC=C1)C=1CCN(CC1)CC(COC1=CC=C(C(C2=CC=CC=C2)=NO)C=C1)O FTHTWSFXCUMECK-UHFFFAOYSA-N 0.000 description 1
- YYTSGNJTASLUOY-UHFFFAOYSA-N 1-chloropropan-2-ol Chemical compound CC(O)CCl YYTSGNJTASLUOY-UHFFFAOYSA-N 0.000 description 1
- MHBQOAILOCNGPI-UHFFFAOYSA-N 1-phenoxy-3-(4-phenylpiperazin-1-yl)propan-2-ol Chemical group C1CN(C=2C=CC=CC=2)CCN1CC(O)COC1=CC=CC=C1 MHBQOAILOCNGPI-UHFFFAOYSA-N 0.000 description 1
- AKFKUPNCTKPNPN-UHFFFAOYSA-N 2-(1,2-dihydropyridin-2-yl)ethanol Chemical compound OCCC1NC=CC=C1 AKFKUPNCTKPNPN-UHFFFAOYSA-N 0.000 description 1
- JHWIEAWILPSRMU-UHFFFAOYSA-N 2-methyl-3-pyrimidin-4-ylpropanoic acid Chemical compound OC(=O)C(C)CC1=CC=NC=N1 JHWIEAWILPSRMU-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
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- 125000004043 oxo group Chemical group O=* 0.000 description 1
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- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 235000019271 petrolatum Nutrition 0.000 description 1
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- YZTJYBJCZXZGCT-UHFFFAOYSA-N phenylpiperazine Chemical compound C1CNCCN1C1=CC=CC=C1 YZTJYBJCZXZGCT-UHFFFAOYSA-N 0.000 description 1
- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 1
- 150000004885 piperazines Chemical class 0.000 description 1
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- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
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- 150000007659 semicarbazones Chemical class 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
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- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
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- 235000012222 talc Nutrition 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
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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
- C07D207/34—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 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
- C07D207/36—Oxygen or sulfur atoms
- C07D207/40—2,5-Pyrrolidine-diones
- C07D207/404—2,5-Pyrrolidine-diones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms, e.g. succinimide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D203/00—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom
- C07D203/04—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D203/06—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D203/08—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no 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 the ring nitrogen atom
- C07D203/10—Radicals substituted by singly bound oxygen atoms
-
- 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
- C07D211/40—Oxygen atoms
- C07D211/44—Oxygen atoms attached in position 4
- C07D211/52—Oxygen atoms attached in position 4 having an aryl radical as the second substituent 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
- C07D211/68—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 one double bond between ring members or between a ring member and a non-ring member
- C07D211/70—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 one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- 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
- C07D211/80—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 two double bonds between ring members or between ring members and non-ring members
- C07D211/82—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 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/04—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/06—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings 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
- C07D263/18—Oxygen atoms
- C07D263/20—Oxygen atoms attached in position 2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/10—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms
- C07D295/104—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/108—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
- C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
- C07D303/02—Compounds containing oxirane rings
- C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
- C07D303/18—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by etherified hydroxyl radicals
- C07D303/20—Ethers with hydroxy compounds containing no oxirane rings
- C07D303/22—Ethers with hydroxy compounds containing no oxirane rings with monohydroxy compounds
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Description
Fremgangsmåte for fremstilling av nye farmakodynamisk virksomme, aromatiske etere.
Nærværende oppfinnelse vedrører en fremgangsmåte for fremstilling av nye farmakodynamisk virksomme aromatiske ethere med den generelle formel
hvor de aromatiske ringene A og/eller B kan være substituert med en eller flere alkyl- , alkoxy- , halogen- , cyano- , carboxy- , nitro- , amino- eller trifluormethyl-grupper og er en 3 ,6-dihydro-l(2H)-pyridylrest, en piperidinorest, en 4-hydroxy-piperidinorest eller en piperazinorest, hvorved disse rester eventuelt i p-stilling er forbundet med en eventuell med en eller flere alkyl- , alkoxy- , halogen- eller tri-fluormethylgrupper substituert fenylrest, X betegner en carbonyl- , hydroxymethylen- , alkanoyloxymethylen-, alkoxycarbonyloxymethylen- eller dihydroxyfosfinyloxymethylen-
gruppe og Y betegner en carbonyl- , methylen- , hydroxymethylen- eller hydroxy-iminomethylengruppe,
såvel som ketaler, syreaddisjonssalter og de optiske isomerer av disse forbindelser.
De heterocykliske rester kan f.eks. være substituert med hydroxy, hvorved hydroxylgruppene kan være forethret f. eks, med alkanoler med inntil 5 karbonatomer som methyl- , ethyl- , isopropylalkohol eller være forestretmed alkancarboxylsyrer med inntil 5 karbonatomer som eddik- , propion- eller smørsyre.
De foran nevnte alkylgrupper er fortrinnsvis lavere alkylgrupper med inntil
5 karbonatomer som methyl, ethyl, isopropyl. Også alkoxygruppene inneholder fortrinnsvis inntil 5 karbonatomer, som methoxy, ethoxy. Av halogenatomene er fluor, klor og brom foretrukket. Tilstedeværende oxogrupper kan være ketalisert med lavere alkanoler eller glykoler, f. eks. med methylalkohol eller ethylenglykol. Som acyloxyrester kommer fremfor alt i betraktning rester, som lar seg avlede av lavere alkancarboxylsyrer med inntil 5 karbonatomer.
De nevnte heterocycliske rester kan allerede i utgangsforbindelsene med formel III og V være ferdig fremstilt. Det er imidlertid også mulig senere å redusere fremgangsmåteproduktene med formel I hvor R^ er en l(2H)-pyridylrest og å overføre til deønskede piperidinbaser.
Fremgangsmåten ifølge oppfinnelsen karakteriseres ved at man
a) omsetter en forbindelse med den generelle formel
hvor Y har foran angitte betydning, X' betegner en carbonyl- eller hydroxymethylengruppe, R„ « betyr halogen eller alkyl- henholdsvis aryl-sulfonyloxy eller X' og R2sammen med methylengruppen i endestilling er resten eller hvis X' og/eller Y betegner en carbonylgruppe, et ketal eller diketal av denne forbindelse med en forbindelse med den generelle formel hvor den med hydrogenatomet forbundne substituent Rj har den foran angitte betydning eller b) omsetter en forbindelse med den generelle formel hvor Y' betegner en carbonyl- , methylen- eller hydroxymethylengruppe eller hvis Y' betegner en carbonylgruppe, et ketal av denne forbindelse med en forbindelse med den generelle formel hvor den med methylengruppen forbundne substituent B.^og X' har foran angitte betydning, Rg betyr halogen, alkyl- henholdsvis aryl-sulfonyloxy eller Rg og X' sammen med methylengruppen i endestilling er resten
hydrerer eventuelt det erholdte produk,t, ketaliserer eller reduserer eller oximerer hvis ønsket en foreliggende carbonylgruppe Y, reduserer eventuelt en forekommende carbonylgruppe X, enten oksyderer eller forestrer hvis ønsket en forekommende hydroxymethylengruppe X og at man hvis ønsket overfører de oppnådde forbindelser til et syreaddisjonssalt og/eller spalter det opp i de tilsvarende optiske isomerer.
Fremgangsmåteproduktene tilhører en ny forbindelsesklasse som strukturelt står nær den i det franske patent nr. 1.382.420 beskrevne gruppe av l-(2-hydroxy-3-fenoxy-propyl)-4-fenyl-piperazin. Disse forbindelser er vasodilatorisk, antiflam-matorisk og hypotensivt virksomme. De forbindelser som fremstilles ifølge oppfinnelsen har derimot på overraskende måte psykosedative egenskaper.
Forbindelser med formel
eller formelen hvor den aromatiske ring A og/eller fenylresten kan være substituert med halogen, inntar en fortrinnsstilling. Følgende gjennom formlene VI og VII karakteriserte forbindelser er f.eks. spesielt verdifulle: 4- [ 3- (3 ,6- dihydr o- 4- f enyl-1 (2H) py ridyl) - 2- hy dr oxy- propoxy] - benzof enon 4-[ 3- (3 ,6- dihydro-4- f enyl-1 (2H) py ridyl) - 2-hydroxy- propoxy] -4 '-klor-benzofenon
4-[3- (4- (p-klor-f enyl) -3 ,6-dihydro-l (2H) pyridyl) -2-hydr oxy-propoxy] - benzofenon
4- [ 3- (4- (p- klor- f enyl) -3,6- dihy dro-1 (2H) pyridyl) - 2- hydr oxy- propoxy] - 4'-klor-benzofenon
4- [ 3- (3 ,6- dihy dr o- 4- f enyl-1 (2H) - pyridyl) - 2- hydr oxy- propoxy] - 4'- f luor-benzofenon
4-[ 3- (4- (p- fluor- f enyl) -3,6- dihydro-1 (2H) pyridyl) - 2-hydroxy- propoxy] - 4'-fluor-benzofenon
4-[ 3- (4- (p- fluor- f enyl) -3,6- dihydro-1 (2H) pyridyl) - 2-hydroxy- propoxy] - 4
klor-benzofenon
4-[3- (4- (p-klor-f enyl) -3 ,6-dihydro-l (2H) pyridyl)-2-hydroxy-propoxy]-4 '-fluor-benzofenon
4-[ 3- (4- (p- fluor- f enyl) - 3 ,6-dihydro-1 (2H) - pyridyl) - 2-hydroxy- propoxy] -4 '-brom-benzof enon
4-[ 3- (4- (p-klor-f enyl) -3,6- dihydro-1 (2H) pyridyl) -2-hydroxy-propoxy] -4 '-brom-benzofenon
4-[ 3- (4- (p- klor- f enyl) -1 - piperazinyl) - 2-hydroxy- propoxy] -benzof enon 4- [ 3- (4- (p- klor- f enyl) -1 - pipe raziny 1) - 2- hydr oxy- propoxy] - 4 *- fluor- benzofenon. ;De som utgangsforbindelser anvendte eventuelt ringsubstituerte difenylmethan-derivater med formel II kan f.eks. fremstilles på følgende måte: Forbindelser med formel II, hvor X' er en hydroxymethylengruppe og Y en carbonylgruppe, lar seg f.eks. fremstille på den måte at man omsetter et 4-alkoxy-benzoyl-halogenid med et eventuelt substituert benzol efter Friedel-Crafts, d.v.s. ved hjelp av en Lewis-syre, som f.eks. aluminiumklorid, sinkklorid, bortrifluorid og andre, avalkylerer og omsetter det dannede eventuelt substituerte 4-hydroxybenzofenon fortrinnsvis med et overskudd av et epihalogenhydrin, i særdeleshet med epiklorhydrin, såvidt mulig i nærvær av en katalytisk virksom mengde av en organisk base, som f.eks. piperidin vedøket temperatur, fortrinnsvis ved ca. 100°C. ;Et eventuelt substituert 4-hydr<p>xybenzofenon kan videre også oppnåes ved at man kondenserer en 4-alkoxy-benzoesyre med et eventuelt substituert benzol i nærvær av polyfosforsyre og avalkylerer. ;Et eventuelt substituert 4-hydroxybenzofenon fremstilles fortrinnsvis på den ~~måte at man omlagrer en eventuelt substituert fenolbenzoesyreester efter Fries. ;Forbindelser med formel II, hvor X' og Y er en hydroxymethylengruppe, lar seg f.eks. fremstille på den måte at man reduserer et eventuelt substituert 4-hydroxy-benzofenon før eller efter innføringen av sidekjeden med et blandet metallhydrid, f.eks. med natriumborhydrid eller lithiumaluminiumhydrid eller at man overfører et eventuelt substituert benzaldehyd med o- , m- eller p-alkoxybrombenzol ved hjelp av en ;Grignard-reaksjon til det tilsvarende 4-hydroxybenzhydrol og forbinder med sidekjeden. ;Forbindelser med formel II, hvor X' er en hydroxymethylengruppe og Y en methylengruppe, lar seg f.eks. fremstille på den måte at man reduserer et eventuelt substituert 4-hydroxy-benzofenon efter Wolff-Kishner - d.v.s. efter overføring til et semicarbazon eller hydrazon, f .eks. i nærvær av et alkalialkoholat ved øket temperatur - eller efter Clemmensen - d.v.s. f.eks. ved hjelp av amalgamert sink i nærvær av saltsyre - og omsetter som foran beskrevet, med epiklorhydrin. ;Forbindelser med formel II, hvor X' er en hydroxymethylengruppe og Y en hydroxyiminomethylerigruppe, lar seg f.eks. fremstille på den måte at man forbinder et eventuelt substituert 4-hydroxybenzofenon med sidekjeden og derefter oximerer. ;Forbindelser med formel II, hvor X' er en hydroxymethylengruppe og Y en carbonylgruppe, kan oxyderes med de vanlige oxydasjonsmidler f.eks. med kalium-permanganat eller med natriumdikromat til forbindelser med formel II, hvor X' og Y betyr en carbonylgruppe. ;Forbindelser med formel II, hvor X' er en hydroxymethylengruppe og Y en methylengruppe, kan oxyderes med en blanding av dimethylsulfoxyd og eddiksyreanhydrid til forbindelser med formel II, hvor X' betyr en carbonylgruppe og Y' en methylengruppe. ;De eventuelt substituerte forbindelser med formel II, hvor R o er halogen eller en alkylsulfonyl- eller arylsulfonyl-oxyrest, i særdeleshet mesyloxy- eller tosyloxy-resten, kan omsettes på i og for seg kjent måte til et oxyran. ;Forbindelser med formel III er oppnåelige på vanlig måte.;Omsetningen av forbindelser med formel II med forbindelser med formel III finner fortrinnsvis sted ved en temperatur mellom værelsetemperatur og koketempera-turen for reaksjonsblandingen, i særdeleshet ved ca. 70 til 100°C. Det er av fordel å tilsette reaksjonsblandingen et oppløsningsmiddel, f.eks. en alkanol som methanol, ethanol eller isopropanol, eller en cyclisk ether som tetrahydrofuran, dioxan eller dimethyl sul f oxyd. ;Forbindelser med formel II, hvor Rg betyr halogen eller alkylsulfonyl oxy- eller arylsulfonyloxy-rest (i særdeleshet mesyloxy- eller tosyloxy-rest) , omsettes fortrinnsvis i nærvær av et syrebindende middel med forbindelser med formel III. Forbindelser med formel II, hvor R.^danner med hydroxylgruppen i resten X' en oxygen-bro, kan omsettes direkte med forbindelser med formel III. ;Forbindelser med formel IV lar seg oppnå efter de for fremstillingen av forbindelser med formel II gitte angivelser. ;Forbindelser med formel V, hvor X' er en hydroxymethylengruppe, kan f.eks. fremstilles ved at man omsetter en base med formel III med et epihalogenhydrin, fortrinnsvis med epiklorhydrin i nærvær av et vandig alkanol som ethanol, ved øket temperatur til en forbindelse med formel V, hvor R^er halogen. Den erholdte forbindelse kan ved behandling med sterke vandige alkalier ved værelsetemperatur lukkes til en oxyranring. Forbindelser med formel V, hvor R„ er en alkylsulfonyloxy- eller arylsulfonyloxy-rest (i særdeleshet mesyloxy- eller tosyloxy-resten) , er likeledes kvalifisert til oxyranring dannelse. ;Forbindelser med formel V, hvor X<1>er en carbonylgruppe, lar seg fremstille fra de tilsvarende forbindelser, hvor X' betegner en hydroxymethylengruppe, f.eks. ved at man oxyderer hydroxygruppen med en blanding av dimethylsulfoxyd og eddiksyreanhydrid ved værelsetemperatur. ;De erholdte forbindelser med formel V kan omsettes under de for reaksjonen av forbindelser med formlene II og III nevnte betingelser. I fall Rg betyr halogen, alkyl- eller aralkyl-sulfonyl-oxy, overfører man forbindelsene med formel IV fortrinnsvis først til et alkalimetallsalt, f. eks. til natrium- eller kalium saltet, eller man foretar bindingen i nærvær av en tertiær base, f.eks. i nærvær av pyridin eller triethylamin. ;De erholdte forbindelser med formel I, hvor X og eller Y er en carbonylgruppe, kan ketaliseres på i og for seg kjent måte, f .eks. ved innvirkning av lavere alkanoler eller glykoler, i særdeleshet med methylalkohol eller ethylenglykol. ;Restene Y' eller X' som er tilstede i de erholdte forbindelser i formel I kan som foran beskrevet ved fremstillingen av utgangsforbindelsene med formel II omdannes til Y og X. ;En f.eks. tilstedeværende hydroxymethylengruppe X' kan i nærvær av en methylen eller carbonylgruppe Y' oxyderes med en blanding av dimethylsulfoxyd og eddiksyreanhydrid til en carbonylgruppe X. i ;På samme måte kan også en tilstedeværende carbonyl- eller hydroxymethylengruppe Y\ hvis ønsket, omdannes til Y. ;En tilstedeværende hydroxymethylengruppe kan forestres på i og for seg kjent ;måte med organiske eller uorganiske, eventuelt substituerte syrer.;Dé erholdte baser med formel I danner salter såvel med uorganiske som også med organiske syrer, f.eks. med halogenhydrogensyre, som klorhydrogensyre, brom-hydrogensyre, jodhydrogensyre, med andre mineralsyrer som svovelsyre, fosforsyre, salpetersyre, såvel som med organiske syrer, som vinsyre, sitronsyre, oxalsyre, ;kamfersulfosyre, ethansulfosyre, toluolsulfosyre, salicylsyre, ascorbinsyre, maleiiy-syre, mandelsyre o.s.v. Foretrukne salter er hydrohalogenidene, i særdeleshet ;hydrokloridene, Syreaddisjonssaltene fremstilles fortrinnsvis i et egnet oppløsnings-—middel som ethanol ved behandling av den frie base med den tilsvarende ikke-vandige syre. ;Fremgangsmåteproduktene opptrer i to optisk isomere former. Disse kan spaltes på i og for seg kjent måte som følger. ;Racematet kan f.eks. spaltes ved at man omsetter basen med en optisk aktivsyre, f. eks. med vinsyre, bromkamfersulfonsyre etc. , spalter det erholdte salt ved fraksjonert krystallisasjon i to fraksjoner og overfører disse til de optiske antipoder. ;Fremgangsmåteproduktene hvor R^er en l(2H)-pyridylrest kan senere hydreres. ;Basene overføres derved på i og for seg kjent måte ved hydrering, fortrinnsvis i nærvær av edelmetallkatalysatorer som palladiumkull, fortrinnsvis i et oppløsningsmiddel, som f.eks. methyl- eller ethylalkohol til de tilsvarende piperidin- henholdsvis piperazin-derivater. ;De ifølge oppfinnelsen oppnåelige forbindelser med formel I, deres ketaler og syreaddisjonssalter utmerker seg gjennom mangfoldige virkninger på nervesystemet, ;i særdeleshet gjennom en sterk psychosederende virkning. Spesielt å nevne er den reserpinlignende hypotensive og sedative virkning av 4-[3-(3 ,6-dihydro-4-fenyl-l(2H) pyridyl)-2-hydroxy-propoxy]-benzofenon såvel som av 4-[3-(4-(p-fluorfenyl)-3 ,6-dihydro-1 (2H) pyridyl) - 2-hydroxy- propoxy] - 4'- klor- benzofenon. ;Forbindelsene med formel I kan finne anvendelse som legemidler, f.eks. i form av farmasøytiske preparater, hvilke inneholder de eller deres salter i blanding med et for den enterale eller parenterale administrasjon egnet farmasøytisk organisk eller uorganisk inert bærematerial, som f.eks. vann, gelatin, gummiarabicum, melkesukker, stivelse, magnesiumstearat, talkum, vegetabilske oljer, polyalkylen-glykoler, vaselin o.s.v. De farmasøytiske preparatene kan foreligge i fast form f.eks. som tabletter, dragéer, suppositorier, kapsler eller i flytende form, f.eks. som oppløsninger, suspensjoner eller emulsjoner. Eventuelt er de sterilisert og/eller inneholder hjelpestoffer, som konserverings- , stabiliserings- , fuktnings- eller emulgermiddel, salter til forandring av det osmotiske trykk eller puffer. De kan også inneholde ennu andre therapeutisk verdifulle stoffer. ;Eksempel 1.;12.7 g 4-[2 ,3-epoxy-propoxy]-benzofenon oppløses i 50 ml dioxan og oppvarmes efter tilsetning av 8 ,0 g 4-fenyl-l ,2 ,3 ,6-tetrahydropyridin i 5 timer ved tilbakeløps-betingelser. Oppløsningsmidlet avdampes derefter under forminsket trykk. Det tilbakeblivende 4-[3-(3 ,6-dihydro-4-fenyl-l(2H)pyridyl)-2-hydroxy-propoxy]-benzofenon oppløses i 20 ml ethanol og innstilles kongosurt med ethanolisk saltsyre. Hydrokloridet som utskiller seg krystallint smelter efter omkrystallisasjon fra ethanol ved 192-194°C. ;På analog måte oppnår man ved anvendelse av:;4-[2 ,3-epoxy-propoxy]-4 '-methoxy-benzof enon og 4-fenyl-l ,2,3 ,6-tetrahydro-pyridin 4-[3-(3 , 6-dihydro-4-fenyl-l(2H) pyridyl)-2-hydroxy-propoxy]-4'-methoxy-benzofenon-""" hydrokloridet, smp. 185-186°C. ;4-[2 ,3-epoxy-propoxy]-3-methyl-benzofenon og 4-fenyl-l ,2,3 ,6-tetrahydro-pyridin 4-[ 3- (3 ,6- dihydro- 4- f enyl-1 (2H) pyridyl) - 2-hydroxy- propoxy] - 3- methyl-benzof enonet, smp. 200-203°C. ;4-(2 ,3-epoxy-propoxy)-4 '-methyl-benzofenon og 4-fenyl-l ,2 ,3 ,6-tetrahydro-pyridin 4-[3-(3 ,6-dihydro-4-f enyl-1(2H) pyridyl)-2-hydroxy- propoxy]-4'-methyl-benzof enon-hydrokloridet, smp. 209-210°C.. ;4-[2 ,3-epoxy-propoxy]-benzofenon og 4-p-fluor-f enyl-1,2 ,3 ,6-tetrahydro-pyridin 4-[ 3- (p- fluor- f enyl) -3,6- dihydro-1 (2H) pyridyl) -2- hydroxy- propoxy] -benzof enon- hydrokloridet, smp. 160°C. ;4-(2 ,3-epoxy-propoxy)-4'-klor-benzofenon og 4-p-klor-f enyl-1,2 ,3 ,6-tetrahydro-pyridin 4-[3- (4- (p-klor- f enyl) -3,6- dihydro-1 (2H) pyridyl) -2-hydroxy-propoxy] -4 '-klor-benzofenon-hydrokloridet, smp. 212°C (spaltning). ;4-(2 ,3-epoxy-propoxy)-3 ',4*-diklorbenzofenon og 4-fenyl-l ,2,3 ,6-tetrahydro-pyridin
4-[3-(3 ,6-dihydro-4-fenyl-l(2H)pyridyl)-2-hydroxy-propoxy]-3 '-4 '-diklor-benzofenon-hydrokloridet, smp. 206°C (spaltning)
4-(2 ,3-epoxy-propoxy)-4'-nitrobenzofenon og 4-fenyl-l ,2 ,3 ,6-tetrahydro-pyridin 4-[3-(3 ,6-dihydro-4-fenyl-l(2H) pyridyl)-2-hydroxy-propoxy]-4 '-nitro-benzofenon-hydrokloridet, smp. 201-203°C.
4-(2 ,3-epoxy-propoxy)-4 '-brom-benzofenon og 4-fenyl-l ,2 ,3 ,6-tetrahydro-pyridin 4-[ 3- (3 ,6- dihydro- 4- f enyl-1 (2H) pyridyl) - 2- hydroxy-propoxy] -4 '-br om-benzof enon-hydrokloridet, smp. 210-212°C.
4-(2 ,3-epoxy-propoxy)-4 '-fluor-benzofenon og 4-fenyl-l ,2,3 ,6-tetrahydro-pyridin 4-[ 3- (3 ,6- dihydro- 4- f enyl-1 (2H) pyridyl) -2-hydroxy- propoxy] -4'- fluor-benzof enon-hydrokloridet, smp. 198-200°C.
4-(2 ,3-epoxy-propoxy)-4 '-fluor-benzofenon og 4-p-fluor-f enyl-1,2,3 ,6-tetrahydro-pyridin 4-[3- (4- (p-fluor-f enyl) -3,6-dihydro-1 (2H) pyridyl) -2-hydroxy-propoxy]-4 '-fluor-benzofenon-hydrokloridet, smp. 192-193°C.
4-(2 ,3-epoxy-propoxy)-4 '-klor-benzofenon og 4-p-fluor-f enyl-1,2 ,3 ,6-tetrahydro-pyridin 4-[3-(4-(p-fluor-fenyl)-3 ,6-dihydro-l(2H)pyridyl)-2-hydroxy-propoxy]4 '-klor-benzofenon-hydrokloridet, smp. 203-204°C.
4-(2 ,3-epoxy-propoxy)-4-klor-benzofenon og 4-hydroxy-4-(p-trifluormethyl-fenyl)-piperidin 4-[3- (4-hydroxy-4(p-trifluormethyl-fenyl)-piperidino) -2-hydroxy-propoxy]-4'-klor-benzofenon-hydrokloridet, smp. 222-223°C.
4-[2,3-epoxy-propoxy]-4 '-klor-benzofenon og 4-fenyl-l ,2,3,6-tetrahydro-pyridin 4T 13- (3 ,6- dihydro- 4- f enyl-1 (2H) pyridyl) - 2-hydroxy- propoxy] - 4klor- benzofenon- hydrokloridet, smp. 202°C . (spaltning).
4-[2,3-epoxy-propoxy]-benzofenon og 4-p-kl or-f enyl-1,2,3,6-tetrahydro-pyridin 4-[ 3- (4- (p-klor- f enyl) -3,6- dihydro-1 (2H) pyridyl) - 2- hydroxy- propoxy] -benzofenon-hydrokloridet, smp. 217-218°C.
4-(2 ,3-epoxy-propoxy)-4'-trifluor-methyl-benzofenon og 4-fenyl-l ,2 ,3 ,6-tetrahydro-pyridin 4-[3-(3 ,6-dihydro-4-f enyl-1(2H) pyridyl)-2-hydroxy-propoxy]-4' -trifluormethyl-benzofenon-hydroklorid, smp. 231°C (spaltning).
4-(2 ,3-epoxy-propoxy)-3'-klor-benzofenon og 4-fenyl-l ,2 ,3 ,6-tetrahydro-pyridin 4-[ 3- (3 ,6- dihydro-4-f enyl-1 (2H) pyridyl) - 2- hydroxy- propoxy] - 3 '-klor- benzof enon-hydroklorid, smp. 175°C (spaltning).
4-(2 ,3-epoxy-propoxy)-benzofenon og 4-fenyl-4-hydroxy-piperidin 4-[3-(4-hydroxy-4-fenyl-piperidino)-2-hydroxy-propoxy]-benzofenon-hydroklorid, smp. 184°C.
4-(2 ,3-epoxy-propoxy)-2',4'-di-klor-benzofenon og 4-fenyl-l ,2 ,3,6-tetrahydro-pyridin 4-[3-(3 ,6-dihydro-4-f enyl-1 (2H) pyridyl) -2-hydroxy-propoxy]-2' ,4 '-di-klor-benzofenon, smp. 132-134°C.
4-(2 ,3-epoxy-propoxy)-3 '-trifluormethyl-benzofenon og 4-p-klor-fenyl-l ,2 ,3 ,6-tetrahydro-pyridin 4-[3- (3 ,6-dihydro-4- (p-klor-f en yl) -1 (2H) pyridyl) -2-hydroxy-propoxy]-3 '-trifluorméthyl-benzofenon-hydroklorid, smp. 130-134°C.
4-(2 ,3-epoxy-propoxy)-4-fluor-benzofenon og 4-p-klor-fenyl-l ,2 ,3 ,6-tetrahydro-pyridin 4-[3-(4-(p-klor-fenyl)-3 ,6-dihydro-1(2H)pyridyl)-2-hydroxy-propoxy]-4 '-fluor-benzofenon-hydroklorid, smp. 204-206°C.
4-(2 ,3-epoxy-propoxy)-4'-brom-benzofenon og 4-p-fluor-fenyl-l ,2 ,3 ,6-tetrahydro-pyridin 4-[3-(4-(p-fluor-fenyl)-3 ,6-dihydro-l(2H)pyridyl)-2-hydroxy-propoxy]-4'-brom-benzofenon-hydrokloridet, smp. 233°C.
4-(2,3-epoxy-propoxy)-4'-brom-benzofenon og 4-(p-klor-f enyl)-1,2 ,3,6-tetrahydro-pyridin 4-[3-(4-(p-klor-fenyl)-3 ,6-dihydro-1(2H) pyridyl)-2-hydroxy-propoxy]-4'-brom-benzof enon-hydrokloridet, smp. 217°C.
4-(2 ,3-epoxy-propoxy)-difenylmethan og 4-fenyl-l ,2 ,3,6-tetrahydro-pyridin ot-[(p-benzyl-fenyloxy)-methyl] 3 ,6-dihydro-4-f enyl-1(2H) pyridin-ethanol-hydrokloridet, smp. 191 °C (spaltning).
Det som utgangsforbindelse anvendte 4-[2 ,3-epoxy-propoxy]-benzofenon er
en kjent forbindelse.
4-[2 ,3-epoxy-propoxy]-3-methyl-benzofenonet kan f. eks. fremstilles på
følgende måte:
10,6 g 4-hydroxy-3-methyl-benzofenon, 50g epiklorhydrin og 3 dråper
piperidin oppvarmes i 12 timer på dampbad. Reaksjonsoppløsningen befries under forminsket trykk fra overskytende epiklorhydrin. Den ovenfor nevnte rest oppløses
i 20 ml kloroform og rystes efter tilsetning av 20 ml 3-n natronlut i 1 time ved værelsetemperatur. Den organiske fase skilles fra, vaskes med vann, tørkes over kalsiumklorid og inndampes til tørrhet. Det tilbakeblivende oljelignende rå 4-[2 ,3-epoxy-propoxy]-3-methyl-benzofenon krystalliserer efter lang henstand. Forbind-
elsen kan uten ytterligere rensning forarbeides videre. Den fra vandig ethylalkohol omkrystalliserte forbindelse smelter ved 56-58°C. Det på analog måte fra 4-hydroxy-4'-methoxy-benzof enon fremstilte 4-[2 ,3-epoxy- propoxy]-4'-methoxy-be.nzofenon smelter ved 123-124°C.
Eksempel 2.
På samme måte som angitt i eksempel 1 får man ved anvendelse av p-[p-(2 ,3-epoksypropoxy) -benzoyl]-benzonitril og 4-(p-fluor-f enyl)-1,2 ,3 ,6-tetrahydropyridin det racemiske -p-/p-[3-(4-(p-fluorfenyl)-3 ,6-dihydro-1(2H)-pyridyl)-2-hydroxypro-poxy]-benzoyl7-benzonitril, smp. 130-133°C (fra alkohol).
Det herfor nødvendige p-[p-(2 ,3-epoxy-propoxy)-benzoyl]-benzonitril kan fremstilles som følger:
En blanding av 4-brom-4'-methoxy-benzofenon, 22 g kobber(I)-cyanid og
400 ml dimethylformamid oppvarmes under omrøring og gassing med nitrogen 15
timer under tilbakeløpsbetingelser. Derpå fordampes oppløsningsmidlet under redusert trykk. Resten ekstraheres flere ganger med varm kloroform, kloroformekstrakt-ene inndampes efter tørring over kalsiumklorid til tørrhet. Resten omkrystalliseres fra methanol. Det rene p-(p-anisoyl)-benzonitril smelter ved 133-134°C. 13 ,5 g p-(p-anisoyl)-benzonitril og 40 g pyridinhydroklorid blandes godt og oppvarmes 30 minutter ved 220°C. Den varme blanding helles i vann, de utfallende krystaller filtreres fra og vaskes grundig med vann. p-(p-hydroxybenzoyl)-benzo-nitrilet smelter efter omkrystallisering fra methanol ved 188-189°C.
9,0 g p-(p-hydroxybenzoyl)-benzonitril, 20 ml epiklorhydrin og 3 dråper piperidin oppvarmes 20 timer på dampbad. Det overskytende epiklorhydrin fordampes under redusert trykk. Resten oppløses i kloroform og rystes 30 minutter med overskudd av natronlut. Kloroformfasen dampes inn. Det tilbakebli vende p-[p-(2 ,3-epoxy-propoxy)-benzoyl]-benzonitril smelter efter omkrystallisering fra methanol ved 110-113°C.
Eksempel 3.
Fremstilling av racemisk -p-/p-[3-(4-(p-fluorfenyl)-3 ,6-dihydro-1(2H)-pyridyl)-2-hydroxy-propoxy]-benzoyl_7-benzoesyre-hydroklorid.
3 g racemisk -p-/p-[3-(4-(p~fluorfenyl)-3 ,6-dihydro-1(2H) pyridyl)-2-hydroxy-propoxy]-benzoyl7-benzonitril oppvarmes i en blanding av 25 ml iseddik og 25 ml saltsyre (20%) 12 timer under tilbakeløpsbetingelser. Efter avkjøling helles blandingen i vann. Den oppnådde forbindelse filtreres fra, vaskes med vann og omkrystal liseres fra ethanol. Det rene racemiske -p-/p-[3-(4-(p-fluorfenyl)-3 ,6-dihydro-l(2H)-pyridyl)-2-hydroxy-propoxy]-benzoyl_7-benzosyre-hydroklorid smelter ved 257-262°C (spaltning).
Eksempel 4.
5 ,1 g 4-[2 ,3-epoxy-propoxy]-benzofenon oppløses i 20 ml dioxan og oppvarmes efter tilsetning av 3,9 g 1-o-methoxy-fenyl-piperazin i 5 timer under til— bakeløpbetingelser. Oppløsningsmidlet avdampes deretter under forminsket trykk. Resten oppløses i 10 ml ethanol og innstilles kongosurt med ethanolisk saltsyre.
Det ved rivning utkrystalliserende 4-[3-(4-o-methoxy-fenyl)-piperazino)-2-hydroxy-propoxy]-benzofenon-hydroklorid smelter efter omkrystallisasjon fra ethanol ved 210-211°C.
På analog måte oppnår man ved anvendelse av: 4-[2 ,3-epoxy-propoxy]-benzofenon og l-(p-klor-fenyl)-piperazin 4-[3-(4-(p-klor-fenyl)-l-piperazinyl)-2-hydroxy-propoxy]-benzofenon-hydrokloridet, smp. 175°C.
4-[2 ,3-epoxy-propoxy]-benzofenon og l-(p-methoxy-fenyl)-piperazin 4[3-(4-(p-methoxy-fenyl)-1-piperazinyl)-2-hydroxy-propoxy]-benzofenon-hydrokloridet, smp. 145°C.
4-(2 ,3-epoxy-propoxy)-benzofenon og l-(m-methoxy-fenyl)-piperazin 4-[3-(4-m-methoxy-fenyl)-l-piperazinyl)-2-hydroxy-propoxyl-benzofenon-dihydrokloridet,
smp. 198-196°C.
4-(2 ,3-epoxy-propoxy)-4'-klor-benzofenon og l-(o-methoxy-fenyl)-piperazin 4-[3-(4-(o-methoxy-f enyl)-1-piperazinyl)-2-hydroxy-propoxy]-4 '-klor-benzofenon-hydrokloridet, smp. 201°C.
4-(2 ,3-epoxy-propoxy)-4'-fluor-benzofenon og 1-(p-klor-fenyl)-piperazin 4-[3-(4-(p-klor- f enyl) -1-piperazinyl) - 2-hydroxy- propoxy] -4 '-fluor-benzofenon- dihydroklor idet, smp. 191-193°C.
4-[2 ,3-epoxy-propoxy]-benzofenon og N-fenyl-piperazin 4-[2-hydroxy-3-(4-fenyl-l-piperazinyl)-propoxy]-benzofenon-hydrokloridet, smp. 210-211°C.
4-(2 ,3-epoxy-propoxy)-benzofenon og 4-(o-klor-fenyl)-piper azin 4-[3-(4-(o-klor-fenyl)-l-piperazinyl)-2-hydroxy-propoxy]-benzofenon-hydrokloridet, smp. 179-180°C.
4-[2 ,3-epoxy-propoxy]-benzofenon og 1-p-tolyl-piper azin 4-[3-(4-p-tolyl-l-piperazinyl) - 2- hydroxy- propoxy] - benzof enonet, smp. 12 8°C.
Eksempel 5.
2 ,25 g 4-[3-(3,6-dihydro-4-fenyl-l(2H)pyridyl)-2-hydroxy-propoxy]-benzofenon-hydroklorid oppløses i 500 ml 96%'ig ethylalkohol og hydreres efter tilstning _ av 0 ,3 g palladiumkull 5% ved værelsetemperatur under normaltrykk. Katalysatoren filtreres fra efter opptagelse av den teoretiske hydrogenmengde. Oppløsningen inndampes under forminsket trykk til nesten tørrhet og tilsettes lite abs. ethylether. Det krystallint utfallende 4-[3-(4-fenyl-piperidino)-2-hydroxy-propoxy]-benzofenon-hydroklorid smelter efter omkrystallisasjon fra ethanol ved 175-177°C.
Eksempel 6.
1,0 g 4-[3-(3 ,6-dihydro-4-fenyl-l(2H)pyridyl)-2-hydroxy-propoxy]-benzofenon oppløses i 10 ml abs. pyridin og tilsettes 2 ml acetanhydrid. Reaksjonsblandingen står til henstand i 12 timer ved værelsetemperatur. Den helles derefter i 50 ml vann og ekstraheres med ether. Den efter avdampning av etheren tilbakeblivende olje oppløses i lite ethylalkohol og innstilles kongosurt med alkoholisk saltsyre. Det efter tilsetning av ether krystallint utfellende 4-[3-(3 ,6-dihydro-4-fenyl-l(2H) pyridyl)-2-acetoxy-propoxy]-benzofenon-hydroklorid smelter efter omfelling fra ethanol/ether ved 181-182°C.
På analog måte oppnår man ved anvendelse av: l-[ (p-benzylf enoxy) - methyl] - 2- (3 ,6-dihydro- 4- f enyl-1 (2H) - pyridin] - ethanol 1[ (p-benzylfenoxy)-methyl]-2-[3 ,6-dihydro-4-fenyl-l(2H)pyridyl]-ethylacetat-hydrokloridet, smp. 178°C (spaltning).
Eksempel 7.
2 ,0 g 4-[3-(3 ,6-dihydro-4-fenyl-l(2H)pyridyl)-2-hydroxy-propoxy]-benzofenon tilsettes en blanding av 15 ml dimethylsulfoxyd og 10 ml acetanhydrid. Reak- > sjonsblåndingen står til henstand i 24 timer ved værelsetemperatur. Den helles derefter i vann i overskudd og tilsettes 2-n NaOH inntil nøytral reaksjon. Den utskillende olje opptaes i ether. Det efter avdampning av oppløsningsmidlet tilbakeblivende 4-[3-(3 ,6-dihydro-4-fenyl-l(2H)pyridyl)-2-oxo-propoxy]-benzofenon over-føres ved behandling med alkanolisk saltsyre til hydrokloridet, som efter omkrystallisasjon fra ethanol smelter ved 179-180°C.
På analog måte oppnår man ved anvendelse av: l-[(p-benzyl-fenoxy)-methyl]-2-[3 ,6-dihydro-4-fenyl-l(2H)pyridin]-ethanol-hydroklorid l-(p-benzyl-fenoxy)-3-[3 ,6-dihydro-4-fenyl-l(2H)pyridyl]-propan-2-on-hydrokloridet, smp. 176°C.
Eksempel 8.
2 ,25 g 4-[3-(3 ,6-dihydro-4-fenyl-l(2H)pyridyl)-2-hydroxy-propoxy]-benzofenon-hydroklorid suspenderes i 50 ml methanol og tilsettes under røring med en oppløsning av 1,0 g natriumborhydrid i 20 ml alkohol (innstilt på pH 9). Den dannede oppløsning røres derefter videre i 30 min. ved værelsetemperatur, konsentreres under forminsket trykk inntil utskillelse av natriumkloridet, filtreres og inndampes til tørrhet. Det tilbakeblivende 4-[3-(3 ,6-dihydro-4-fenyl-l(2H)pyridyl)-2-hydroxy-propoxy]-benzhydrol smelter efter omkrystallisasjon fra methanol ved 94°C.
På analog måte oppnår man ved anvendelse av.
4-[ 3- (4- (o-methoxy- f enyl) -1-piperazinyl) - 2-hydroxy- propoxy] - benzofenon- hydroklorid 4-[3-(4-(o-methoxy-fenyl)-1-piperazinyl)-2-hydroxy-propoxy]-benz-hydrokloridet, smp. 173°C.
Eksempel 9.
8,26 g 4-[3-(3 ,6-dihydro-4-fenyl-l(2H)pyridyl)-2-hydroxy-propoxy]-benzofenon og 1,53 g hydroxylamin-hydroklorid oppvarmes med 4-ml abs. pyridin og 200 ml abs. ethanol i en autoklav i 15 timer ved 100°C. Den efter avdampning av ethanolen under forminsket trykk tilbakeblivende olje rives med 200 ml eddikester og 100 ml l-n natronlut. Det herved krystallint utskillende 4-[3-(3 ,6-dihydro-4-fenyl-l(2H)pyridyl)-2-hydroxy-propoxy]-benzofenon-oxim smelter efter omkrystallisasjon fra methanol ved 178°C (spaltning).
På analog måte oppnår man ved anvendelse av: 4-[3-(3 ,6-dihydro-4-fenyl-l(2H)pyridyl)-2-hydroxy-propoxy]-4 '-klor-benzofenon 4-[3-(3,6-dihydro-4-fenyl-l(2H) pyridyl)-2-hydroxy-propoxy]-4 '-klor-benzofenon-oximet, smp. 178-182°C.
Eksempel 10.
Til en smelte av 25 g o-fosforsyre tilsettes efter tilsetning av 5 g fosforpentoxyd under røring ved 60°C i løpet av 1 time 4 ,5 g 4-[3-(3 ,6-dihydro-4-fenyl-l(2H)pyridyl)-2-hydroxy-propoxy]-benzofenon-hydroklorid. Reaksjonsblandingen røres ytterligere i 4 timer ved 60°C. Det fritt blivende klorhydrogen fjernes fra tid til annen ved evakuering. Den efter avkjølning og fortynning med vann utskillende tyktflytende olje kokes i 20 min. med 30 ml 2-n saltsyre. Det i kulde krystallint utfellende l-[(p-benzoyl- f enoxy) - methyl] - 2-[ 3 ,6- dihydro- 4- f enyl-1 (2H) pyridyl] - ethyl- or thof osf at smelter ved 246-248°C.
Eksempel 11.
4,48 g 4-[3-(3 ,6-dihydro-4-fenyl-l(2H)pyridyl)-2-hydroxy-propoxy]-4 '-klor-benzofenon og 1,06 g natriumcarbonat suspenderes under røring i 50 ml aceton og tilsettes i løpet av 30 min. under tilbakeløpsbetingelser en oppløsning av 1,89 g klormauersyre-methylester i 10 ml aceton. Reaksjonsblandingen oppvarmes i 6 timer under tilbakeløpsbetingelser og står derefter til henstand i 12 timer ved værelsetemperatur. Det utf ellende natriumklorid filtreres fra. Oppløsningen inndampes under forminsket trykk til tørrhet. Resten oppløses i lite benzol og absorberes på silisiumgel. Det ved eluering oppnåelige l-[(p-klor-benzoyl-fenoxy)-methyl]-[3 ,6-dihydro-4-fenyl-l(2H)pyridyl]-ethyl-methylcarbonat smelter efter omkrystallisasjon fra methanol ved 93-96°C.
Eksempel 12,
4,5 g 4-[3-(3 ,6-dihydro-4-fenyl-l(2H)pyridyl)-2-hydroxy-propoxy]-benzofenon suspenderes i 400 ml benzol og oppvarmes under tilbakeløpsbetingelser inntil koking. Gjennom denne suspensjon ledes i 1 time gassformig klorhydrogen. Derefter tilsettes 6,2 g destillert ethylenglykol og 3 ,44 g p-toluolsulfosyre. Den dannede klare oppløsning inndampes under forminsket trykk. Resten opptas i eddiksyreethylester. Oppløsningen utrystes tre ganger med l-n natronlut, tørkes over natriumsulfat og inndampes under forminsket trykk. Det tilbakeblivende 3 ,6-dihydro-4- f enyl-oH (p- (2- f enyl-1,3- dioxolan- 2- yl) - f enoxy) -methyl] -1 (2H) pyridin-ethanol smelter efter omkrystallisasjon fra methanol ved 120°C.
på analog måte oppnår man ved anvendelse av: 4-[3-(3 ,6-dihydro-4-fenyl-l(2H)pyridyl)-2-hydroxy-propoxy]-benzofenon og 1,3-propandiol 3 ,6-dihydro-4-fenyl-a-[(p-(2-fenyl-m-dioxan-2-yl)-fenoxy)-methyl]-1 (2H)pyridin-ethanol, smp. 116,5°C.
Eksempel 13.
4,74 g 4-hydroxy-benzofenon tilsettes til en oppløsning av 552 mg natrium
i 100 ml absolutt ethanol. Blandingen oppvarmes under tilbakeløpsbetingelser til koking og tilsettes i løpet av 1 time dråpevis en oppløsning av 6,0 g l-[4-fenyl-1,2 ,3 ,6-tetrahydro-pyridyl]-2-hydroxy-3-klor-propan i 100 ml absolutt ethanol. Reaksjonsblandingen kokes i 4 timer og inndampes deretter under forminsket trykk. Den tilbakeblivende olje oppløses i eddiksyreethylester. Oppløsningen utrystes to ganger med l-n natronlut, vaskes med vann, tørkes over natriumsulfat og inndampes under forminsket trykk. Det tilbakeblivende oljelignende 4-[3-(3 ,6-dihydro-4-fenyl-l(2H)pyridyl)-2-hydroxy-propoxy]-benzofenon omkrystalliseres to ganger fra isopropanol. Hydrokloridet av denne forbindelse smelter ved 192-194 o C.
Det som utgangsforbindelse anvendte l-[4-fenyl-l ,2 ,3,6-tetrahydro-pyridyl] -
2-hydroxy-3-klor-propan kan fremstilles på følgende måte:
6,37 g 4-fenyl-l ,2 ,3 ,6-tetrahydro-pyridin, 2 dråper piperidin og 40 ml absolutt ethylether avkjøles til 0° og tilsettes i løpet av 30 minutter 3 ,70 g epiklorhydrin i 10 ml absolutt ethylether. Reaksjonsblandingen står til henstand i 24 timer ved værelsetemperatur og deretter 60 timer ved ca. 0°C. Oppløsningen filtreres blank og inndampes under forminsket trykk. Den tilbakeblivende olje opptas i benzol, absorberes på kiselgel (kornstørrelse ca. 0,2 - 0,5 mm) og elueres med benzol/ethylether 4:1. Den efter avdampningen av eluatet tilbakeblivende olje oppløses i ethylether. Oppløsningen rystes med avfargningskull, filtreres og konsentreres under forminsket trykk. Det krystallint utfelte l-[4-fenyl-l ,2 ,3 ,6-tetrahydro-pyridyl]-2-hydroxy-3-klor-propan smelter ved 69,5 - 71°C.
Eksempel 14.
3,55 g l-[4-fenyl-l ,2 ,3 ,6-tetrahydro-pyridyl]-2 ,3-epoxi-propan, 3,27 g 4-hydroxy-benzofenon, 2 dråper piperidin kokes efter tilsetning av 50 ml dioxan i 15 timer under tilbakeløpsbetingelser. Reaksjonsoppløsningen inndampes derefter
under forminsket trykk. Den tilbakeblivende olje oppløses i eddiksyre-ethylester. Oppløsningen utrystes to ganger med l-n natronlut, vaskes med vann, tørkes over natriumsulfat og inndampes under forminsket trykk. Resten oppløses i benzol. Opp-løsningen renses ved adsorpsjon på kiselgel. Det efter avdampningen av eluatet tilbakeblivende oljelignende 4-[3-(3 ,6-dihydro-4-fenyl-l(2H)-pyridyl)-2-hydroxy-propoxy]-benzofenon omkrystalliseres to ganger fra isopropanol. Hydrokloridet av denne forbindelse smelter ved 192-194°C.
Det som utgangsforbindelse anvendte l-[4-fenyl-l ,2 ,3 ,6-tetrahydro-pyridyl]-2,3-epoxi-propan kan fremstilles på følgende måte: 6,37 g 4-fenyl-l ,2 ,3 ,6-tetrahydro-pyridin tilsettes dråpevis efter tilsetning av 2 dråper piperidin under røring og avkjøling 3 ,7 g epiklorhydrin. Reaksjonsblandingen står til henstand i 12 timer ved færelsetemperatur og derefter 60 timer ved ca. 0°C. Oljen oppløses derefter i kloroform. Oppløsningen tilsettes 30 ml 3-n natronlut og rystes i 1 time. Kloroformekstraktet vaskes efter adskillelse av den vandige fase med vann, tørkes over natriumsulfat og inndampes under forminsket trykk. Den tilbakeblivende olje oppløses i benzol, adsorberes på kiselgel og elueres med benzol/ethylether 4:1. Det efter avdampning av eluatet tilbakeblivende oljelignende l-[4-fenyl-l ,2 ,3 ,6-tetrahydro-pyridyl]-2 ,3-epoxi-propan kan forarbeides videre uten ytterligere rensning.
Eksempel 15.
8,26 g racemisk 4-[3-(4-fenyl-3 ,6-dihydro-l(2H)pyridyl)-2-hydroxy-propoxy]-benzofenon og 7 ,2 g (+) 0 ,0-dibenzoyl-vinsyre oppløses varmt i 50 ml methanol og filtreres. Ved avkjøling skiller (-t) 4-[3-(4-fenyl-3 ,6-dihydro-1(2H)-pyridyl)-2-hydroxy-propoxy]-benzofenon-dibenzoyltartrat seg ut i krystallinsk form. Antipoden forblir i oppløsning og kan oppnås fra denne ved saltdannelse med den frie base med (-) 0 ,0-dibenzoyl-vinsyre. Det (+)-dreiende salt smelter efter omkrystallisering fra 250 ml methanol ved 169°C , [d<2>^ = + 26,7° (i dimethylsulfoxyd, c - 1). Det rystes med 20 ml l-n natronlut og 50 ml kloroform. Den fra den organiske fase oppnådde frie base smelter efter omkrystallisering fra methanol ved 101-102°C , [al<2>^ - -13,1° (i dioxan, c - 1). For fremstilling av hydrokloridet oppløses basen varmt i 60 ml abs. ethanol, ansyres med alkoholisk saltsyre inntil kongosur reaksjon og tilsettes 60 ml eddiksyre-ethylesther. (+) 4-[3-(4-fenyl-3,6-dihydro-l(2H)pyridyl)-2-hydroxy-propoxy]-benzofenon-hydrokloridet smelter ved 193-195°C , [a]2^ - +13,1° (i dimethylsulfoxyd , c = 1).
Det (-)-dreiende hydroklorid kan oppnås på samme måte ved omsetning av racemisk 4-[ 3- (4- f enyl- 3 ,6- dihydro-1 (2H) pyridyl) - 2- hydroxy- propoxy] - benzofenon med (-) 0 ,0-dibenzoyl-vinsyre.
Claims (5)
1. Fremgangsmåte for fremstilling av nye, farmokodynamisk virksomme aromatiske ethere med den generelle formel
i hvilken de aromatiske ringer A og/eller B kan være substituert med en eller flere alkyl- , alkoxy- , halogen- , cyano- , carboxy- , nitro- , amino- eller trifluormethyl-grupper, R er en 3 ,6-dihydro-l(2H)-pyridylrest, en piperidinorest, en 4-hydroxy-piperidinorest eller en piperazinorest, hvorved disse rester eventuelt i p-stilling er forbundet med en eventuell med en eller flere alkyl- , alkoxy- , halogen- eller tri-fluormethylgrupper substituert fenylrest, X betegner en carbonyl- , hydroxymethylen- ,
alkanoyloxymethylen- , alkoxycarbonyloxymethylen- eller dihydroxyfosfinyloxymethylen-gruppe og Y en carbonyl- , methylen- , hydroxymethylen- eller hydroxyiminomethylen-gruppe, såvel som av ketaler, syreaddisjonssalter og de optiske isomerer av disse forbindelser , karakterisert ved atmana) omsetter en forbindelse med den generelle formel
. hvor Y har foran angitte betydning, X' betegner en carbonyl- eller hydroxymethylengruppe, Rg betyr halogen eller alkyl- henholdsvis aryl-sulfonyloxy eller X' og R sammen med methylengruppen i endestilling er resten
eller hvis X' og/eller Y betegner en carbonylgruppe, et ketal eller diketal av denne forbindelse med en forbindelse med den generelle formel
hvor den med hydrogenatomet forbundne substituent R^ har den foran angitte betyd-
- ning, ellerb) omsetter en forbindelse med den generelle formel
hvor Y' betegner en carbonyl- , methylen- eller hydroxymethylengruppe eller hvis Y' betegner en carbonylgruppe, et ketal av denne forbindelse med en forbindelse med den generelle formel
hvor den med methylengruppen forbundne substituent og X' har foran angitte betydning, R„ betyr halogen, alkyl- henholdsvis aryl-sulfonyloxy eller R„ og X' sammen med methylengruppen i endestilling er resten -
hydrerer eventuelt det erholdte produkt, ketaliserer eller reduserer eller oximerer hvis ønsket en foreliggende carbonylgruppe Y, reduserer eventuelt en forekommende carbonylgruppe X, enten oxyderer eller forestrer hvis ønsket en forekommende hydroxymethylengruppe X og at man hvis ønsket overfører de oppnådde forbindelser til et syreaddisjonssalt og/eller spalter det opp i de tilsvarende optiske isomerer.
2. Fremgangsmåte efter krav 1, karakterisert ved at man omsetter 4-[2 ,3-epoxy-propoxy]-benzofenon eller 4-[2-hydroxy-3-halogen (henholdsvis mesyloxy eller tosyloxy)-propoxy]-benzofenon med 4-fenyl-l ,2 ,3 ,6-tetrahydropyridin.
3.. Fremgangsmåte efter krav 1, karakterisert ved at man omsetter 4-hydroxy-benzofenon med l-[2,3-epoxy-propyl]-4-fenyl-l ,2 ,3 ,6-tetrahydropyridin
eller med l-[2-hydroxy-3-halogen(henholdsvis mesyloxy eller tosyloxy)-propyl]-4-
i f enyl-1,2,3 ,6-tetrahydropyridin.
4. Fremgangsmåte efter krav 1, karakterisert ved at man omsetter 4-[2 ,3-epoxy-propoxy]-4'-fluor-benzofenon eller 4-[2-hydroxy-3-hologen(henholdsvis mesyloxy eller .tosyloxy)-propoxy]-4'-fluor-benzofenon med 4-[p-klorfenyl]-piper azin.
5. Fremgangsmåte efter krav 1, karakterisert ved at man omsetter 4-hydroxy-4'-fluor-benzofenon med l-[2,3-epoxy-propyl]-4-[p-klorfenyl]-piperazin eller med l-[2-hydroxy-3-halogen(henholdsvis mesyloxy eller tosyloxy)-propyl]-4-[p-klor-f enyl] - piperazin.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CH1076965A CH475242A (de) | 1966-06-24 | 1966-06-24 | Verfahren zur Herstellung von aromatischen Äthern |
DEH0059753 | 1966-06-24 |
Publications (1)
Publication Number | Publication Date |
---|---|
NO121212B true NO121212B (no) | 1971-02-01 |
Family
ID=25707254
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NO164109A NO121212B (no) | 1966-06-24 | 1966-07-29 |
Country Status (11)
Country | Link |
---|---|
US (2) | US3528976A (no) |
BE (1) | BE684600A (no) |
BR (1) | BR6681621D0 (no) |
CH (1) | CH479603A (no) |
DE (2) | DE1695146A1 (no) |
FR (1) | FR6263M (no) |
GB (2) | GB1085106A (no) |
IL (1) | IL26198A (no) |
NL (2) | NL6610566A (no) |
NO (1) | NO121212B (no) |
SE (1) | SE322775B (no) |
Families Citing this family (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
NL133317C (no) * | 1966-06-24 | 1900-01-01 | ||
US3879405A (en) * | 1970-06-19 | 1975-04-22 | Hoffmann La Roche | Tetrahydropyridine derivatives |
US3951987A (en) * | 1970-06-19 | 1976-04-20 | Hoffmann-La Roche Inc. | Tetrahydropyridine derivatives |
US3927006A (en) * | 1970-06-19 | 1975-12-16 | Hoffmann La Roche | Tetrahydropyridine derivatives |
US5182296A (en) * | 1989-10-26 | 1993-01-26 | Tanabe Seiyaky Co., Ltd. | Naphthyloxazolidone derivatives |
US5698565A (en) * | 1995-06-09 | 1997-12-16 | Hoffmann-La Roche Inc. | Use of phenoxy-pyridine derivatives |
CA2464109A1 (en) * | 2001-10-18 | 2003-12-24 | Michigan State University | Process for the preparation of oxazolidinones and method of use thereof |
WO2008036662A2 (en) * | 2006-09-18 | 2008-03-27 | Starfire Systems, Inc. | Process for preparing siloxane-based compositions and derivative compositions thereof |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3108115A (en) * | 1959-10-23 | 1963-10-22 | Allied Chem | Production of 2-oxazolidones |
US3231577A (en) * | 1960-07-25 | 1966-01-25 | Dow Chemical Co | Production of oxazolidinones |
NL133317C (no) * | 1966-06-24 | 1900-01-01 |
-
0
- NL NL133317D patent/NL133317C/xx active
-
1966
- 1966-06-24 DE DE19661695146 patent/DE1695146A1/de active Pending
- 1966-06-28 DE DE19661695148 patent/DE1695148A1/de active Pending
- 1966-07-19 US US566214A patent/US3528976A/en not_active Expired - Lifetime
- 1966-07-22 GB GB33016/66A patent/GB1085106A/en not_active Expired
- 1966-07-22 IL IL26198A patent/IL26198A/en unknown
- 1966-07-26 BE BE684600D patent/BE684600A/xx unknown
- 1966-07-27 NL NL6610566A patent/NL6610566A/xx unknown
- 1966-07-28 BR BR181621/66A patent/BR6681621D0/pt unknown
- 1966-07-28 FR FR71191A patent/FR6263M/fr not_active Expired
- 1966-07-28 GB GB34028/66A patent/GB1111917A/en not_active Expired
- 1966-07-29 SE SE10328/66A patent/SE322775B/xx unknown
- 1966-07-29 NO NO164109A patent/NO121212B/no unknown
-
1967
- 1967-06-23 CH CH895667A patent/CH479603A/de not_active IP Right Cessation
-
1970
- 1970-05-21 US US39505A patent/US3706755A/en not_active Expired - Lifetime
Also Published As
Publication number | Publication date |
---|---|
US3528976A (en) | 1970-09-15 |
IL26198A (en) | 1970-10-30 |
DE1695148A1 (de) | 1970-12-17 |
GB1085106A (en) | 1967-09-27 |
NL133317C (no) | 1900-01-01 |
SE322775B (no) | 1970-04-20 |
FR6263M (no) | 1968-08-26 |
BE684600A (no) | 1967-01-26 |
NL6610566A (no) | 1967-01-31 |
CH479603A (de) | 1969-10-15 |
US3706755A (en) | 1972-12-19 |
DE1695146A1 (de) | 1970-12-17 |
GB1111917A (en) | 1968-05-01 |
BR6681621D0 (pt) | 1973-12-27 |
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