NO127919B - - Google Patents
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- NO127919B NO127919B NO314268A NO314268A NO127919B NO 127919 B NO127919 B NO 127919B NO 314268 A NO314268 A NO 314268A NO 314268 A NO314268 A NO 314268A NO 127919 B NO127919 B NO 127919B
- Authority
- NO
- Norway
- Prior art keywords
- benzyl
- tetrahydropyridine
- hexahydro
- formula
- solution
- Prior art date
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- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 17
- 238000000034 method Methods 0.000 claims description 12
- 150000001875 compounds Chemical class 0.000 claims description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- 238000010438 heat treatment Methods 0.000 claims description 7
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 6
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 6
- 239000012279 sodium borohydride Substances 0.000 claims description 6
- 238000003747 Grignard reaction Methods 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- 239000002841 Lewis acid Substances 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 150000007517 lewis acids Chemical class 0.000 claims description 4
- VSWICNJIUPRZIK-UHFFFAOYSA-N 2-piperideine Chemical class C1CNC=CC1 VSWICNJIUPRZIK-UHFFFAOYSA-N 0.000 claims description 3
- 230000001476 alcoholic effect Effects 0.000 claims description 3
- 150000004820 halides Chemical class 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 3
- 239000011707 mineral Substances 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- 238000007363 ring formation reaction Methods 0.000 claims description 3
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims description 2
- 239000000376 reactant Substances 0.000 claims description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 56
- 239000000243 solution Substances 0.000 description 31
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 21
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 20
- 239000000203 mixture Substances 0.000 description 19
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 239000007787 solid Substances 0.000 description 15
- -1 methoxy, ethoxy Chemical group 0.000 description 13
- 239000000047 product Substances 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- 238000002844 melting Methods 0.000 description 12
- 230000008018 melting Effects 0.000 description 12
- 239000011541 reaction mixture Substances 0.000 description 11
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- 238000010992 reflux Methods 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 7
- 239000012458 free base Substances 0.000 description 7
- 239000011777 magnesium Substances 0.000 description 7
- 229910052749 magnesium Inorganic materials 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 6
- 239000003921 oil Substances 0.000 description 5
- 239000002244 precipitate Substances 0.000 description 5
- NURQLCJSMXZBPC-UHFFFAOYSA-N 3,4-dimethylpyridine Chemical compound CC1=CC=NC=C1C NURQLCJSMXZBPC-UHFFFAOYSA-N 0.000 description 4
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 235000019441 ethanol Nutrition 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- MOHYOXXOKFQHDC-UHFFFAOYSA-N 1-(chloromethyl)-4-methoxybenzene Chemical compound COC1=CC=C(CCl)C=C1 MOHYOXXOKFQHDC-UHFFFAOYSA-N 0.000 description 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 3
- 239000000908 ammonium hydroxide Substances 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 239000012259 ether extract Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000002002 slurry Substances 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- YXFZCACEHYCPHA-UHFFFAOYSA-N 1,2-dibenzyl-3,4-dimethyl-2H-pyridine Chemical compound C(C1=CC=CC=C1)N1C(C(=C(C=C1)C)C)CC1=CC=CC=C1 YXFZCACEHYCPHA-UHFFFAOYSA-N 0.000 description 2
- OQKHDOZOAIDXNV-UHFFFAOYSA-N 1,6-dibenzyl-4,5-dimethyl-3,6-dihydro-2h-pyridine Chemical compound C=1C=CC=CC=1CN1CCC(C)=C(C)C1CC1=CC=CC=C1 OQKHDOZOAIDXNV-UHFFFAOYSA-N 0.000 description 2
- SPGJRQAEUMRKOO-UHFFFAOYSA-M 1-benzyl-3,4-dimethylpyridin-1-ium iodide Chemical compound [I-].C(C1=CC=CC=C1)[N+]1=CC(=C(C=C1)C)C SPGJRQAEUMRKOO-UHFFFAOYSA-M 0.000 description 2
- OWVMQHCIDREXSX-UHFFFAOYSA-M 1-benzyl-3,4-dimethylpyridin-1-ium;bromide Chemical compound [Br-].C1=C(C)C(C)=CC=[N+]1CC1=CC=CC=C1 OWVMQHCIDREXSX-UHFFFAOYSA-M 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 239000007818 Grignard reagent Substances 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- 229940035676 analgesics Drugs 0.000 description 2
- 239000000730 antalgic agent Substances 0.000 description 2
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 2
- 229940073608 benzyl chloride Drugs 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000010520 demethylation reaction Methods 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000012362 glacial acetic acid Substances 0.000 description 2
- 150000004795 grignard reagents Chemical class 0.000 description 2
- 238000007327 hydrogenolysis reaction Methods 0.000 description 2
- 239000000155 melt Substances 0.000 description 2
- 235000010755 mineral Nutrition 0.000 description 2
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- 150000003891 oxalate salts Chemical class 0.000 description 2
- 235000006408 oxalic acid Nutrition 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- AOCXXQNURLBPMB-UHFFFAOYSA-N 1,13-dimethyl-10-azatricyclo[7.3.1.02,7]trideca-2,4,6-triene Chemical compound C1C2=CC=CC=C2C2(C)C(C)C1NCC2 AOCXXQNURLBPMB-UHFFFAOYSA-N 0.000 description 1
- ZDZRSXDYPGEIBS-UHFFFAOYSA-N 1,6-dibenzyl-4,5-dimethyl-3,6-dihydro-2h-pyridine;oxalic acid Chemical compound OC(=O)C(O)=O.C=1C=CC=CC=1CN1CCC(C)=C(C)C1CC1=CC=CC=C1 ZDZRSXDYPGEIBS-UHFFFAOYSA-N 0.000 description 1
- KSKPCURZYVZTBP-UHFFFAOYSA-N 1-benzyl-2-[(4-methoxyphenyl)methyl]-3,4-dimethyl-2h-pyridine Chemical group C1=CC(OC)=CC=C1CC1C(C)=C(C)C=CN1CC1=CC=CC=C1 KSKPCURZYVZTBP-UHFFFAOYSA-N 0.000 description 1
- CWNOHDOVDQQNRN-UHFFFAOYSA-N 1-benzyl-3,4-dimethyl-2H-pyridine Chemical compound C(C1=CC=CC=C1)N1CC(=C(C=C1)C)C CWNOHDOVDQQNRN-UHFFFAOYSA-N 0.000 description 1
- LQJZTXYKZKEWHV-UHFFFAOYSA-N 1-benzyl-4,5-dimethyl-3,6-dihydro-2H-pyridine oxalic acid Chemical compound C(C(=O)O)(=O)O.C(C1=CC=CC=C1)N1CC(=C(CC1)C)C LQJZTXYKZKEWHV-UHFFFAOYSA-N 0.000 description 1
- SICFQRREHHVVBL-UHFFFAOYSA-N 1-benzyl-4-ethyl-3-methyl-2H-pyridine Chemical compound C(C1=CC=CC=C1)N1CC(=C(C=C1)CC)C SICFQRREHHVVBL-UHFFFAOYSA-N 0.000 description 1
- FHGJMCCUVVAWNM-UHFFFAOYSA-M 1-benzyl-4-ethyl-3-methylpyridin-1-ium;iodide Chemical compound [I-].C1=C(C)C(CC)=CC=[N+]1CC1=CC=CC=C1 FHGJMCCUVVAWNM-UHFFFAOYSA-M 0.000 description 1
- FGVXHUJLIAKCEK-UHFFFAOYSA-N 1-benzyl-6-[(4-methoxyphenyl)methyl]-4,5-dimethyl-3,6-dihydro-2h-pyridine Chemical compound C1=CC(OC)=CC=C1CC1C(C)=C(C)CCN1CC1=CC=CC=C1 FGVXHUJLIAKCEK-UHFFFAOYSA-N 0.000 description 1
- RPMPAQXGZYLEST-UHFFFAOYSA-N 3-benzyl-6,11-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocin-8-ol Chemical compound CC1C2CC3=CC=C(O)C=C3C1(C)CCN2CC1=CC=CC=C1 RPMPAQXGZYLEST-UHFFFAOYSA-N 0.000 description 1
- FTAHXMZRJCZXDL-UHFFFAOYSA-N 3-piperideine Chemical compound C1CC=CCN1 FTAHXMZRJCZXDL-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 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 1
- XADCESSVHJOZHK-UHFFFAOYSA-N Meperidine Chemical compound C=1C=CC=CC=1C1(C(=O)OCC)CCN(C)CC1 XADCESSVHJOZHK-UHFFFAOYSA-N 0.000 description 1
- 239000004743 Polypropylene Substances 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 238000006640 acetylation reaction Methods 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- ATDGTVJJHBUTRL-UHFFFAOYSA-N cyanogen bromide Chemical compound BrC#N ATDGTVJJHBUTRL-UHFFFAOYSA-N 0.000 description 1
- 230000020335 dealkylation Effects 0.000 description 1
- 238000006900 dealkylation reaction Methods 0.000 description 1
- 238000006264 debenzylation reaction Methods 0.000 description 1
- 239000003599 detergent Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000004744 fabric Substances 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 238000005187 foaming Methods 0.000 description 1
- 238000004508 fractional distillation Methods 0.000 description 1
- 239000000295 fuel oil Substances 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 150000004694 iodide salts Chemical group 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 229960005181 morphine Drugs 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- DXESFJJJWBHLJX-UHFFFAOYSA-N norcyclazocine Chemical compound C1C2=CC=C(O)C=C2C2(C)C(C)C1NCC2 DXESFJJJWBHLJX-UHFFFAOYSA-N 0.000 description 1
- GEVPUGOOGXGPIO-UHFFFAOYSA-N oxalic acid;dihydrate Chemical compound O.O.OC(=O)C(O)=O GEVPUGOOGXGPIO-UHFFFAOYSA-N 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 229960000482 pethidine Drugs 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 229920001155 polypropylene Polymers 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
Landscapes
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Hydrogenated Pyridines (AREA)
- Other In-Based Heterocyclic Compounds (AREA)
Description
Fremgangsmåte til fremstilling av 1,2,3,4,5,6-heksahydro-8- Process for the preparation of 1,2,3,4,5,6-hexahydro-8-
(H eller OH)-2,6-metano-3-benzazociner. (H or OH)-2,6-methano-3-benzazocines.
Foreliggende oppfinnelse vedrører en ny.fremgangsmåte til fremstilling av 1,2,3,4,5,6-heksahydro-8-(H eller OH)-2,6-metano-3-benzazociner, som er verdifulle som farmasøytiske mellomprodukter, og som har den generelle formel: The present invention relates to a new process for the production of 1,2,3,4,5,6-hexahydro-8-(H or OH)-2,6-methano-3-benzazocines, which are valuable as pharmaceutical intermediates, and which has the general formula:
hvor R 1 og R 2 hver betyr alkyl med 1-4 karbonatomer, og Z betyr hydrogen eller hydroksy. Denne fremgangsmåte er kjennetegnet ved at et N-benzyl-3-(R 2 )-4-(R 1)-pyridiniumhalogenid med formelen: 1 • 2 hvor R og R har den ovenfor angitte betydning, og Hal betyr halogen, omsettes med p-Y-benzylmagnesiumhalogenid ved en Grignard-raaksjon til dannelse av N-benzyl-2-(p-Y-benzyl)- J>-(R 2 )-4-(R 1)-l,2-dihydropyridin med. formelen: hvor R 1 og R 2 har den ovenfor angitte betydning, og Y betyr hydrogen eller alkoksy, og denne forbindelse reduseres med natriumborhydrid i vandig alkoholisk oppløsning til dannelse av N-benzyl-2-(p-Y-benzyl)-3-(R 2 )-4-(R L)-l,2,5,6-tetrahydropyridin med formelen: 1 2 hvor Y, R og R har den ovenfor angitte betydning, hvoretter denne tetrahydropyridin ringsluttes ved oppvarming med en sterk mineralsyre eller med aluminiumklorid eller en annen sterk Lewis-syre til dannelse av l,2,3,4,5,6-heksahydro-3-benzyl-6-(R<1>)-ll-(R<2>)-8-(Z)-2,6-metano-3-benzazocin med formelen: where R 1 and R 2 each mean alkyl with 1-4 carbon atoms, and Z means hydrogen or hydroxy. This method is characterized by the fact that an N-benzyl-3-(R 2 )-4-(R 1)-pyridinium halide with the formula: 1 • 2 where R and R have the above meaning, and Hal means halogen, is reacted with p-Y -benzylmagnesium halide by a Grignard reaction to form N-benzyl-2-(p-Y-benzyl)-J>-(R 2 )-4-(R 1)-1,2-dihydropyridine with. the formula: where R 1 and R 2 have the meaning given above, and Y means hydrogen or alkoxy, and this compound is reduced with sodium borohydride in aqueous alcoholic solution to form N-benzyl-2-(p-Y-benzyl)-3-(R 2 )-4-(R L )-1,2,5,6-tetrahydropyridine with the formula: 1 2 where Y, R and R have the meaning given above, after which this tetrahydropyridine is ring-closed by heating with a strong mineral acid or with aluminum chloride or a other strong Lewis acid to form 1,2,3,4,5,6-hexahydro-3-benzyl-6-(R<1>)-11-(R<2>)-8-(Z)- 2,6-methano-3-benzazocine with the formula:
1 2 1 2
hvor R , R og Z har den ovenfor angitte betydning, og denne forbindelse N-debenzyleres ved katalytisk hydrogenering. where R , R and Z have the above meaning, and this compound is N-debenzylated by catalytic hydrogenation.
I en foretrukken fremgangsmåte for utførelse av den ovenfor omtalte prosess, behandles mellomproduktet N-benzyl-2-(p-Y-benzyl)-3- (R 2 )-4-(R 1)-l,2,5,6-tetrahydropyridin, dannet ved reduksjonen med natriumborhydrid, med oksalsyre for å gi N-benzyl-2-(p-Y-benzyl)-3-(R p)-4- (R1)-1,2,5,6-tetrahydropyridinoksalat, som.er et krystallinsk syre-addisjonssalt, og dette salt blir deretter isolert og omdannet til den frie base ved behandling med sterk alkali eller oksalatet blir med for-del anvendt som sådant istedenfor den frie base ved ringslutningen i prosessen. In a preferred method for carrying out the above-mentioned process, the intermediate N-benzyl-2-(p-Y-benzyl)-3-(R 2 )-4-(R 1 )-1,2,5,6-tetrahydropyridine is treated, formed by the reduction with sodium borohydride, with oxalic acid to give N-benzyl-2-(p-Y-benzyl)-3-(R p)-4-(R1)-1,2,5,6-tetrahydropyridine oxalate, which is a crystalline acid addition salt, and this salt is then isolated and converted to the free base by treatment with strong alkali or the oxalate is advantageously used as such instead of the free base in the cyclization of the process.
R 1 og R 2er like eller forskjellige alkylgrupper, om omfatter både rettkjedede og forgrenede grupper inneholdende 1-4 karbonatomer, f.eks. metyl, etyl, isopropyl, n-butyl og lignende. Når Y er alkoksy omfatter denne gruppe både rettkjedede og forgrenede alkyler, fortrinnsvis inneholdende 1-4 karbonatomer, f.eks. metoksy, etoksy, ■", n-propoksy, isobutoksy og lignende. • ' • ' p 1 Halogemdet i reaktantene N-benzyl-3-(R )-4-(R )-pyridiniumhalogenid og (p-Y-benzyl) magnesiumhalogenid er vanligvis klorid, bromid eller jodid., hvor det foretrukne halogenid er jodid i den først-nevnte forbindelse og klorid i den sistnevnte. R 1 and R 2 are the same or different alkyl groups, if they include both straight-chain and branched groups containing 1-4 carbon atoms, e.g. methyl, ethyl, isopropyl, n-butyl and the like. When Y is alkoxy, this group includes both straight-chain and branched alkyls, preferably containing 1-4 carbon atoms, e.g. methoxy, ethoxy, ■", n-propoxy, isobutoxy and the like. • ' • ' p 1 The halogen in the reactants N-benzyl-3-(R )-4-(R )-pyridinium halide and (p-Y-benzyl) magnesium halide is usually chloride, bromide or iodide, where the preferred halide is iodide in the first-mentioned compound and chloride in the latter.
1,2,3,4,5,6-heksahydro-6-(R<1>)-11-(R<2>)-8-(Z)-2,6-metano-3-benzazociner fremstilt ved fremgangsmåten ifølge oppfinnelsen, er kjemiske mellomprodukter som er kjent for å være egnede for omdan- 1,2,3,4,5,6-hexahydro-6-(R<1>)-11-(R<2>)-8-(Z)-2,6-methano-3-benzazocines prepared by the method according to the invention, chemical intermediates which are known to be suitable for conversion are
nelse til N-substituerte derivater derav, hvilke derivater er nyttige som farmasøytiske midler, f.eks. som analgetika og som.antagonister av sterke analgetiske midler, slik som morfin og meperidin. Den kon-vensjonelle metode for tilveiebringelse av disse kjemiske mellompro- nelse to N-substituted derivatives thereof, which derivatives are useful as pharmaceutical agents, e.g. as analgesics and as antagonists of strong analgesics, such as morphine and meperidine. The conventional method for providing these chemical intermediates
dukter omfatter fremstilling av 1,2,3,4,5, 6-heksahydro—3~metyl-6-12 ducts include the preparation of 1,2,3,4,5, 6-hexahydro-3~methyl-6-12
(R )-ll-(R )-8-(Z)-2,6-metano-3-benzazocin og deretter N-demetylering av denne forbindelse. Således omsettes (benzyl eller p-metoksybenzyl9 magnesiumhalogenid med N-metyl-3-(R 2 )-4-(R i)pyridiniumhalogenid for å gi N-metyl-2-(benzyl eller p-metoksybenzyl)-3-(R<2>)-4-(R<1>)-!,2-dihydropyridin, som deretter reduseres til N-metyl-2-(benzyl eller p-metoksybenzyl)-3_(R 2 )-4-(R 1)-l,2,5,6-tetrahydropyridin, hvor denne sistnevnte forbindelse ringsluttes ved oppvarming med en sterk mine- (R )-11-(R )-8-(Z)-2,6-methano-3-benzazocine and then N-demethylation of this compound. Thus (benzyl or p-methoxybenzyl9 magnesium halide is reacted with N-methyl-3-(R 2 )-4-(R i )pyridinium halide to give N-methyl-2-(benzyl or p-methoxybenzyl)-3-(R< 2>)-4-(R<1>)-!,2-dihydropyridine, which is then reduced to N-methyl-2-(benzyl or p-methoxybenzyl)-3_(R 2 )-4-(R 1)- 1,2,5,6-tetrahydropyridine, where this latter compound is ring-closed by heating with a strong mine-
ralsyre (eller med aluminiumklorid eller en annen sterk Lewis-syre) ralic acid (or with aluminum chloride or another strong Lewis acid)
for å gi l,2,3,4,5,6-heksahydro-3-metyl-6-(R<1>)-ll-(R<2>)-8-(Z)-2,6-metano-3-benzazocin, og deretter fjerning av N- (eller 3-) metyl- to give 1,2,3,4,5,6-hexahydro-3-methyl-6-(R<1>)-11-(R<2>)-8-(Z)-2,6-methano -3-benzazocine, and then removal of the N- (or 3-) methyl-
gruppen ved behandling med cyanogenbromid (etter O-acetylering hvis Z er hydroksy) for å danne N-cyanoderivatet, som deretter hydrolyseres group on treatment with cyanogen bromide (after O-acetylation if Z is hydroxy) to form the N-cyano derivative, which is then hydrolyzed
til den ønskede N-desmetyl (dvs. N-H)-forbindelse, 1,2,3,4,5,6-heksa-hydro-6-(R<1>)-ll-(R<2>)-8-(Z)-2,6-metano-3-benzazocin, hvor R<1>, R<2>, Y to the desired N-desmethyl (ie N-H) compound, 1,2,3,4,5,6-hexa-hydro-6-(R<1>)-ll-(R<2>)-8- (Z)-2,6-methano-3-benzazocine, where R<1>, R<2>, Y
og Z har den .samme betydning som angitt ovenfor. En ulempe med denne tidligere kjente fremgangsmåte er at N-demetyleringen gir realtivt dårlig utbytte. På den annen side gir foreliggende fremgangsmåte relativt høyt utbytte av et produkt med utmerket kvalitet. and Z has the same meaning as set forth above. A disadvantage of this previously known method is that the N-demethylation gives a relatively poor yield. On the other hand, the present method gives a relatively high yield of a product of excellent quality.
Det innledende trinn i den nye fremgangsmåten omfatter omsetning mellom N-benzyl-3-(R 2 )-4-(R 1)-pyridiniumhalogenid og $?-Y-benzyl) magnesiumhalogenid, under typiske betingelser for en Grignard-reaksjon, og isolering av produktet på vanlig måte. The initial step in the new process involves reaction between N-benzyl-3-(R 2 )-4-(R 1 )-pyridinium halide and $?-Y-benzyl) magnesium halide, under typical conditions for a Grignard reaction, and isolation of the product in the usual way.
N-benzyl-2-(p-Y-benzyl)-3-(R<2>)-4-(R<1>)-l,2-dihydropyridin N-benzyl-2-(p-Y-benzyl)-3-(R<2>)-4-(R<1>)-1,2-dihydropyridine
som resulterer fra Grignard-reaksjonen, blir deretter redusert til den tilsvarende 1,2,5,6-tetrahydropyridin. Denne reduksjon utføres på egnet måte ved bruk av en vandig alkoholisk oppløsning av natrium- which results from the Grignard reaction, is then reduced to the corresponding 1,2,5,6-tetrahydropyridine. This reduction is conveniently carried out using an aqueous alcoholic solution of sodium
borhydrid. Det er oppdaget en spesielt fordelaktig måte for"å be-virke, isolering og ren-sing av'reduksj onsproduktet, dvs. N-benzyl-2-(p-Y-benzyl')-3-(R )-4-(R )^-l,2,5,6-tetrahydropyridin. Til en oppløs-ning av den urene tetrapyridinforbindélse i et egnet oppløsnlngs-middel, f.eks. aceton, tilsettes således tilstrekkelig oksalsyre til å omdanne basen til dens oksalatsålt.- Dette krystallinske salt iso-leres lett med utmerket utbytte-og på samme tid oppnås en uvanlig ren og effektiv separering av de ønskede N-benzyl-2-(p-Y-benzyI)~3_ borohydride. A particularly advantageous way of making, isolating and purifying the reduction product has been discovered, i.e. N-benzyl-2-(p-Y-benzyl)-3-(R )-4-(R ) ^-1,2,5,6-tetrahydropyridine To a solution of the impure tetrapyridine compound in a suitable solvent, eg acetone, sufficient oxalic acid is thus added to convert the base into its oxalate salt.- This crystalline salt is easily isolated with excellent yield - and at the same time an unusually clean and efficient separation of the desired N-benzyl-2-(p-Y-benzyI)~3_ is achieved
(R )-4-(R )-l,2,5,6-tetrahydropyridin-mellomprodukter fra uønskede biprodukter som oppstår ved Grignard-reaksjonen og reduksjonen. Selv om dat således oppnådde oksalat lett kan omdannes til den rene frie base, er dette ikke nødvendig, men isteden er det i alminnelighet foretrukket å benytte oksalatet som sådant ved krystalliseringen. (R )-4-(R )-1,2,5,6-tetrahydropyridine intermediates from unwanted byproducts arising from the Grignard reaction and reduction. Although the oxalate thus obtained can easily be converted into the pure free base, this is not necessary, but instead it is generally preferred to use the oxalate as such during the crystallization.
N-benzyl-2-(p-Y-benzyl)-3-(R<2>)-4-(R<1>)-1,2,5,6-tetrahydropyridin ringsluttes ved oppvarming med en sterk mineralsyre, f,eks. 85% fosforsyre eller fortrinnsvis konsentrert hydrobromsyre eller om ønsket med en sterk Lewis-syre, til 1,2,3,4,5,6-heksahydro-3-benzyl-6-(R<1>)-ll-(R<2>)-8-(Z)-2,6-metano-3-benzazocin. Når Y er lavere alkoksy, omdannes denne gruppe til hydroksy ved dealkylering samtidig med ringslutningsreaksjnnen. N-benzyl-2-(p-Y-benzyl)-3-(R<2>)-4-(R<1>)-1,2,5,6-tetrahydropyridine is ring-closed by heating with a strong mineral acid, e.g. . 85% phosphoric acid or preferably concentrated hydrobromic acid or if desired with a strong Lewis acid, to 1,2,3,4,5,6-hexahydro-3-benzyl-6-(R<1>)-ll-(R< 2)-8-(Z)-2,6-methano-3-benzazocine. When Y is lower alkoxy, this group is converted to hydroxy by dealkylation at the same time as the ring closure reaction.
Til slutt, N-debenzyleres 3-(eller N-) benzyl-ringslut-ningsproduktet ved katalytisk hydrogenolyse i nærvær av en kataly-sator av edelt metall slik som palladium, for således å -gi den ønskede l,2,3,4,5,6-heksahydro-6-(R<1>)-ll-(R<2>)-8-(Z)-2,6-metano-3-benzazocin. Finally, the 3-(or N-) benzyl ring closure product is N-debenzylated by catalytic hydrogenolysis in the presence of a noble metal catalyst such as palladium, thus giving the desired 1,2,3,4, 5,6-hexahydro-6-(R<1>)-11-(R<2>)-8-(Z)-2,6-methano-3-benzazocine.
Følgende eksempler illustrerer oppfinnelsen. The following examples illustrate the invention.
Eksempel 1. Example 1.
A. En blanding av 30 g natriumjodid og 120 ml aceton om-røres inntil den fullstendige oppløsning oppnås. Til denne blanding tilsettes 25,3 g benzylklorid på en gang og omrøring fortsettes i l£ time. Reaksjonsblandingen filtreres for å fjerne natriumklorid. Den svakt blakkede acetonoppløsning filtreres gjennom diatomé sili-siumdioksyd og til det således oppnådde filtrat tilsettes 21,4 g 3,4-dimetylpyridin. Den resulterende blanding settes til side natten over ved romtemperatur og det således tildannede bunnfall oppsamles på et filter og vaskes med én liten mengde aceton. På denne måten oppnås 60,5 g N-benzyl-3,4-dimetylpyridiniumjodid, smeltepunkt l45-147°C- En annen' del åV dette produkt,' smeltepunktet 137-l40°C, med vekt på 3,7 g oppnås fra filtratet. A. A mixture of 30 g of sodium iodide and 120 ml of acetone is stirred until complete dissolution is achieved. To this mixture, 25.3 g of benzyl chloride are added at once and stirring is continued for 1 hour. The reaction mixture is filtered to remove sodium chloride. The slightly cloudy acetone solution is filtered through diatomaceous silicon dioxide and 21.4 g of 3,4-dimethylpyridine are added to the filtrate thus obtained. The resulting mixture is set aside overnight at room temperature and the precipitate thus formed is collected on a filter and washed with one small amount of acetone. In this way, 60.5 g of N-benzyl-3,4-dimethylpyridinium iodide, melting point 145-147°C are obtained. Another part of this product, melting point 137-140°C, with a weight of 3.7 g is obtained from the filtrate.
En.'3'~ hals et kolbe gpyles med nitrogen og fylles deretter med 11,0 g magnesiumspon, 11,0 g magnesiumpulver og 60 ml vannfri dietyleter. Et jod-krystall og 0,5 g p^-metoksybenzylklorid tilsettes til blandingen, som deretter oppvarmes under tilbåkeløpstemperatur ved vannfrie betingelser inntil reaksjonen begynner. Oppvarming stop-pes og en oppløsning av 35>8 g p-metoksybenzylklorid.i 0,6 liter vannfri dietyleter tilsettes gradvis til reaksjonsblandingen i en slik hastighet at blandingen holdes ved en svak tilbakeløpskoking. Reak-sj onsblandingen omrøres og tilbakeløpskokes i 1^ time og filtreres deretter for å fjerne overskudd av magnesium. Til filtratet tilsettes så 45,7 g N-benzyl-3,4-dimetylpyridiniumjodid porsjonsvis. Et krem-target-orange, gummilignende halvfast stoff separeres umiddelbart fra oppløsningen. Blandingen omrøres og kokes under tilbakeløp i l£ time slik at det gummilignende materiale i løpet av denne tiden forandres til en nesten fargeløs olje. Denne reaksjonsblanding blir, etter å ha stått natten over ved romtemperatur, blandet med en oppløsning av 14,0 g ammoniumklorid i 200 ml vann. Etter omrøring av blandingen i \\ time omdannes det gummilignende materiale som til å begynne med utskilles til et lysegult fast stoff. Dette faste stoff fjernes ved filtrering. Eterlaget i filtratet separeres fra det vandige lag og vaskes med vann og deretter fjernes eteren under forminsket trykk for således å gi en oljerest som veier 57,5 g« Dette produkt er N-benzyl-2-(p-metoksybenzyl)-3,4-dimetyl-l,2-dihydropyridin. A 3-neck flask is purged with nitrogen and then filled with 11.0 g of magnesium shavings, 11.0 g of magnesium powder and 60 ml of anhydrous diethyl ether. An iodine crystal and 0.5 g of p-methoxybenzyl chloride are added to the mixture, which is then heated below reflux temperature under anhydrous conditions until the reaction begins. Heating is stopped and a solution of 35>8 g of p-methoxybenzyl chloride in 0.6 liters of anhydrous diethyl ether is gradually added to the reaction mixture at such a rate that the mixture is kept at a gentle reflux. The reaction mixture is stirred and refluxed for 1^ hour and then filtered to remove excess magnesium. 45.7 g of N-benzyl-3,4-dimethylpyridinium iodide are then added in portions to the filtrate. A cream-target-orange, gummy semi-solid separates immediately from the solution. The mixture is stirred and refluxed for l£ hour so that during this time the rubber-like material changes to an almost colorless oil. After standing overnight at room temperature, this reaction mixture is mixed with a solution of 14.0 g of ammonium chloride in 200 ml of water. After stirring the mixture for \\ hour, the rubber-like material which initially separates is converted to a pale yellow solid. This solid is removed by filtration. The ether layer in the filtrate is separated from the aqueous layer and washed with water and then the ether is removed under reduced pressure to thus give an oil residue weighing 57.5 g« This product is N-benzyl-2-(p-methoxybenzyl)-3,4 -dimethyl-1,2-dihydropyridine.
B. 57,5 g av den således oppnådde N-benzyl-2-(p-metoksybenzyl)^,4-dimetyl-l,2-dihydropyridin, blandes med 165 ml metylalkohol og den resulterende oppløsning, hvori noe av materialet forblir i suspensjonen, omrøres mens det tilsettes en fin strøm av en oppløs-ning av 3,9 g natriumborhydrid i 50 ml vann. Reaksjonsblandingen om-røres deretter ved romtemperatur i 19 timer. Metylalkoholen avdestil-leres fra reaksjonsblandingen under forminsket trykk og den resterende vandige blanding ekstraheres med dietyleter. Eteroppløsningen separeres og ekstraheres fire ganger: to ganger med en oppløsning av 8,0 g av 85$ fosforsyre i 150 ml vann; en gang med en oppløsning av 1,5 g av 85% fosforsyre i 100 ml vann; og til slutt med 100 ml vann. Disse fire ekstrakter kombineres og gjøres sterkt alkalisk ved tilsetning av 35% vandig natriumhydroksydoppløsning, og ekstraheres deretter flere ganger med dietyleter. Eterekstråktene kombineres og tørkes over vannfritt natriumsulfat og eteren avdestilieres under forminsket trykk. Dette gir 32,5 g resterende olje som er uren N- B. 57.5 g of the thus obtained N-benzyl-2-(p-methoxybenzyl)^,4-dimethyl-1,2-dihydropyridine are mixed with 165 ml of methyl alcohol and the resulting solution, in which some of the material remains in suspension , is stirred while a fine stream of a solution of 3.9 g of sodium borohydride in 50 ml of water is added. The reaction mixture is then stirred at room temperature for 19 hours. The methyl alcohol is distilled off from the reaction mixture under reduced pressure and the remaining aqueous mixture is extracted with diethyl ether. The ether solution is separated and extracted four times: twice with a solution of 8.0 g of 85% phosphoric acid in 150 ml of water; once with a solution of 1.5 g of 85% phosphoric acid in 100 ml of water; and finally with 100 ml of water. These four extracts are combined and made strongly alkaline by the addition of 35% aqueous sodium hydroxide solution, and then extracted several times with diethyl ether. The ether extracts are combined and dried over anhydrous sodium sulfate and the ether is distilled off under reduced pressure. This gives 32.5 g of residual oil which is impure N-
benzyl-2- (p-metoksybenzyl)-3 ,4-dimetyl-l,2.,5,6-tetrahydropyridin. benzyl-2-(p-methoxybenzyl)-3,4-dimethyl-1,2,5,6-tetrahydropyridine.
C. Den således oppnådde urene tetrahydropyridinbasen til-, settes til en oppløsning av 9,1 g vannfri oksalsyre i 100,ml aceton.. Dette resulterer i en øyeblikkelig utfelling. Blandingen avkjøles, og filtreres og det oppsamlede faste stoff vaskes med et lite volum kald aceton og tørkes.ved 6l°C under forminsket trykk. Dette gir 31,2 g N-benzyl-3,4-dimetyl-l,2,5,6-tetrahydropyridinoksalat i fora , av et hvitt krystallinsk fast stoff som smelter ved 153-158°C. D. Én blanding av 53,8 g N-benzyl-2-(p-metoksybenzyl ).-3,4-dimetyl-1,2,5,6-tetrahydropyridinoksalat, 144 ml iseddik og 285 ml av 62% hydrobromsyre, kokes under tilbakeløp i 22 timer. Reaksjonsblandingen konsentreres deretter under forminsket trykk, hvilket gir et rødbrunt gummilignende stoff. 800 ml isopropylalkohol tilsettes og den resulterende blanding oppvarmes og omrøres for å bryte opp den gummilignende rest. Dette gir en ufullstendig oppløsning inneholdende en betydelig mengde av uoppløst lyserødt fast stoff. Blandingen konsentreres under forminsket trykk til et volum på omtrent 250 ml. Den konsentrerte blanding avkjøles i 1 time og filtreres deretter for å oppsamle et lyserødt bunnfall. Det således oppsamlede faste stoff vaskes med et lite volum kald isopropylalkohol og tørkes ved 65°C.under forminsket trykk. Dette produkt, som veier 35,8 g og smelter ved 130-250°C, oppløses i 450 ml kokende vannfri etylalkohol. Alkoholoppløsningen avkjøles litt og fortynnes med 550 ml vannfri dietyleter og avkjøles i et kjøleskap natten over. Det faste stoff som utfelles oppsamles på et filter og tørkes ved 65°C under forminsket trykk. Dette gir 23,7 g 1,2,3,4,5,6-heksahydro-3-benzyl-6,11-dimetyl-8-hydroksy-2,6-metano-3-benzazocin i- form av et lyserødt fast stoff som smelter ved 259-262°C. C. The impure tetrahydropyridine base thus obtained is added to a solution of 9.1 g of anhydrous oxalic acid in 100 ml of acetone. This results in an immediate precipitation. The mixture is cooled, and filtered and the collected solid is washed with a small volume of cold acetone and dried at 61°C under reduced pressure. This gives 31.2 g of N-benzyl-3,4-dimethyl-1,2,5,6-tetrahydropyridine oxalate in fora, of a white crystalline solid melting at 153-158°C. D. One mixture of 53.8 g of N-benzyl-2-(p-methoxybenzyl ).-3,4-dimethyl-1,2,5,6-tetrahydropyridine oxalate, 144 ml of glacial acetic acid and 285 ml of 62% hydrobromic acid, is boiled under reflux for 22 hours. The reaction mixture is then concentrated under reduced pressure to give a red-brown gummy substance. 800 ml of isopropyl alcohol is added and the resulting mixture is heated and stirred to break up the gummy residue. This gives an incomplete solution containing a significant amount of undissolved pale pink solid. The mixture is concentrated under reduced pressure to a volume of approximately 250 ml. The concentrated mixture is cooled for 1 hour and then filtered to collect a pale red precipitate. The thus collected solid is washed with a small volume of cold isopropyl alcohol and dried at 65°C under reduced pressure. This product, which weighs 35.8 g and melts at 130-250°C, is dissolved in 450 ml of boiling anhydrous ethyl alcohol. The alcohol solution is cooled slightly and diluted with 550 ml anhydrous diethyl ether and cooled in a refrigerator overnight. The solid that precipitates is collected on a filter and dried at 65°C under reduced pressure. This gives 23.7 g of 1,2,3,4,5,6-hexahydro-3-benzyl-6,11-dimethyl-8-hydroxy-2,6-methano-3-benzazocine in the form of a pink solid substance that melts at 259-262°C.
E. En oppløsning av 11,8 g 1,2,3,4,5,6-heksahydro-3~benzyl-6,ll-dimetyl-8-hydroksy-2,6-metano-3-benzazocin i 150 ml dimetylformamid, N-debenzyleres katalytisk ved anvendelse av hydrogen ved et trykk på 56 kg/cm2 ved 50-55°C i nærvær av 0,3 g 10% palladium-på-trekull-katalysator. Hydrdgenolysen er fullstendig i løpet av 3 timer, idet den teoretiske mengde hydrogen blir absorbert. Katalysatoren fjernes ved filtrering og filtratet konsentreres ved inndamp-ning under forminsket trykk til et volum på ca. 60 ml, hvoretter det avkjøles, fortynnes med omtrent 150 ml konsentrert ammoniumhydroksyd og avkjøles på nytt. Det faste stoffet som utfelles, oppsamles på et filter, vaskes med vann og tørkes ved 65°C under forminsket trykk. Dette gir 6 g 1,2,3,4,5,6-heksahydro-6,ll-dimetyl-8-hydroksy-2,6-metano-3-benzazocin i form av et Tysegrønt fast stoff som smelter ved 234-235°C...•... <: V ' Eksempel 2. E. A solution of 11.8 g of 1,2,3,4,5,6-hexahydro-3-benzyl-6,11-dimethyl-8-hydroxy-2,6-methane-3-benzazocine in 150 ml of dimethylformamide , is N-debenzylated catalytically using hydrogen at a pressure of 56 kg/cm2 at 50-55°C in the presence of 0.3 g of 10% palladium-on-charcoal catalyst. Hydrogenolysis is complete within 3 hours, as the theoretical amount of hydrogen is absorbed. The catalyst is removed by filtration and the filtrate is concentrated by evaporation under reduced pressure to a volume of approx. 60 ml, after which it is cooled, diluted with about 150 ml of concentrated ammonium hydroxide and cooled again. The solid which precipitates is collected on a filter, washed with water and dried at 65°C under reduced pressure. This gives 6 g of 1,2,3,4,5,6-hexahydro-6,11-dimethyl-8-hydroxy-2,6-methano-3-benzazocine in the form of a quiet green solid melting at 234-235 °C...•... <: V ' Example 2.
Ved å gå frem på lignende måte som beskrevet i eksempel 1. ovenfor, men ved bruk av- N-benzyl-3-metyl-4-etyipyridin istedenfor N-benzyl-3,4-dimetylpyridin, oppnås først N-benzyl-3-metyl-4-etyl-pyridiniumjodid', smeltepunkt 130-133°C. Når 30,5 g av dette produkt omsettes med den Grignard-reagent som fremstilles fra 24,8 g p-metoksybenzylklorid i 64 ml vannfri dietyleter, 6,9 g magnesiumspon og 6,9 g magnesiumpulver i vannfri dietyleter, oppnås 36,5 g N-benzyl-2-(p-metoksybenzyl)-3-metyl-4-etyl-l,2-dihydropyridin i form av en gulfarget olje. Reduksjon av en oppløsning av dette produkt i 105 ml metylalkohol med en oppløsning av 2,5 g natriumborhydrid i 12,5 ml vann, gir 16,4 g N-benzyl-2-(p-metoksybenzyl)-3_metyl-4-etyl-l,2,5,6-tetrahydropyridin i form av en tung olje. Denne base omsettes med 4,4 g vannfri oksalsyre i 50 ml aceton for således å gi 13,3 g av oksalatsaltet av .basen som nesten hvite krystaller, smeltepunkt 143,5~ l46°C. Når 115,7 g N-benzyl-2-(p-metoksybenzyl)-3-metyl-4-etyl-1,2,5,6-tetrahydropyridinoksalat fremstilt på denne måte, kokes under tilbakeløp og omrøres med 136 ml av 62% hydrobromsyre og 68 ml iseddik i 40 timer, oppnås 69,3 g 1,2,3,4,5,6-heksahydro-3-benzyl-6-etyl-ll-metyl-8-hydroksy-2,6-metano-3-benzazocin i et første utbytte, smeltepunkt 290-293°C, og et annet utbytte av dette produkt, smeltepunkt 295~300°C, med en vekt på 14,0 g oppnås ved bearbeidelse av modervæsken. N-debenzylening' av 69,3 g av dette produkt ved bruk av hydrogen ved et trykk på 27,3 kg/cm<2> ved 60°C i 1 time, gir 33,9 g 1,2,3,4,5,6-heksahydro-6-etyl-ll-metyl-8-hydroksy-2,6-met'ano-3-benzazocin, smeltepunkt 265_269°C. Et ytterligere utbytte av dette produkt gjenvinnes fra modervæsken. By proceeding in a similar manner as described in example 1 above, but using N-benzyl-3-methyl-4-ethylpyridine instead of N-benzyl-3,4-dimethylpyridine, N-benzyl-3- methyl-4-ethyl-pyridinium iodide', melting point 130-133°C. When 30.5 g of this product is reacted with the Grignard reagent which is prepared from 24.8 g of p-methoxybenzyl chloride in 64 ml of anhydrous diethyl ether, 6.9 g of magnesium shavings and 6.9 g of magnesium powder in anhydrous diethyl ether, 36.5 g are obtained N-benzyl-2-(p-methoxybenzyl)-3-methyl-4-ethyl-1,2-dihydropyridine in the form of a yellow oil. Reduction of a solution of this product in 105 ml of methyl alcohol with a solution of 2.5 g of sodium borohydride in 12.5 ml of water gives 16.4 g of N-benzyl-2-(p-methoxybenzyl)-3-methyl-4-ethyl- 1,2,5,6-tetrahydropyridine in the form of a heavy oil. This base is reacted with 4.4 g of anhydrous oxalic acid in 50 ml of acetone to thus give 13.3 g of the oxalate salt of the base as almost white crystals, melting point 143.5~146°C. When 115.7 g of N-benzyl-2-(p-methoxybenzyl)-3-methyl-4-ethyl-1,2,5,6-tetrahydropyridine oxalate prepared in this way is refluxed and stirred with 136 ml of 62% hydrobromic acid and 68 ml of glacial acetic acid for 40 hours, 69.3 g of 1,2,3,4,5,6-hexahydro-3-benzyl-6-ethyl-11-methyl-8-hydroxy-2,6-methano- 3-benzazocine in a first yield, melting point 290-293°C, and a second yield of this product, melting point 295~300°C, with a weight of 14.0 g is obtained by working up the mother liquor. N-debenzylation' of 69.3 g of this product using hydrogen at a pressure of 27.3 kg/cm<2> at 60°C for 1 hour gives 33.9 g of 1,2,3,4, 5,6-hexahydro-6-ethyl-11-methyl-8-hydroxy-2,6-methane-3-benzazocine, melting point 265-269°C. A further yield of this product is recovered from the mother liquor.
Eksempel 3»Example 3»
A. En blanding av 20,6 g 3,4-dimetylpyridin, 32,9 g benzyl-bromid og 120 ml isopropylalkohol, kokes under tilbakeløp i 3 timer for å gi 51,0 g N-benzyl-3,4-dimetylpyridiniumbromid, smeltepunkt 202-204°C. A. A mixture of 20.6 g of 3,4-dimethylpyridine, 32.9 g of benzyl bromide and 120 ml of isopropyl alcohol is refluxed for 3 hours to give 51.0 g of N-benzyl-3,4-dimethylpyridinium bromide, melting point 202-204°C.
En oppløsning av 12,7 g benzylklorid i 70 ml vannfri dietyleter, tilsettes gradvis til 2,7 g magnesiumspon 1 "50 ml dietyleter i.en slik hastighet at reaksjonsblandingen holdes under tilbake-løpskoking. Den resulterende Grignard-reagens helles gradis i en godt omrørt tilbakeløpskokende suspensjon av 16,7 g N-benzyl-3,4-dimetylpyridiniumbromid i 100 ml dietyleter. Damp anvendes om nødsrendig for å holde tilbakeløpskokingen ved like i 3 timer. Reak-sj onsblandingen helles i en godt omrørt blanding av isvann inneholdende 10 g ammoniumklorid. Det organiske ]^g av den resulterende, blanding separeres og den vandige fase ekstraheres i flere ekstraksjoner med et totalt volum på 40 ml dietyleter. Et.erekstraktene kombineres og konsentreres til en olje som veier 18,1 g.. Dette materiale er uren N,2-dibenzyl-3,4-dimetyl-l,2-dihydropyridin. A solution of 12.7 g of benzyl chloride in 70 ml of anhydrous diethyl ether is gradually added to 2.7 g of magnesium filings in 50 ml of diethyl ether at such a rate that the reaction mixture is kept under reflux. The resulting Grignard reagent is gradually poured into a well stirred refluxing suspension of 16.7 g of N-benzyl-3,4-dimethylpyridinium bromide in 100 ml of diethyl ether. Steam is used if necessary to maintain reflux for 3 hours. The reaction mixture is poured into a well-stirred mixture of ice water containing 10 g of ammonium chloride. The organic 1^g of the resulting mixture is separated and the aqueous phase is extracted in several extractions with a total volume of 40 ml of diethyl ether. The ether extracts are combined and concentrated to an oil weighing 18.1 g.. This material is impure N,2-dibenzyl-3,4-dimethyl-1,2-dihydropyridine.
B. Den ovenfor oppnådde urene N,2-dibenzyl-3,4-dimetyl-1,2-dihydropyridin, oppløses, i 64 ml vannfri etylalkohol og til . denne oppløsning tilsettes under omrøring en oppløsning av 1,3 g natriumborhydrid i 6,4 ml vann. Reaksjonsblandingen omrøres i 6 timer uten utvendig oppvarming eller avkjøling, og settes deretter til side natten over ved romtemperatur. Alkoholen inndampes under forminsket trykk og resten omrøres med en blanding av 40 ml vann og 50 ml dietyleter. Eterlaget separeres og det vandige lag ekstraheres med 30 ml dietyleter. Dette ekstrakt kombineres med det innledningsvis oppnådde eterlag. Eteren inndampes og dette resulterer i 16,9 g uren N,2-dibenzyl-3,4-dimetyl-l,2,5,6-tetrahydropyridin i form av en olje. C. Den ovenfor oppnådde urene N,2-dibenzyl-3,4-dimetyl-l, 2, 5,6-tetrahydropyridin oppløstes i 52 ml aceton og til denne oppløs-ning tilsettes en oppløsning av 8,06 g oksalsyre dihydrat i 40 ml aceton. Separering av krystaller fra denne blandingen foregår hurtig. Den resulterende oppslemming settes til side natten over ved 3°C i et kjøleskap. Det krystallinske bunnfall oppsamles, vaskes med 40 ml kald aceton (0°C), og tørkes natten over i en vakuum-ovn ved 6o°C-Dette gir 13,2 g N,2-dibenzyl~3,4-dimetyl-l,2,5,6-tetrahydropyridin-oksalat, smeltepunkt 172-176°C. D. En blanding av 18 g N,2-dibenzy1-3,4-dimetyl-l,2,5,6-tetrahydropyridinoksalat og 114 ml av 48% hydrobromsyre, oppvarmes gradvis til tilbakeløpstemperat.ur. Oppløsningen er fullstendig, ved 155°C. Når fast stoff kommer til syne er det nødvendig, å senke temperaturen ca. 5°C under tilbakeløpstemperatur for å forhindre skumdannelse. Oppvarming ved 112-122°C begynner og fortsettes i 12 timer. Etter avkjøling av reaksjonsblandingen til 10°C oppsamles det faste stoffet i blandingen på en polypropylen-filterduk og vaskes med 80 ml kaldt vann. Den fuktige filterkaken oppslemmes i 40 ml til- B. The impure N,2-dibenzyl-3,4-dimethyl-1,2-dihydropyridine obtained above is dissolved in 64 ml of anhydrous ethyl alcohol and until . a solution of 1.3 g of sodium borohydride in 6.4 ml of water is added to this solution while stirring. The reaction mixture is stirred for 6 hours without external heating or cooling, and is then set aside overnight at room temperature. The alcohol is evaporated under reduced pressure and the residue is stirred with a mixture of 40 ml of water and 50 ml of diethyl ether. The ether layer is separated and the aqueous layer is extracted with 30 ml of diethyl ether. This extract is combined with the initially obtained ether layer. The ether is evaporated and this results in 16.9 g of impure N,2-dibenzyl-3,4-dimethyl-1,2,5,6-tetrahydropyridine in the form of an oil. C. The impure N,2-dibenzyl-3,4-dimethyl-1,2,5,6-tetrahydropyridine obtained above is dissolved in 52 ml of acetone and to this solution is added a solution of 8.06 g of oxalic acid dihydrate in 40 ml of acetone. Separation of crystals from this mixture takes place quickly. The resulting slurry is set aside overnight at 3°C in a refrigerator. The crystalline precipitate is collected, washed with 40 ml of cold acetone (0°C), and dried overnight in a vacuum oven at 6o°C. This gives 13.2 g of N,2-dibenzyl~3,4-dimethyl-l ,2,5,6-tetrahydropyridine oxalate, melting point 172-176°C. D. A mixture of 18 g of N,2-dibenzyl-3,4-dimethyl-1,2,5,6-tetrahydropyridine oxalate and 114 ml of 48% hydrobromic acid is gradually heated to reflux temperature. The solution is complete, at 155°C. When solid matter appears, it is necessary to lower the temperature approx. 5°C below reflux temperature to prevent foaming. Heating at 112-122°C begins and is continued for 12 hours. After cooling the reaction mixture to 10°C, the solid in the mixture is collected on a polypropylene filter cloth and washed with 80 ml of cold water. The moist filter cake is suspended in 40 ml of
bakeløpskokende. isopropylalkohol.,, Oppslemmingen avkjøles til 5°C backflow boiling. isopropyl alcohol.,, The slurry is cooled to 5°C
og filtreres og det oppsamlede faste stoff vaskes med 20 ml kald .. and filtered and the collected solid washed with 20 ml cold ..
(5°C) isopropylalkohol og tørkes deretter natten over i en vakuum-ovn ved 60°C. Dette gir 12,6 g 1,2,3,4,5,6-heksahydro-3-benzyl-6,ll-dimetyl-2,6-metano-3-benzazocin-hydrobromid, smeltepunkt 285-287°C. (5°C) isopropyl alcohol and then dried overnight in a vacuum oven at 60°C. This gives 12.6 g of 1,2,3,4,5,6-hexahydro-3-benzyl-6,11-dimethyl-2,6-methano-3-benzazocine hydrobromide, melting point 285-287°C.
E. En oppløsning av 64,3 g 1,2,3,4,5,6-heksahydro-3-benzyl-6,ll-dimetyl-2,6-metano-3-benzazocin-hydrobromid i 600 ml dimetylformamid, N-debenzyleres katalytisk i løpet av en time ved bruk av, hydrogen ved et trykk på 2,8-3,5 kg/cm2 ved 45"- 70°C i nærvær av 0,65 g 60% piladiumklorid og 5,9 g trekull. Katalysatoren fjernes ved filtrering ved bruk av ytterligere 200 ml dimetylformamid som vaskemiddel. -Oppløsningsmidlet inndampet fra filtratet under forminsket trykk og åen således oppnådde resterende sirup oppløses i isopropylalkohol, avkjøles og gjøres basisk ved tilsetning av 12,6 ml konsentrert ammoniumhydroksyd. (Snarere enn å fortsette gjennom hemi-hydrobromidsaltet som beskrevet nedenunder, hvis sluttprodukt ønskes direkte i form av fri base, er det foretrukket å oppløse den resterende sirup i vann og gjøre oppløsningen basisk ved tilsetning av natriumhydroksydoppløsning snarere enn ammoniumhydroksyd). Den resulterende oppslemming avkjøles natten over ved 3°C i et kjøleskap og filtreres. Det således oppsamlede faste stoff vaskes med 20 ml kald (3°C) isopropylalkohol fulgt av 20 ml pentan og' tørkes ved 60°C i en vakuum-ovn. Dette gir 27,9 g 1,2,3,4,5,6-heksahydro-6,ll-di-metyl-2 , 6-metano-3_benzazocin hemi-hydrobromid (c14Hi9N•2HBr)• Filtratet konsentreres til tørrhet lnvilket gir en tykk masse som ikke kan røres. Denne masse oppløses i 20 ml vann og oppløsningen gjøres basisk ved tilsetning av 10 ml 35% vandig natriumhydroksydoppløsning og ekstraheres, i flere ekstraksjoner med 40 ml dietyleter. Eterek-straktene tørkes over natriumhydroksyd-pellets, oppløsningsmidlet fjernes og resten utsettes for fraksjonert destillasjon under forminsket trykk. Fraksjonen som koker ved 126-130°C ved 0,3-0,5 mm Hg E. A solution of 64.3 g of 1,2,3,4,5,6-hexahydro-3-benzyl-6,11-dimethyl-2,6-methane-3-benzazocine hydrobromide in 600 ml of dimethylformamide, N -debenzylated catalytically within one hour using hydrogen at a pressure of 2.8-3.5 kg/cm2 at 45"-70°C in the presence of 0.65 g 60% piladium chloride and 5.9 g charcoal . The catalyst is removed by filtration using a further 200 ml of dimethylformamide as detergent. - The solvent is evaporated from the filtrate under reduced pressure and the remaining syrup thus obtained is dissolved in isopropyl alcohol, cooled and made basic by the addition of 12.6 ml of concentrated ammonium hydroxide. (Rather than proceeding through the hemi-hydrobromide salt as described below, if the end product is desired directly in the free base form, it is preferred to dissolve the remaining syrup in water and make the solution basic by adding sodium hydroxide solution rather than ammonium hydroxide).The resulting slurry is cooled overnight at 3°C in a refrigerator and covered reres. The thus collected solid is washed with 20 ml of cold (3°C) isopropyl alcohol followed by 20 ml of pentane and dried at 60°C in a vacuum oven. This gives 27.9 g of 1,2,3,4,5,6-hexahydro-6,11-dimethyl-2,6-methano-3_benzazocine hemi-hydrobromide (c14Hi9N•2HBr) • The filtrate is concentrated to dryness, which gives a thick mass that cannot be touched. This mass is dissolved in 20 ml of water and the solution is made basic by the addition of 10 ml of 35% aqueous sodium hydroxide solution and extracted, in several extractions with 40 ml of diethyl ether. The ether extracts are dried over sodium hydroxide pellets, the solvent is removed and the residue is subjected to fractional distillation under reduced pressure. The fraction boiling at 126-130°C at 0.3-0.5 mm Hg
2!50C 2!50C
har nDv =1.5600, Z 22,7 og veier 12,6 g. Dette produkt er 1,2,3, 4,5,6-heksahydro-6,ll-dimetyl-2,6-metano-3-benzazoein. has nDv =1.5600, Z 22.7 and weighs 12.6 g. This product is 1,2,3,4,5,6-hexahydro-6,11-dimethyl-2,6-methano-3-benzazoin.
1,2,3,4,5,6-heksahydro-6,ll-dimetyl-2,6-metano-3-benza-zocin hemi-hydrobromid (27,9 g) som oppnådd ovenfor, omdannes til den frie base ved behandling av en vandig oppløsning av saltet med 12 ml 35% vandig natriumhydroksydoppløsning. Dette gir ytterligere 21,3 g av den frie base, slik at det totale utbytte er 33,9 g fri base. 1,2,3,4,5,6-hexahydro-6,11-dimethyl-2,6-methano-3-benzazocine hemihydrobromide (27.9 g) as obtained above is converted to the free base by treatment of an aqueous solution of the salt with 12 ml of 35% aqueous sodium hydroxide solution. This gives a further 21.3 g of the free base, so that the total yield is 33.9 g of free base.
Claims (2)
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US67039167A | 1967-09-25 | 1967-09-25 |
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NO314268A NO127919B (en) | 1967-09-25 | 1968-08-09 |
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JP (2) | JPS5317596B1 (en) |
AT (1) | AT285615B (en) |
IL (1) | IL30338A (en) |
NO (1) | NO127919B (en) |
-
1968
- 1968-07-09 IL IL30338A patent/IL30338A/en unknown
- 1968-07-24 AT AT717468A patent/AT285615B/en not_active IP Right Cessation
- 1968-08-09 NO NO314268A patent/NO127919B/no unknown
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1971
- 1971-11-09 JP JP8874571A patent/JPS5317596B1/ja active Pending
- 1971-11-09 JP JP8874471A patent/JPS4833751B1/ja active Pending
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IL30338A (en) | 1972-10-29 |
AT285615B (en) | 1970-11-10 |
JPS5317596B1 (en) | 1978-06-09 |
JPS4833751B1 (en) | 1973-10-16 |
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