NO125271B - - Google Patents
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- Publication number
- NO125271B NO125271B NO250270A NO250270A NO125271B NO 125271 B NO125271 B NO 125271B NO 250270 A NO250270 A NO 250270A NO 250270 A NO250270 A NO 250270A NO 125271 B NO125271 B NO 125271B
- Authority
- NO
- Norway
- Prior art keywords
- erythro
- benzyl alcohol
- aminoethyl
- ether
- compound
- Prior art date
Links
- 238000000034 method Methods 0.000 claims description 24
- 150000001875 compounds Chemical class 0.000 claims description 15
- 239000002253 acid Substances 0.000 claims description 11
- 239000007858 starting material Substances 0.000 claims description 11
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 9
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 claims description 8
- 150000003839 salts Chemical class 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims 1
- WVDDGKGOMKODPV-UHFFFAOYSA-N benzyl alcohol Substances OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 25
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 24
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 23
- -1 3-benzyloxy-α-(1-aminoethyl)-benzyl Chemical group 0.000 description 18
- 239000000243 solution Substances 0.000 description 17
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- 239000002585 base Substances 0.000 description 12
- 239000000203 mixture Substances 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 11
- 239000011541 reaction mixture Substances 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 10
- 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
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- 238000002844 melting Methods 0.000 description 8
- 230000008018 melting Effects 0.000 description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 7
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 7
- 238000002360 preparation method Methods 0.000 description 7
- WXFIGDLSSYIKKV-RCOVLWMOSA-N L-Metaraminol Chemical compound C[C@H](N)[C@H](O)C1=CC=CC(O)=C1 WXFIGDLSSYIKKV-RCOVLWMOSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 239000003054 catalyst Substances 0.000 description 6
- 150000002170 ethers Chemical class 0.000 description 6
- 229960003663 metaraminol Drugs 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- 238000001953 recrystallisation Methods 0.000 description 5
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 5
- FWWOWPGPERBCNJ-UHFFFAOYSA-N 2-hydroxy-4-(2-hydroxyethoxy)-4-oxobutanoic acid Chemical compound OCCOC(=O)CC(O)C(O)=O FWWOWPGPERBCNJ-UHFFFAOYSA-N 0.000 description 4
- 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 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 150000001414 amino alcohols Chemical class 0.000 description 4
- 239000000538 analytical sample Substances 0.000 description 4
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- PSLIMVZEAPALCD-UHFFFAOYSA-N ethanol;ethoxyethane Chemical compound CCO.CCOCC PSLIMVZEAPALCD-UHFFFAOYSA-N 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- MZBFZHPHBGPWDT-UHFFFAOYSA-N 3-methoxy-1-phenylpropan-1-one Chemical compound COCCC(=O)C1=CC=CC=C1 MZBFZHPHBGPWDT-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- 238000005917 acylation reaction Methods 0.000 description 3
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 3
- 235000019445 benzyl alcohol Nutrition 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 230000020176 deacylation Effects 0.000 description 3
- 238000005947 deacylation reaction Methods 0.000 description 3
- MHDVGSVTJDSBDK-UHFFFAOYSA-N dibenzyl ether Chemical class C=1C=CC=CC=1COCC1=CC=CC=C1 MHDVGSVTJDSBDK-UHFFFAOYSA-N 0.000 description 3
- 239000002024 ethyl acetate extract Substances 0.000 description 3
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 3
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 3
- 239000011976 maleic acid Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical class OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 230000010933 acylation Effects 0.000 description 2
- 150000008064 anhydrides Chemical class 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
- 230000036772 blood pressure Effects 0.000 description 2
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 238000003776 cleavage reaction Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000006266 etherification reaction Methods 0.000 description 2
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 2
- 150000004820 halides Chemical class 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 235000010755 mineral Nutrition 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 229910000510 noble metal Inorganic materials 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 229960002748 norepinephrine Drugs 0.000 description 2
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 125000001453 quaternary ammonium group Chemical group 0.000 description 2
- 229910052703 rhodium Inorganic materials 0.000 description 2
- 239000010948 rhodium Substances 0.000 description 2
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 2
- 229910052707 ruthenium Inorganic materials 0.000 description 2
- 230000007017 scission Effects 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 239000011343 solid material Substances 0.000 description 2
- 239000012258 stirred mixture Substances 0.000 description 2
- 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
- LLAPDLPYIYKTGQ-UHFFFAOYSA-N 1-aminoethyl Chemical group C[CH]N LLAPDLPYIYKTGQ-UHFFFAOYSA-N 0.000 description 1
- PLDWAJLZAAHOGG-UHFFFAOYSA-N 1-bromo-3-methoxybenzene Chemical compound COC1=CC=CC(Br)=C1 PLDWAJLZAAHOGG-UHFFFAOYSA-N 0.000 description 1
- HPZCAKYHISJOIK-UHFFFAOYSA-N 2-amino-1-phenylpropan-1-one;hydron;chloride Chemical compound Cl.CC(N)C(=O)C1=CC=CC=C1 HPZCAKYHISJOIK-UHFFFAOYSA-N 0.000 description 1
- KMGUEILFFWDGFV-UHFFFAOYSA-N 2-benzoyl-2-benzoyloxy-3-hydroxybutanedioic acid Chemical compound C=1C=CC=CC=1C(=O)C(C(C(O)=O)O)(C(O)=O)OC(=O)C1=CC=CC=C1 KMGUEILFFWDGFV-UHFFFAOYSA-N 0.000 description 1
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- PXACTUVBBMDKRW-UHFFFAOYSA-M 4-bromobenzenesulfonate Chemical group [O-]S(=O)(=O)C1=CC=C(Br)C=C1 PXACTUVBBMDKRW-UHFFFAOYSA-M 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical class OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical group CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 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 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000001800 adrenalinergic effect Effects 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 1
- 150000008041 alkali metal carbonates Chemical class 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 150000004703 alkoxides Chemical class 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- UNRNJMFGIMDYKL-UHFFFAOYSA-N aluminum copper oxygen(2-) Chemical compound [O-2].[Al+3].[Cu+2] UNRNJMFGIMDYKL-UHFFFAOYSA-N 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 230000003276 anti-hypertensive effect Effects 0.000 description 1
- 229940030600 antihypertensive agent Drugs 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 239000011260 aqueous acid Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- MIOPJNTWMNEORI-UHFFFAOYSA-N camphorsulfonic acid Chemical compound C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- JGDFBJMWFLXCLJ-UHFFFAOYSA-N copper chromite Chemical compound [Cu]=O.[Cu]=O.O=[Cr]O[Cr]=O JGDFBJMWFLXCLJ-UHFFFAOYSA-N 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 239000012259 ether extract Substances 0.000 description 1
- 125000001033 ether group Chemical group 0.000 description 1
- UREBWPXBXRYXRJ-UHFFFAOYSA-N ethyl acetate;methanol Chemical compound OC.CCOC(C)=O UREBWPXBXRYXRJ-UHFFFAOYSA-N 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
- 239000000284 extract Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 210000004051 gastric juice Anatomy 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical group 0.000 description 1
- 210000005003 heart tissue Anatomy 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 229910010272 inorganic material Inorganic materials 0.000 description 1
- 239000011147 inorganic material Substances 0.000 description 1
- OWFXIOWLTKNBAP-UHFFFAOYSA-N isoamyl nitrite Chemical compound CC(C)CCON=O OWFXIOWLTKNBAP-UHFFFAOYSA-N 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 150000002688 maleic acid derivatives Chemical class 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 150000004706 metal oxides Chemical class 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 150000002923 oximes Chemical class 0.000 description 1
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229910003446 platinum oxide Inorganic materials 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M potassium chloride Inorganic materials [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
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- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
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- 239000003826 tablet Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
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- 150000003512 tertiary amines Chemical class 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical group CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 239000000341 volatile oil Substances 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
Analogifremgang.småte ved fremstilling av tera- Analogy progress.small in the production of tera-
peutisk aktiv 3-methoxy- og 3-benzyloxy-a-(1-aminoethyl)-benzylalkohol. therapeutically active 3-methoxy- and 3-benzyloxy-α-(1-aminoethyl)-benzyl alcohol.
Foreliggende oppfinnelse angår en analogifremgangsmåte ved fremstilling av erythro-3-methoxy- og 3-benzyloxy-a-(1-aminoethyl)-benzylalkohol (1R,2S). The present invention relates to an analogous process for the production of erythro-3-methoxy- and 3-benzyloxy-α-(1-aminoethyl)-benzyl alcohol (1R,2S).
Den absolutte konfigurasjon av optisk aktive forbindelser kan beskrives ved anvendelse av "rekkefølgeregel"-metoden. Ved denne metode gies de fire grupper bundet til et asymmetrisk carbonatom, Cabcd' Prioriteter °9 ordnes i rekkefølge slik at de stereokjemiske symboler R og S kan bestemmes. Nar det asymmetriske carbonatom betraktes fra den side som er fjernest fra gruppen med lavest prioritet d, og når man går fra a til b til c, beskrives enten et forløp med urviseren eller mot urviseren. Hvis retningen er med urviseren, anvendes symbolet R for å beskrive stereokjemien av dette asymmetriske carbonatom. Hvis det er imot urviseren, anvendes symbolet S. Når molekylet inneholder mere enn ett asymmetrisk senter, anvendes metoden på begge, og stereokjemien uttrykkes ved flere R- eller S-symboler. The absolute configuration of optically active compounds can be described using the "order rule" method. In this method, the four groups attached to an asymmetric carbon atom are given, Cabcd' Priorities °9 are arranged in order so that the stereochemical symbols R and S can be determined. When the asymmetric carbon atom is considered from the side furthest from the group with the lowest priority d, and when going from a to b to c, either a clockwise or counter-clockwise progression is described. If the direction is clockwise, the symbol R is used to describe the stereochemistry of this asymmetric carbon atom. If it is counter-clockwise, the symbol S is used. When the molecule contains more than one asymmetric center, the method is applied to both, and the stereochemistry is expressed by several R or S symbols.
"Metaraminol" [(-) erythro-3-hydroxy-a-(1-aminoethyl)-benzylalkohol (IR,2S-konfigurasjon)] har nylig vært angitt å være et antihypertensivt middel for mennesker. Den antihypertensive virk-ning antaes å skyldes at "Metaraminol" har evnen til å trenge inn i og erstatte norepinefrin i adrenergiske nerver. Det har vist seg at visse 3-etherderivat er av 3_hydroxy-a-( 1-aminoet.hyl)-benzylalkohol også kan utarme mushjertevev på norepinefrin. Det har videre vist seg at visse 3-etherderivater av (-) erythro-3-hydroxy-a-(l-aminoethyl)-benzylalkohol (1R,2S) dealkyleres in vivo under dannelse av "Metaraminol". Dessuten har de nye etherderivater av "Metaraminol" [(-) erythro-3-hydroxy-α-(1-aminoethyl)-benzyl alcohol (IR,2S configuration)] has recently been reported to be an antihypertensive agent for humans. The antihypertensive effect is believed to be due to "Metaraminol" having the ability to penetrate and replace norepinephrine in adrenergic nerves. It has been shown that certain 3-ether derivatives of 3_hydroxy-α-(1-aminoeth.yl)-benzyl alcohol can also deplete mouse heart tissue of norepinephrine. It has also been shown that certain 3-ether derivatives of (-) erythro-3-hydroxy-α-(1-aminoethyl)-benzyl alcohol (1R,2S) are dealkylated in vivo to form "Metaraminol". In addition, they have new ether derivatives of
(-) erythro-3-hydroxy-a-(1-aminoethyl)-benzylalkohol (1R,2S), særlig benzyletherne, en fordel fremfor "Metaraminol", idet de ikke bevirker en økning i blodtrykk og hjertehastighet til å begynne med, som av og til opptrer ved "Metaraminol". [Dette er påvist (-) erythro-3-hydroxy-α-(1-aminoethyl)-benzyl alcohol (1R,2S), especially the benzyl ethers, an advantage over "Metaraminol", in that they do not initially cause an increase in blood pressure and heart rate, which occasionally appears at "Metaraminol". [This has been proven
i Journal of Medicinal Chemistry 13_, 1057-61 (1970)]. in Journal of Medicinal Chemistry 13_, 1057-61 (1970)].
De nye 3-etherderivater av 3-hydroxy-a-(1-aminoethyl)-benzylalkohol kan også anvendes som inhibitorer for mavesaftutskillelse. The new 3-ether derivatives of 3-hydroxy-α-(1-aminoethyl)-benzyl alcohol can also be used as inhibitors for gastric juice secretion.
Forbindelsene fremstilt ifølge oppfinnelsen kan anvendes sammen med en bærer som kan være enten et fast materiale eller en steril parenteral væske. Preparatet kan være i form av tabletter, pulvere, kapsler eller andre doseringsformer, som er særlig nyttige for oral inntagelse. Flytende fortynningsmidler anvendes i steril tilstand ved parenteral anvendelse. I alminnelighet gies forbindelsene fremstilt ifølge oppfinnelsen til pasienter i doser på 5 - 500 mg pr. dag. Fortrinnsvis anvendes de oralt i områder fra 5 - 500 mg pr. dag, særlig i hyppige mindre doser. The compounds produced according to the invention can be used together with a carrier which can be either a solid material or a sterile parenteral liquid. The preparation can be in the form of tablets, powders, capsules or other dosage forms, which are particularly useful for oral intake. Liquid diluents are used in sterile condition for parenteral use. In general, the compounds produced according to the invention are given to patients in doses of 5 - 500 mg per day. Preferably, they are used orally in ranges from 5 - 500 mg per day, especially in frequent smaller doses.
Etherderivatene som fremstilles ifølge oppfinnelsen, kan illustreres ved følgende generelle formel: The ether derivatives produced according to the invention can be illustrated by the following general formula:
med (1R,2S) erythrokonfigurasjon, with (1R,2S) erythro configuration,
hvor R"*" er hydrogen eller fenyl. where R"*" is hydrogen or phenyl.
Fremgangsmåteforbindelser av formel I er de som eksisterer i den venstredreiende form av erythrokonfigurasjonen. Dette betegnes også som IR,2S-konfigurasjonen. Det har videre vist seg at forbindelser som er særlig nyttige for å nedsette blodtrykk, er de av formel I hvor R"*" er hydrogen. Process compounds of formula I are those that exist in the levorotatory form of the erythro configuration. This is also referred to as the IR,2S configuration. It has further been found that compounds which are particularly useful for lowering blood pressure are those of formula I where R"*" is hydrogen.
De nye forbindelser fremstilt ifølge oppfinnelsen er: erythro-3-methoxy-a-(1-aminoethyl)-benzylalkohol og erythro-3-benzyloxy-a-(1-aminoethyl)-benzylalkohol. The new compounds produced according to the invention are: erythro-3-methoxy-α-(1-aminoethyl)-benzyl alcohol and erythro-3-benzyloxy-α-(1-aminoethyl)-benzyl alcohol.
De nye forbindelser kan ifølge oppfinnelsen fremstilles på tre forskjellige, måter. Slike måter illustreres av følgende prosesskjemaer.: „ a)According to the invention, the new compounds can be produced in three different ways. Such ways are illustrated by the following process diagrams.: „ a)
Fremgangsmåte a ) Procedure a)
hvor R 3 er lavere alkyl, som methyl, ethyl, propyl eller isopropyl og R1 er som ovenfor angitt . 'where R 3 is lower alkyl, such as methyl, ethyl, propyl or isopropyl and R 1 is as indicated above. '
Utgangsmaterialet for fremgangsmåte a) fremstilles ved et acyleringstrinn og et forethringstrinn som antydet i reaksjonsskjemaet under hvor X er klor eller brom, og X er halogen, tosylat, mesylat, brosylat eller en kvartær ammoniumgruppe. The starting material for method a) is prepared by an acylation step and an ether ring step as indicated in the reaction scheme below where X is chlorine or bromine, and X is halogen, tosylate, mesylate, brosylate or a quaternary ammonium group.
hvor R<1> oq R<3> er som ovenfor angitt, utgangsmaterialet underkastes så ifølge oppfinnelsen en deacylering. where R<1> and R<3> are as indicated above, the starting material is then subjected to deacylation according to the invention.
Ved fremstilling av utgangsmaterialet acyleres først amino-gruppen i den opprinnelige aminoalkohol for å beskytte den under forethringen i det annet trinn. Acyleringen kan utføres under anvendelse av et anhydrid av en lavere alkansyre, eller et lavere alkanoylklorid eller -bromid, som acetylklorid eller benzoylklorid. Reaksjonen kan utføres i et oppløsningsmiddel, som pyridin eller vann. Vanligvis anvendes et overskudd av anhydrid eller syrehalo-genid. Acyleringsreaksjonen kan også utføres i nærvær av en base. En hvilken som helst base som vil nøytralisere den frigjorte syre, kan anvendes. Eksempler på anvendbare baser er alkalimetallhydroxyder, -carbonater eller -bicarbonater, som natrium- eller kaliumhydroxyd, -carbonat eller -bicarbonat, jordalkalimetallhydroxyder eller tertiære aminer. Reaksjonen føres til fullstendighet, vanligvis ved moderate temperaturer, fortrinnsvis temperaturer på lo - 25°C. Det dannede acylerte materiale isoleres vanligvis på dette punkt under anvendelse av i og for seg kjente metoder. When preparing the starting material, the amino group in the original amino alcohol is first acylated to protect it during the etherification in the second step. The acylation can be carried out using an anhydride of a lower alkanoic acid, or a lower alkanoyl chloride or bromide, such as acetyl chloride or benzoyl chloride. The reaction can be carried out in a solvent, such as pyridine or water. Usually an excess of anhydride or acid halide is used. The acylation reaction can also be carried out in the presence of a base. Any base which will neutralize the liberated acid can be used. Examples of usable bases are alkali metal hydroxides, carbonates or bicarbonates, such as sodium or potassium hydroxide, carbonate or bicarbonate, alkaline earth metal hydroxides or tertiary amines. The reaction is carried to completion, usually at moderate temperatures, preferably temperatures of -25°C. The acylated material formed is usually isolated at this point using methods known per se.
Den dannede acylerte forbindelse omsettes så med et molart overskudd av det passende substituerte halogenid, sulfonsyreester eller kvartære ammoniumderivat for å danne det passende substituerte acylerte etherderivat, som anvendes som utgangsmateriale ifølge oppfinnelsen. Forethringsreaksjonen utføres vanligvis i et organisk oppløsningsmiddel , som aceton, methanol el-ler ethanol, og i nærvær av en base. Eksempler på slike baser er alkalimetallhydroxyder, (natrium- eller kaliumhydroxyd), natriumalkoxyder, alkalimetall-carbonater, som natrium- eller kaliumcarbonat, og lignende. The acylated compound formed is then reacted with a molar excess of the suitably substituted halide, sulphonic acid ester or quaternary ammonium derivative to form the suitably substituted acylated ether derivative, which is used as starting material according to the invention. The etherification reaction is usually carried out in an organic solvent, such as acetone, methanol or ethanol, and in the presence of a base. Examples of such bases are alkali metal hydroxides (sodium or potassium hydroxide), sodium alkoxides, alkali metal carbonates, such as sodium or potassium carbonate, and the like.
Temperaturen er ikke kritisk, og reaksjonen utføres vanligvis ved en temperatur på ca. 40 - HO°C i tilstrekkelig tid til å full-føre reaksjonen. The temperature is not critical, and the reaction is usually carried out at a temperature of approx. 40 - HO°C for sufficient time to complete the reaction.
Ved fremgangsmåte a) deacyleres det acylerte etherutgangs - materiale for å danne det ønskede ethersluttprodukt. Deacyleringen utføres ved å oppvarme den passende substituerte acylerte ether i en vandig oppløsning av en base eller syre ved ca. 6o - 120°C, fortrinnsvis ved ca. 8o°C, inntil reaksjonen er praktisk talt fullstendig. Et hvilket som helst alkalimetallhydroxyd, som natrium-eller kaliumhydroxyd, og en hvilken som helst mineralsyre, som saltsyre eller svovelsyre, kan anvendes for å bevirke deacyleringen. Foruten vann kan oppløsningsmidlet også være en lavere alkanol, som methanol, ethanol eller isopropanol. In method a) the acylated ether starting material is deacylated to form the desired ether end product. The deacylation is carried out by heating the suitably substituted acylated ether in an aqueous solution of a base or acid at approx. 6o - 120°C, preferably at approx. 8o°C, until the reaction is practically complete. Any alkali metal hydroxide, such as sodium or potassium hydroxide, and any mineral acid, such as hydrochloric or sulfuric acid, can be used to effect the deacylation. Besides water, the solvent can also be a lower alkanol, such as methanol, ethanol or isopropanol.
De ønskede etherderivat er av 3-hydroxy-a.-( 1-aminoethyl) - benzylalkohol kan så isoleres fra den deacylerte reaksjonsblanding ved i og for seg kjente metoder, idet en slik metode er å ekstrahere produktet med et inert organisk, lavtkokende oppløsningsmiddel, for-dampe oppløsningsmidlet til tørrhet og omkrystallisere det dannede faste materiale. De ønskede 3-etherderivater av 3-hydroxy-a-(1-aminoethyl)-benzylalkohol kan isoleres som. ikke-giftige salter, som et mineralsyre-addisjonssalt, som hydrokloridsaltet, maleatsaltet, f umaratsaltet, sulf .at salt et , og lignende. The desired ether derivatives are of 3-hydroxy-α-(1-aminoethyl)-benzyl alcohol can then be isolated from the deacylated reaction mixture by methods known per se, one such method being to extract the product with an inert organic, low-boiling solvent, evaporate the solvent to dryness and recrystallize the solid material formed. The desired 3-ether derivatives of 3-hydroxy-α-(1-aminoethyl)-benzyl alcohol can be isolated as non-toxic salts, such as a mineral acid addition salt, such as the hydrochloride salt, the maleate salt, the fumarate salt, the sulfate salt, and the like.
Fremgangsmåte b) Procedure b)
Den annen fremgangsmåte, b), angitt i reaksjonsskjemaet ovenfor, for fremstilling av 3-etherderivater av 3-hydroxy-a-(1-aminoethyl )-benzylalkohol er særlig nyttig ved fremstilling av benzyl-ethere og innbefatter en direkte entrinns overføring av aminoalkoholen til de ønskede 3-etherderivater av 3-hydroxy-a-(1-aminoethyl)-benzylalkohol. Ved denne fremgangsmåte omsettes aminoalkoholen eller den passende kjernesubstituerte aninoalkohol med en støkio-metrisk mengde eller et lite overskudd av et benzylhalogenid, fortrinnsvis benzylklorid eller benzylbromid, i nærvær av eri base som er tilstrekkelig sterk til å danne fenolanionet av utgangsfor-bindelsen. Slike baser kan være en alkaliraetall- eller jordalkali-metallbase, som natriumhydroxyd eller en base som natriumhydrid eller et alkoxyd som kalium-t-butoxyd. Reaksjonen mellom fenolen, benzylhalogenidet og basen må utføres i et oppløsningsmiddel, som dimethylsulfoxyd eller dimethylformamid. Reaksjonen gir et ut-merket utbytte av etheren, i alminnelighet ca. 90%> og er fullstendig i løpet av kort tid, vanligvis fra 1/2 til 2 timer. Temperaturen ved hvilken reaksjonen utføres, kan variere fra værelsetemperatur til ca. lOO°C, men den foretrukne temperatur er 8o°C. Ved en temperatur på 8o°C er reaksjonen fullstendig i løpet av ca. 1/2 time. Vanligvis reagerer benzylhalogenidet med nitrogenet i aminoalkoholen, men i dimethylsulfoxyd eller dimethylformamid reagerer fenoxydanionet preferensielt med alkyleringsmidlene. The second method, b), indicated in the reaction scheme above, for the preparation of 3-ether derivatives of 3-hydroxy-α-(1-aminoethyl)-benzyl alcohol is particularly useful in the preparation of benzyl ethers and involves a direct one-step transfer of the amino alcohol to the desired 3-ether derivatives of 3-hydroxy-α-(1-aminoethyl)-benzyl alcohol. In this method, the amino alcohol or the suitable core-substituted anino alcohol is reacted with a stoichiometric amount or a small excess of a benzyl halide, preferably benzyl chloride or benzyl bromide, in the presence of an eri base which is sufficiently strong to form the phenol anion of the starting compound. Such bases may be an alkali metal or alkaline earth metal base, such as sodium hydroxide or a base such as sodium hydride or an alkoxide such as potassium t-butoxide. The reaction between the phenol, the benzyl halide and the base must be carried out in a solvent, such as dimethylsulfoxide or dimethylformamide. The reaction gives an excellent yield of the ether, generally approx. 90%> and is complete within a short time, usually from 1/2 to 2 hours. The temperature at which the reaction is carried out can vary from room temperature to approx. lOO°C, but the preferred temperature is 8o°C. At a temperature of 8o°C, the reaction is complete within approx. 1/2 hour. Usually the benzyl halide reacts with the nitrogen of the amino alcohol, but in dimethylsulfoxide or dimethylformamide the phenoxydanion reacts preferentially with the alkylating agents.
Benzyletherderivatene av 3-hydroxy-a-(1-aminoethyl)-benzylalkohol fremstilt ved fremgangsmåte b) isoleres fra reaksjonsblandingen på lignende måte som vist i fremgan gsmåte a). Produktene kan likeledes isoleres i form av de ikke-giftige salter derav. The benzyl ether derivatives of 3-hydroxy-α-(1-aminoethyl)-benzyl alcohol produced by method b) are isolated from the reaction mixture in a similar manner as shown in method a). The products can likewise be isolated in the form of the non-toxic salts thereof.
Ved den tredje fremgangsmåte, c), reduseres forbindelsen med formel: In the third method, c), the compound is reduced by formula:
katalytisk. catalytic.
Reduksjon utføres bekvemt ved katalytisk hydrogenering under anvendelse av en katalysator som nikkel, f.eks. Raney-nikkel, et edelmetall eller edelmetalloxyd som platina, ruthenium, rhodium, platinaoxyd, eller andre effektive katalysatorer som kobber-aluminiumoxyd, kobber-kromoxyd, etc. De foretrukne katalysatorer er ruthenium og rhodium. Katalytisk hydrogenering utføres ved atmosfæretrykk eller høyere, opptil ca. 10 atm, ved temperaturer omkring ca. 25°C til ca. 250°C. Reduksjonen utføres fortrinnsvis i et inert oppløsningsmiddel som lavere alkanoler, dimethylformamid, eddiksyre, benzen, xylen, vandig saltsyre, vandig alkohol, etc. Reduction is conveniently carried out by catalytic hydrogenation using a catalyst such as nickel, e.g. Raney nickel, a noble metal or noble metal oxide such as platinum, ruthenium, rhodium, platinum oxide, or other effective catalysts such as copper-aluminum oxide, copper-chromium oxide, etc. The preferred catalysts are ruthenium and rhodium. Catalytic hydrogenation is carried out at atmospheric pressure or higher, up to approx. 10 atm, at temperatures around approx. 25°C to approx. 250°C. The reduction is preferably carried out in an inert solvent such as lower alkanols, dimethylformamide, acetic acid, benzene, xylene, aqueous hydrochloric acid, aqueous alcohol, etc.
For å fremstille erythro-formen av de ønskede 3-etherderivater (formel I) bør de tre fremgangsmåter beskrevet ovenfor gå ut fra utgangsmaterialet av den spesielle konfigurasjon som ønskes, nemlig (1R,2S) erythro. Det kan derfor være nødvendig å adskille det racemiske 3-hydroxy-a-(1-aminoethyl)-benzylalkohol-ut gangs - materiale eller ether-sluttproduktene. En hvilken som helst alminnelig metode for å skille aminer, spesielt metoden ved dannelse av et optisk aktivt salt under anvendelse av optisk aktive syrer, som optisk aktiv vinsyre, dibenzoylvinsyre, kamfersulfonsyre eller mandelsyre, og skille de diastereoisomere fulgt av regenerer-ing av den optisk aktive base, kan anvendes. Andre adskillelses-metoder, som spontan adskillelse eller adskillelse ved enzymatiske midler, er like anvendbare og kan også anvendes for å isolere de erythro- eller threo-enantiomorfe fra de racemiske blandinger. In order to prepare the erythro form of the desired 3-ether derivatives (formula I), the three methods described above should proceed from the starting material of the particular configuration desired, namely (1R,2S) erythro. It may therefore be necessary to separate the racemic 3-hydroxy-α-(1-aminoethyl)-benzyl alcohol starting material or the ether end products. Any common method of separating amines, especially the method of forming an optically active salt using optically active acids, such as optically active tartaric acid, dibenzoyltartaric acid, camphorsulphonic acid or mandelic acid, and separating the diastereoisomers followed by regeneration of the optically active base, can be used. Other separation methods, such as spontaneous separation or separation by enzymatic means, are equally applicable and can also be used to isolate the erythro- or threo-enantiomorphs from the racemic mixtures.
Eksempel 1 Example 1
(-) erythro-3-methoxy-a-(aminoethyl)-benzylalkohol-hydrogenmaleat ( 1R. 2S) (-) erythro-3-methoxy-α-(aminoethyl)-benzyl alcohol hydrogen maleate ( 1R. 2S)
A. (-) erythro- 3- hydroxy- g-( 1- acetamidoethyl)- benzylalkohol ( 1R, 2S) A. (-) erythro- 3- hydroxy- g-( 1- acetamidoethyl)- benzyl alcohol ( 1R, 2S)
Til en omrørt oppløsning av 75 g (0,237 mol) (-) erythro-3-hydroxy-a-(1-aminoethyl)-benzylalkohol-(+)-hydrogentart rat ("Meta - raminol"-bitart rat) i 750 ml vann tilsettes 195 g natriumbicarbonat. Oppløsningen avkjøles til 5 - 10°C, og efter at 120 ml eddiksyre-anhydrid er tilsatt dråpevis i løpet av 30 minutter, får reaksjonsblandingen lov til å oppvarmes til værelsetemperatur i løpet av 2 timer. Efter omrøring ved værelsetemperatur i 15 - 20 timer tilsettes fast natriumbicarbonat for å nøytralisere eventuelt gjen-værende syre. Råproduktet isoleres ved ekst raksjon med 3 x 400 ml ethylacetat som så forenes og tørres over vannfritt natriumsulfat, filtreres og konsentreres til en sirup. Dette produkt tilsettes til 200 ml 10%-ig natriumhydroxydoppløsning og får lov til å stå ved værelsetemperatur i 24 timer. Efter avkjøling i et isbad tilsettes konsentrert saltsyre for å innstille oppløsningens pH på 1 - 2. To a stirred solution of 75 g (0.237 mol) (-) erythro-3-hydroxy-α-(1-aminoethyl)-benzyl alcohol-(+)-hydrogen tart rat ("Meta-raminol"-bitart rat) in 750 ml of water 195 g of sodium bicarbonate are added. The solution is cooled to 5 - 10°C, and after 120 ml of acetic anhydride has been added dropwise over the course of 30 minutes, the reaction mixture is allowed to warm to room temperature over the course of 2 hours. After stirring at room temperature for 15 - 20 hours, solid sodium bicarbonate is added to neutralize any remaining acid. The crude product is isolated by extraction with 3 x 400 ml ethyl acetate, which is then combined and dried over anhydrous sodium sulfate, filtered and concentrated to a syrup. This product is added to 200 ml of 10% sodium hydroxide solution and allowed to stand at room temperature for 24 hours. After cooling in an ice bath, concentrated hydrochloric acid is added to adjust the pH of the solution to 1 - 2.
Det utfelte lysebrune faste stoff isoleres ved filtrering og tørres ved 65°C, hvilket gir 49 g (-) erythro-3-hydroxy-a-(1-acet-amidoethyl)-benzylalkohol-(IR,2S)-hydrat, smp. 95 - 102°C. The precipitated light brown solid is isolated by filtration and dried at 65°C, which gives 49 g (-) erythro-3-hydroxy-α-(1-acet-amidoethyl)-benzyl alcohol (IR,2S)-hydrate, m.p. 95 - 102°C.
,a,MeOH 18;5° (Ci5). ■ ,v- ' ■ ,α,MeOH 18.5° (Ci5). ■ ,v- ' ■
En prøve ble omkrystallisert tre ganger fra en ethylacetat-hexanbianding,' hvi lket ga en hygroskopisk analytisk prøve' som hadde et smeltepunkt på 122,5 - 123,5°C. , A sample was recrystallized three times from an ethyl acetate-hexane mixture, which gave a hygroscopic analytical sample having a melting point of 122.5-123.5°C. ,
Analyse ;beregnet, for C^H-^NO^C 63,15; H 7,23; Analysis ; calculated, for C^H-^NO^C 63.15; H 7.23;
Funnet: C 62,73; H 7,26. Found: C 62.73; H 7.26.
B. (-) erythro.-3.-methoxy-a-( aminoethyl) -benzylalkohol -hydrogen-maleat ( 1R. 2S) . ; . _^ ., B. (-) erythro.-3.-methoxy-α-(aminoethyl)-benzyl alcohol -hydrogen maleate (1R.2S). ; . _^ .,
En-.omrørt'.,, blanding av 15 g (0<0719 mol)<:> ( -) erythro-3-hydr-■ oxy.-a-( l.r.acetamidoethyl) -benzylalkoholt (IR ,2S);, < 30 g-. vannf ritt. ■ ' : - ka-liumea.rbpnat ,13,2 g dimethylsulf at og 500 ml aceton oppvarmes ; under tilbakeløp i 8 timer. Uorganiske salter fjernes ved filtrering.. Aeetonoppløsningen konsentreres under vakuum til et oljeaktig residuum.. som så oppvarmes under tilbakeløp i 24 timer med 50 ml A stirred mixture of 15 g (0<0719 mol) <:> ( -) erythro-3-hydr-■ oxy.-a-(l.r.acetamidoethyl)-benzyl alcohol (IR ,2S);, < 30 g. water free. ■ ': - potassium chloride, 13.2 g of dimethylsulphate and 500 ml of acetone are heated; under reflux for 8 hours. Inorganic salts are removed by filtration. The acetone solution is concentrated under vacuum to an oily residue.. which is then heated under reflux for 24 hours with 50 ml
10%-ig natriumhydroxydoppløsning Og 150 ml ethanol. Reaksjonsblandingen konsentreres under vakuum for å fjerne det meste av ethanolen, og vann tilsettes for å bringe det samlede volum til ca. lOO ml. Eftér* metning med nat riumklorid ekstraheres råproduktet i 3 x lOO. ml ethylåcétat. Ethylacetatekstraktene forenes, tørres over vannfritt nat.riumsulf at , filtreres og inndampes . Residuet, 13 g, oppløses i ethanol,.behandles med 15 g maleinsyre, og•hydrogenmaleatsaltet felles med ethylether, hvilket gir. 10,4 g-(48 ,8%) av methoxydéri-vatet med smeltepunkt 153,4 - 155,9°C. under' spaltning.. Omkrystalli - sasjon fra en ethanol-ethyletherblanding ga.en analyseprøve med smeltepunkt 153,4 - 154,4°C under spaltning..; -.. • 10% sodium hydroxide solution and 150 ml of ethanol. The reaction mixture is concentrated under vacuum to remove most of the ethanol, and water is added to bring the total volume to approx. lOO ml. After* saturation with sodium chloride, the crude product is extracted in 3 x lOO. ml of ethyl acetate. The ethyl acetate extracts are combined, dried over anhydrous sodium sulfate, filtered and evaporated. The residue, 13 g, is dissolved in ethanol, treated with 15 g of maleic acid, and the hydrogen maleate salt is combined with ethyl ether, which gives 10.4 g-(48.8%) of the methoxy derivative with melting point 153.4 - 155.9°C. during cleavage.. Recrystallization from an ethanol-ethyl ether mixture gave an analytical sample with melting point 153.4 - 154.4°C during cleavage..; -.. •
[a 1^2° = (.-) 24° (C=2). [a 1^2° = (.-) 24° (C=2).
Analyse beregnet for C^H^NOg: C 56,56;. H 6,445 N 4,70; Analysis calculated for C^H^NOg: C 56.56;. H 6.445 N 4.70;
Funnet: C 56,62; H 6,15; N 5,01. Found: C 56.62; H 6.15; N 5.01.
Eksempel 2.. :.. ; •. Example 2.. :.. ; •.
( -) erythro-3-benzylioxy-^a-^ 1 -aminoethyl ) -benzylalkohol -hydrogeri-maleat ( 1R, 2S) „. xk-, v. u ■" ( -) erythro-3-benzylioxy-^a-^ 1 -aminoethyl ) -benzyl alcohol -hydrogeri-maleate ( 1R, 2S) „. xk-, v. u ■"
A. :( -) ■- erythro- 3- benzyl^ xy- E-(- l--- adetamidoethyl) - benzylalkohol ( IR , 2S) A. :( -) ■- erythro- 3- benzyl^ xy- E-(- l--- adetamidoethyl) - benzyl alcohol ( IR , 2S)
En blanding<1> av 7,5 g (0,0330 mol.(-) erythro-3-hy,droxy-a-(1-aceta'midoethy'i) -benzylalkohol-hydrat, (1R,2S), 15. g vannf ritt kaliumca rbonat, 6,9 g "benzylbromid og 200 ml aceton om røres-, i 24 timer under tilbakeløp. Efter avkjøling filtreres reaksjonsblandingen fri for uorganisk materiale, og det meste av acetonoppløsnings-midlet fjernes under vakuum. Vann tilsettes "til residuet, og det utfelte faste stoff frafiltreres og tørres, hvilket gir 8,2 g (82,8%) (-) erythro-3-benzyloxy-a-(l-acetamidoethyl)-benzylalkohol (1R.2S), smp. 137.0 - 146,0°C. Omkrystallisasjon fra en ethylåcétat -hexanblanding gir en analyseprøve méd smeltepunkt 138,0 - 140,o°c. ' ' ; A mixture<1> of 7.5 g (0.0330 mol.(-) erythro-3-hydroxy-α-(1-aceta'midoethyl)-benzyl alcohol hydrate, (1R,2S), 15 g of anhydrous potassium carbonate, 6.9 g of benzyl bromide and 200 ml of acetone are stirred for 24 hours under reflux. After cooling, the reaction mixture is filtered free of inorganic material, and most of the acetone solvent is removed under vacuum. Water is added. to the residue, and the precipitated solid is filtered off and dried, yielding 8.2 g (82.8%) (-) erythro-3-benzyloxy-α-(1-acetamidoethyl)-benzyl alcohol (1R.2S), m.p. 137.0 - 146.0° C. Recrystallization from an ethyl acetate - hexane mixture gives an analytical sample with a melting point of 138.0 - 140.0° C. ' ' ;
Analyse beregnet for C^gH^NO^ C 72,21; H 7,07; Analysis calculated for C^gH^NO^ C 72.21; H 7.07;
Funnet: C 72,50; H 6,93- Found: C 72.50; H 6.93-
B. (-) eryt h ro-3-benzyloxy-a-(1-aminoet hy1)-benzylalkohol-hydrogen - B. (-) erythro-3-benzyloxy-α-(1-aminoethyl)-benzylalcohol-hydrogen -
maleat - { 1R. 2S) ' ■■ . ■ maleate - { 1R. 2S) ' ■■ . ■
En oppløsning av 12,1 g (6,0405 mol) (-) erythro-3-benzyloxy-a-(1-acetamidoethyl)-benzylalkohol (1R.2S) i 150 ml ethanol og 50 ml 10%-ig nat riumhydroxydoppløsning oppvarmes.i 24 timer under tilbake-løp og inndampes så under vakuum for å fjerne det meste av ethanolen. Vann tilsettes, og produktet ekstraheres med 3 x lOO ml ethylacetat. Ethylacetat ekst raktene forenes, tørres over vannfritt nat ri umsulfat, filtreres og konsentreres, hvilket gir 10,6 g' av eri olje. Dette rå-produkt oppløses i ethanol og behandles med 6;0 g niaieinsyre, Hydrogenea 1 eat salt et'av ( -) eryt hro-3-bénzyloxy-a-(1-aminoet hy 1)-benzylalkohol ( IR ,2S) felles méd et hylet'her . Omkrystallisasjon "f ra en ethanol-et.hy let herblanding gir 5 ; 3' g ( 35 ,2%) av praktisk talt rent• (-)\eryt hro-3-benzyloxy-a—(1-ami noét hyl)-benzyl alkohol-hyd ro - genmaleat me.d smeltepunkt 157 i 8 - 159,8°C under spaltning.' I n iMeOH _: , a_o . • '• A solution of 12.1 g (6.0405 mol) (-) erythro-3-benzyloxy-α-(1-acetamidoethyl)-benzyl alcohol (1R.2S) in 150 ml of ethanol and 50 ml of 10% sodium hydroxide solution is heated .for 24 hours under reflux and then evaporated under vacuum to remove most of the ethanol. Water is added, and the product is extracted with 3 x 100 ml ethyl acetate. The ethyl acetate extracts are combined, dried over anhydrous sodium sulfate, filtered and concentrated, which gives 10.6 g of essential oil. This crude product is dissolved in ethanol and treated with 6.0 g of niacin acid, Hydrogenea 1 eat salt et'av (-)erythro-3-bénzyloxy-a-(1-aminoet hy 1)-benzyl alcohol ( IR ,2S) together with a howl here. Recrystallization "from an ethanol-ether mixture gives 5; 3' g (35.2%) of practically pure • (-)\erythro-3-benzyloxy-a-(1-aminoethyl)- benzyl alcohol hydrogen maleate with melting point 157 in 8 - 159.8°C during decomposition.' I n iMeOH _: , a_o . • '•
Analyse beregnet for C^H^NO^: C 64 ,.33; . H 6,21; N 3 , 75 ;: : ■ Analysis calculated for C^H^NO^: C 64 .33; . H 6.21; N 3 , 75 ;: : ■
Funnet : C 64,51; H,6,06;: N-3,91. - / : Found : C 64.51; H, 6.06;: N-3.91. - / :
Eksempel 3 ....<.>..Example 3 ....<.>..
( -) erythro-3-benzyloxy-a-( 1 -aminoethyl) -benzy lalkohol-hydrogen -' maleat ( 1R. 2S) (-) erythro-3-benzyloxy-α-(1-aminoethyl)-benzylalcohol-hydrogen-' maleate (1R.2S)
En omrørt blanding av 2,0 g (0,012 mol) (-) erythro-3-hydroxy-a-(1-aminoethyl)-benzylalkohol, lOO ml dimethylsulfoxyd og 6,0 ml av en 2N nat riumhydroxydoppløsning oppvarmes til 85°C. En oppløsning av 2,1 g (0,013 mol) benzyIbromid.i IO ml dimethylsulfoxyd tilsettes langsomt til reaksjonsblandingen, og den dannede blanding om røres ved 85°C i 2 timer og helles så i 500 ml is og vann. Den dannede oppløsning mettes med nat riumklorid,< ekstraheres med 4 x 200 ml porsjoner ethylacetat ,, og,.de organiske ekstrakter forenes. Efter tørring over vannfritt natriumsulfat, filtrering og inndampning, fåes 3,9 g urent erythro-3-benzyloxy-a-(1-aminoethyl)-benzylalkohol. Dette urene produkt oppløses i varm ethanol og behandles med 5,8 g maleinsyre. Ved fortynning med ethylether felles 3,5 9 (97%) (-) erythro-3-benzyloxy-a-(1-aminoethyl)-benzylalkohol-hydrogenmaleat med smeltepunkt 149 - 152°C. Omkrystallisasjon fra en ethanol-ethyletherblanding ga 3,2 g (90%) (-) erythro-3-benzyl-oxy-a-(1-aminoethyl)-benzylalkohol-hydrogenmaleat med smeltepunkt 150,0 - 154,o°c. A stirred mixture of 2.0 g (0.012 mol) (-) erythro-3-hydroxy-α-(1-aminoethyl)-benzyl alcohol, 100 ml of dimethylsulfoxide and 6.0 ml of a 2N sodium hydroxide solution is heated to 85°C. A solution of 2.1 g (0.013 mol) of benzyl bromide in 10 ml of dimethylsulfoxide is added slowly to the reaction mixture, and the resulting mixture is stirred at 85° C. for 2 hours and then poured into 500 ml of ice and water. The resulting solution is saturated with sodium chloride, extracted with 4 x 200 ml portions of ethyl acetate, and the organic extracts are combined. After drying over anhydrous sodium sulfate, filtration and evaporation, 3.9 g of impure erythro-3-benzyloxy-α-(1-aminoethyl)-benzyl alcohol are obtained. This impure product is dissolved in hot ethanol and treated with 5.8 g of maleic acid. On dilution with ethyl ether, 3.5 9 (97%) (-) erythro-3-benzyloxy-α-(1-aminoethyl)-benzyl alcohol hydrogen maleate with melting point 149 - 152°C separate. Recrystallization from an ethanol-ethyl ether mixture gave 3.2 g (90%) (-) erythro-3-benzyl-oxy-α-(1-aminoethyl)-benzyl alcohol hydrogen maleate, melting point 150.0 - 154.0°C.
Ved å følge ovenstående fremgangsmåte, men ved å anvende en ekvimolar mengde benzylklorid istedenfor benzylbromid, fåes også (-) erythro-3-benzyloxy-a-(1-aminoethyl)-benzylalkohol (1R,2S). By following the above procedure, but using an equimolar amount of benzyl chloride instead of benzyl bromide, (-) erythro-3-benzyloxy-α-(1-aminoethyl)-benzyl alcohol (1R,2S) is also obtained.
Eksempel 4 Example 4
Fremstilling av utgangsmaterialer Production of starting materials
A. Fremstilling av 3- methoxypropiofenon A. Preparation of 3-Methoxypropiophenone
En oppløsning av 3,8 g (0,069 mol) propionitril i 25 ml vannfri ethylether tilsettes dråpevis til en omrørt oppløsning av Grighard-reagenset fremstilt fra 12,9 g (0,069 mol) m-bromanisol og 1,7 g (0,069 g atomer) magnesiumspon i lOO ml vannfri ethylether. Efter at tilsetningen er avsluttet, oppvarmes reaksjonsblandingen i ytterligere 15 timer under tilbakeløp. Reaksjonsblandingen av-kjøles så til 0°C og behandles med 50 ml kold konsentrert saltsyre. Det vandige syreskikt fraskilles, oppvarmes under tilbakeløp i 90 minutter, avkjøles til værelsetemperatur og ekstraheres med 250 ml ethylether. Etherekstraktet tørres over vannfritt natriumsulfat , filtreres og inndampes til en mørk olje som renses ved destillasjon gjennom en kort Vigreux-kolonne, hvorved man får 3-methoxypropiofenon. A solution of 3.8 g (0.069 mol) of propionitrile in 25 ml of anhydrous ethyl ether is added dropwise to a stirred solution of the Grighard reagent prepared from 12.9 g (0.069 mol) of m-bromoanisole and 1.7 g (0.069 g atoms) magnesium shavings in lOO ml anhydrous ethyl ether. After the addition is finished, the reaction mixture is heated for a further 15 hours under reflux. The reaction mixture is then cooled to 0°C and treated with 50 ml of cold concentrated hydrochloric acid. The aqueous acid layer is separated, heated under reflux for 90 minutes, cooled to room temperature and extracted with 250 ml of ethyl ether. The ether extract is dried over anhydrous sodium sulphate, filtered and evaporated to a dark oil which is purified by distillation through a short Vigreux column, whereby 3-methoxypropiophenone is obtained.
B. Fremstilling av 3- methoxy- g- hydroxyiminopropiofenon B. Preparation of 3-methoxy-g-hydroxyiminopropiophenone
En oppløsning av 2,1 g (0,018 mol) friskt destillert isoamyl-nitrit i 50 ml vannfri ethylether tilsettes dråpevis til en oppløs-ning av 2,79 g (0,017 mol) 3-methoxypropiofenon i 50 ml vannfri ethylether ved værelsetemperatur. Tørr hydrogenkloridgass bobles kontinuerlig gjennom reaksjonsblandingen under tilsetningen og i ytterligere 30 minutter efter at tilsetningen er avsluttet. Reaksjonsblandingen omrøres så ved værelsetemperatur i 3 timer. Overskudd av hydrogenklorid og ether fjernes under vakuum, og det erholdte faste stoff vaskes med hexan og tørres, hvorved man får A solution of 2.1 g (0.018 mol) of freshly distilled isoamyl nitrite in 50 ml of anhydrous ethyl ether is added dropwise to a solution of 2.79 g (0.017 mol) of 3-methoxypropiophenone in 50 ml of anhydrous ethyl ether at room temperature. Dry hydrogen chloride gas is continuously bubbled through the reaction mixture during the addition and for a further 30 minutes after the addition is complete. The reaction mixture is then stirred at room temperature for 3 hours. Excess hydrogen chloride and ether are removed under vacuum, and the resulting solid is washed with hexane and dried, thereby obtaining
oximet . the oxime.
C. Fremstilling av 3- methoxy- g- aminopropiofenon- hydroklorid C. Preparation of 3-methoxy-g-aminopropiophenone hydrochloride
En blanding av 5,4 g (0,028 mol) 3-methoxy-g<->hydroxyiminopropiofenon i lOO ml av en 2N éthanolisk hydrogenkloridoppløsning °9 0,5 g 5%-ig palladium-på-carbonkatalysator hydrogeneres ved 25°C og atmosfæretrykk inntil 2 ekvivalenter hydrogen er opptatt. Kata-lysatoren fjernes så ved filtrering, og oppløsningsmidlet fordampes i vakuum. Residuet omkrystalliseres fra en methanol-ethylacetat-blanding, hvorved man får a-amino-keton-hydroklorid. A mixture of 5.4 g (0.028 mol) 3-methoxy-g<->hydroxyiminopropiophenone in lOO ml of a 2N ethanolic hydrogen chloride solution °9 0.5 g of 5% palladium-on-carbon catalyst is hydrogenated at 25°C and atmospheric pressure until 2 equivalents of hydrogen are occupied. The catalyst is then removed by filtration, and the solvent is evaporated in vacuo. The residue is recrystallized from a methanol-ethyl acetate mixture, whereby α-amino ketone hydrochloride is obtained.
Fremstilling av sluttprodukt Production of final product
D. Fremstilling av erythro-3-methoxy-a-[1-aminoethyl]-benzylalkohol D. Preparation of erythro-3-methoxy-α-[1-aminoethyl]-benzyl alcohol
En blanding av l,4l 9 (6,55 mmol) 3-methoxy-g<->aminopropiofenon-hydroklorid og 0,5 g 10%-ig palladium-på-carbonkatalysator i 30 ml vann hydrogeneres ved atmosfæretrykk og 25°C inntil en ekvi-valent hydrogen er absorbert. Reaksjonsblandingen filtreres og gjøres alkalisk med 10%-ig natriumhydroxydoppløsning. Efter metning med natriumklorid ekstraheres råproduktet i 3 x lOO ml ethylacetat. Ethylacetatekstraktene forenes, tørres over vannfritt natriumsulfat, filtreres og inndampes. Residuet oppløses i ethanol, behandles med 1,0 g maleinsyre og hydrogenmaleatsalt et av produktet felles med ethylether. En analyseprøve med smeltepunkt 153,4 - 154,4°C er-holdes ved omkrystallisasjon fra en ethanol-ethyletherblanding. A mixture of 1.4l 9 (6.55 mmol) 3-methoxy-g<->aminopropiophenone hydrochloride and 0.5 g of 10% palladium-on-carbon catalyst in 30 ml of water is hydrogenated at atmospheric pressure and 25°C until an equivalent of hydrogen is absorbed. The reaction mixture is filtered and made alkaline with 10% sodium hydroxide solution. After saturation with sodium chloride, the crude product is extracted into 3 x 100 ml ethyl acetate. The ethyl acetate extracts are combined, dried over anhydrous sodium sulfate, filtered and evaporated. The residue is dissolved in ethanol, treated with 1.0 g of maleic acid and the hydrogen maleate salt of one of the products together with ethyl ether. An analytical sample with a melting point of 153.4 - 154.4°C is obtained by recrystallization from an ethanol-ethyl ether mixture.
Anal. beregn, for C1QH15N02.C^H^O^: C 56,56; H 6,44; N 4.70. Anal. calculate, for C1QH15N02.C^H^O^: C 56.56; H 6.44; N 4.70.
Funnet: C 56,62; H 6,15; N 5,Ol. Found: C 56.62; H 6.15; N 5, Ol.
Claims (2)
Priority Applications (1)
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NO250270A NO125271B (en) | 1967-05-08 | 1970-06-26 |
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US63658667A | 1967-05-08 | 1967-05-08 | |
NO1655/68A NO124108B (en) | 1967-05-08 | 1968-04-29 | |
NO250270A NO125271B (en) | 1967-05-08 | 1970-06-26 |
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