NO161596B - PROCEDURE FOR RECOVERING PROTEINS AND OTHER NUTRIENTS FROM PROTEIN CONTAINING WATER. - Google Patents
PROCEDURE FOR RECOVERING PROTEINS AND OTHER NUTRIENTS FROM PROTEIN CONTAINING WATER. Download PDFInfo
- Publication number
- NO161596B NO161596B NO870582A NO870582A NO161596B NO 161596 B NO161596 B NO 161596B NO 870582 A NO870582 A NO 870582A NO 870582 A NO870582 A NO 870582A NO 161596 B NO161596 B NO 161596B
- Authority
- NO
- Norway
- Prior art keywords
- general formula
- compound
- denotes
- group
- hydrogen
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 title description 18
- 102000004169 proteins and genes Human genes 0.000 title 2
- 108090000623 proteins and genes Proteins 0.000 title 2
- 235000015097 nutrients Nutrition 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 25
- -1 phenylisopropyl Chemical class 0.000 claims description 21
- 150000003839 salts Chemical class 0.000 claims description 17
- 229910052739 hydrogen Inorganic materials 0.000 claims description 15
- 239000001257 hydrogen Substances 0.000 claims description 15
- 238000002360 preparation method Methods 0.000 claims description 13
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 10
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 9
- 229910052794 bromium Inorganic materials 0.000 claims description 9
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 9
- 230000009467 reduction Effects 0.000 claims description 9
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 7
- 150000001412 amines Chemical class 0.000 claims description 7
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 3
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims description 3
- QCCDLTOVEPVEJK-UHFFFAOYSA-N phenylacetone Chemical class CC(=O)CC1=CC=CC=C1 QCCDLTOVEPVEJK-UHFFFAOYSA-N 0.000 claims description 3
- 125000001424 substituent group Chemical group 0.000 claims description 3
- 239000002168 alkylating agent Substances 0.000 claims description 2
- 229940100198 alkylating agent Drugs 0.000 claims description 2
- 150000007522 mineralic acids Chemical class 0.000 claims description 2
- 150000007524 organic acids Chemical class 0.000 claims description 2
- 229910052727 yttrium Inorganic materials 0.000 claims description 2
- 125000001246 bromo group Chemical group Br* 0.000 claims 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 51
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 35
- 239000000203 mixture Substances 0.000 description 22
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 17
- 239000002585 base Substances 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 14
- QWFZLPCCMVNBCM-UHFFFAOYSA-N 2-bromo-n-methyl-n-propan-2-ylaniline Chemical compound CC(C)N(C)C1=CC=CC=C1Br QWFZLPCCMVNBCM-UHFFFAOYSA-N 0.000 description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 239000002904 solvent Substances 0.000 description 11
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 238000002425 crystallisation Methods 0.000 description 9
- 230000008025 crystallization Effects 0.000 description 9
- 239000011541 reaction mixture Substances 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 7
- 239000000284 extract Substances 0.000 description 7
- IPTKGAPMKWJCKH-UHFFFAOYSA-N 4-bromo-n-methyl-n-propan-2-ylaniline Chemical compound CC(C)N(C)C1=CC=C(Br)C=C1 IPTKGAPMKWJCKH-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 150000002431 hydrogen Chemical class 0.000 description 6
- 238000002844 melting Methods 0.000 description 6
- 230000008018 melting Effects 0.000 description 6
- FRCFWPVMFJMNDP-UHFFFAOYSA-N n-propan-2-ylaniline Chemical class CC(C)NC1=CC=CC=C1 FRCFWPVMFJMNDP-UHFFFAOYSA-N 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 238000004821 distillation Methods 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 235000011121 sodium hydroxide Nutrition 0.000 description 5
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 4
- 125000003118 aryl group Chemical group 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 238000004508 fractional distillation Methods 0.000 description 4
- 238000005984 hydrogenation reaction Methods 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 230000004899 motility Effects 0.000 description 4
- WPFVERYDIPOZGG-UHFFFAOYSA-N 2-nitro-n-propan-2-ylaniline Chemical class CC(C)NC1=CC=CC=C1[N+]([O-])=O WPFVERYDIPOZGG-UHFFFAOYSA-N 0.000 description 3
- MLQQPTGNKKTRAE-UHFFFAOYSA-N N-phenyl-N-propan-2-ylnitramide Chemical class [N+](=O)([O-])N(C(C)C)C1=CC=CC=C1 MLQQPTGNKKTRAE-UHFFFAOYSA-N 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 229910052742 iron Inorganic materials 0.000 description 3
- 239000000155 melt Substances 0.000 description 3
- 239000012452 mother liquor Substances 0.000 description 3
- VPNQLBMDVGKMHC-UHFFFAOYSA-N n-methyl-3-phenyl-n-propan-2-ylprop-1-yn-1-amine Chemical compound CC(C)N(C)C#CCC1=CC=CC=C1 VPNQLBMDVGKMHC-UHFFFAOYSA-N 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- YORCIIVHUBAYBQ-UHFFFAOYSA-N propargyl bromide Chemical compound BrCC#C YORCIIVHUBAYBQ-UHFFFAOYSA-N 0.000 description 3
- 235000010288 sodium nitrite Nutrition 0.000 description 3
- BBKJMHUSPDZBDB-UHFFFAOYSA-N 1-phenyl-1-propan-2-ylhydrazine Chemical class CC(C)N(N)C1=CC=CC=C1 BBKJMHUSPDZBDB-UHFFFAOYSA-N 0.000 description 2
- AXWCQJBMXKXFIO-UHFFFAOYSA-N 2-bromo-n-propan-2-ylaniline Chemical compound CC(C)NC1=CC=CC=C1Br AXWCQJBMXKXFIO-UHFFFAOYSA-N 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- MMYLXYQBVGZFMR-UHFFFAOYSA-N 4-nitro-n-propan-2-ylaniline;hydrochloride Chemical compound Cl.CC(C)NC1=CC=C([N+]([O-])=O)C=C1 MMYLXYQBVGZFMR-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 2
- YZCKVEUIGOORGS-UHFFFAOYSA-N Hydrogen atom Chemical compound [H] YZCKVEUIGOORGS-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 2
- 230000000202 analgesic effect Effects 0.000 description 2
- 239000000935 antidepressant agent Substances 0.000 description 2
- 229940005513 antidepressants Drugs 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 230000031709 bromination Effects 0.000 description 2
- 238000005893 bromination reaction Methods 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 230000002349 favourable effect Effects 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- RHCSKNNOAZULRK-UHFFFAOYSA-N mescaline Chemical compound COC1=CC(CCN)=CC(OC)=C1OC RHCSKNNOAZULRK-UHFFFAOYSA-N 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
- HTHVOYCNVSQGRO-UHFFFAOYSA-N n-methyl-4-nitro-n-propan-2-ylaniline Chemical class CC(C)N(C)C1=CC=C([N+]([O-])=O)C=C1 HTHVOYCNVSQGRO-UHFFFAOYSA-N 0.000 description 2
- 150000002828 nitro derivatives Chemical class 0.000 description 2
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 239000003368 psychostimulant agent Substances 0.000 description 2
- 150000003335 secondary amines Chemical class 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- 150000003512 tertiary amines Chemical class 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- 239000011701 zinc Substances 0.000 description 2
- 229910052725 zinc Inorganic materials 0.000 description 2
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 2
- MKJIEFSOBYUXJB-HOCLYGCPSA-N (3S,11bS)-9,10-dimethoxy-3-isobutyl-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one Chemical compound C1CN2C[C@H](CC(C)C)C(=O)C[C@H]2C2=C1C=C(OC)C(OC)=C2 MKJIEFSOBYUXJB-HOCLYGCPSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- TZIAZLUAMDLDJF-UHFFFAOYSA-N 1-(2-bromophenyl)propan-2-one Chemical compound CC(=O)CC1=CC=CC=C1Br TZIAZLUAMDLDJF-UHFFFAOYSA-N 0.000 description 1
- KFBWOALCZNEASZ-UHFFFAOYSA-N 2-chloro-n-methyl-n-propan-2-ylaniline Chemical compound CC(C)N(C)C1=CC=CC=C1Cl KFBWOALCZNEASZ-UHFFFAOYSA-N 0.000 description 1
- VYWYYJYRVSBHJQ-UHFFFAOYSA-M 3,5-dinitrobenzoate Chemical compound [O-]C(=O)C1=CC([N+]([O-])=O)=CC([N+]([O-])=O)=C1 VYWYYJYRVSBHJQ-UHFFFAOYSA-M 0.000 description 1
- VYWYYJYRVSBHJQ-UHFFFAOYSA-N 3,5-dinitrobenzoic acid Chemical compound OC(=O)C1=CC([N+]([O-])=O)=CC([N+]([O-])=O)=C1 VYWYYJYRVSBHJQ-UHFFFAOYSA-N 0.000 description 1
- ZABSADPYOZOTDR-UHFFFAOYSA-N 4-chloro-n-methyl-n-propan-2-ylaniline Chemical compound CC(C)N(C)C1=CC=C(Cl)C=C1 ZABSADPYOZOTDR-UHFFFAOYSA-N 0.000 description 1
- SXNODIHYZKKFGW-UHFFFAOYSA-N 4-n-methyl-4-n-propan-2-ylbenzene-1,4-diamine Chemical compound CC(C)N(C)C1=CC=C(N)C=C1 SXNODIHYZKKFGW-UHFFFAOYSA-N 0.000 description 1
- 229910000761 Aluminium amalgam Inorganic materials 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 229910021591 Copper(I) chloride Inorganic materials 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
- 206010052804 Drug tolerance Diseases 0.000 description 1
- 241000282326 Felis catus Species 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
- 229910021577 Iron(II) chloride Inorganic materials 0.000 description 1
- NHNZIIHHXQCTEZ-UHFFFAOYSA-N N-bromo-N-propan-2-ylaniline Chemical compound BrN(C(C)C)C1=CC=CC=C1 NHNZIIHHXQCTEZ-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 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
- 229920002472 Starch Polymers 0.000 description 1
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
- VNDYJBBGRKZCSX-UHFFFAOYSA-L Zinc bromide Inorganic materials Br[Zn]Br VNDYJBBGRKZCSX-UHFFFAOYSA-L 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 1
- 239000004411 aluminium Substances 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 1
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 1
- 239000003218 coronary vasodilator agent Substances 0.000 description 1
- 229940045803 cuprous chloride Drugs 0.000 description 1
- VRLDVERQJMEPIF-UHFFFAOYSA-N dbdmh Chemical compound CC1(C)N(Br)C(=O)N(Br)C1=O VRLDVERQJMEPIF-UHFFFAOYSA-N 0.000 description 1
- 230000000994 depressogenic effect Effects 0.000 description 1
- 239000002274 desiccant Substances 0.000 description 1
- 230000000916 dilatatory effect Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000008098 formaldehyde solution Substances 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 229940083124 ganglion-blocking antiadrenergic secondary and tertiary amines Drugs 0.000 description 1
- 230000026781 habituation Effects 0.000 description 1
- 230000003400 hallucinatory effect Effects 0.000 description 1
- 239000000380 hallucinogen Substances 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- TVZISJTYELEYPI-UHFFFAOYSA-N hypodiphosphoric acid Chemical compound OP(O)(=O)P(O)(O)=O TVZISJTYELEYPI-UHFFFAOYSA-N 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- FBAFATDZDUQKNH-UHFFFAOYSA-M iron chloride Chemical compound [Cl-].[Fe] FBAFATDZDUQKNH-UHFFFAOYSA-M 0.000 description 1
- NMCUIPGRVMDVDB-UHFFFAOYSA-L iron dichloride Chemical compound Cl[Fe]Cl NMCUIPGRVMDVDB-UHFFFAOYSA-L 0.000 description 1
- 150000004658 ketimines Chemical class 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 230000005923 long-lasting effect Effects 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 229910052753 mercury Inorganic materials 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 230000037323 metabolic rate Effects 0.000 description 1
- 229910052987 metal hydride Inorganic materials 0.000 description 1
- 150000004681 metal hydrides Chemical class 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 229960005181 morphine Drugs 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- PXHVJJICTQNCMI-UHFFFAOYSA-N nickel Substances [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 1
- 238000006396 nitration reaction Methods 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000002385 psychotomimetic effect Effects 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 229940125723 sedative agent Drugs 0.000 description 1
- 239000000932 sedative agent Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- KEAYESYHFKHZAL-OUBTZVSYSA-N sodium-24 Chemical compound [24Na] KEAYESYHFKHZAL-OUBTZVSYSA-N 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 229960005333 tetrabenazine Drugs 0.000 description 1
- 239000011135 tin Substances 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 229940102001 zinc bromide Drugs 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
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Description
Analogifremgangsmåte ved fremstilling av Analogy method in the production of
terapeutisk aktive fenylisopropylderivater. therapeutically active phenylisopropyl derivatives.
I patentinnehaverens franske medisinske patentskrift nr. 2635 er det beskrevet en fremgangsmåte for fremstilling av fenylisopropylaminderivater av den generelle formel: In the patentee's French medical patent document No. 2635, a method for the production of phenylisopropylamine derivatives of the general formula is described:
hvor R1- betegner en lavere alkylgruppe og R<2> betegner en propyl-, propenyl- eller propynylgruppe, som kan være substituert med et halogenatom eller en hydroxylgruppe. De i nevnte patentskrift where R1- denotes a lower alkyl group and R<2> denotes a propyl, propenyl or propynyl group, which may be substituted with a halogen atom or a hydroxyl group. Those in the aforementioned patent document
beskrevne forbindelser, blant hvilke fenylisopropylmethylpropynylamin foretrekkes, kan med fordel benyttes i farmasien, f.eks. som psykostimulerende midler, antidepressive midler, som midler for å fremme stoffskiftet eller som avmagringsmidler. described compounds, among which phenylisopropylmethylpropynylamine is preferred, can be used with advantage in pharmacy, e.g. as psychostimulants, antidepressants, as agents to promote metabolism or as slimming agents.
Det har nu vist seg at en gruppe nye fenylisopropylderivater av den generelle formel: It has now been found that a group of new phenylisopropyl derivatives of the general formula:
hvor R 2 betegner hydrogen eller en propynylgruppe, R 3 betegner hydrogen» brom, nitro eller amino, og R<4> betegner hydrogen, brom, nitro eller amino, idet minst én av substituentene R 3 og R 4 er brom, og deres salter, kan anvendes i farmasien med bedre resultat enn de ovennevnte, fra fransk medisinsk patentskrift nr. 2635 kjentefenylisopropylaminderivater, f.eks. som coronardilatorer, halusinogene midler, antidepressive midler og beroligende midler eller som analgetika og avmagringsmidler. Gjenstanden for den foreliggende oppfinnelse er en analogifremgangsmåte ved fremstilling av de nye fenylisopropylderivater av den ovenfor angitte generelle formel (I), hvilken fremgangsmåte utmerker seg ved at man a) omsetter en forbindelse av den .generelle formel: med en forbindélse av den generelle formel: where R 2 denotes hydrogen or a propynyl group, R 3 denotes hydrogen» bromine, nitro or amino, and R<4> denotes hydrogen, bromine, nitro or amino, at least one of the substituents R 3 and R 4 being bromine, and their salts , can be used in pharmacy with better results than the above, from French medical patent document no. 2635 known phenylisopropylamine derivatives, e.g. as coronary dilators, hallucinogenic agents, antidepressants and sedatives or as analgesics and slimming agents. The object of the present invention is an analogous process for the production of the new phenylisopropyl derivatives of the above-mentioned general formula (I), which process is characterized by a) reacting a compound of the general formula: with a connection of the general formula:
Ri Ride
hvor enten X beregner gruppen -NH og Y betegner halogen eller en where either X calculates the group -NH and Y denotes halogen or a
sulfonsyreestergruppe, eller Y betegner gruppen -NH(R ) og X be-3» 4 > tegner halogen eller en sulfonsyreestergruppe; R og R har de sulphonic acid ester group, or Y denotes the group -NH(R ) and X be-3» 4 > denotes halogen or a sulphonic acid ester group; They have R and R
3 4 2 samme betydninger som R og R eller betegner hydrogen, og R er som ovenfor angitt, eller 3 4 2 same meanings as R and R or denotes hydrogen, and R is as indicated above, or
b) omsetter et fenylacetonderivat av den generelle formel: b) reacts a phenylacetone derivative of the general formula:
3' 4' 3 4 hvor R og R har dé samme betydninger som R og R eller betegner hydrogen, med et amin av den generelle formel: 3' 4' 3 4 where R and R have the same meanings as R and R or denote hydrogen, with an amine of the general formula:
hvor R og R har de ovenfor angitte betydninger, med samtidig eller påfølgende reduksjon, eller where R and R have the meanings given above, with simultaneous or subsequent reduction, or
c) omsetter et amin av den generelle formel: c) reacts an amine of the general formula:
3' 4' . 3 4 hvor R o I og R har de samme betydninger som R og R eller betegner hydrogen, med en forbindelse av den generelle formel: 12 • hvor R og R har de ovenfor angitte betydninger, med samtidig eller påfølgende reduksjon, eller d) alkylerer en forbindelse av den generelle formel: 3' 4' 2 hvor R , R og R har de ovenfor angitte betydninger, ved hjelp av et alkyleringsmiddel som er egnet til å innføre gruppen R<1>, eller e) kondenserer en forbindelse av den generelle formel: 3' 4'. 3 4 where R o I and R have the same meanings as R and R or denote hydrogen, with a compound of the general formula: 12 • where R and R have the above meanings, with simultaneous or subsequent reduction, or d) alkylate a compound of the general formula: 3' 4' 2 where R , R and R have the meanings given above, by means of an alkylating agent suitable for introducing the group R<1>, or e) condenses a compound of the general formula:
1 3' 41 1 3' 41
hvor R , R og R har de ovenfor angitte betydninger, med formal-dehyd og acetylen, where R , R , and R have the meanings given above, with formaldehyde and acetylene,
hvoretter man i den ved hjelp av en av fremgangsmåtene a), b), after which one in it using one of the methods a), b),
c), d) og e) fremstilte forbindelse av den generelle formel: c), d) and e) produced compound of the general formula:
1 2 3' 4' 1 2 3' 4'
hvor R , R , R og R har de ovanfor angitte betydninger, erstat-3' 41 where R , R , R and R have the meanings given above, replace-3' 41
ter hydrogenatomet i stillingene R og/eller R med brom, nitro eller amino, eller om ønskes omdanner en R 3 -gruppe og/eller en R 4-gruppe til en annen og/eller om ønskes erstatter hydrogenatomet i R 2-stillingen med en propynylgruppe, og om ønskes overfører den erholdte forbindelse til et salt med en organisk eller uorganisk syre eller frigjør basen fra et salt av denne. ter the hydrogen atom in the positions R and/or R with bromine, nitro or amino, or if desired converts an R 3 group and/or an R 4 group into another and/or if desired replaces the hydrogen atom in the R 2 position with a propynyl group, and, if desired, transfers the resulting compound to a salt with an organic or inorganic acid or liberates the base from a salt thereof.
Fremgangsmåtealternativ (a) kan utføres i nærvær av et oppløsningsmiddel eller i fravær av oppløsningsmiddel. Som opp-løsningsmiddel kan det anvendes vann, alkoholer, aromatiske eller alifatiske hydrocarboner, dimethylformamid, osv. For å binde den under reaksjonen frigjorte syre kan det anvendes organiske eller anorganiske baser eller et overskudd av aminet. Method option (a) can be carried out in the presence of a solvent or in the absence of a solvent. Water, alcohols, aromatic or aliphatic hydrocarbons, dimethylformamide, etc. can be used as solvents. To bind the acid released during the reaction, organic or inorganic bases or an excess of the amine can be used.
Fremgangsmåtealternativ (b) utføres ved at man omsetter det på den aromatiske ring passende substituerte fenylaceton med et alkyl- eller alkylpropynylamin og reduserer det erholdte keti-min eller oxyamin til det tilsvarende fenylisopropylalkylamin eller fenylisopropylalkylpropynylamin. Omsetningen av ketonet med aminet kan utføres i nærvær eller i fravær av oppløsningsmiddel. Reaksjonen kan aksellereres ved oppvarming av de to komponenter. Som oppløsningsmiddel kan det anvendes organiske sådanne, f.eks. benzen, ethanol, dimethylformamid, osv. De således erholdte forbindelser reduseres. Reduksjonen kan utføres ved katalysert hydrering, med nascerende hydrogen (jern + syre, aluminiumamalgam + vann, sink, tinn + syre osv.) eller med komplekse metallhydrider. Man kan også fullføre kondensasjonen og reduksjonen i ett trinn. Process alternative (b) is carried out by reacting the suitably substituted phenylacetone on the aromatic ring with an alkyl or alkylpropynylamine and reducing the resulting ketimine or oxamine to the corresponding phenylisopropylalkylamine or phenylisopropylalkylpropynylamine. The reaction of the ketone with the amine can be carried out in the presence or in the absence of solvent. The reaction can be accelerated by heating the two components. Organic solvents can be used as solvents, e.g. benzene, ethanol, dimethylformamide, etc. The compounds thus obtained are reduced. The reduction can be carried out by catalyzed hydrogenation, with nascent hydrogen (iron + acid, aluminum amalgam + water, zinc, tin + acid, etc.) or with complex metal hydrides. One can also complete the condensation and reduction in one step.
De erholdte sekundære eller tertiære aminer kan skilles fra hverandre ved fraksjonert destillasjon og/eller fraksjonert krystallisasjon av basene eller av deres salter. I det tilfelle hvor man har å gjøre med sekundære og tertiære aminer, kan man også gå således frem at man underkaster blandingen av de erholdte sekundære og tertiære baser en acylering, hvorved de sekundære aminer acyleres og blir uoppløselige i fortynnede syrer, mens de tertiære aminer oppløses i fortynnede syrer og derved kan utskilles fra blandingen. The secondary or tertiary amines obtained can be separated from each other by fractional distillation and/or fractional crystallization of the bases or of their salts. In the case where you are dealing with secondary and tertiary amines, you can also proceed in such a way that you subject the mixture of the secondary and tertiary bases obtained to an acylation, whereby the secondary amines are acylated and become insoluble in dilute acids, while the tertiary amines dissolves in dilute acids and can thereby be separated from the mixture.
Den aromatiske kjernes substituenter kan også innføres etter oppbyggingen av det fullstendige molekyl, eller de kan endres. The aromatic core's substituents can also be introduced after the construction of the complete molecule, or they can be changed.
Ved fremstillingen av nitroderivater blir f.eks. de i In the production of nitroderivatives, e.g. those in
den aromatiske kjerne usubstituerte derivater nitrert. Reaksjonen kan med fordel utføres således at man oppløser aminet under av-kjøling i en 50 - 100 %'ig svovelsyre, tilsetter salpetersyre drå-pevis til den erholdte oppløsning og lar blandingen etter-reagere i 1 - 24 timer. Deretter helles reaksjonsblandingen over i vann eller isvann og gjøres alkalisk. Den etter alkaliseringen utskilte olje fraskilles, og den vandige fase ekstraheres om nødvendig med et oppløsningsmiddel. De således erholdte nitrofenylisopropylami-ner befries for vann og oppløsningsmiddel. Produktet renses ved the aromatic core unsubstituted derivatives nitrated. The reaction can advantageously be carried out by dissolving the amine while cooling in a 50 - 100% sulfuric acid, adding nitric acid dropwise to the solution obtained and allowing the mixture to react for 1 - 24 hours. The reaction mixture is then poured into water or ice water and made alkaline. The oil separated after the alkalization is separated, and the aqueous phase is extracted, if necessary, with a solvent. The nitrophenylisopropylamines thus obtained are freed from water and solvent. The product is cleaned with
destillasjon og/eller - når man har å gjøre med saltene eller en fast base - ved krystallisasjon av basen. distillation and/or - when dealing with the salts or a solid base - by crystallization of the base.
De ved nitreringen erholdte para- og ortho-nitroderivater kan fraskilles ved destillasjon av det urene nitrofenylisopropylamin. Som den første fraksjon som destillerer over, gjenvinnes det ikke-nitrerte fenylisopropylamin, og som hoveddestillat erholdes en blanding av p- og o-nitrofenyl-isopropylamin-isomere. Det er fordelaktig å danne hydrogenkloridet av hoveddestillatet, hvorved p-nitrofenylisopropylaminhydrokloridet utkrystalliseres på grunn av dets dårligere oppløselighet, mens ortho-isomeren forblir i moderluten. o-Nitrofenylisopropylamin kan isoleres f.eks. ved frigjøring og fraksjonert destillasjon av basen fra moderluten. Dersom det av destillatet ikke fåes noe krystalliserende hydroklorid med saltsyreholdig ethanol, kan produktet betraktes som ortho-isomeren. Man kan også gå frem således at man ut fra den ved kry-stalliseringen av p-nitrofenylisopropylamin-hydrokloridet erholdte moderlut fremstiller et salt (f.eks. oxalatet, tartratet eller 3,5-dinitrobenzoatet) som muliggjør krystallisering av o-nitro-iso-merer. I dette tilfelle renses o-nitro-isomeren i form av dens salt ved krystallisering. The para- and ortho-nitro derivatives obtained during the nitration can be separated by distillation of the impure nitrophenylisopropylamine. As the first fraction that distills over, the non-nitrated phenylisopropylamine is recovered, and as the main distillate a mixture of p- and o-nitrophenyl-isopropylamine isomers is obtained. It is advantageous to form the hydrogen chloride of the main distillate, whereby the p-nitrophenylisopropylamine hydrochloride is crystallized due to its poorer solubility, while the ortho-isomer remains in the mother liquor. o-Nitrophenylisopropylamine can be isolated, e.g. by liberation and fractional distillation of the base from the mother liquor. If no crystallizing hydrochloride is obtained from the distillate with ethanol containing hydrochloric acid, the product can be considered the ortho-isomer. One can also proceed in such a way that from the mother liquor obtained during the crystallization of the p-nitrophenylisopropylamine hydrochloride, a salt (e.g. the oxalate, the tartrate or the 3,5-dinitrobenzoate) is prepared which enables the crystallization of o-nitro-iso - more. In this case, the o-nitro isomer is purified in the form of its salt by crystallization.
De erholdte p- og o-ni^rofenylisopropylaminer kan ved reduksjon (f.eks. katalysert hydrering) overføres til de tilsvarende aminofenylisopropylaminer. Reduksjonen kan imidlertid også utføres ved hjelp av andre, kjente metoder, med nascerende hydrogen (jern + saltsyre, sink + saltsyre) eller med FeCl2> SnC^» NajS, osv. The obtained p- and o-nirophenylisopropylamines can by reduction (e.g. catalyzed hydrogenation) be transferred to the corresponding aminophenylisopropylamines. However, the reduction can also be carried out using other, known methods, with nascent hydrogen (iron + hydrochloric acid, zinc + hydrochloric acid) or with FeCl2> SnC^» NajS, etc.
Dersom det benyttes katalysert hydrering, omsettes saltet av nitroforbindelsen i nærvær av en katalysator (Pd, Pt, Ni) i et oppløsningsmiddel med hydrogen, hvoretter katalysatoren etter endt reaksjon fraskilles, og aminoforbindelsen erholdes ved inn-dampning i form av et salt. Man kan også frigjøre basen og, om nødvendig, rense denne ved destillasjon eller krystallisasjon eller ved krystallisasjon av et salt av denne. Dersom det som ut-gangsmateriale anvendes rent p- eller o-nitrofenylisopropylamin, erholdes den tilsvarende p- eller o-amino-isomer i ren tilstand. If catalyzed hydrogenation is used, the salt of the nitro compound is reacted in the presence of a catalyst (Pd, Pt, Ni) in a solvent with hydrogen, after which the catalyst is separated after completion of the reaction, and the amino compound is obtained by evaporation in the form of a salt. One can also liberate the base and, if necessary, purify it by distillation or crystallization or by crystallization of a salt thereof. If pure p- or o-nitrophenylisopropylamine is used as starting material, the corresponding p- or o-amino isomer is obtained in a pure state.
Man kan også gå frem således at man etter hydrering av det urene nitrofenylisopropylamin fraskiller den erholdte amino-fenylisopropylamin-isomere 'ved krystallisasjon eller destillasjon (f.eks. på grunn av den dårlige oppløselighet av p-aminoisopropyl-amin-dihydroklorid) i alkohol. I dette tilfelle kan ortho-isomeren renses ved krystallisering av dens salt med 3,5-dinitrobenzoesyre. One can also proceed in such a way that, after hydrogenation of the impure nitrophenylisopropylamine, the resulting amino-phenylisopropylamine isomer is separated by crystallization or distillation (e.g. due to the poor solubility of p-aminoisopropylamine dihydrochloride) in alcohol. In this case, the ortho isomer can be purified by crystallization of its salt with 3,5-dinitrobenzoic acid.
For fremstilling av bromderivatene oppløses aminofenyl-isopropylalkylaminet i en mineralsyre og diazoteres ved tilsetning av natriumnitrit, fortrinnsvis ved en temperatur under 10° Cj og det tilsvarende bromfenylisopropylamin fremstilles i nærvær av det tilsvarende bromidanion (fortrinnsvis av kuprosaltet). Produktet kan utvinnes f.eks. ved alkalisering av reaksjonsblandingen. Basen utskilles i form av en olje, som fraskilles og/eller ekstraheres med et oppløsningsmiddel. For the preparation of the bromine derivatives, the aminophenyl-isopropylalkylamine is dissolved in a mineral acid and diazotized by the addition of sodium nitrite, preferably at a temperature below 10° Cj and the corresponding bromophenylisopropylamine is prepared in the presence of the corresponding bromide anion (preferably of the cuprous salt). The product can be extracted e.g. by alkalinizing the reaction mixture. The base is secreted in the form of an oil, which is separated and/or extracted with a solvent.
De etter inndamping erholdte baser renses ved destillasjon og ved krystallisasjon av basene, henholdsvis av deres salter. The bases obtained after evaporation are purified by distillation and by crystallization of the bases, respectively of their salts.
Bromderivatene kan også fremstilles således at man bro-merer det i den aromatiske ring usubstituerte fenylisopropylalkylamin. Bromeringen kan med fordel utføres i nærvær av elementært brom og katalysatorer (jern, aluminium, jernklorid, aluminiumklo-rid, sinkklorid eller -bromid) og i nærvær eller fravær av oppløs-ningsmiddel. Fortrinnsvis anvendes oppløsningsmidler som er inerte overfor bromeringen, f.eks. carbontetraklorid eller nitrobenzen. The bromine derivatives can also be prepared by brominating the unsubstituted phenylisopropylalkylamine in the aromatic ring. The bromination can advantageously be carried out in the presence of elemental bromine and catalysts (iron, aluminium, iron chloride, aluminum chloride, zinc chloride or bromide) and in the presence or absence of a solvent. Solvents which are inert to the bromination are preferably used, e.g. carbon tetrachloride or nitrobenzene.
De erholdte, para-substituerte forbindelser oppviser en 10 - 20 ganger sterkere halusinogen virkning enn mescalin og har en depressiv, henholdsvis analgetisk virkning som er like stor som virkningen av tetrabenzazin. Disse forbindelser er imidlertid ikke beheftet med de bivirkninger som hefter ved de nevnte forbindelser (eksempelvis er det ingen fare for tilvenning). Forholdet mellom den psykotomimetiske virkning og toksisiteten (sikkerhetsmarginen) er 4 - 5 ganger gunstigere for p-bromfenylisopropylmethylamin enn for de tilsvarende p-jod-, p-klor-, p-amino- og p-nitrofenyliso-propylmet:*ylaminer. Mens dessutm den kjente forbindelse p-klor-fenylisopropylmethylamin sterkt øker motiliteten, har p-bromfenylisopropylmethylamin ingen nevneverdig innvirkning på motiliteten. The para-substituted compounds obtained exhibit a 10-20 times stronger hallucinogenic effect than mescaline and have a depressant or analgesic effect which is as great as the effect of tetrabenzazine. However, these compounds are not affected by the side effects that are associated with the aforementioned compounds (for example, there is no risk of habituation). The relationship between the psychotomimetic effect and the toxicity (margin of safety) is 4 - 5 times more favorable for p-bromophenylisopropylmethylamine than for the corresponding p-iodo-, p-chloro-, p-amino- and p-nitrophenyliso-propylmethylamines. While in addition the known compound p-chloro-phenylisopropylmethylamine greatly increases motility, p-bromophenylisopropylmethylamine has no significant effect on motility.
Den ortho-substituerte forbindelse oppviser sterk og langvarig coronaria-utvidende virkning. The ortho-substituted compound exhibits strong and long-lasting coronary dilating action.
En ved analogifremgangsmåten ifølge oppfinnelsen frem-stilt forbindelse, o-bromfenylisopropylmethylamin, har sammenlig-net med de kjente fenylisopropylaminderivater den betydelige fordel at den ikke oppviser noen primar stimulerende virkning. A compound produced by the analog method according to the invention, o-bromophenylisopropylmethylamine, has, compared with the known phenylisopropylamine derivatives, the significant advantage that it does not exhibit any primary stimulating effect.
Når gitt i en dose av 20 - 30 mg/kg forårsaker o-bromfenylisopropylmethylamin ingen økning av forsøksdyrenes motilitet men nedsetter sogar denne i noen grad. Den :kjente forbindelse fenylisopropylamin frembringer derimot allerede i en dose av 5 mg/kg en 100 %-ig økning av motiliteten. Fenylisopropylmethylpropynylamin har denne virkning allerede når det gis i en dose av When given in a dose of 20 - 30 mg/kg, o-bromophenylisopropylmethylamine causes no increase in the experimental animals' motility, but even reduces this to some extent. The known compound phenylisopropylamine, on the other hand, already produces a 100% increase in motility in a dose of 5 mg/kg. Phenylisopropylmethylpropynylamine already has this effect when given in a dose of
20 mg/kg. 20 mg/kg.
Når gitt i en dose av 15 mg/kg antagoniserer o-bromfenylisopropylmethylamin akutt tetrabenazin-depresjon, mens den MAO-hemménde virkning - som ofte kan være uheldig - selv i doser av 20 mg/kg gitt subcutant bare er 50 %. I denne dose utøver det kjente fenylisopropylmethylpropynylamin en 100 %-ig MAO-hemmende virkning. When given in a dose of 15 mg/kg, o-bromophenylisopropylmethylamine antagonizes acute tetrabenazine depression, while the MAO-inhibitory effect - which can often be unfortunate - even in doses of 20 mg/kg given subcutaneously is only 50%. In this dose, the known phenylisopropylmethylpropynylamine exerts a 100% MAO-inhibiting effect.
Forholdet mellom den ønskelige psykostimulerende virkning og den uønskede økning av stoffskiftehastigheten er minst dobbelt så gunstig for o-bromfenylisopropylmethylamin som for o-klorfenyl-isopropylmethylamin. The relationship between the desirable psychostimulant effect and the undesirable increase in metabolic rate is at least twice as favorable for o-bromophenylisopropylmethylamine as for o-chlorophenylisopropylmethylamine.
I motsetning til de kjente fenylisopropylaminderivater har o-bromfenylisopropylmethylamin analgetiske egenskaper. Etter "varmplate"-metoden bestemmes denne forbindelsesEDgg-verdi til 15,1 mg/kg. In contrast to the known phenylisopropylamine derivatives, o-bromophenylisopropylmethylamine has analgesic properties. Following the "hot plate" method, this compound's EDgg value is determined to be 15.1 mg/kg.
o-Bromfenylisopropylmethylamin forårsaker i doser av EDgQ<=> 6,3 mg/kg en 50 %-ig nedsettelse av blodtrykket hos narkoti-serte katter. Hos hunder fåes det ved administrering av 1 mg/kg o-Bromophenylisopropylmethylamine in doses of EDgQ <=> 6.3 mg/kg causes a 50% reduction in blood pressure in anesthetized cats. In dogs, it is obtained by administering 1 mg/kg
av forbindelsen en 56 %-ig økning av coronargjennomstrømningen etter 2 minutter, mens det etter 10 minutter iakttas en 3 %-ig økning av denne og etter 30 minutter en 30 %-ig økning av samme. Coronar-sirkulasjonen ble undersøkt ved kunstig åndedrett, i en tilstand av heroinisert narkose frembragt ved hjelp av 30 mg/kg Evipan-Na etter forbehandling med 1 mg/kg morfin. of the compound a 56% increase in coronary flow after 2 minutes, while after 10 minutes a 3% increase of this is observed and after 30 minutes a 30% increase of the same. The coronary circulation was examined by artificial respiration, in a state of heroinized anesthesia produced by means of 30 mg/kg Evipan-Na after pretreatment with 1 mg/kg morphine.
Ytterligere enkeltheter ved analogifremgangsmåter ifølge oppfinnelsen vil fremgå av de følgende eksempler. Further details of analog methods according to the invention will appear from the following examples.
Eksempel 1 Fremstilling av p-bromfenylisopropylmethylamin og hydrobromidet av dette Example 1 Preparation of p-bromophenylisopropylmethylamine and its hydrobromide
9,8 g p-aminofenylisopropylmethylamin oppløses i en blanding av 28,8 ml 48 %-ig bromhydrogensyre og 54 ml vann, hvoretter det ved en temperatur lavere enn 0° C tildryppes en oppløsning av 4,2 g natriumnitrit og 24 ml vann ved en pH-verdi på 1. Blandingen omrøres i \ time, hvoretter den prøves på innhold av NHOj med kaliumjodid-stivelse. Eventuelt tilsettes ytterligere 0,2 g NaNOj-10,8 g kobbersulfat oppløses i 92 ml vann, og det til- 9.8 g of p-aminophenylisopropylmethylamine is dissolved in a mixture of 28.8 ml of 48% hydrobromic acid and 54 ml of water, after which, at a temperature lower than 0° C, a solution of 4.2 g of sodium nitrite and 24 ml of water is added dropwise at a pH value of 1. The mixture is stirred for \ hour, after which it is tested for NHOj content with potassium iodide-starch. If necessary, a further 0.2 g of NaNOj is added - 10.8 g of copper sulphate is dissolved in 92 ml of water, and the
settes 10,8 g KBr i 25 ml vann og deretter 39,6 ml 48 %-ig bromhydrogensyre og 4,32 g pulverisert kobber. Den destillerte bases kokepunkt er ved 0,2 mm Hg 81 - 83° C. (n20 = 1,54 54). put 10.8 g of KBr in 25 ml of water and then 39.6 ml of 48% hydrobromic acid and 4.32 g of powdered copper. The boiling point of the distilled base is at 0.2 mm Hg 81 - 83° C. (n20 = 1.54 54).
Den destillerte base surgjøres ved temperatur lavere enn 50° C og under kjøling med en 48 %-ig oppløsning av bromhydrogensyre. De utskilte krystaller frafiltreres, findeles, tørres under forminsket trykk og krystalliseres fra vannfri alkohol. Smeltepunkt 156 - 158° C. The distilled base is acidified at a temperature lower than 50° C and under cooling with a 48% solution of hydrobromic acid. The separated crystals are filtered off, crushed, dried under reduced pressure and crystallized from anhydrous alcohol. Melting point 156 - 158° C.
Eksempel 2 Fremstilling av o- bromfenylisopropylmethylamin Example 2 Preparation of o-bromophenylisopropylmethylamine
Forbindelsen fremstilles som beskrevet i eksempel 1. Den destillerte o-bromfenylisopropylmethylamin-base koker ved 7 2 - 76°C/0,1 mm Hg (n20 = 1,5452). Hydrobromidets semltepunkt: 174 - 175° C. Analyse: N % - 4,25; Br % = 52,4; Br % = 26,o (beregnet: 4,54; 51,8; 25,9). The compound is prepared as described in Example 1. The distilled o-bromophenylisopropylmethylamine base boils at 7 2 - 76°C/0.1 mm Hg (n20 = 1.5452). Melting point of the hydrobromide: 174 - 175° C. Analysis: N % - 4.25; Br% = 52.4; Br % = 26.0 (calculated: 4.54; 51.8; 25.9).
Eksempel 3 Fremstilling av p-bromfenylisopropylmethylpropynylamin og hydrobromidet av dette 20 g p-bromfenylisopropylmethylamin oppløses i 25 ml vannfritt toluen, hvoretter det under omrøring ved temperatur lavere enn 50° C tildryppes 3,45 ml propargylbromid. Reaksjonsblandingen omrøres i 2 timer ved 80° C, kjøles til romtemperatur og ekstraheres med 5 %-ig saltsyre inntil den saltsure ekstrakt ikke lenger gir noen utfelling ved alkalisering. Example 3 Preparation of p-bromophenylisopropylmethylpropynylamine and the hydrobromide of this 20 g of p-bromophenylisopropylmethylamine are dissolved in 25 ml of anhydrous toluene, after which 3.45 ml of propargyl bromide is added dropwise while stirring at a temperature lower than 50° C. The reaction mixture is stirred for 2 hours at 80° C, cooled to room temperature and extracted with 5% hydrochloric acid until the hydrochloric acid extract no longer gives any precipitation upon alkalization.
De saltsure ekstrakter slåes sammen og gjøres alkaliske med natronlut. Den utskilte olje ekstraheres med benzen, benzen-fasen tørres over kaliumcarbonat, og den tørrede oppløsning inndampes. Residuet fraksjoneres under formnisket trykk. The hydrochloric acid extracts are combined and made alkaline with caustic soda. The separated oil is extracted with benzene, the benzene phase is dried over potassium carbonate, and the dried solution is evaporated. The residue is fractionated under reduced pressure.
Som fordestillat erholdes ved en temperatur av 74 - 80° C/0,1 mm Hg p-bromfenylisopropylmethylamin (n^ 2 0 <=> 1,5502).As a pre-distillate, p-bromophenylisopropylmethylamine (n^ 2 0 <=> 1.5502) is obtained at a temperature of 74 - 80° C/0.1 mm Hg.
Som hoveddestillatet fåes ved 95 - 102° C/0,1 mm Hg p-bromfenylisopropylmethylpropynylamin (n^ 20 = 1,5502). As the main distillate is obtained at 95 - 102° C/0.1 mm Hg p-bromophenylisopropylmethylpropynylamine (n^ 20 = 1.5502).
Av p-bromfenylisopropylmethylpropynylamin-basen fremstilles hydrobromidet med bromhydrogensyre. Hydrobromidet krystalliseres fra ethylacetat inneholdende 20 % vannfri ethanol. Smeltepunkt 167 - 168° C. From the p-bromophenylisopropylmethylpropynylamine base, the hydrobromide is prepared with hydrobromic acid. The hydrobromide is crystallized from ethyl acetate containing 20% anhydrous ethanol. Melting point 167 - 168° C.
Analyse: C % = 45,13; H % = 4,98; Br % = 23,5 (beregnet: 45,0; 4,92; 23,0). Analysis: C% = 45.13; H% = 4.98; Br % = 23.5 (calculated: 45.0; 4.92; 23.0).
Eksempel 4 Fremstilling av o-bromfenylisopropylmethylpropynylamin og hydrobromidet av dette Example 4 Preparation of o-bromophenylisopropylmethylpropynylamine and its hydrobromide
8,8 g o-bromfenylisopropylmethylamin-base oppløses i 11 ml toluen, hvoretter det tilsettes 1,53 ml propargylbromid. Blandingen omrøres i 1 time ved en temperatur på 80° C, hvoretter det tilsettes 5,95 ml triethylamin og omrøringen fortsettes ved 80° C 8.8 g of o-bromophenylisopropylmethylamine base are dissolved in 11 ml of toluene, after which 1.53 ml of propargyl bromide is added. The mixture is stirred for 1 hour at a temperature of 80° C, after which 5.95 ml of triethylamine is added and the stirring is continued at 80° C
i 15 minutter. Etter tilsetning av 1,53 ml propargylbromid omrøres reaksjonsblandingen ytterligere i 2 timer ved 80° C, hvoretter den avkjøles og toluenfasen ekstraheres med 5 %-ig saltsyre inntil den saltsure oppløsning ikke gir noen utfelling ved alkalisering. De sammenslåtte saltsure ekstrakter gjøres alkaliske, den utskilte ol-je ekstraheres med benzen, og benzenoppløsningen tørres og inndampes. for 15 minutes. After the addition of 1.53 ml of propargyl bromide, the reaction mixture is stirred for a further 2 hours at 80° C., after which it is cooled and the toluene phase is extracted with 5% hydrochloric acid until the hydrochloric acid solution does not precipitate upon alkalization. The combined hydrochloric acid extracts are made alkaline, the separated oil is extracted with benzene, and the benzene solution is dried and evaporated.
Til residuet tildryppes samtidig, under omrøring og ved en temperatur av 50° C, 9,5 ml benzoylklorid og 66 ml av en 10 %-ig vandig natriumhydroxydoppløsning. Deretter omrøres blandingen i 1 time ved 50° C og ekstraheres med benzen. Benzenoppløsningen ekstraheres med 5 %-ig saltsyre inntil den saltsure oppløsning ikke lenger gir noen utfelling ved alkalisering. De saltsure ekstrakter gjøres alkaliske, den utskilte olje ekstraheres med benzen, benzen-oppløsningen tørres over kaliumcarbonat og inndampes under forminsket trykk, hvoretter residuet tilslutt destilleres i vann. Ved 110° C/0,15 mm Hg erholdes o-bromfenylisopropylmethylpropynylamin (nj° = 1,55525). 9.5 ml of benzoyl chloride and 66 ml of a 10% aqueous sodium hydroxide solution are added dropwise to the residue at the same time, with stirring and at a temperature of 50° C. The mixture is then stirred for 1 hour at 50° C. and extracted with benzene. The benzene solution is extracted with 5% hydrochloric acid until the hydrochloric acid solution no longer gives any precipitation upon alkalization. The hydrochloric acid extracts are made alkaline, the separated oil is extracted with benzene, the benzene solution is dried over potassium carbonate and evaporated under reduced pressure, after which the residue is finally distilled in water. At 110° C/0.15 mm Hg, o-bromophenylisopropylmethylpropynylamine is obtained (nj° = 1.55525).
Hydrobromidet fåes ut fra en blanding av alkohol og ether. Produktet sintrer ved 89° C og smelter ved 97° C. The hydrobromide is obtained from a mixture of alcohol and ether. The product sinters at 89° C and melts at 97° C.
Analyse: N % = 4,2; Br % = 23,1 (beregnet: 4,05; 23,0). Analysis: N% = 4.2; Br % = 23.1 (calculated: 4.05; 23.0).
Eksempel 5 Fremstilling av 2-brom-4-nitrofenylisopropylmethylamin Example 5 Preparation of 2-bromo-4-nitrophenylisopropylmethylamine
388,5 g p-nitrofenylisopropylmethylamin oppløses under avkjøling og omrøring i en blanding av 1082 ml konsentrert svovelsyre og 650 ml vann, hvoretter det under omrøring ved 55° % tilsettes 372 g 5,5-dimethyl-l,3-dibromhydantoin. Temperaturen stiger til 70 - 80° C. Blandingen omrøres ved 70° C i 5 timer. Etter av-kjøling tilsettes en natriumsulfittoppløsning for å omsette aktivt, uomsatt brom, og oppløsningen filtreres. Det erholdte klare filtrat avkjøles og gjøres alkalisk med en 40 %-ig natriumhydroxydoppløs-ning. Den utskilte brune olje ekstraheres med benzen, og skilles fra vannfasen. Den erholdte benzenekstrakt tørres over vannfritt kaliumcarbonat og inndampes etter filtrering. Residuet er en brun 388.5 g of p-nitrophenylisopropylmethylamine is dissolved while cooling and stirring in a mixture of 1082 ml of concentrated sulfuric acid and 650 ml of water, after which 372 g of 5,5-dimethyl-1,3-dibromohydantoin is added while stirring at 55%. The temperature rises to 70 - 80° C. The mixture is stirred at 70° C for 5 hours. After cooling, a sodium sulfite solution is added to react active, unreacted bromine, and the solution is filtered. The resulting clear filtrate is cooled and made alkaline with a 40% sodium hydroxide solution. The separated brown oil is extracted with benzene and separated from the water phase. The benzene extract obtained is dried over anhydrous potassium carbonate and evaporated after filtration. The residue is a brown
olje (542 g). oil (542 g).
Analyse: Br S = 29,5 (beregnet: 29,3 %). Analysis: Br S = 29.5 (calculated: 29.3%).
Eksempel 6 Fremstilling av 2- brom- 4- aminofenylisopropylmethylamin Example 6 Preparation of 2-bromo-4-aminophenylisopropylmethylamine
Til en blanding av 31,4 g jernpulver og 4 3 ml vann tilsettes under omrøring og oppvarming i løpet av 3 timer en varm opp-løsning av 54,6 g 2-beom-4-nitrofenylisopropylmethylamin og 32 ml saltsyre. Etter tilsetningen kokes blandingen med tilbakeløp og under omrøring i £ time. Etter avkjpøling gjøres reaksjonsblandingen alkalisk med en 40 %-ig natriumhydroxydoppløsning. Den alkaliske blanding inndampes til tørrhet under forminsket trykk, hvorpå residuet ekstraheres med benzen. Ved inndamping av benzenekstrakten erholdes 2-brom-4-amino-fenylisopropylmethylamin. A hot solution of 54.6 g of 2-beom-4-nitrophenylisopropylmethylamine and 32 ml of hydrochloric acid is added to a mixture of 31.4 g of iron powder and 4 3 ml of water with stirring and heating over the course of 3 hours. After the addition, the mixture is refluxed and stirred for £ hour. After cooling, the reaction mixture is made alkaline with a 40% sodium hydroxide solution. The alkaline mixture is evaporated to dryness under reduced pressure, after which the residue is extracted with benzene. By evaporation of the benzene extract, 2-bromo-4-amino-phenylisopropylmethylamine is obtained.
Analyse: Br % = 32,5 (beregnet: 32,9 %). Analysis: Br % = 32.5 (calculated: 32.9%).
Eksempel 7 Fremstilling av o- bromfenylisopropylmethylamin Example 7 Preparation of o-bromophenylisopropylmethylamine
12,1 g 2-brom-4-aminofenylisopropylmethylamin oppløses 12.1 g of 2-bromo-4-aminophenylisopropylmethylamine are dissolved
i 184 30 %-ig hypofosforsyre, hvoretter det tildryppes en oppløs-ning av 3,8 g natriumnitritt og 10 ml vann ved 0 - 5° C under om-røring og kjøling. Reaksjonsblandingen tillates å anta romtemperatur og tillates å stå i 4 timer ved denne temperatur. Blandingen gjøres alkalisk, den utskilte olje ekstraheres med benzen, benzen-oppløsningen inndampes og residuet destilleres under forminsket trykk. Det erholdte produkt er o-bromfenylisopropylmethylamin. Kokepunkt: 84 - 85° C/0,4 mm Hg. n<20> = 1,5492. in 184 30% hypophosphoric acid, after which a solution of 3.8 g of sodium nitrite and 10 ml of water is added dropwise at 0 - 5° C with stirring and cooling. The reaction mixture is allowed to reach room temperature and is allowed to stand for 4 hours at this temperature. The mixture is made alkaline, the separated oil is extracted with benzene, the benzene solution is evaporated and the residue is distilled under reduced pressure. The product obtained is o-bromophenylisopropylmethylamine. Boiling point: 84 - 85° C/0.4 mm Hg. n<20> = 1.5492.
Hydrobromidets smeltepunkt er 170 - 171° C, mens hydro-kloridets smeltepunkt er 159 - 160° C. The melting point of the hydrobromide is 170 - 171° C, while the melting point of the hydrochloride is 159 - 160° C.
Eksempel 8 Fremstilling av o-bromfenylisopropylmethylaminhydroklorid Example 8 Preparation of o-bromophenylisopropylmethylamine hydrochloride
2,13 g o-brombenzylmethylketon oppløses i 10 ml vannfri ethanol. Etter tilsetning av 10 ml av en 30 %-ig methylaminopp-løsning i vannfri ethanol tillates blandingen å stå i 24 timer. Det tilsettes deretter 0,2 g natriumbprhydrid. Reaksjonsblandingen tillates å stå i ytterligere 4 timer og inndampes deretter under forminsket trykk. Residuet tilsettes vann, hvoretter blandingen ekstraheres med benzen. Benzenekstrakten tørres over vannfritt natriumsulfat, tørkemidlet frafiltreres, og filtratet inndampes. Hydrokloridet fremstilles ut fra det oljeaktige residuum med alko-holisk saltsyre. Saltet utfelles ved tilsetning av ethylacetat. 2.13 g of o-bromobenzyl methyl ketone are dissolved in 10 ml of anhydrous ethanol. After adding 10 ml of a 30% methylamine solution in anhydrous ethanol, the mixture is allowed to stand for 24 hours. 0.2 g of sodium biprohydride is then added. The reaction mixture is allowed to stand for a further 4 hours and is then evaporated under reduced pressure. Water is added to the residue, after which the mixture is extracted with benzene. The benzene extract is dried over anhydrous sodium sulfate, the drying agent is filtered off, and the filtrate is evaporated. The hydrochloride is prepared from the oily residue with alcoholic hydrochloric acid. The salt is precipitated by the addition of ethyl acetate.
Det erholdte o-bromfenylisopropylmethylaminhydroklorid smelter ved 160° C. The obtained o-bromophenylisopropylmethylamine hydrochloride melts at 160° C.
Eksempel 9 Fremstilling av o-bromfenylisopropylmethylamin-hydroklorid Example 9 Preparation of o-bromophenylisopropylmethylamine hydrochloride
2,14 g o-bromfenylisopropylamin oppvarmes i 6 timer med 2.14 g o-bromophenylisopropylamine is heated for 6 hours with
10 ml 98 %-ig maursyre, hvoretter blandingen inndampes. Spor av maursyren fjernes under forminsket trykk. Residuet oppløses i 20 10 ml of 98% formic acid, after which the mixture is evaporated. Traces of formic acid are removed under reduced pressure. The residue dissolves in 20
ml vannfri ether, og oppløsningen tilsettes ved 0° C 9,3 8 g lithium-aluminiumhydrid. Blandingen omrøres i 3 timer, hvorpå det under nitrogenatmosfære og under omrøring tildryppes 10 ml vann. Blandingen helles over i en dråpetrakt, den vandige fase fjernes, og den etheriske oppløsning vaskes med 10 ml lut og deretter 4 ganger med porsjoner å 20 ml vann. Etheroppløsningen tørres over magnesium-sulfat og inndampes. Residuet oppløses i litt ethanol, og oppløs-ningen surgjøres med ethanolisk saltsyre. Ved inntredende uklarhet tilsettes ethylacetat. De utskilte krystaller isoleres, vaskes med en 1:3 blanding av ethanol og ethylacetat og tørres. Det erholdte o-bromfenylisopropylmethylamin-hydroklorid smelter ved 159 - 160° C. ml of anhydrous ether, and the solution is added at 0° C. 9.3 8 g of lithium aluminum hydride. The mixture is stirred for 3 hours, after which 10 ml of water is added dropwise under a nitrogen atmosphere and with stirring. The mixture is poured into a dropping funnel, the aqueous phase is removed, and the ethereal solution is washed with 10 ml of lye and then 4 times with portions of 20 ml of water. The ether solution is dried over magnesium sulfate and evaporated. The residue is dissolved in a little ethanol, and the solution is acidified with ethanolic hydrochloric acid. If cloudiness occurs, ethyl acetate is added. The separated crystals are isolated, washed with a 1:3 mixture of ethanol and ethyl acetate and dried. The obtained o-bromophenylisopropylmethylamine hydrochloride melts at 159 - 160° C.
Eksempel 10 Fremstilling av o- bromfenylisopropyl- methylamin Example 10 Preparation of o-bromophenylisopropylmethylamine
En oppløsning av 21,4 g o-bromfenylisopropylamin i 2o ml ethanol tilsettes 66 ml av en 30 %-ig formaldehydoppløsning, hvorpå blandingen rystes under hydrogenatmosfære med 5 g Raney-nikkel. Etter opptagelse av 2200 ml hydrogen frafiltreres katalysatoren og inndampes filtratet. Residuet underkastes fraksjonert destillasjon under forminsket trykk. Den ved 73 - 75° C/0,1 mm Hg kokende hoved-fraksjon består av o-bromfenylisopropylmethylamin. (nD 2D =1,549). Hydrokloridet smeltepunkt er 159 - 160° C. A solution of 21.4 g of o-bromophenylisopropylamine in 20 ml of ethanol is added to 66 ml of a 30% formaldehyde solution, after which the mixture is shaken under a hydrogen atmosphere with 5 g of Raney nickel. After absorption of 2200 ml of hydrogen, the catalyst is filtered off and the filtrate is evaporated. The residue is subjected to fractional distillation under reduced pressure. The main fraction boiling at 73 - 75° C/0.1 mm Hg consists of o-bromophenylisopropylmethylamine. (nD 2D =1.549). The hydrochloride melting point is 159 - 160° C.
Eksempel 11 Fremstilling av p- bromfenylisopropylmethylpropynylamin Example 11 Preparation of p-bromophenylisopropylmethylpropynylamine
44,1 g p-bromfenylisopropylmethylamin oppløses i 160 ml dioxan, hvoretter det tilsettes 12 g paraformaldehyd og 2 g cupro-klorid. Gassformig acetylen innføres under omrøring, mens reaksjonsblandingen oppvarmes ved 80° C i 30 timer. Reaksjonsblandingen inndampes, residuet vaskes med vann, og den erholdte olje underkastes fraksjonert destillasjon i vakuum. Det erhoides således 15,2 g p-bromfenylisopropylmethylpropynylamin ved 95 - 102° C/0,1 mm Hg; 44.1 g of p-bromophenylisopropylmethylamine is dissolved in 160 ml of dioxane, after which 12 g of paraformaldehyde and 2 g of cuprous chloride are added. Gaseous acetylene is introduced with stirring, while the reaction mixture is heated at 80° C. for 30 hours. The reaction mixture is evaporated, the residue is washed with water, and the oil obtained is subjected to fractional distillation in vacuum. 15.2 g of p-bromophenylisopropylmethylpropynylamine are thus obtained at 95 - 102° C/0.1 mm Hg;
20 20
n<£u> = 1,5502. n<£u> = 1.5502.
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