NO142523B - Fremgangsmaate ved fremstilling av aminosyreamider av dopamin - Google Patents
Fremgangsmaate ved fremstilling av aminosyreamider av dopamin Download PDFInfo
- Publication number
- NO142523B NO142523B NO741143A NO741143A NO142523B NO 142523 B NO142523 B NO 142523B NO 741143 A NO741143 A NO 741143A NO 741143 A NO741143 A NO 741143A NO 142523 B NO142523 B NO 142523B
- Authority
- NO
- Norway
- Prior art keywords
- dopamine
- dihydroxy
- phenethyl
- acid
- carbobenzyloxyamino
- Prior art date
Links
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 title claims description 44
- 229960003638 dopamine Drugs 0.000 title claims description 21
- -1 AMINO ACIDAMIDES Chemical class 0.000 title claims description 16
- 238000000034 method Methods 0.000 title claims description 11
- 238000002360 preparation method Methods 0.000 title claims description 8
- 229940024606 amino acid Drugs 0.000 claims description 11
- 235000001014 amino acid Nutrition 0.000 claims description 9
- 150000001413 amino acids Chemical class 0.000 claims description 9
- 150000002148 esters Chemical class 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 5
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- NMHMNPHRMNGLLB-UHFFFAOYSA-N phloretic acid Chemical compound OC(=O)CCC1=CC=C(O)C=C1 NMHMNPHRMNGLLB-UHFFFAOYSA-N 0.000 claims description 4
- FSYKKLYZXJSNPZ-UHFFFAOYSA-N sarcosine Chemical compound C[NH2+]CC([O-])=O FSYKKLYZXJSNPZ-UHFFFAOYSA-N 0.000 claims description 4
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 229960000310 isoleucine Drugs 0.000 claims description 3
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 claims description 2
- JJYPMNFTHPTTDI-UHFFFAOYSA-N 3-methylaniline Chemical compound CC1=CC=CC(N)=C1 JJYPMNFTHPTTDI-UHFFFAOYSA-N 0.000 claims description 2
- ODHCTXKNWHHXJC-VKHMYHEASA-N 5-oxo-L-proline Chemical compound OC(=O)[C@@H]1CCC(=O)N1 ODHCTXKNWHHXJC-VKHMYHEASA-N 0.000 claims description 2
- 239000004475 Arginine Substances 0.000 claims description 2
- NIGWMJHCCYYCSF-UHFFFAOYSA-N Fenclonine Chemical compound OC(=O)C(N)CC1=CC=C(Cl)C=C1 NIGWMJHCCYYCSF-UHFFFAOYSA-N 0.000 claims description 2
- 239000004471 Glycine Substances 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 claims description 2
- WTDRDQBEARUVNC-LURJTMIESA-N L-DOPA Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-LURJTMIESA-N 0.000 claims description 2
- WTDRDQBEARUVNC-UHFFFAOYSA-N L-Dopa Natural products OC(=O)C(N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-UHFFFAOYSA-N 0.000 claims description 2
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 claims description 2
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 claims description 2
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 claims description 2
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 claims description 2
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 claims description 2
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 claims description 2
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 claims description 2
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 claims description 2
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 claims description 2
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 claims description 2
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 claims description 2
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 claims description 2
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 claims description 2
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 claims description 2
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 claims description 2
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 claims description 2
- 239000004472 Lysine Substances 0.000 claims description 2
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 claims description 2
- ODHCTXKNWHHXJC-GSVOUGTGSA-N Pyroglutamic acid Natural products OC(=O)[C@H]1CCC(=O)N1 ODHCTXKNWHHXJC-GSVOUGTGSA-N 0.000 claims description 2
- 108010077895 Sarcosine Proteins 0.000 claims description 2
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 claims description 2
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 claims description 2
- 239000004473 Threonine Substances 0.000 claims description 2
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 claims description 2
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 claims description 2
- ODHCTXKNWHHXJC-UHFFFAOYSA-N acide pyroglutamique Natural products OC(=O)C1CCC(=O)N1 ODHCTXKNWHHXJC-UHFFFAOYSA-N 0.000 claims description 2
- 235000004279 alanine Nutrition 0.000 claims description 2
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims description 2
- 235000003704 aspartic acid Nutrition 0.000 claims description 2
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 claims description 2
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 claims description 2
- 235000018417 cysteine Nutrition 0.000 claims description 2
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 claims description 2
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 claims description 2
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 claims description 2
- 229930182817 methionine Natural products 0.000 claims description 2
- 235000006109 methionine Nutrition 0.000 claims description 2
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 claims description 2
- 229940043230 sarcosine Drugs 0.000 claims description 2
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 claims description 2
- 239000004474 valine Substances 0.000 claims description 2
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 claims 2
- OGNSCSPNOLGXSM-UHFFFAOYSA-N (+/-)-DABA Natural products NCCC(N)C(O)=O OGNSCSPNOLGXSM-UHFFFAOYSA-N 0.000 claims 1
- 229960003692 gamma aminobutyric acid Drugs 0.000 claims 1
- 238000005984 hydrogenation reaction Methods 0.000 claims 1
- 229960004452 methionine Drugs 0.000 claims 1
- 230000001681 protective effect Effects 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- 238000006243 chemical reaction Methods 0.000 description 11
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 3
- 238000005859 coupling reaction Methods 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- CTENFNNZBMHDDG-UHFFFAOYSA-N Dopamine hydrochloride Chemical compound Cl.NCCC1=CC=C(O)C(O)=C1 CTENFNNZBMHDDG-UHFFFAOYSA-N 0.000 description 2
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 239000002220 antihypertensive agent Substances 0.000 description 2
- 229940030600 antihypertensive agent Drugs 0.000 description 2
- UCMIRNVEIXFBKS-UHFFFAOYSA-N beta-alanine Chemical group NCCC(O)=O UCMIRNVEIXFBKS-UHFFFAOYSA-N 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 229960001149 dopamine hydrochloride Drugs 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 229940095064 tartrate Drugs 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 229940124549 vasodilator Drugs 0.000 description 2
- 239000003071 vasodilator agent Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- JSHXJPFZKBRLFU-JQWIXIFHSA-N (2s,3s)-3-methyl-2-(phenylmethoxycarbonylamino)pentanoic acid Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)OCC1=CC=CC=C1 JSHXJPFZKBRLFU-JQWIXIFHSA-N 0.000 description 1
- ADFXKUOMJKEIND-UHFFFAOYSA-N 1,3-dicyclohexylurea Chemical compound C1CCCCC1NC(=O)NC1CCCCC1 ADFXKUOMJKEIND-UHFFFAOYSA-N 0.000 description 1
- LSVSIOOFOQJHPY-UHFFFAOYSA-N 2-(4-methylpiperazin-1-yl)butanedioic acid Chemical compound CN1CCN(C(CC(O)=O)C(O)=O)CC1 LSVSIOOFOQJHPY-UHFFFAOYSA-N 0.000 description 1
- QWVNCIRRVAEKFU-UHFFFAOYSA-N 2-phenyl-n,n-bis(phenylmethoxy)ethanamine Chemical compound C=1C=CC=CC=1CON(OCC=1C=CC=CC=1)CCC1=CC=CC=C1 QWVNCIRRVAEKFU-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 206010019280 Heart failures Diseases 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
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 229960003767 alanine Drugs 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 229940000635 beta-alanine Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000036770 blood supply Effects 0.000 description 1
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
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- 239000013078 crystal Substances 0.000 description 1
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- 238000003810 ethyl acetate extraction Methods 0.000 description 1
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- 239000012467 final product Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 125000006289 hydroxybenzyl group Chemical group 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 229940117803 phenethylamine Drugs 0.000 description 1
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- 239000011734 sodium Substances 0.000 description 1
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D295/145—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/15—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/46—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with hetero atoms directly attached to the ring nitrogen atom
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Peptides Or Proteins (AREA)
- Pyrrole Compounds (AREA)
- Indole Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Description
Nærværende oppfinnelse vedrorer en forbedret fremgangsmåte
for syntetisering av aminosyreamider av dopamin.
Dopamin er blitt beskrevet å være anvendelig for behandling
av hjertesvikt ved foroket blodtilforsel og sjokk. Imidler-
tid var det antatt at dopamin bare var aktivt ad intravenos administrasjonsvei og forskjellige forskere har utviklet derivater av dopamin som er oralt virksomme og lengere vir-kende enn dopamin. En slik klasse av forbindelser er aminosyreamidene av dopamin som er anvendelige vasodilatoriske og antihypertensive midler i forbindelse med nyrene. (Se U.S. patent nr. 3.676.492).
Skjont aminosyreamidene av dopamin er utmerket vasodilatoriske og antihypertensive midler i forbindelse med nyrene har synte-sen av disse både vært vanskelig og dyr.
I US patent nr. 3.676.492 fremstilles aminosyreamider av dopamin av formlen
hvor R betegner hydrogen, laverealkyl, hydroksymetyl, hydroksybenzyl, (3-hydroksyetyl, merkaptometyl,
metylmerkaptoetyl, 3-indolylmetyl, karboksymetyl,
(3-karboksyetyl, y-guanidinopropyl, /\-aminobutyl ,
eller 5-imidazolylmetyl,
ved å omsette dibenzyloksyfenetylamin eller et salt av dette med den onskede N-karbobenzyloksyaminosyre for å oppnå det beskyttede N-karbobenzyloksy-aminosyreamid av 3,4-dibenzyl-oksy-|3-f enetylamin som derpå reduseres til 3,4-dihydroksy-ami no sy r eami d.
Det er nå funnet at hoyere utbytter oppnås og storre enkelthet ved fremstillingen fås ved å fremstille en aktiv ester av den onskede N-karbobenzyloksyaminosyre og omsette den direkte med et salt av dopamin (3,4-dihydroksyfenetylamin). Koblingsreak-sjonen er i det vesentlige kvantitativ, og reduksjon for å spalte av den karbobenzyloksy-beskyttende gruppe gir en i det vesentlige kvantitativ utvinning av det onskede aminosyreamid av dopamin (utbyttene er vanligvis over 90 %.)
Dette er fullstendig overraskende, da det tidligere var antatt at 3,4-dihydroksy-gruppene av dopamin måtte beskyttes for koblingstrinnet med den aktuelle aminosyre.
Fremgangsmåte etter nærværende oppfinnelse gir også et karbo-benzyloksymellomprodukt av hoy renhet, hvilket forer til et rent sluttprodukt. Ved den tidligere kjente prosess måtte temperaturene omhyggelig overvåkes for å forebygge racemise-ring, og karbobenzyloksyamid-forurensninger vil være tilstede i sluttproduktet. Nærværende oppfinnelse eliminerer i tillegg til forannevnte ulemper racemiseringsproblemet såvel som karbobenzyloksy-forurensningsproblemet.
Folgelig kan aminosyreamider av dopamin av formelen
hvor R1 er hydrogen eller lavere alkyl, oq er Ø-alanin, (3-metylalanin, f enylalanin, 3, 4-dihydroksyfenyl-alanin, 4-klorfenylalanin, glycin, tyrosin, valin, leucin, iso-leucin, serin, treonin, cystein, metio-nin, tryptofan, asparaginsyre, glutamin, arginin, lysin, histidin, y-aminosmorsyre, pyroglutaminsyre, alanin, prolin, sarkosin, N-metylpiperazinosmor-syre eller
hvor n er et helt tall fra 1 til 4,
med fordel fremstilles ved å omsette en reaktiv ester, slik som N-hydroksysuccinimidesteren av en N-karbobenzyloksyaminosyre med dopamin eller et salt av dopamin, slik som dopaminhydroklorid, ved en temperatur på fra 20° til 50°C over en tidsperiode på 3 til 20 timer for oppnåelse av N-karboben-zyloksyaminosyreamidet av dopamin. Den beskyttende gruppe spaltes derpå ved den vanlige metode, f.eks. ved hydrogen-reduksjon. De foretrukne reaksjonsbetingelser for det direkte koblingstrinn er 40°C over minst 16 timer. Ved å gå ut fra
den passende d-, 1- eller dl-aminosyre oppnås det tilsvarende d-, 1- reller dl-aminosyreamid.
Representative forbindelser som kan fremstilles ved fremgangs-måten ifolge nærværende oppfinnelse omfatter: N-3 1 4 ' -dihydroksy-(3-f enetyl-L-3, 4-dihydroksyf enylalaninamid N-3 ' ,4 ' -dihydroksy-(3-f enetyl-L-alaninamid
N-3 ' , 4 '-dihydroksy-ct-metyl-(3-f enetyl-L-alaninamid N-3 1 j 4' -dihydroksy(3-f enetyl-L-tyrosinamid
N-3', 4'-dihydroksy-a-metyl-p-fenetyl-L-tyrosinamid N-3<1>,4!-dihydroksy-P-fenetylglycinamid
N-3',4<1->dihydroksy-a-metyl-p-fenetylglycinamid N-3 1 , 4 • -dihydroksy-(3-f enetyl-DL-valinamidhydroklorid N-3<1>,4<1->dihydroksy-a-metyl-P-fenetyl-DL-valinamidhydroklorid
■■N-3 ' , 4 1 -dihydroksy-p-f enetyl-D-isoleucinamidoksalat N-3', 4'-dihydroksy-a-metyl-P-fenetyl-D-isoleucinamidoksalat N-3',4<1->dihydroksy-p-fenetyl-L-leucinamidtartrat N-3 1 , 4 1 -dihydroksy-a-metyl-(3-fenetyl-L-leucinamidtartrat N-3'j4'-dihydroksy-P-fenetyl-L-fenylalaninamid N-3 >,4'-dihydroksy-a-metyl-P-fenetyl-L-fenylalaninamid N-31, 4'-dihydroksy-P-fenetyl-D-serinamidsulfat N-3' , 4' -dihydroksy-oc-metyl-(3-fenetyl-D-serinamidsulfat N-3',4'-dihydroksy-p-fenetyl-L-treoninamid
N-3<1>,4'-dihydroksy-a-metyl-P-fenetyl-L-treoninamid N-3', 4'-dihydroksy-P-fenetyl-L-cysteinamid
N-3 *, 4'-dihydroksy-a-metyl-p-fenetyl-L-cysteinamid N-3', 4'-dihydroksy-p-fenetyl-DL-metioninamid N-3', 4'-dihydroksy-a-metyl-P-fenetyl-DL-metioninamid N-3<1>,4<1->dihydroksy-p-fenetyl-L-tryptofanamid N-3',4'-dihydroksy-a-metyl-P-fenetyl-L-tryptofanamid N-3',4'-dihydroksy-P-fenetyl-D-aspartylamidtosylat N-3<1>,4<1->dihydroksy-a-metyl-p-fenetyl-D-aspartylamidtosylat N-3',4'-dihydroksy-P-fenetyl-DL-glutamylamid N-3',4<1->dihydroksy-a-metyl-P-fenetyl-DL-glutamylamid N-3',4'-dihydroksy-P-fenetyl-L-argininamid
N-3',4'-dihydroksy-a-metyl-P-fenetyl-L-argininamid
N-3', 4'-dihydroksy-a-isopropyl-p-fenetyl-DL-argininamid N-3',4'-dihydroksy-P-fenetyl-D-lysinamid
N-3' , 4 1 -dihydroksy-a-metyl-(3-f enetyl-D-lysinamid N-3',4'-dihydroksy-P-fenetyl-DL-histidinamid N-3',4'-dihydroksy-a-metyl-P-fenetyl-DL-histidinamid N-3',4'-dihydroksy-P-fenetyl-DL-4-klorfenylalaninamid N-3',4'-dihydroksy-a-metyl-P-fenetyl-DL-4-klorfenylalanin-amid.
De reaktive estrene kan fremstilles etter den metode som er angitt i J. A. C. S. 86, 1839 (1964) eller japansk patent nr. 4 2943/67.
De folgende eksempler illustrerer oppfinnelsen ytterligere.
EKSEMPEL 1
Fremstilling av N-(N'-karbobenzyloksyalanyl)-P-(3,4-dihy dr oksy f enetylamin)
N-hydroksysuccinimidesteren av karbobenzyloksy-dopamin (6,1 g 0,020 mol( J.A.C.S. 86, 1839 (1964) ble tilsatt til 3,8 g dopaminhydroklorid opplost i 30 ml dimetylformamid (DMF). Reaksjonsblåndingen ble rort om, 8 ml trietylamin ble tilsatt og reaksjonen ble rbrt om i 3 til 4 timer.
EKSEMPEL 2
Fremstilling av N- 34'- dihydroksy- P- fenetyl- L- alaninamid
N'-3',4'-dihydroksy-P-fenetyl-L-fenylalaninamid, s.p. 278-283 ble fremstilt ved å hydrogenere 20 g N-(N Lkarbobenzyloksyala-myl)-P-(3,4-dihydroksyfenetylamin) i 200 ml absolutt etanol, 1,1 ekvivalent 12 N HC1 og 10% katalysatorforhold under an-vendelse av 5% Pd/C som katalysatoren. Den hydrogenerte re-aksjon ble filtrert, etanolen drevet av, og resten behandlet azeotropt med etanol for å fjerne overskytende saltsyre. Resten ble tatt opp i en minimal mengde metanol, og produktet bunnfelt med Et20.
EKSEMPEL 3
Fremstilling av N-hydroksysuccinimid-
esteren av N- karbobenzyloksy- l- isoleucin
I en ren reaktor satset med 20 liter tort dioksan ble tilsatt 2.653 g N-karbobenzyloksy-l-isoleucin og 1151 g N-hydroksy-succinimid. Reaksjonsblandingen ble oppvarmet til 40°C under omroring for å forårsake opplosning. I et separat kar ble 2.060 g dicykloheksylkarbodiimid opplost i 6 liter tort dioksan ved å oppvarme blandingen til en temperatur på fra 35-4o°C. Dicykloheksylkarbodiimidopplbsningen ble tilsatt hurtig under omroring til reaksjonsblandingen. Temperaturen ble holdt ved 40-45°C i 16 timer, avkjolt til 2o°C og de faste stoffer (di-cykloheksylurea) ble filtrert fra og kaken vasket 2-3 ganger med dioksan. Filtratet og vaskevæskene ble forenet og overfort til en reaktor egnet for vakuumavdrivning. Reaksjonen ble drevet av i vakuum til en tykk sirupp ved en maksimumstemperatur på 60°C. Vakuumet ble opphevet, 20 liter isopropanol ble tilsatt og reaksjonen ble oppvarmet til 60-70°C
for å opplose de faste stoffer. Opplosningen filtreres, av-kjoles til 10-15°C under omroring og holdt ved 10-15°C i 3 timer. Bunnfallet ble sentrifugert, vasket med en liten mengde kold isopropanol og vakuumtorket ved 45°C for å gi 3100 g av det onskede mellomprodukt.
EKSEMPEL 4
Fremstilling av N-karbobenzyloksy-L-isoleucyl-3- 3. 4- dihydroksyfenetylamin
Dimetylformamid (15 liter), 1991 g (10,5 mol) av den foran fremstilte N-hydroksysuccinimidester av N-karbobenzyloksy-1-leucin ble anbragt under en nitrogenskjerm og oppvarmet til 40°C. Trietylamin (3000 g, 29,74 mol) ble tilsatt og reaksjonen ble rort om i 16 timer ved 40°C. Reaksjonen ble avkjolt til 20°C og 2,5 liter kaldt vann ble tilsatt til reaksjonen fulgt av tilsetningen av 40 liter av en 0,5 %'s na-triumbisulfittoppldsning. Reaksjonen ble rort om i 30 minut-ter, fikk avsette seg i 1 time og det vandige lag ble skilt fra, fulgt av reekstraksjon to ganger med 10 liter etylacetat. Etylacetatekstraksjonene ble forenet og vasket tre ganger med 15 liter 0,5 %'s natriumbisulfatopplosning. Vannfritt natriumsulfat (6,8 kg) og 1,8 kg "Darco6-60" trekull ble tilsatt til etylacetatopplosningen. Blandingen ble slemmet opp i 2 timer, filtrert, filtratet ble overfort til en reaktor egnet for vakuum-avdrivning, og etylacetatet ble drevet av i vakuum ved en maksimumstemperatur på 60°C. Benzen (30 liter) ble tilsatt og reaksjonen oppvarmet til 50°C inntil opplosning var gjennomfort. Reaksjonen ble kjolt til 15-20°C og rort om i 6-8 timer, sentrifugert, vasket med en liten mengde benzen og vakuumtorket ved 45°C for å gi det onskede rå pro-dukt..
EKSEMPEL 5
Fremstilling av 3„ 4- dihydroksy- P- fenetyl- L- isoleucylamid
4 g av det foran fremstilte N-karbobenzyloksy-L-isoleucyl (3-3,4-dihydroksyfenetylamin ble tatt opp i 100 ml etylacetat og ekstrahert med lOO ml 1 N HC1 opplosning. Den gule opplos-
ning ble nesten fargelos. Etylacetatlaget ble vasket tre ganger med 100 ml's porsjoner destillert vann. Etylacetatet ble torket over Na^SO^, filtrert og konsentrert i vakuum for å
gi en gjennomsiktig tykk film. Denne film ble tatt opp i metanol, 100 ml, og avfarget med "Darco" for å gi en nesten far-velos opplosning. Denne oppldsning ble konsentrert i vakuum for å gi en gjennomsiktig tykk film. Filmen ble tatt opp i et minimum av eter og fikk henstå ved romtemperatur for å gi 3,6 g av produktet som hvite nålelignende krystaller, s.p. 105-107°.
Claims (4)
1. Fremgangsmåte ved fremstilling av et aminosyreamid av dopamin av formelen
hvor betegner hydrogen eller lavere alkyl, og 1^ er S-alanin, (3-metylalanin, f enylalanin, 3,4-dihydroksyf enylalanin, 4-klorfenylalanin, glycin, tyrosin, valin, leucin, isoleucin, serin, treonin, cystein, metio-nin, tryptofan, asparaginsyre, glutamin, arginin, lysin, histidin, y-aminosmorsyre, pyroglutaminsyre, alanin, prolin, sarkosin, N-metylpiperazinosmor-
syre, eller
hvor n er et helt tall fra 1 til 4,
karakterisert ved at en reaktiv ester av den egnede N-karbobenzyloksyaminosyre omsettes med dopamin eller et salt derav, og at N-karbobenzyloksy-gruppen avspåltés for å oppnå aminosyreamidet.
2. Fremgangsmåte etter krav 1. karakterisert ved at det som reaktiv ester anvendes N-hydroksysuccinimidesteren av N-karbobenzyloksyaminosyre.
3'. Fremgangsmåte etter krav 1, karakterisert ved at esteren omsettes med dopamin eller et salt av dopamin ved en temperatur på fra 20°C til 50°C over en tidsperiode på fra 3 til 20 timer for å oppnå N-karboben-zyloksyaminosyreamidet av dopamin.
4. Fremgangsmåte etter krav 3, karakterisert ved at den beskyttende N-karbobenzyloksygruppe spaltes av ved hydrogenering.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US348440A US3903077A (en) | 1973-04-05 | 1973-04-05 | Direct synthesis of dopamine amino acid amides |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| NO741143L NO741143L (no) | 1974-10-08 |
| NO142523B true NO142523B (no) | 1980-05-27 |
| NO142523C NO142523C (no) | 1980-09-03 |
Family
ID=23368067
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO741143A NO142523C (no) | 1973-04-05 | 1974-03-29 | Fremgangsmaate ved fremstilling av aminosyreamider av dopamin |
Country Status (13)
| Country | Link |
|---|---|
| US (1) | US3903077A (no) |
| JP (1) | JPS49127936A (no) |
| CA (1) | CA1012546A (no) |
| CH (1) | CH582131A5 (no) |
| DE (1) | DE2416355A1 (no) |
| FI (1) | FI59987C (no) |
| FR (1) | FR2224450B1 (no) |
| GB (1) | GB1436971A (no) |
| NL (1) | NL7403520A (no) |
| NO (1) | NO142523C (no) |
| PH (1) | PH10698A (no) |
| SE (1) | SE407798B (no) |
| ZA (1) | ZA741270B (no) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3910988A (en) * | 1973-10-23 | 1975-10-07 | Abbott Lab | Esters of {65 -glutamyl amide of dopamine |
| US4033997A (en) * | 1976-02-26 | 1977-07-05 | Abbott Laboratories | Preparation of dopamine derivatives |
| NO139734C (no) * | 1976-06-25 | 1979-05-02 | Sentralinst For Ind Forskning | Analogifremgangsmaate for fremstilling av fysiologisk aktive koblingsprodukter mellom et asparaginsyrederivat og et biologisk aktivt amin |
| US4051183A (en) * | 1976-09-02 | 1977-09-27 | American Cyanamid Company | 1-benzoyl-3-(1,2,3,4-tetrahydro-4-oxo-1-naphthyl)-urea, a novel and useful intermediate for the preparation of animal growth promoting agents |
| CA1110628A (en) * | 1978-08-25 | 1981-10-13 | Tosaku Miki | N-phenethylacetamide compounds and process for preparation thereof |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3676492A (en) * | 1970-12-09 | 1972-07-11 | Aldrich Chem Co Inc | Amino acid amides of disubstituted phenethylamines |
-
1973
- 1973-04-05 US US348440A patent/US3903077A/en not_active Expired - Lifetime
-
1974
- 1974-02-25 CA CA193,348A patent/CA1012546A/en not_active Expired
- 1974-02-26 ZA ZA00741270A patent/ZA741270B/xx unknown
- 1974-03-15 NL NL7403520A patent/NL7403520A/xx not_active Application Discontinuation
- 1974-03-29 NO NO741143A patent/NO142523C/no unknown
- 1974-04-02 PH PH15685A patent/PH10698A/en unknown
- 1974-04-02 SE SE7404455A patent/SE407798B/xx unknown
- 1974-04-03 JP JP49037022A patent/JPS49127936A/ja active Pending
- 1974-04-03 FI FI1026/74A patent/FI59987C/fi active
- 1974-04-03 GB GB1486274A patent/GB1436971A/en not_active Expired
- 1974-04-04 DE DE2416355A patent/DE2416355A1/de active Pending
- 1974-04-04 FR FR7412027A patent/FR2224450B1/fr not_active Expired
- 1974-04-05 CH CH479874A patent/CH582131A5/xx not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| PH10698A (en) | 1977-08-18 |
| NO142523C (no) | 1980-09-03 |
| CH582131A5 (no) | 1976-11-30 |
| JPS49127936A (no) | 1974-12-07 |
| NL7403520A (no) | 1974-10-08 |
| FI59987C (fi) | 1981-11-10 |
| GB1436971A (en) | 1976-05-26 |
| FI59987B (fi) | 1981-07-31 |
| ZA741270B (en) | 1975-01-29 |
| DE2416355A1 (de) | 1974-10-24 |
| FR2224450B1 (no) | 1979-07-27 |
| FR2224450A1 (no) | 1974-10-31 |
| CA1012546A (en) | 1977-06-21 |
| AU6613174A (en) | 1975-08-28 |
| NO741143L (no) | 1974-10-08 |
| US3903077A (en) | 1975-09-02 |
| SE407798B (sv) | 1979-04-23 |
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