CH462841A - Process for the production of new amino acids - Google Patents
Process for the production of new amino acidsInfo
- Publication number
- CH462841A CH462841A CH1468866A CH1468866A CH462841A CH 462841 A CH462841 A CH 462841A CH 1468866 A CH1468866 A CH 1468866A CH 1468866 A CH1468866 A CH 1468866A CH 462841 A CH462841 A CH 462841A
- Authority
- CH
- Switzerland
- Prior art keywords
- compound
- formula
- salts
- compounds
- amino acids
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 16
- 150000001413 amino acids Chemical class 0.000 title claims description 5
- 238000004519 manufacturing process Methods 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims description 26
- 150000003839 salts Chemical class 0.000 claims description 20
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 8
- 238000006243 chemical reaction Methods 0.000 claims description 6
- 238000006114 decarboxylation reaction Methods 0.000 claims description 5
- 239000011541 reaction mixture Substances 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 3
- 230000007062 hydrolysis Effects 0.000 claims description 3
- 238000006460 hydrolysis reaction Methods 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 230000001419 dependent effect Effects 0.000 claims 3
- 125000001309 chloro group Chemical group Cl* 0.000 claims 1
- 125000001153 fluoro group Chemical group F* 0.000 claims 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 8
- 239000007858 starting material Substances 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- -1 heterocyclic carboxylic Chemical class 0.000 description 4
- KPYSYYIEGFHWSV-UHFFFAOYSA-N Baclofen Chemical group OC(=O)CC(CN)C1=CC=C(Cl)C=C1 KPYSYYIEGFHWSV-UHFFFAOYSA-N 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- GLJATYFHELDGEA-UHFFFAOYSA-N 1-chloro-4-(2-nitroethenyl)benzene Chemical compound [O-][N+](=O)C=CC1=CC=C(Cl)C=C1 GLJATYFHELDGEA-UHFFFAOYSA-N 0.000 description 2
- HVBSAKJJOYLTQU-UHFFFAOYSA-N 4-aminobenzenesulfonic acid Chemical compound NC1=CC=C(S(O)(=O)=O)C=C1 HVBSAKJJOYLTQU-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 238000010531 catalytic reduction reaction Methods 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- BEPAFCGSDWSTEL-UHFFFAOYSA-N dimethyl malonate Chemical compound COC(=O)CC(=O)OC BEPAFCGSDWSTEL-UHFFFAOYSA-N 0.000 description 2
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Inorganic materials [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- QXQAPNSHUJORMC-UHFFFAOYSA-N 1-chloro-4-propylbenzene Chemical compound CCCC1=CC=C(Cl)C=C1 QXQAPNSHUJORMC-UHFFFAOYSA-N 0.000 description 1
- FZKCAHQKNJXICB-UHFFFAOYSA-N 2,1-benzoxazole Chemical compound C1=CC=CC2=CON=C21 FZKCAHQKNJXICB-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- ALYNCZNDIQEVRV-UHFFFAOYSA-N 4-aminobenzoic acid Chemical compound NC1=CC=C(C(O)=O)C=C1 ALYNCZNDIQEVRV-UHFFFAOYSA-N 0.000 description 1
- WUBBRNOQWQTFEX-UHFFFAOYSA-N 4-aminosalicylic acid Chemical compound NC1=CC=C(C(O)=O)C(O)=C1 WUBBRNOQWQTFEX-UHFFFAOYSA-N 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N 4-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 229940090248 4-hydroxybenzoic acid Drugs 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 125000002723 alicyclic group Chemical group 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910001854 alkali hydroxide Inorganic materials 0.000 description 1
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 1
- 150000008041 alkali metal carbonates Chemical class 0.000 description 1
- 150000001447 alkali salts Chemical class 0.000 description 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229960004909 aminosalicylic acid Drugs 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- WXBLLCUINBKULX-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1.OC(=O)C1=CC=CC=C1 WXBLLCUINBKULX-UHFFFAOYSA-N 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 239000012876 carrier material Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 150000001991 dicarboxylic acids Chemical class 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 150000003951 lactams Chemical group 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910000000 metal hydroxide Inorganic materials 0.000 description 1
- 150000004692 metal hydroxides Chemical class 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-N picric acid Chemical class OC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-N 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 229950000244 sulfanilic acid Drugs 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- NLVXSWCKKBEXTG-UHFFFAOYSA-N vinylsulfonic acid Chemical compound OS(=O)(=O)C=C NLVXSWCKKBEXTG-UHFFFAOYSA-N 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/273—2-Pyrrolidones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
- C07D207/277—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
Verfahren zur Herstellung neuer Aminosäuren
Die vorliegende Erfindung betrifft ein Verfahren zur Herstellung von Aminosäuren der allgemeinen Formel
EMI1.1
worin R ein Halogenatom, z.B. ein Fluor, Chlor- oder Bromatom oder das Pseudohalogen Trifluormethyl, bedeutet, und ihrer Salze.
Die neuen Verbindungen besitzen wertvolle pharmakologische, insbesondere zentralhemmende Eigenschaften. So hemmen sie beispielsweise bei Versuchen an Mäusen, Katzen, Kaninchen und Hunden die Aktivität von Neuren, die an der Steuerung der Motorik beteiligt sind. Sie können dementsprechend als zentralhemmende Mittel verwendet werden. Die neuen Verbindungen sind aber auch als Zwischenprodukte, z.B. zur Herstellung von Heilmitteln, wertvoll.
Besonders hervorzuheben ist die γ-Amino-ss-(p- chlorphenyl)-buttersäure.
Das erfindungsgemässe Verfahren zur Herstellung der neuen Verbindungen ist dadurch gekennzeichnet, dass man in einer Verbindung der Formel
EMI1.2
worin R die angegebene Bedeutung hat, oder einem Salz davon eine der beidien Carboxylgruppen durch Decarboxylierung abspaltet.
Die Decarboxylierung kann in üblicher Weise erfolgen, z.B. unter gelindem Erwärmen oder Erhitzen, vorzugsweise, in Anwesenheit von Verdünnungs- und/ oder Lösungsmitteln.
Jenach den Verfahrensedingungen und Ausgangsstoffen erhält man die Endstoffe in freier Form oder in der ebenfalls in der Erfindung inbegriffenen Form ihrer Salze.
So können beispielsweise basische, neutrale, saure oder gemischte Salze; gegebenenfalls auch Hemi-, Mono-, Sesqui- oder Polyhydrate davon erhalten werden.
Die Salze der neuen Verbindungen können in an sich bekannter Weise in die freien Verbindungen übergeführt werden; Säureadditionssalze z.B. it basischen Mitteln, wie Alkalien oder Ionenaustauscher, Salze mit Basen 'durch Reaktion mit sauren Mitteln, wie Säuren. Anderseits können erhaltene freie Aminosäuren. mit Basen, insbesondere mit therapeutisch verwendbaren Basen, z. B. Metallhydroxyden oder basischen Salzen, speziell Alkali- oder Erdalkalimetallhydroxyden, wie Natrium-, Kalium- oder Calciumhydroxyd, Alkalimetallcarbona ten, wie Natrium-oder Kaliumcarbonat, Ammoniak oder organischen Aminen, oder mit organischen oder anorganischen Säuren, Sal2e bilden.
Zur Herstellung von Säureadditionssaslzen werden insbesondere therapeutisch verwendbare Säuren verwendet, z.B. Halogenwasserstoffsäuren, Schwefelsäure, Phosphorsäuren, Salpetersäure, Perchlorsäure; aliphatische, alicyclische, aro maische oder heterocyclische Carbon- oder Sulfonsäuren, wie Ameisen-, Essig-, Propion Bernstein-, Glykol-, Milch-, Äpfel-, Wein-, Zitfonen-, Ascorbin-, Malein-, Hydroxymalein oder Brenztraubensäure; Phenylessig-, Benzoe-, p-Aminobenzoe-, Anthranil-, p-Hydroxy-benzoe-, Salicyl- oder p-Aminosalicylsäure, Embonsäure, Methansulfon- Äthansulfon-, Hydroxy äthansulfon-, Äthylensulfonsäure;
Halogenbenzolsulfon-, Toluolsulfon0, Naphthalinsulfonsäuren oder Sulfanil säure Methionin, Tryptophan, Lysin oder Arginin.
Diese oder andere Salze der neuen Verbindungen, wie z.B. die Pikrate, können auch zur Reiniguug der erhaltenen freien Verbindungen dienen, indem man die freien Verbindungen in Salze überfährt, diese abtrennt und aus den Salzen wiederum die freien Verbindungen freimacht.
Die neuen Verbindungen können in Form von Racematen vcrlligen, die sich in üblicher Weise in die optischen Antipoden zerlegen lassen.
Für die erfindungsgemässen Reaktionen werden vornehmlich solche Ausgangsstoffe verwendet, die die obenerwähnten bevorzugten Verbindungen ergeben.
Die Ausgangsstoffe können auch in Form eines unter den Reaktionsbedingungen gebildeten Reaktionsge- mischs eingesetzt werden. So kann man beispielsweise die als Ausgangsstoffe verwendeten Dicarbonsäuren durch Hydrolyse einer Verbindung der Formel
EMI2.1
oder
EMI2.2
worin R die angegebene Bedeutung hat, Z eine gege- benenfalls veresterte Carboxylgruppe, wie eine Carbalkoxygruppe, oder die Carboxylgruppe, bedeutet und Z'und Z" für veresterte Carboxylgruppen, z. B. Carb alkoxyreste, stehen, oder gegebenenfalls eines Salzes dieser Verbindungen, herstellen. Die Decarboxylierung kann gerade anschliessend erfolgen, ohne dass der erfindungsgemässe Ausgangsstoff isoliert werden muss.
Die Ausgangsstoffe sind bekannt oder können nach an sich bekannten Methoden gewonnen werden.
Die neuen Verbindungen könnten als Heilmittel, z. B. in Form pharmazeutischer Präparate, Verwendung finden, welche sie in freier Form. oder in Form ihrer Salze in Mischung mit einem für die enterale oder parenterale Applikation geeigneten pharmazeutischen organischen oder anorganischen, festen oder flüssigen Trägermaterial enthalten.
Die neuen Verbindungen können auch in der Tiermedizin, z.B. in einer der obengenannten Formen oder in Form von Futtermitteln oder von Zusatzmitteln für Tierfutter, verwendet werden.
In den folgenden Beispielen sind die Temperaturen in Celsiusgraden angegeben.
Beispiel I
1,2 g 3-Carbomethoxy-4-(p-chlorphenyl)-pyrrolidon-(2) werden mit 12 ml 6n Salzsäure 17 Stunden unter Rückfluss gekocht. Dabei wird der Lactamring geöffnet, die veresterte Carboxylgruppe verseift und das so erhaltene Produkt decarboxyliert. Es entsteht eine klare Lösung, die im Wasserstrahlvakuum bei 50 bis 600 eingedampft wird. Der kristalline, farblose Trocken rückstand wird in 5 ml Aceton suspendiert und abfiltriert. Man löst das Kristallisat in 5 ml Wasser und stellt mit in Natronlauge auf den pH-Wert 7 ein. Hierbei kristallisiert die γ-Amino-ss-(p-chlorphenyl)-buttersäure der Formel
EMI2.3
aus. Die Reinigung erfolgt durch Umkristallisation aus Wasser, F. 206 bis 2080.
Das als Ausgangsmaterial verwendete 3-Carbo- methox-4-(p-chlorphenyl)-pyrrolidon-(2) kann durch katalytische Reduktion des aus p-Chlor-ss-nitrostyrol und Malonsäuredimethylester erhältlichen 7-Nitro-ss-(pchlor- phenyl)-α-(carbomethoxy)-buttertsäuremethylesters hergestellt werden.
Beispiel 2
0,5 g γ-Amino-ss(p-chlorphenyl)-α-(carbomethoxy)- buttersäuremethylester-hydrochlorid werden mit 5 mi 6n Salzsäure 6 Stunden unter Rückfluss gekocht. Dabei werden die veresterten Carboxyigruppen verseift und die so erhaltene Dicarbonsäure wird decarboxyliert. Die entstandene Lösung wird mit Norit entfärbt und dann im Wasserstrahlvakuum bei 50 bis 600 eingedampft. Der kristalline, farblose Trockenrückstand wird in 2 ml Aceton suspendiert und abfiltriert. Man löst das Kristallisat in 2 ml Wasser und stellt mit in Natronlauge auf den pH-Wert 7 ein. Hierbei kristallisiert y-Amino-ss- (p-chlorphenyl)-buttersäure aus, die zur Reinigung aus Wasser umkristallisiert wird, F. 206 bis 208.
Sie ist mit dem in Beispiel 1 beschriebenen Produkt identisch.
Auf analoge Weise kann man die γ-Amino-ss-(p- bromphenyl)-buttersäure, F. 228 bis 2290, erhalten.
Das als Ausgangsmaterial verwendete y-Aminss-(p chlorphenyl)-α-(carbomethoxy)-buttersäuremethylester- hydrochlorid kann durch katalytische Reduktion des aus p-Chlor-ss-nitrostyrol. und Malonsäuredimethylester erhältlichen γ-Nitro-ss-(p-chlorphenyl)-α-(carbomethoxy)- buttersäuremethylesters in Gegenwart von Salzsäure hergestellt werden.
Process for the production of new amino acids
The present invention relates to a process for the preparation of amino acids of the general formula
EMI1.1
wherein R is a halogen atom, e.g. a fluorine, chlorine or bromine atom or the pseudohalogen trifluoromethyl, and their salts.
The new compounds have valuable pharmacological, especially central inhibiting properties. In experiments on mice, cats, rabbits and dogs, for example, they inhibit the activity of neurs involved in controlling motor skills. Accordingly, they can be used as central inhibitors. The new compounds are also available as intermediates, e.g. for the manufacture of remedies, valuable.
Particularly noteworthy is γ-amino-ss- (p-chlorophenyl) -butyric acid.
The inventive method for preparing the new compounds is characterized in that in a compound of the formula
EMI1.2
wherein R has the meaning given, or a salt thereof splits off one of the two carboxyl groups by decarboxylation.
The decarboxylation can be carried out in a conventional manner, e.g. with gentle warming or heating, preferably in the presence of diluents and / or solvents.
Depending on the process conditions and starting materials, the end products are obtained in free form or in the form of their salts, which is also included in the invention.
For example, basic, neutral, acidic or mixed salts; optionally hemi-, mono-, sesqui- or polyhydrates thereof can also be obtained.
The salts of the new compounds can be converted into the free compounds in a manner known per se; Acid addition salts e.g. with basic agents such as alkalis or ion exchangers, salts with bases by reaction with acidic agents such as acids. On the other hand, you can get free amino acids. with bases, in particular with therapeutically useful bases, e.g. B. metal hydroxides or basic salts, especially alkali or alkaline earth metal hydroxides such as sodium, potassium or calcium hydroxide, alkali metal carbonates such as sodium or potassium carbonate, ammonia or organic amines, or with organic or inorganic acids, form salts.
For the preparation of acid addition salts, therapeutically useful acids are used in particular, e.g. Hydrohalic acids, sulfuric acid, phosphoric acids, nitric acid, perchloric acid; aliphatic, alicyclic, aromatic or heterocyclic carboxylic or sulfonic acids, such as formic, acetic, propionic, succinic, glycolic, lactic, apple, tartaric, citric, ascorbic, maleic, hydroxymalic or pyruvic acid; Phenyl acetic, benzoic, p-aminobenzoic, anthranil, p-hydroxy-benzoic, salicylic or p-aminosalicylic acid, emboxylic acid, methanesulphonic, ethanesulphonic, hydroxyethanesulphonic, ethylene sulphonic acid;
Halobenzenesulfonic, toluenesulfonic, naphthalenesulfonic or sulfanilic acid methionine, tryptophan, lysine or arginine.
These or other salts of the new compounds, e.g. the picrates can also be used to purify the free compounds obtained by converting the free compounds into salts, separating them and in turn liberating the free compounds from the salts.
The new compounds can complete in the form of racemates, which can be broken down into the optical antipodes in the usual way.
The starting materials used for the reactions according to the invention are primarily those which give the above-mentioned preferred compounds.
The starting materials can also be used in the form of a reaction mixture formed under the reaction conditions. So you can, for example, the dicarboxylic acids used as starting materials by hydrolysis of a compound of the formula
EMI2.1
or
EMI2.2
where R has the meaning given, Z denotes an optionally esterified carboxyl group, such as a carbalkoxy group, or the carboxyl group, and Z ′ and Z ″ represent esterified carboxyl groups, for example carbalkoxy radicals, or optionally a salt of these compounds, The decarboxylation can then take place without the starting material according to the invention having to be isolated.
The starting materials are known or can be obtained by methods known per se.
The new compounds could be used as remedies, e.g. B. in the form of pharmaceutical preparations, use which they are in free form. or in the form of their salts as a mixture with a pharmaceutical, organic or inorganic, solid or liquid carrier material suitable for enteral or parenteral administration.
The new compounds can also be used in veterinary medicine, e.g. in one of the above forms or in the form of feed or additives for animal feed.
In the following examples the temperatures are given in degrees Celsius.
Example I.
1.2 g of 3-carbomethoxy-4- (p-chlorophenyl) -pyrrolidone- (2) are refluxed with 12 ml of 6N hydrochloric acid for 17 hours. The lactam ring is opened, the esterified carboxyl group is saponified and the product thus obtained is decarboxylated. A clear solution is formed which is evaporated at 50 to 600 in a water jet vacuum. The crystalline, colorless dry residue is suspended in 5 ml of acetone and filtered off. The crystals are dissolved in 5 ml of water and the pH is adjusted to 7 with sodium hydroxide solution. The γ-amino-ss- (p-chlorophenyl) -butyric acid of the formula crystallizes here
EMI2.3
out. The purification takes place by recrystallization from water, mp 206-2080.
The 3-carbomethox-4- (p-chlorophenyl) -pyrrolidone- (2) used as starting material can be obtained by catalytic reduction of the 7-nitro-ss- (pchlorophenyl) obtainable from p-chloro-ss-nitrostyrene and dimethyl malonate. - methyl α- (carbomethoxy) -buttertate.
Example 2
0.5 g of γ-amino-ss (p-chlorophenyl) -α- (carbomethoxy) -butyric acid methyl ester hydrochloride are refluxed with 5 ml of 6N hydrochloric acid for 6 hours. The esterified carboxy groups are saponified and the dicarboxylic acid thus obtained is decarboxylated. The resulting solution is decolorized with Norit and then evaporated at 50 to 600 in a water jet vacuum. The crystalline, colorless dry residue is suspended in 2 ml of acetone and filtered off. The crystals are dissolved in 2 ml of water and the pH is adjusted to 7 with sodium hydroxide solution. Here, γ-amino-ss- (p-chlorophenyl) butyric acid crystallizes out, which is recrystallized from water for purification, F. 206 to 208.
It is identical to the product described in Example 1.
The γ-amino-ss- (p-bromophenyl) -butyric acid, mp 228-2290, can be obtained in an analogous manner.
The γ-amine ß- (p-chlorophenyl) -α- (carbomethoxy) -butyric acid methyl ester hydrochloride used as starting material can be obtained from p-chloro-ß-nitrostyrene by catalytic reduction. γ-nitro-ss- (p-chlorophenyl) -α- (carbomethoxy) -butyric acid methyl ester obtainable and dimethyl malonate can be prepared in the presence of hydrochloric acid.
Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH1468866A CH462841A (en) | 1963-07-09 | 1963-07-09 | Process for the production of new amino acids |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH1468866A CH462841A (en) | 1963-07-09 | 1963-07-09 | Process for the production of new amino acids |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH462841A true CH462841A (en) | 1968-09-30 |
Family
ID=4403010
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH1468866A CH462841A (en) | 1963-07-09 | 1963-07-09 | Process for the production of new amino acids |
Country Status (1)
| Country | Link |
|---|---|
| CH (1) | CH462841A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2229402A1 (en) * | 1973-05-18 | 1974-12-13 | Le |
-
1963
- 1963-07-09 CH CH1468866A patent/CH462841A/en unknown
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2229402A1 (en) * | 1973-05-18 | 1974-12-13 | Le |
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