CH372684A - Process for the preparation of substituted amino acid hydrazides - Google Patents
Process for the preparation of substituted amino acid hydrazidesInfo
- Publication number
- CH372684A CH372684A CH6425258A CH6425258A CH372684A CH 372684 A CH372684 A CH 372684A CH 6425258 A CH6425258 A CH 6425258A CH 6425258 A CH6425258 A CH 6425258A CH 372684 A CH372684 A CH 372684A
- Authority
- CH
- Switzerland
- Prior art keywords
- acid
- formula
- dependent
- substituted amino
- amino acid
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 13
- 229940042795 hydrazides for tuberculosis treatment Drugs 0.000 title claims description 9
- 150000001413 amino acids Chemical class 0.000 title claims description 7
- 238000002360 preparation method Methods 0.000 title claims description 4
- 239000002253 acid Substances 0.000 claims description 21
- 150000007513 acids Chemical class 0.000 claims description 8
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 7
- 235000001014 amino acid Nutrition 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 4
- 150000008064 anhydrides Chemical class 0.000 claims description 4
- PMLJIHNCYNOQEQ-UHFFFAOYSA-N aspartic 1-amide Chemical compound NC(=O)C(N)CC(O)=O PMLJIHNCYNOQEQ-UHFFFAOYSA-N 0.000 claims description 4
- 150000004820 halides Chemical class 0.000 claims description 4
- -1 N, N'-disubstituted carbodiimide Chemical class 0.000 claims description 3
- 125000002252 acyl group Chemical group 0.000 claims description 3
- 125000000623 heterocyclic group Chemical group 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 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
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 claims description 2
- AEFLONBTGZFSGQ-VKHMYHEASA-N L-isoglutamine Chemical compound NC(=O)[C@@H](N)CCC(O)=O AEFLONBTGZFSGQ-VKHMYHEASA-N 0.000 claims description 2
- 125000002723 alicyclic group Chemical group 0.000 claims description 2
- 125000003277 amino group Chemical group 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
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 238000009833 condensation Methods 0.000 claims description 2
- 230000005494 condensation Effects 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- 235000013922 glutamic acid Nutrition 0.000 claims description 2
- 239000004220 glutamic acid Substances 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 229920006395 saturated elastomer Polymers 0.000 claims description 2
- 230000001419 dependent effect Effects 0.000 claims 6
- NHOWLEZFTHYCTP-UHFFFAOYSA-N benzylhydrazine Chemical compound NNCC1=CC=CC=C1 NHOWLEZFTHYCTP-UHFFFAOYSA-N 0.000 claims 1
- 150000001718 carbodiimides Chemical class 0.000 claims 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 150000002429 hydrazines Chemical class 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- OYIFNHCXNCRBQI-UHFFFAOYSA-N 2-aminoadipic acid Chemical compound OC(=O)C(N)CCCC(O)=O OYIFNHCXNCRBQI-UHFFFAOYSA-N 0.000 description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 229940093915 gynecological organic acid Drugs 0.000 description 2
- 239000000155 melt Substances 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 150000003672 ureas Chemical class 0.000 description 2
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- HGFIFOSVDVQFMV-LURJTMIESA-N (4s)-4-amino-5-oxo-5-(2-propan-2-ylhydrazinyl)pentanoic acid Chemical compound CC(C)NNC(=O)[C@@H](N)CCC(O)=O HGFIFOSVDVQFMV-LURJTMIESA-N 0.000 description 1
- NHFBOIIKTDKSRE-JTQLQIEISA-N (4s)-5-amino-5-oxo-4-(phenylmethoxycarbonylamino)pentanoic acid Chemical compound OC(=O)CC[C@@H](C(=O)N)NC(=O)OCC1=CC=CC=C1 NHFBOIIKTDKSRE-JTQLQIEISA-N 0.000 description 1
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 1
- ADFXKUOMJKEIND-UHFFFAOYSA-N 1,3-dicyclohexylurea Chemical compound C1CCCCC1NC(=O)NC1CCCCC1 ADFXKUOMJKEIND-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- WSNDAYQNZRJGMJ-UHFFFAOYSA-N 2,2,2-trifluoroethanone Chemical compound FC(F)(F)[C]=O WSNDAYQNZRJGMJ-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- ONWORFCWNLEBMF-UHFFFAOYSA-N 5,6-diamino-6-oxohexanoic acid Chemical compound NC(=O)C(N)CCCC(O)=O ONWORFCWNLEBMF-UHFFFAOYSA-N 0.000 description 1
- 206010006895 Cachexia Diseases 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
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 102000010909 Monoamine Oxidase Human genes 0.000 description 1
- 108010062431 Monoamine oxidase Proteins 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical group C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 239000012670 alkaline solution Substances 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 230000001430 anti-depressive effect Effects 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 229920001429 chelating resin Polymers 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 150000002431 hydrogen Chemical group 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 238000007327 hydrogenolysis reaction Methods 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 229940098895 maleic acid Drugs 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 150000002763 monocarboxylic acids Chemical class 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C241/00—Preparation of compounds containing chains of nitrogen atoms singly-bound to each other, e.g. hydrazines, triazanes
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Verfahren zur Herstellung substituierter Aminosäurehydrazide
Die vorliegende Erfindung betrifft ein Verfahren zur Herstellung von substituierten Aminosäurehydraziden der Formel
EMI1.1
in der R1 einen Aralkylrest oder einen bis zu 7 Kohlenstoffatome enthaltenden alicyclischen oder einen gesättigten, geradkettigen oder verzweigten aliphatischen Kohlenwasserstoffrest, R2 Wasserstoff oder eine Alkylgruppe, R3 Wasserstoff, eine Alkyloder Acylgruppe und R4 die Hydroxyl- oder Aminogruppe bedeuten, wobei R2 und R3 auch zusammen einen heterocyclischen Ring bilden können, und x eine Zahl von 1 bis 3 darstellt, welches dadurch gekennzeichnet ist, dass man eine Säure der Formel
EMI1.2
oder ein reaktionsfähiges Derivat einer solchen Säure mit einem Hydrazin der Formel H2N-NH-R1 III kondensiert.
Geeignete Ausgangsmaterialien sind die nachstehend angeführten Säuren sowie deren reaktionsfähige Derivate, wie z. B. Ester, Halogenide und Anhydride: Glutaminsäure, Isoglutamin, Asparaginsäure, Isoasparagin, a-Amino-adipinsäure, a-Aminoadipinsäuremonoamid. Man kann sowohl von den optisch aktiven wie von den racemischen Säuren bzw. deren Derivaten ausgehen. Die optische Konfiguration des Ausgangsmaterials bleibt während der Umsetzung erhalten. R3 ist, wie gesagt, eine Alkyl- oder eine Acylgruppe. Geeignete Acylreste sind z. B. in alkalischer Lösung abspaltbare Reste von Monocarbonsäuren, wie der Trifluoracetylrest, oder durch Hydrogenolyse abspaltbare Acylreste, wie z. B. der Carbobenzoxyrest. Gewünschtenfalls können, wie gesagt, R2 und R3 auch zusammen einen heterocyclischen Ring, z. B. den Piperidin-, Morpholin- oder Pyrrolidinring, bilden.
Vorzugsweise bedeutet R, den Isopropyl-, sekundären Butyl-, Benzyl- oder Benzyläthylrest.
Zweckmässig wird so vorgegangen, dass man eine Säure der Formel II in Gegenwart eines N,N'-disubstituierten Carbodiimides mit den Hydrazinen der Formel III kondensiert. Als Ausgangsstoffe eignen sich insbesondere a-Acylaminosäuren. Es können, wie gesagt, direkt die Säuren verwendet werden.
Eine Umwandlung in die reaktionsfähigen Ester, Halogenide, Anhydride usw. erübrigt sich. Die als Kondensationsmittel verwendbaren N,N'-disubstituierten Carbodiimide können z. B. durch Behandeln disubstituierter Harnstoffderivate mit p-Toluolsulfochlorid in Pyridin hergestellt werden. Bei der erfindungsgemässen Reaktion werden die Harnstoffderivate in der Regel zurückgewonnen und fallen als Nebenprodukte an, welche vom Reaktionsprodukt leicht abgetrennt werden können. Die Reaktion kann bei Raumtemperatur oder bei leicht erhöhter Temperatur durchgeführt werden. Es ist zweckmässig, ein Lösungsmittel zu verwenden. Es kann sowohl ein organisches Lösungsmittel, wie z. B. Methylenchlorid, Chloroform, Dioxan, Tetrahydrofuran, Dimethylformamid oder Acetonitril, als auch Wasser, gewählt werden.
Verwendet man Alkylester, Halogenide, Amide oder Anhydride von Säuren der Formel II, so wird die Kondensation mit den Hydrazinen der Formel III zweckmässig durch Erwärmen beschleunigt.
Man kann die Hydrazinsalze der Säuren auch auf hohe Temperaturen erhitzen.
Die erfindungsgemäss erhaltenen substituierten Aminosäurehydrazide bilden wohldefinierte Salze sowohl mit anorganischen wie mit organischen Säuren, z. B. mit Halogenwasserstoffsäuren, wie Chlorwasserstoffsäure, Bromwasserstoffsäure, Jodwasser toffsäure; mit andern Mineralsäuren, wie Schwefelsäure, Phosphorsäure, Salpetersäure, und mit organischen Säuren, wie Weinsäure, Citronensäure, Camphersulfosäure, Athansulfosäure, Salicylsäure, Ascorbinsäure, Maleinsäure, Mandelsäure usw. Bevorzugte Salze sind die Hydrohalogenide, insbesondere die Hydrochloride. Die Säureadditionssalze werden vorzugsweise in einem inerten Lösungsmittel durch Behandlung der erfindungsgemäss erhaltenen Hydrazide mit einem Überschuss der verwendeten Säure hergestellt.
Die erfindungsgemäss erhaltenen substituierten Säurehydrazide beziehungsweise deren Salze besitzen wertvolle therapeutische Eigenschaften. Sie hemmen die Monoaminoxydase; einzelne Vertreter zeichnen sich durch ihre besonders ausgeprägte antidepressive Wirkung aus und wirken bei Kachexie gewichtssteigernd.
Beispiel I
28 g N-Carbobenzoxy-L (+)-isoglutamin und 14,1 cm3 Triäthylamin werden in 300 cm3 Methylenchlorid gelöst. Unter Rühren werden 20,6 g N,N'-Dicyclohexyl-carbodiimid mit wenig Methylenchlorid vermischt dazugetropft. Nach 3 Stunden wird der aus dem Reaktionsprodukt und aus N,N'-Dicyclo- hexyl-harnstoff bestehende Niederschlag abgenutscht und in 300 cm Dimethylformamid aufgeschwemmt.
Man nutscht erneut ab, dampft im Vakuum ein, und kristallisiert den Rückstand aus Acetonitril um. Das so erhaltene 1 - [N - Carbobenzoxy - L(+)-y-isoglut- aminyl]-2-isopropyl-hydrazin schmilzt bei 161 bis 164" C; [alD =-50 (c = 1 in n Salzsäure).
23 g des so erhaltenen Produktes werden in einem Gemisch von 20 cm3 konzentrierter Salzsäure und 200 cm3 Wasser gelöst und in Gegenwart von Palladiumkohle hydriert. Nach beendeter Wasserstoffaufnahme wird vom Katalysator abgenutscht, das Filtrat mit Wasser auf 3000 cm3 verdünnt und durch eine Amberlitsäule ( Amberlit IRA-400 , Markenprodukt) filtriert. Die Säule wird mit Wasser nachgewaschen, bis das pH auf etwa 7 gestiegen ist.
Das Filtrat wird im Vakuum zur Trockne eingedampft und der Rückstand aus Acetonitril umgelöst.
Das erhaltene l-[L (+)-n-Isoglutaminyl]-2-isopropyl- hydrazin schmilzt bei 91-93 C; bald D = OG (c = 1 in Wasser); + 10,5" (c = 1 in n Salzsäure).
In analoger Weise können hergestellt werden: 1-(N-Tosyl-L-glutamyl)-2-isopropyl-hydrazin
Schmelzpunkt: 196-197 C; [a] D = + 15, 5 , (c = 1 in n Salzsäure). l-L-Glutamyl-2-isopropyl-hydrazin
Schmelzpunkt: 181-1820 C; [aln - + 37,80, (c = 1 in n Salzsäure).
1-L-Glutamyl-2-benzyl-hydrazin
Schmelzpunkt: 196 C.
1 -L--Glutamyl-2-(a-methyl-a-benzyl- äthyl)-hydrazin. Schmelzpunkt: 168-169" C.
Process for the preparation of substituted amino acid hydrazides
The present invention relates to a process for the preparation of substituted amino acid hydrazides of the formula
EMI1.1
in which R1 is an aralkyl radical or an alicyclic or a saturated, straight-chain or branched aliphatic hydrocarbon radical, R2 is hydrogen or an alkyl group, R3 is hydrogen, an alkyl or acyl group and R4 is the hydroxyl or amino group, where R2 and R3 also together can form a heterocyclic ring, and x represents a number from 1 to 3, which is characterized in that an acid of the formula
EMI1.2
or a reactive derivative of such an acid is condensed with a hydrazine of the formula H2N-NH-R1 III.
Suitable starting materials are the acids listed below and their reactive derivatives, such as. B. Esters, halides and anhydrides: glutamic acid, isoglutamine, aspartic acid, isoasparagine, α-amino-adipic acid, α-aminoadipic acid monoamide. One can start from both the optically active and the racemic acids or their derivatives. The optical configuration of the starting material is retained during the conversion. As mentioned, R3 is an alkyl or an acyl group. Suitable acyl radicals are, for. B. residues of monocarboxylic acids that can be split off in alkaline solution, such as the trifluoroacetyl radical, or acyl radicals that can be split off by hydrogenolysis, such as. B. the carbobenzoxy radical. If desired, as said, R2 and R3 can also together form a heterocyclic ring, e.g. B. form the piperidine, morpholine or pyrrolidine ring.
Preferably, R is the isopropyl, secondary butyl, benzyl or benzylethyl radical.
It is expedient to proceed in such a way that an acid of the formula II is condensed with the hydrazines of the formula III in the presence of an N, N'-disubstituted carbodiimide. Α-Acylamino acids are particularly suitable as starting materials. As mentioned, the acids can be used directly.
Conversion into the reactive esters, halides, anhydrides, etc. is unnecessary. The N, N'-disubstituted carbodiimides which can be used as condensing agents can, for. B. be prepared by treating disubstituted urea derivatives with p-toluenesulfonyl chloride in pyridine. In the reaction according to the invention, the urea derivatives are generally recovered and are obtained as by-products which can easily be separated from the reaction product. The reaction can be carried out at room temperature or at a slightly elevated temperature. It is advisable to use a solvent. It can be both an organic solvent, such as. B. methylene chloride, chloroform, dioxane, tetrahydrofuran, dimethylformamide or acetonitrile, as well as water, can be selected.
If alkyl esters, halides, amides or anhydrides of acids of the formula II are used, the condensation with the hydrazines of the formula III is expediently accelerated by heating.
The hydrazine salts of the acids can also be heated to high temperatures.
The substituted amino acid hydrazides obtained according to the invention form well-defined salts with both inorganic and organic acids, e.g. B. with hydrohalic acids such as hydrochloric acid, hydrobromic acid, hydriodic acid; with other mineral acids, such as sulfuric acid, phosphoric acid, nitric acid, and with organic acids, such as tartaric acid, citric acid, camphor sulfonic acid, ethanesulfonic acid, salicylic acid, ascorbic acid, maleic acid, mandelic acid, etc. Preferred salts are the hydrohalides, especially the hydrochlorides. The acid addition salts are preferably prepared in an inert solvent by treating the hydrazides obtained according to the invention with an excess of the acid used.
The substituted acid hydrazides or salts thereof obtained according to the invention have valuable therapeutic properties. They inhibit monoamine oxidase; individual representatives are characterized by their particularly pronounced antidepressant effect and have a weight-increasing effect in cachexia.
Example I.
28 g of N-carbobenzoxy-L (+) - isoglutamine and 14.1 cm3 of triethylamine are dissolved in 300 cm3 of methylene chloride. While stirring, 20.6 g of N, N'-dicyclohexyl-carbodiimide mixed with a little methylene chloride are added dropwise. After 3 hours, the precipitate consisting of the reaction product and N, N'-dicyclohexyl urea is suction filtered and suspended in 300 cm of dimethylformamide.
It is suction filtered again, evaporated in vacuo, and the residue is recrystallized from acetonitrile. The 1 - [N - carbobenzoxy - L (+) - γ-isoglutaminyl] -2-isopropylhydrazine thus obtained melts at 161 to 164 "C; [alD = -50 (c = 1 in hydrochloric acid).
23 g of the product thus obtained are dissolved in a mixture of 20 cm3 of concentrated hydrochloric acid and 200 cm3 of water and hydrogenated in the presence of palladium carbon. When the hydrogen uptake has ended, the catalyst is suction filtered, the filtrate is diluted to 3000 cm3 with water and filtered through an Amberlite column (Amberlit IRA-400, branded product). The column is washed with water until the pH has risen to about 7.
The filtrate is evaporated to dryness in vacuo and the residue is redissolved from acetonitrile.
The l- [L (+) - n-isoglutaminyl] -2-isopropylhydrazine obtained melts at 91-93 C; soon D = OG (c = 1 in water); + 10.5 "(c = 1 in n hydrochloric acid).
The following can be prepared in an analogous manner: 1- (N-tosyl-L-glutamyl) -2-isopropylhydrazine
Melting point: 196-197 C; [a] D = + 15.5, (c = 1 in n hydrochloric acid). l-L-glutamyl-2-isopropylhydrazine
Melting point: 181-1820 C; [aln - + 37.80, (c = 1 in n hydrochloric acid).
1-L-glutamyl-2-benzylhydrazine
Melting point: 196 C.
1 -L - Glutamyl-2- (a-methyl-a-benzyl-ethyl) -hydrazine. Melting point: 168-169 "C.
Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH6425258A CH372684A (en) | 1958-09-23 | 1958-09-23 | Process for the preparation of substituted amino acid hydrazides |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH6425258A CH372684A (en) | 1958-09-23 | 1958-09-23 | Process for the preparation of substituted amino acid hydrazides |
| CH368191T | 1958-09-23 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH372684A true CH372684A (en) | 1963-10-31 |
Family
ID=25737327
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH6425258A CH372684A (en) | 1958-09-23 | 1958-09-23 | Process for the preparation of substituted amino acid hydrazides |
Country Status (1)
| Country | Link |
|---|---|
| CH (1) | CH372684A (en) |
-
1958
- 1958-09-23 CH CH6425258A patent/CH372684A/en unknown
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