CH369471A - Process for the preparation of substituted acid hydrazides - Google Patents
Process for the preparation of substituted acid hydrazidesInfo
- Publication number
- CH369471A CH369471A CH6424958A CH6424958A CH369471A CH 369471 A CH369471 A CH 369471A CH 6424958 A CH6424958 A CH 6424958A CH 6424958 A CH6424958 A CH 6424958A CH 369471 A CH369471 A CH 369471A
- Authority
- CH
- Switzerland
- Prior art keywords
- acid
- formula
- hydrazine
- dependent
- radical
- Prior art date
Links
- 239000002253 acid Substances 0.000 title claims description 26
- 238000000034 method Methods 0.000 title claims description 11
- 229940042795 hydrazides for tuberculosis treatment Drugs 0.000 title claims description 9
- 238000002360 preparation method Methods 0.000 title claims description 4
- -1 N, N'-disubstituted carbodiimide Chemical class 0.000 claims description 13
- 150000003839 salts Chemical class 0.000 claims description 9
- OAKJQQAXSVQMHS-UHFFFAOYSA-N hydrazine Substances NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 7
- 150000007513 acids Chemical class 0.000 claims description 5
- 150000002429 hydrazines Chemical class 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 150000008064 anhydrides Chemical class 0.000 claims description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 3
- 238000009833 condensation Methods 0.000 claims description 3
- 230000005494 condensation Effects 0.000 claims description 3
- 150000004820 halides Chemical class 0.000 claims description 3
- PMPVIKIVABFJJI-UHFFFAOYSA-N Cyclobutane Chemical compound C1CCC1 PMPVIKIVABFJJI-UHFFFAOYSA-N 0.000 claims description 2
- 125000002723 alicyclic group Chemical group 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 claims description 2
- 150000003140 primary amides Chemical class 0.000 claims description 2
- 229920006395 saturated elastomer Chemical group 0.000 claims description 2
- 230000001419 dependent effect Effects 0.000 claims 3
- NZNMSOFKMUBTKW-UHFFFAOYSA-N cyclohexanecarboxylic acid Chemical compound OC(=O)C1CCCCC1 NZNMSOFKMUBTKW-UHFFFAOYSA-N 0.000 claims 2
- NHOWLEZFTHYCTP-UHFFFAOYSA-N benzylhydrazine Chemical compound NNCC1=CC=CC=C1 NHOWLEZFTHYCTP-UHFFFAOYSA-N 0.000 claims 1
- VZFUCHSFHOYXIS-UHFFFAOYSA-N cycloheptane carboxylic acid Natural products OC(=O)C1CCCCCC1 VZFUCHSFHOYXIS-UHFFFAOYSA-N 0.000 claims 1
- KJAQRHMKLVGSCG-UHFFFAOYSA-N propan-2-ylhydrazine Chemical compound CC(C)NN KJAQRHMKLVGSCG-UHFFFAOYSA-N 0.000 claims 1
- 239000007858 starting material Substances 0.000 claims 1
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 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
- 239000000155 melt Substances 0.000 description 3
- 150000003672 ureas Chemical class 0.000 description 3
- PTGXSXYMEHNCCN-UHFFFAOYSA-N 2-methyl-n'-propan-2-ylpropanehydrazide Chemical compound CC(C)NNC(=O)C(C)C PTGXSXYMEHNCCN-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
- CGWBFZCBNLMLDT-UHFFFAOYSA-N N'-propan-2-ylcyclobutanecarbohydrazide Chemical compound C1(CCC1)C(=O)NNC(C)C CGWBFZCBNLMLDT-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 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
- PRBLRLQZOKOQCQ-UHFFFAOYSA-N benzylhydrazine;hydron;chloride Chemical compound Cl.NNCC1=CC=CC=C1 PRBLRLQZOKOQCQ-UHFFFAOYSA-N 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- YMGUBTXCNDTFJI-UHFFFAOYSA-N cyclopropanecarboxylic acid Chemical compound OC(=O)C1CC1 YMGUBTXCNDTFJI-UHFFFAOYSA-N 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 229940093915 gynecological organic acid Drugs 0.000 description 2
- ILULYDJFTJKQAP-UHFFFAOYSA-N hydron;propan-2-ylhydrazine;chloride Chemical compound [Cl-].CC(C)N[NH3+] ILULYDJFTJKQAP-UHFFFAOYSA-N 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- SYMQJSAALKSMDI-UHFFFAOYSA-N n'-propan-2-ylcyclopropanecarbohydrazide Chemical compound CC(C)NNC(=O)C1CC1 SYMQJSAALKSMDI-UHFFFAOYSA-N 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- FWWDFDMCZLOXQI-UHFFFAOYSA-N pivhydrazine Chemical compound CC(C)(C)C(=O)NNCC1=CC=CC=C1 FWWDFDMCZLOXQI-UHFFFAOYSA-N 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 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
- 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
- BUWSHNOMVQKVHJ-UHFFFAOYSA-N 2,2-dimethyl-n'-(2-methylpropyl)propanehydrazide Chemical compound CC(C)CNNC(=O)C(C)(C)C BUWSHNOMVQKVHJ-UHFFFAOYSA-N 0.000 description 1
- ADPTWQGNSDWONP-UHFFFAOYSA-N 2,2-dimethyl-n'-propan-2-ylpropanehydrazide Chemical compound CC(C)NNC(=O)C(C)(C)C ADPTWQGNSDWONP-UHFFFAOYSA-N 0.000 description 1
- SLRMQYXOBQWXCR-UHFFFAOYSA-N 2154-56-5 Chemical compound [CH2]C1=CC=CC=C1 SLRMQYXOBQWXCR-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
- IFSYMERPHZDWPL-UHFFFAOYSA-N C(C)C(C(=O)NNC(C)C)(CC)CC Chemical compound C(C)C(C(=O)NNC(C)C)(CC)CC IFSYMERPHZDWPL-UHFFFAOYSA-N 0.000 description 1
- YUCKNZJSEIGEHP-UHFFFAOYSA-N C(C)C(C(=O)NNC(C)C)CCCC Chemical compound C(C)C(C(=O)NNC(C)C)CCCC YUCKNZJSEIGEHP-UHFFFAOYSA-N 0.000 description 1
- LYSHKATWYCVPBN-UHFFFAOYSA-N C1(CC1)C(=O)NNC(C)CC Chemical compound C1(CC1)C(=O)NNC(C)CC LYSHKATWYCVPBN-UHFFFAOYSA-N 0.000 description 1
- SVWIQAGGCZRETE-UHFFFAOYSA-N CC(C(=O)C(CC1=CC=CC=C1)NN)(C)C Chemical compound CC(C(=O)C(CC1=CC=CC=C1)NN)(C)C SVWIQAGGCZRETE-UHFFFAOYSA-N 0.000 description 1
- QRMGNDAWPXZGGM-UHFFFAOYSA-N CC(C(=O)NNC(C)C)(CC)C Chemical compound CC(C(=O)NNC(C)C)(CC)C QRMGNDAWPXZGGM-UHFFFAOYSA-N 0.000 description 1
- ZCAWRASWLNRKRK-UHFFFAOYSA-N CC(C(=O)NNC(C)CC)(C)C Chemical compound CC(C(=O)NNC(C)CC)(C)C ZCAWRASWLNRKRK-UHFFFAOYSA-N 0.000 description 1
- YAJKXZPYOGVGRB-UHFFFAOYSA-N CC(C(=O)NNCC1=CC=CC=C1)(CC)C Chemical compound CC(C(=O)NNCC1=CC=CC=C1)(CC)C YAJKXZPYOGVGRB-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
- 102000010909 Monoamine Oxidase Human genes 0.000 description 1
- 108010062431 Monoamine oxidase Proteins 0.000 description 1
- MQHWOCDLCIPJNH-UHFFFAOYSA-N N'-benzylcyclobutanecarbohydrazide Chemical compound C1(CCC1)C(=O)NNCC1=CC=CC=C1 MQHWOCDLCIPJNH-UHFFFAOYSA-N 0.000 description 1
- LLQGNFNOLKUJFN-UHFFFAOYSA-N N'-ethyl-2-methylpropanehydrazide Chemical compound C(C(C)C)(=O)NNCC LLQGNFNOLKUJFN-UHFFFAOYSA-N 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
- 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
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000001430 anti-depressive effect Effects 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 229940005513 antidepressants Drugs 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
- SFSUYFSIKDDLOL-UHFFFAOYSA-N butan-2-ylhydrazine Chemical compound CCC(C)NN SFSUYFSIKDDLOL-UHFFFAOYSA-N 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- TXWOGHSRPAYOML-UHFFFAOYSA-N cyclobutanecarboxylic acid Chemical compound OC(=O)C1CCC1 TXWOGHSRPAYOML-UHFFFAOYSA-N 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 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
- FPIQZBQZKBKLEI-UHFFFAOYSA-N ethyl 1-[[2-chloroethyl(nitroso)carbamoyl]amino]cyclohexane-1-carboxylate Chemical compound ClCCN(N=O)C(=O)NC1(C(=O)OCC)CCCCC1 FPIQZBQZKBKLEI-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229940071870 hydroiodic acid Drugs 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
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- RMVGKJHWIUFNLM-UHFFFAOYSA-N n'-benzyl-2-methylpropanehydrazide Chemical compound CC(C)C(=O)NNCC1=CC=CC=C1 RMVGKJHWIUFNLM-UHFFFAOYSA-N 0.000 description 1
- IEMAUAQJNPHUBQ-UHFFFAOYSA-N n'-benzylcyclohexanecarbohydrazide Chemical compound C1CCCCC1C(=O)NNCC1=CC=CC=C1 IEMAUAQJNPHUBQ-UHFFFAOYSA-N 0.000 description 1
- KFQQEKCFTGBATQ-UHFFFAOYSA-N n'-benzylcyclopropanecarbohydrazide Chemical compound C1CC1C(=O)NNCC1=CC=CC=C1 KFQQEKCFTGBATQ-UHFFFAOYSA-N 0.000 description 1
- WZHVHIZNXIZYCW-UHFFFAOYSA-N n'-propan-2-ylcyclohexanecarbohydrazide Chemical compound CC(C)NNC(=O)C1CCCCC1 WZHVHIZNXIZYCW-UHFFFAOYSA-N 0.000 description 1
- 229910017604 nitric acid Inorganic materials 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
- 239000003208 petroleum Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 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
- 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)
Description
Verfahren zur Herstellung substituierter Säurehydrazide
Die vorliegende Erfindung betrifft ein Verfahren zur Herstellung von substituierten Säurehydraziden der Formel
EMI1.1
worin Rt und R2 niedere Alkylreste oder zusammen einen niederen Alkylenrest, R3 Wasserstoff oder einen niederen Alkylrest und R4 einen.Aralkylrest, oder einen bis zu 6 Kohlenstoffatome enthaltenden alicyclischen oder gesättigten, geradkettigen oder verzweigten aliphatischen Kohlenwasserstoffrest bedeuten, welches dadurch gekennzeichnet ist, dass man eine Säure der Formel
EMI1.2
oder ein funktionelles Derivat einer solchen Säure mit einem substituierten Hydrazin der Formel
H2N-NH-R4 III kondensiert. Die Kondensation wird vorzugsweise in Gegenwart eines N,N'-disubstituierten Carbodiimides durchgeführt.
Die erfindungsgemäss erhaltenen Säurehydrazide der Formel I können in ein Salz überführt werden.
Zur Umsetzung können direkt die Säuren oder deren Salze, z. B. die Alkalimetallsalze, verwendet werden. Eine Umwandlung in die reaktionsfähigeren Ester, Halogenide, Anhydride usw. erübrigt sich. Die verwendeten N,N'-disubstituierten Carbodiimide können z. B. durch Behandeln disubstituierter Harnstoffderivate mit p-Toluolsulfochlorid in Pyridin hergestellt werden. Bei der Verwendung derselben als Kondensationsmittel werden die entsprechenden Harnstoffderivate zurückgewonnen. Auf diese Weise erhält man als Nebenprodukte Harnstoffderivate, welche vom Reaktionsprodukt leicht abgetrennt werden können. Als N,N'-disubstituiertes Carbodiimid kann man beispielsweise N,N'-Dicyclohexyl-carbodiimid verwenden.
Die Reaktion kann z. B. bei einer Temperatur zwischen 0 und 500, vorzugsweise bei Raumtemperatur oder leicht erhöhter Temperatur, durchgeführt werden. Es ist zweckmässig, ein Lösungsmittelp zu verwenden. Es kann sowohl ein organisches Lösungsmittel, wie z. B. Methylenchlorid, Chloroform, Dioxan, Tetrahydrofuran, Dimethylformamid oder Acetonitril als auch Wasser gewählt werden.
Man kann z. B. einen Ester, ein Halogenid, das Anhydrid oder das primäre Amid einer Säure der Formel II unter Erwärmen mit einem substituierten Hydrazin der Formel III kondensieren. Weiterhin kann man die aus den Säuren der Formel II mit den Hydrazinen der Formel III gebildeten Salze auf hohe Temperaturen erhitzen.
Nach dem erfindungsgemässen Verfahren können beispielsweise folgende Säurehydrazide hergestellt werden:
1 -Trimethylacetyl-2-benzyl-hydrazin, l-Trimethylacetyl-2-isopropyl-hydrazin,
1 -Trimethylacetyl-2-tert.-butyl-hydrazin,
1 -Trimethylacetyl-2-phenyläthyl-hydrazin,
1-Trimethylacetyl-2-isobutyl-hydrazin,
1 -Trimethylacetyl-2-sek.-butyl-hydrazin, 1-(Dimethyl-äthyl-acetyl)-2-isopropyl-hydrazin,
1 -(Dimethyl-äthyl-acetyl)-2-benzyl-hydrazin,
1 -Methyl-diäthyl-acetyl)-2-benzyl-hydrazin,
1 -Triäthylacetyl-2-isopropyl-hydrazin, 1-[ 1-Methyl-cyclobutyl-(1)-carbonyl]-2-iso- propyl-hydrazin, l-[l-Methyl-cyclobutyl-(l)-carbonyl]-2-iso- butyl-hydrazin, 1 -[1 -Methyl-cyclopropyl-( 1 )-carbonyl]-2-iso- propyl-hydrazin, l-[l-Methyl-cyclopropyl-(l)
-carbonyl]-phenyl- äthyl-hydrazin, 1-[1-Methyl-cyclohexyl-(l)-carbonyl]-2-benzyl- hydrazin, 1 -[1 -Methyl-eyclohexyl-( 1 )-carbonyl]-2-iso- propyl-hydrazin,
1 -Isobutyryl-2-isopropyl-hydrazin, 1-Isobutyryl-2-benzyl-hydrazin,
1-Isobutyryl-2-äthyl-hydrazin,
1 -Cyclopropylcarbonyl-2-isopropyl-hydrazin, 1 -Cyclopropylcarbonyl-2-benzyl-hydrazin,
1 -Cyclopropylcarbonyl-2-sek.-butyl-hydrazin, 1-Cyclobutylcarbonyl-2-isopropyl-hydrazin,
1 -Cyclobutylcarbonyl-2-benzyl-hydrazin, 1 -Cyclohexylcarbonyl-2-isopropyl-hydrazin,
1 -Cyclohexylcarbonyl-2-tert.-butyl-hydrazin, l-Cyclohexylcarbonyl-2-n-propyl-hydrazin und 1 -Cyclohexylcarbonyl-2-benzyl-hydrazin.
In pharmakologischer Hinsicht besonders wertvoll sind diejenigen Säurehydrazide, in welchen Rt, R2 und R3 Methylreste sind oder Rl und R2 zusammen mit dem der Carbonylgruppe benachbarten Kohlenstoffatom einen Cyclobutan- oder Cyclohexanring bilden und R4 der Isopropyl- oder Benzylrest ist.
Die erfindungsgemäss erhältlichen substituierten Säurehydrazide bilden wohldefinierte Salze sowohl mit anorganischen als auch mit organischen Säuren, z. B. mit Halogenwasserstoffsäuren, wie Chlorwasserstoffsäure, Bromwasserstoffsäure, Jodwasserstoffsäure, mit andern Mineralsäuren wie Schwefelsäure, Phosphorsäure, Salpetersäure und mit organischen Säuren, wieWeinsäure, Citronensäure, Camphersulfosäure, Äthansulfosäure, Salicylsäure, Ascorbinsäure, Maleinsäure, Mandelsäure usw. Bevorzugte Salze sind die Hydrohalogenide, insbesondere die Hydrochloride. Die Säureadditionssalze werden vorzugsweise in einem inerten Lösungsmittel durch Behandlung des erfindungsgemäss erhaltenen Hydrazins mit einem Überschuss der betreffenden Säure hergestellt.
Die erfindungsgemäss erhältlichen substituierten Säurehydrazide und deren Salze hemmen die Mono aminoxydase; einzelne Vertreter zeichnen sich durch ihre ausgeprägte antidepressive Wirksamkeit aus und wirken bei Kachexie gewichtssteigernd. Sie stellen damit eine wertvolle Bereicherung des Arzneimittelschatzes dar.
Beispiel I
10,2 g Trimethylessigsäure, 10,1 g Triäthylamin und 15,8 g Benzylhydrazin-monohydrochlorid werden in 300 cm3 Acetonitril während einer Stunde bei Raumtemperatur gerührt. Nach Zugabe von 20,6 g Dicyclohexylcarbodiimid rührt man noch etwa 3 Stunden weiter, wobei man dafür sorgt, dass die Temperatur des Reaktionsgemisches 300 C nicht übersteigt.
Nachdem man von ausgefallenem Dicyclohexylharnstoff abfiltriert hat, dampft man das Lösungsmittel im Vakuum ab und nimmt den Rückstand in Äther auf. Die ätherische Lösung wird zuerst mit Natriumbicarbonatlösung geschüttelt. Anschliessend wird die Lösung mehrmals mit 3n Chlorwasserstoffsäure extrahiert. Die vereinigten Auszüge werden durch Zugabe von Natronlauge auf pH 7-8 gebracht.
Durch Extraktion mit Ather und Verdampfen des Lösungsmittels erhält man das l-Trimethylacetyl-2- benzyl-hydrazin, welches bei 68-690 C schmilzt.
In analoger Weise erhält man, ausgehend von 8,6 g Cyclopropancarbonsäure, 10,1 g Triäthylamin, 11,05 g Isopropylhydrazin-monohydrochlorid und 20,6 g Dicyclohexylcarbodiimid in 150 cm3 Acetonitril das 1 -Cyclopropylcarbonyl-2-isopropyl-hydrazin, welches aus Essigsäureäthylester in farblosen Blättchen vom Schmelzpunkt 123-126 C kristallisiert.
Ausgehend von 12,8 g Cyclohexancarbonsäure, 10,1 g Triäthylamin und 11,05 g Isopropylhydrazinmonohydrochlorid in 150 cm Acetonitril, erhält man in analoger Weise unter Verwendung von 20,6 g Dicyclohexylcarbodiimid das l-Cyclohexylcarbonyl2-isopropyl-hydrazin, welches aus Essigsäureäthylester/Petroläther umkristaliisiert wird und bei 122 bis 123 C schmilzt.
In analoger Weise erhält man unter Verwendung von 8,6 g Cyclopropancarbonsäure, 8,8 g sek.-Butylhydrazin und 20,6 g Dicyclohexylcarbodiimid in 150 cm3 Acetonitril rohes l-Cyclopropylcarbonyl-2sek.-butyl-hydrazin, welches durch Umkristallisieren aus Essigsäureäthylester gereinigt wird, wobei farb lose Prismen vom Schmelzpunkt 92-930 C anfallen.
Ausgehend von 5,0 g Cyclobutancarbonsäure, 5,05 g Triäthylamin, 7,9 g Benzylhydrazin-monohydrochlorid und 10,3 g Dicyclohexylcarbodiimid in
150 cm3 Acetonitrl erhält man in analoger Weise 1 - Cyclobutylcarbonyl -2- benzy 1 -hydrazin, welches nach dem Umkristallisieren aus Benzol und Wasser bei 95-97" schmilzt.
In analoger Weise können folgende weitere Verbindungen hergestellt werden:
1 -Trimethylacetyl-2-isopropyl-hydrazin
FP: 83-840.
1-Cyclobutylcarbonyl-2-isopropyl-hydrazin
FP: 116-118 . l-Isobutyryl-2-isopropyl-hydrazin FP : 66-680.
1-(2-Äthylcaproyl)-2-isopropyl-hydrazin
FP: 89-900.
Process for the preparation of substituted acid hydrazides
The present invention relates to a process for the preparation of substituted acid hydrazides of the formula
EMI1.1
wherein Rt and R2 are lower alkyl radicals or together a lower alkylene radical, R3 is hydrogen or a lower alkyl radical and R4 is an.aralkyl radical, or an alicyclic or saturated, straight-chain or branched aliphatic hydrocarbon radical containing up to 6 carbon atoms, which is characterized in that one Acid of the formula
EMI1.2
or a functional derivative of such an acid with a substituted hydrazine of the formula
H2N-NH-R4 III condensed. The condensation is preferably carried out in the presence of an N, N'-disubstituted carbodiimide.
The acid hydrazides of the formula I obtained according to the invention can be converted into a salt.
To implement the acids or their salts, eg. B. the alkali metal salts can be used. Conversion into the more reactive esters, halides, anhydrides, etc. is unnecessary. The N, N'-disubstituted carbodiimides used can, for. B. be prepared by treating disubstituted urea derivatives with p-toluenesulfonyl chloride in pyridine. When using the same as a condensing agent, the corresponding urea derivatives are recovered. In this way, urea derivatives are obtained as by-products, which can easily be separated from the reaction product. N, N'-dicyclohexyl-carbodiimide, for example, can be used as the N, N'-disubstituted carbodiimide.
The reaction can e.g. B. at a temperature between 0 and 500, preferably at room temperature or slightly elevated temperature, carried out. 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 and water can be selected.
You can z. B. condense an ester, a halide, the anhydride or the primary amide of an acid of the formula II with heating with a substituted hydrazine of the formula III. Furthermore, the salts formed from the acids of the formula II with the hydrazines of the formula III can be heated to high temperatures.
The following acid hydrazides, for example, can be prepared by the process according to the invention:
1-trimethylacetyl-2-benzyl-hydrazine, l-trimethylacetyl-2-isopropyl-hydrazine,
1-trimethylacetyl-2-tert.-butylhydrazine,
1-trimethylacetyl-2-phenylethylhydrazine,
1-trimethylacetyl-2-isobutylhydrazine,
1-trimethylacetyl-2-sec-butyl-hydrazine, 1- (dimethyl-ethyl-acetyl) -2-isopropyl-hydrazine,
1 - (dimethyl-ethyl-acetyl) -2-benzyl-hydrazine,
1 -Methyl-diethyl-acetyl) -2-benzyl-hydrazine,
1 -triethylacetyl-2-isopropylhydrazine, 1- [1-methylcyclobutyl- (1) carbonyl] -2-isopropylhydrazine, 1- [l-methylcyclobutyl- (l) carbonyl] - 2-isobutyl hydrazine, 1 - [1 -methyl-cyclopropyl- (1) -carbonyl] -2-isopropyl-hydrazine, l- [l-methyl-cyclopropyl- (l)
-carbonyl] -phenyl-ethyl-hydrazine, 1- [1-methyl-cyclohexyl- (l) -carbonyl] -2-benzyl-hydrazine, 1 - [1-methyl-eyclohexyl- (1) -carbonyl] -2- isopropyl hydrazine,
1 -isobutyryl-2-isopropylhydrazine, 1-isobutyryl-2-benzylhydrazine,
1-isobutyryl-2-ethylhydrazine,
1-cyclopropylcarbonyl-2-isopropyl-hydrazine, 1-cyclopropylcarbonyl-2-benzyl-hydrazine,
1-cyclopropylcarbonyl-2-sec-butyl-hydrazine, 1-cyclobutylcarbonyl-2-isopropyl-hydrazine,
1 -cyclobutylcarbonyl-2-benzylhydrazine, 1 -cyclohexylcarbonyl-2-isopropylhydrazine,
1-cyclohexylcarbonyl-2-tert.-butylhydrazine, l-cyclohexylcarbonyl-2-n-propylhydrazine and 1-cyclohexylcarbonyl-2-benzylhydrazine.
Particularly valuable from a pharmacological point of view are those acid hydrazides in which Rt, R2 and R3 are methyl radicals or Rl and R2 together with the carbon atom adjacent to the carbonyl group form a cyclobutane or cyclohexane ring and R4 is the isopropyl or benzyl radical.
The substituted acid hydrazides obtainable 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, hydroiodic acid, with other mineral acids such as sulfuric acid, phosphoric acid, nitric acid and with organic acids such as tartaric acid, citric acid, camphorsulfonic acid, ethanesulfonic acid, salicylic acid, ascorbic acid, maleic acid, mandelic acid, etc. Preferred salts are the hydrochloric acid the hydrochloride. The acid addition salts are preferably prepared in an inert solvent by treating the hydrazine obtained according to the invention with an excess of the acid in question.
The substituted acid hydrazides obtainable according to the invention and their salts inhibit mono amine oxidase; individual representatives are characterized by their pronounced antidepressant effectiveness and have a weight-increasing effect in cachexia. They thus represent a valuable addition to the medicinal treasure trove.
Example I.
10.2 g of trimethyl acetic acid, 10.1 g of triethylamine and 15.8 g of benzylhydrazine monohydrochloride are stirred in 300 cm3 of acetonitrile for one hour at room temperature. After adding 20.6 g of dicyclohexylcarbodiimide, stirring is continued for about 3 hours, ensuring that the temperature of the reaction mixture does not exceed 300.degree.
After the precipitated dicyclohexylurea has been filtered off, the solvent is evaporated off in vacuo and the residue is taken up in ether. The ethereal solution is first shaken with sodium bicarbonate solution. The solution is then extracted several times with 3N hydrochloric acid. The combined extracts are brought to pH 7-8 by adding sodium hydroxide solution.
1-trimethylacetyl-2-benzylhydrazine, which melts at 68-690 ° C., is obtained by extraction with ether and evaporation of the solvent.
In an analogous manner, starting from 8.6 g of cyclopropanecarboxylic acid, 10.1 g of triethylamine, 11.05 g of isopropylhydrazine monohydrochloride and 20.6 g of dicyclohexylcarbodiimide in 150 cm3 of acetonitrile, 1-cyclopropylcarbonyl-2-isopropylhydrazine is obtained Ethyl acetate crystallizes in colorless flakes with a melting point of 123-126 ° C.
Starting from 12.8 g of cyclohexanecarboxylic acid, 10.1 g of triethylamine and 11.05 g of isopropylhydrazine monohydrochloride in 150 cm of acetonitrile, l-cyclohexylcarbonyl2-isopropylhydrazine is obtained in an analogous manner using 20.6 g of dicyclohexylcarbodiimide, which is obtained from ethyl acetate / Petroleum ether is recrystallized and melts at 122 to 123 C.
In an analogous manner, using 8.6 g of cyclopropanecarboxylic acid, 8.8 g of sec-butylhydrazine and 20.6 g of dicyclohexylcarbodiimide in 150 cm3 of acetonitrile, crude l-cyclopropylcarbonyl-2-sec-butylhydrazine is obtained, which is purified by recrystallization from ethyl acetate colorless prisms with a melting point of 92-930 C.
Starting from 5.0 g cyclobutanecarboxylic acid, 5.05 g triethylamine, 7.9 g benzylhydrazine monohydrochloride and 10.3 g dicyclohexylcarbodiimide in
150 cm3 of acetonitrile are obtained in an analogous manner 1-cyclobutylcarbonyl -2-benzy 1 -hydrazine, which, after recrystallization from benzene and water, melts at 95-97 ".
The following additional connections can be established in a similar manner:
1-trimethylacetyl-2-isopropylhydrazine
FP: 83-840.
1-cyclobutylcarbonyl-2-isopropylhydrazine
FP: 116-118. 1-Isobutyryl-2-isopropylhydrazine FP: 66-680.
1- (2-ethylcaproyl) -2-isopropylhydrazine
FP: 89-900.
Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH6424958A CH369471A (en) | 1958-09-23 | 1958-09-23 | Process for the preparation of substituted acid hydrazides |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH6424958A CH369471A (en) | 1958-09-23 | 1958-09-23 | Process for the preparation of substituted acid hydrazides |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH369471A true CH369471A (en) | 1963-05-31 |
Family
ID=4525534
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH6424958A CH369471A (en) | 1958-09-23 | 1958-09-23 | Process for the preparation of substituted acid hydrazides |
Country Status (1)
| Country | Link |
|---|---|
| CH (1) | CH369471A (en) |
-
1958
- 1958-09-23 CH CH6424958A patent/CH369471A/en unknown
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