DE2438619A1 - Substd. 2-ketopiperazine deriv. prepn. - from amino acid esters by aralkylation, cyanomethylation, catalytic reductive cyclosation and use as cardaic remedy inter. - Google Patents
Substd. 2-ketopiperazine deriv. prepn. - from amino acid esters by aralkylation, cyanomethylation, catalytic reductive cyclosation and use as cardaic remedy inter.Info
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- DE2438619A1 DE2438619A1 DE2438619A DE2438619A DE2438619A1 DE 2438619 A1 DE2438619 A1 DE 2438619A1 DE 2438619 A DE2438619 A DE 2438619A DE 2438619 A DE2438619 A DE 2438619A DE 2438619 A1 DE2438619 A1 DE 2438619A1
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- carbon atoms
- group
- hydrogen atom
- ketopiperazine
- general formula
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- -1 amino acid esters Chemical class 0.000 title claims abstract description 14
- IWELDVXSEVIIGI-UHFFFAOYSA-N piperazin-2-one Chemical compound O=C1CNCCN1 IWELDVXSEVIIGI-UHFFFAOYSA-N 0.000 title claims abstract description 11
- 230000002829 reductive effect Effects 0.000 title abstract description 6
- 230000003197 catalytic effect Effects 0.000 title abstract 2
- 238000006215 cyanomethylation reaction Methods 0.000 title description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims abstract description 10
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims abstract description 10
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 9
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 4
- 125000003710 aryl alkyl group Chemical group 0.000 claims abstract description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 15
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 13
- 239000003054 catalyst Substances 0.000 claims description 6
- LELOWRISYMNNSU-UHFFFAOYSA-N hydrogen cyanide Chemical compound N#C LELOWRISYMNNSU-UHFFFAOYSA-N 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 5
- 150000001875 compounds Chemical class 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- 239000003929 acidic solution Substances 0.000 claims description 2
- 239000007795 chemical reaction product Substances 0.000 claims description 2
- 238000006476 reductive cyclization reaction Methods 0.000 claims description 2
- 150000004885 piperazines Chemical class 0.000 claims 1
- 229940066771 systemic antihistamines piperazine derivative Drugs 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 7
- 239000002253 acid Substances 0.000 abstract description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 abstract 2
- 235000001014 amino acid Nutrition 0.000 abstract 1
- 230000001225 therapeutic effect Effects 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 66
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- 229910001868 water Inorganic materials 0.000 description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 8
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 239000000243 solution Substances 0.000 description 5
- 125000002774 3,4-dimethoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C(OC([H])([H])[H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 150000004702 methyl esters Chemical class 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- PXHVJJICTQNCMI-UHFFFAOYSA-N nickel Substances [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- CRVBQABBEKLFIN-UHFFFAOYSA-N 1-phenylethane-1,2-diamine Chemical compound NCC(N)C1=CC=CC=C1 CRVBQABBEKLFIN-UHFFFAOYSA-N 0.000 description 1
- WZSOEUAQKKEHFE-UHFFFAOYSA-N 2-chloro-2-phenylacetonitrile Chemical compound N#CC(Cl)C1=CC=CC=C1 WZSOEUAQKKEHFE-UHFFFAOYSA-N 0.000 description 1
- XQNQZGCILWSUSW-UHFFFAOYSA-N 3-benzyl-5-phenylpiperazin-2-one Chemical compound C(C1=CC=CC=C1)C1C(NCC(N1)C1=CC=CC=C1)=O XQNQZGCILWSUSW-UHFFFAOYSA-N 0.000 description 1
- BBZXOEDSLMIDDJ-UHFFFAOYSA-N 3-benzyl-6-phenylpiperazin-2-one Chemical compound O=C1NC(C=2C=CC=CC=2)CNC1CC1=CC=CC=C1 BBZXOEDSLMIDDJ-UHFFFAOYSA-N 0.000 description 1
- PGNYGDAFMUYUNJ-UHFFFAOYSA-N 6-benzylpiperazin-2-one Chemical compound N1C(=O)CNCC1CC1=CC=CC=C1 PGNYGDAFMUYUNJ-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 150000003934 aromatic aldehydes Chemical class 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- CBHOOMGKXCMKIR-UHFFFAOYSA-N azane;methanol Chemical compound N.OC CBHOOMGKXCMKIR-UHFFFAOYSA-N 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 229910017052 cobalt Inorganic materials 0.000 description 1
- 239000010941 cobalt Substances 0.000 description 1
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000008098 formaldehyde solution Substances 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- PYZLRNMGUBDIHK-UHFFFAOYSA-N molecular hydrogen;nickel Chemical compound [Ni].[H][H] PYZLRNMGUBDIHK-UHFFFAOYSA-N 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229940066765 systemic antihistamines substituted ethylene diamines Drugs 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/06—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members
- C07D241/08—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
Verfahren zur Herstellung von substituierten 2-Ketopiperazin-Derivaten Die Erfindung betrifft ein Verfahren zur Herstellung neuer substituierter 2-Ketopiperazin-Derivate sowie diese neuen Derivate selbst.Process for the preparation of substituted 2-ketopiperazine derivatives The invention relates to a process for the preparation of new substituted 2-ketopiperazine derivatives as well as these new derivatives themselves.
Verfahren zur Herstellung von substituierten 2-Ketopiperazin-Derivaten sind bereits in der Literatur beschrieben.Process for the preparation of substituted 2-ketopiperazine derivatives are already described in the literature.
So erhält man substituierte 2-Ketopiperazin-Derivate in mässiger Ausbeute unter anderem durch Umsetzung von unsubstituierten oder substituierten Äthylendiaminen mit a-Halogen-Carbonsäureestern (vgl. R. C. Elderfield: Heterocyclic Compounds Band 6, Kap. 8 Seite 450; Aspinall, S. R.; J.Substituted 2-ketopiperazine derivatives are thus obtained in moderate yield inter alia by reacting unsubstituted or substituted ethylene diamines with α-halogen carboxylic acid esters (cf. R. C. Elderfield: Heterocyclic Compounds Band 6, chap. 8 page 450; Aspinall, S. R .; J.
Amer. Chem. Soc. 62, 1202-1204 (1940)) oder durch Umsetzung von substituierten Chloracetonitrilen mit a-Aminosäureestern. Die Ausbeuten dieser Reaktionen sind teilweise jedoch sehr unbefriedigend und die Herstellung der Ausgangsmaterialien ist aufwendig.Amer. Chem. Soc. 62, 1202-1204 (1940)) or by reacting substituted Chloroacetonitriles with a-amino acid esters. The yields of these reactions are but sometimes very unsatisfactory and the production of the starting materials is complex.
K. Mazuzawa und Mitarbeiter (Bull. Chem. Soc. Japan 38, 2078-81 (1965), vgl. Chemical Abstracts 64, 9726 e (1966)) erhielten durch Umsetzung von 2-Phenyl-äthylendiamin mit a-Brom-ß-phenyl-propionsäureäthylester in Benzol nur 37,6 % Ausbeute an 3-Benzyl-6-phenyl-2-ketopiperazin und das isomere 3-Benzyl-5-phenyl-2-ketopiperazin in 1,7%iger Ausbeute.K. Mazuzawa et al. (Bull. Chem. Soc. Japan 38, 2078-81 (1965), See Chemical Abstracts 64, 9726 e (1966)) obtained by reacting 2-phenyl-ethylenediamine with ethyl a-bromo-ß-phenyl-propionate in benzene only 37.6% yield of 3-benzyl-6-phenyl-2-ketopiperazine and the isomeric 3-benzyl-5-phenyl-2-ketopiperazine in 1.7% yield.
Um das 3-Benzyl-5-ketopiperazin zu erhalten, führten die gleichen Autoren eine Umsetzung von Phenylalaninester mit Phenylchlor-acetonitril durch und erhielten in nur 31,5%iger Ausbeute den entsprechenden N-(a-Phenyl-cyanomethyl)-alaninester, welcher in äthanolischer Lösung mit Raney-Nickel-Wasserstoff zum Endpunkt reduktiv cyclisiert wurde. Die Ausbeute beträgt bei diesem Schritt ebenfalls nur 29,3 %.To obtain the 3-benzyl-5-ketopiperazine, the same performed Authors a reaction of phenylalanine ester with phenylchloroacetonitrile by and received the corresponding N- (a-phenyl-cyanomethyl) -alanine ester in only 31.5% yield, which in ethanolic solution with Raney nickel hydrogen to the end point reductive was cyclized. The yield in this step is also only 29.3%.
Es wurde nun gefunden, dass sich 2-Ketopiperazin-Derivate auf sehr einfache Weise in guter Ausbeute gewinnen lassen.It has now been found that 2-ketopiperazine derivatives are very can easily be obtained in good yield.
Gegenstand der Erfindung ist ein Verfahren zur Herstellung von substituierten 2-Ketopiperazin-Derivaten der allgemeinen Formel worin R1 ein Aralkylrest, R2 ein Wasserstoffatom oder ein Alkylrest mit 1 - 4 Kohlenstoffatomen, R3 ein Wasserstoffatom, eine Hydroxygruppe, eine Alkoxygruppe mit 1 - 4 Kohlenstoffatomen oder eine Benzyloxygruppe und R4 und R5 ein Wasserstoffatom, eine Alkoxygruppe mit 1 - 4 Kohlenstoffatomen oder die Benzyloxygruppe sein können, dadurch gekennzeichnet, dass man Aminosäureester der allgemeinen Formel worin R2 ein Wasserstoffatom oder ein Alkylrest mit 1 - 4 Kohlenstoffatomen, R3, R4 und R Wasserstoffatome oder Al-5 koxygruppen mit 1 - 4 Kohlenstoffatomen oder Benzyloxygruppen und R6 ein Alkylrest mit 1 - 4 Kohlenstoffatomen sein können, aralkyliert, in saurer Lösung mit Formaldehyd und Cyanwasserstoffsäure bei niederer Temperatur umsetzt und das Reaktionsprodukt unter Einfluss eines Katalysators einer reduktiven Cyclisierung unterwirft.The invention relates to a process for the preparation of substituted 2-ketopiperazine derivatives of the general formula where R1 is an aralkyl group, R2 is a hydrogen atom or an alkyl group with 1 - 4 carbon atoms, R3 is a hydrogen atom, a hydroxyl group, an alkoxy group with 1 - 4 carbon atoms or a benzyloxy group and R4 and R5 are a hydrogen atom, an alkoxy group with 1 - 4 carbon atoms or the Benzyloxy group, characterized in that one amino acid esters of the general formula where R2 can be a hydrogen atom or an alkyl radical with 1 - 4 carbon atoms, R3, R4 and R hydrogen atoms or Al-5 koxy groups with 1 - 4 carbon atoms or benzyloxy groups and R6 an alkyl radical with 1 - 4 carbon atoms, aralkylated in acidic solution with formaldehyde and reacting hydrocyanic acid at a low temperature and subjecting the reaction product to reductive cyclization under the influence of a catalyst.
Die Aralkylierung erfolgt im allgemeinen bei erhöhter Temperatur durch Einwirkung eines aromatischen Aldehyds auf den Aminosäureester in einem mit Wasser nicht mischbaren Lösungsmittel und nachfolgender Hydrierung der entstandenen Benzalverbindung.The aralkylation is generally carried out at an elevated temperature Action of an aromatic aldehyde on the amino acid ester in one with water immiscible solvent and subsequent hydrogenation of the resulting benzal compound.
Der für die Cyanomethylierung erforderliche Aldehyd kann sowohl in Form von Paraformaldehyd als auch 35%iger wässriger Formalin-Lösung verwendet werden.The aldehyde required for the cyanomethylation can be used both in Form of paraformaldehyde as well as 35% aqueous formalin solution can be used.
Es ist vorteilhaft, die Cyanwasserstoffsäure in Form ihres Kalium- oder Natriumsalzes in wässriger oder alkoholischer Lösung einzusetzen.It is advantageous to use hydrocyanic acid in the form of its potassium or sodium salt in aqueous or alcoholic solution.
Die Reaktionstemperatur kann variiert werden, sie liegt im Bereich von -5 bis +800C, und die Reaktionsdauer beträgt 2 bis 24 Stunden.The reaction temperature can be varied; it is in the range from -5 to + 800C, and the reaction time is 2 to 24 hours.
Man erhält in hoher Ausbeute den entsprechenden N-Benzyl-N-cyanomethylaminosäureester.The corresponding N-benzyl-N-cyanomethylamino acid ester is obtained in high yield.
Letzterer wird in einem geeigneten Lösungsmittelgemisch unter Einwirkung eines Metallkatalysators und Wasserstoff bei erhöhtem Druck reduktiv cyclisiert.The latter is applied in a suitable solvent mixture a metal catalyst and hydrogen reductively cyclized at elevated pressure.
Die Ausbeuten liegen über 90 % der Theorie.The yields are over 90% of theory.
Als Komponenten der Lösungsgemische werden vorzugsweise aromatische Kohlenwasserstoffe wie Benzol, Toluol oder Xylol sowie mit gasförmigen Ammoniak gesättigte niedrige Alkohole~ wie Methanol, Äthanol oder Isopropanol verwendet. Als Katalysator hat sich Raney-Covbalt bewährt, während Rapey-Nickel nur mässige Ausbeuten an Ringschlussprodukt ergibt.The components of the mixed solutions are preferably aromatic Hydrocarbons such as benzene, toluene or xylene as well as with gaseous ammonia saturated lower alcohols ~ such as methanol, ethanol or isopropanol are used. Raney-Covbalt has proven itself as a catalyst, while Rapey-Nickel is only moderate Yields of ring closure product results.
Die Umsetzungen erfolgen im allgemeinen bei Temperaturen zwischen 25 und 1200C vorzugsweise bei 20 bis 600C; der bevorzugte Druckbereich liegt bei 10 bis 140 atü.The reactions are generally carried out at temperatures between 25 and 1200C preferably at 20 to 600C; the preferred pressure range is 10 to 140 atm.
Die Reaktion ist nach 1 bis 2 Stunden beendet. Man erhält in hoher Ausbeute die entsprechend substituierten Plperazinone.The reaction is over after 1 to 2 hours. You get in high Yield the appropriately substituted plperazinones.
Gegenstand der Erfindung sind weiter die Verbindungen der allgemeinen Formel I.The invention also relates to the compounds of the general Formula I.
Diese Verbindungen eignen sich sehr gut zur Herstellung von Verbindungen, in denen die Ketogruppe in der 2-Stellung des Piperazinon-Rings reduziert ist. Diese Reduktion kann z.B.These connections are very suitable for making connections, in which the keto group is reduced in the 2-position of the piperazinone ring. These Reduction can e.g.
Lithiumaluminiumhydrid in an sich bekannter Weise erfolgen.Lithium aluminum hydride take place in a manner known per se.
Die so erhaltenen Verbindungen eignen sich sehr gut zur Behandlung von Herzstörungen.The compounds thus obtained are very suitable for treatment of heart disorders.
Beispiel a) In einem Rundkolben mit Wasserabscheider und Rückflusskühler werden 75,9 g 97%iger 3, 4-Dimethoxyphenyl-a-alanin-methylester in 150,0 ml Toluol gelöst, mit 33,4 g Benzaldehyd versetzt und unter Rückfluss erhitzt. Nach kurzer Zeit beginnt die Wasserabscheidung. Nach etwa 2 Stunden haben sich 5,4 ml Wasser abgeschieden, welche abgetrennt werden. Example a) In a round bottom flask with water separator and reflux condenser 75.9 g of 97% 3, 4-dimethoxyphenyl-a-alanine methyl ester in 150.0 ml of toluene dissolved, mixed with 33.4 g of benzaldehyde and heated under reflux. After short Time begins to separate the water. After about 2 hours you will have 5.4 ml of water deposited, which are separated.
Danach destilliert man das Toluol unter vermindertem Druck ab. Der rohe Benzalester wird in 200 ml Methanol aufgenommen, mit einem Teelöffel wasserfreiem, methanolfeuchtem Raney-Nickel versetzt und unter Schütteln hydriert. The toluene is then distilled off under reduced pressure. Of the raw benzal ester is taken up in 200 ml of methanol, with a teaspoon of anhydrous, methanol-moist Raney nickel was added and hydrogenated with shaking.
Innerhalb 3 Stunden nimmt der Ansatz 8,6 Liter Wasserstoff auf. Die Temperatur steigt von 250C auf 340C an und sollte nicht überschritten werden. The batch absorbs 8.6 liters of hydrogen within 3 hours. the The temperature rises from 250C to 340C and should not be exceeded.
Nach beendeter Hydrierung wird die methanolische Lösung vom Katalysator abgesaugt. Das Methanolfiltrat wird im Wasserstrahlvakuum zur Trockene eingedampft. Man erhält ein bräunliches Öl, welches mit 100 ml 3 n- HC1 verrührt wird. Das Hydrochlorid des Benzylesters kristallisiert aus, wird abgesaugt und 3 mal mit eiskalter 3 n - HC1 gewaschen. After the hydrogenation has ended, the methanolic solution is removed from the catalyst sucked off. The methanol filtrate is evaporated to dryness in a water jet vacuum. A brownish oil is obtained which is stirred with 100 ml of 3N HCl. The hydrochloride of the benzyl ester crystallized off, is sucked off and 3 times with ice-cold 3N HC1 washed.
Ausbeute: 90 g (90 % der Theorie) N-Benzyl-3,4-dimethoxybenzyl-oc-alanin-methylester F = 43 - 450C b) 171,6 g N-Benzyl-3, 4-dimethoxybenzyl-oc-alanin-methylester werden unter Rühren in 430,0 ml Eisessig gelöst, auf 100C abgekühlt und mit 33,0 g Eis versetzt, 10 Minuten gerührt, danach 44,6 g 35%ige wässrige Formaldehydlösung zugegeben und weiter auf 50C abgekühlt. Yield: 90 g (90% of theory) of N-benzyl-3,4-dimethoxybenzyl-oc-alanine methyl ester F = 43-450C b) 171.6 g of N-benzyl-3, 4-dimethoxybenzyl-oc-alanine methyl ester dissolved with stirring in 430.0 ml of glacial acetic acid, cooled to 100 ° C. and poured with 33.0 g of ice added, stirred for 10 minutes, then 44.6 g of 35% strength aqueous formaldehyde solution were added and further cooled to 50C.
Bei 5 - 60C wird eine Lösung von 41,5 g Kaliumcyanid in 81, 0 ml Wasser innerhalb einer Stunde eingetropft und noch eine weitere Stunde bei 5 - 60C und 18 Stunden bei 400C nachgerührt. A solution of 41.5 g of potassium cyanide in 81.0 ml Water was added dropwise within an hour and another hour at 5 - 60C and stirred at 40 ° C. for 18 hours.
Danach wird drei Stunden lang in einem Eisbad gerührt, abgesaugt, mit wenig Eiswasser gewaschen und im Vakuum bei 400C getrocknet. Then it is stirred for three hours in an ice bath, suctioned off, washed with a little ice water and dried in vacuo at 40.degree.
Man erhält 182,1 g (95,3 % der Theorie) N-Benzyl-N-cyanomethyl- 3, 4-dimethoxybenzyl-a-alanin-methylester. 182.1 g (95.3% of theory) of N-benzyl-N-cyanomethyl-3 are obtained, 4-dimethoxybenzyl-a-alanine methyl ester.
F 94 - 960C (Methanol) c) In einem Autoklaven werden 38,2 g N-Benzyl-N-cyanomethyl-3,4-dimethoxybenzyl-α-alanin-methylester sowie ein Lösungsmittelgemisch bestehend aus 200 ml Toluol, 400 ml mit Ammoniak gesättigtes Methanol sowie ein Teelöffel wasserfreies, methanolfeuchtes Raney-Cobalt eingefüllt. bei 40°C werden 100 atu Wasserstoffgas aufgeprest. nach ca. F 94 - 960C (methanol) c) Be in an autoclave 38.2 g of N-benzyl-N-cyanomethyl-3,4-dimethoxybenzyl-α-alanine methyl ester and a mixed solvent consisting of 200 ml of toluene, 400 ml saturated with ammonia Methanol and a teaspoon of anhydrous, methanol-moist Raney cobalt. 100 atu hydrogen gas are pressed on at 40 ° C. after approx.
1 bis 2 Stunden ist die Reaktion beendet. Der Katalysator wird abgesaugt, mit Methanol gewaschen und das Filtrat unter vermindertem Druck eingedampft. Der Rückstand wird in der Wärme in 400 ml Toluol gelöst, Kohle zugesetzt, vom schmierigen Rückstand abgesaugt und das Filtrat im Wasserstrahlvakuuni bei 90°C Badtemperatur zur Trockene eingedampft. The reaction is complete for 1 to 2 hours. The catalyst is sucked off, washed with methanol and the filtrate evaporated under reduced pressure. Of the The residue is dissolved in 400 ml of toluene while warm, and charcoal is added, from the greasy Sucked off residue and the filtrate in a water jet vacuum at 90 ° C bath temperature evaporated to dryness.
Der Rückstand wird aus 250 ml Methanol umkristallisiert. The residue is recrystallized from 250 ml of methanol.
Man erhält 32,5 g (91,7 % der Theorie) 3-Methyl-3(3,4-dimethoxybenzyl)-4-benzyl-piperazino-(2). 32.5 g (91.7% of theory) of 3-methyl-3 (3,4-dimethoxybenzyl) -4-benzyl-piperazino- (2) are obtained.
F 148 - 1490C. F 148-1490C.
Analog wurden hergestellt aus A) (D)-3, 4-Dimethoxy-a-alanin-methylester 'über (D)-N-Benzyl-3, 4-dimethoxybenzyl-a-alaninmethylester (FHCl197 - 199°C (H2O); FBase 53 - 55°C; [cc3D0 C = 81,60 (c = 1, Methanol)) und (D)-N-benzyl-N-cyanomethyl-3,4-dimethoxybenzyl-α-alanin-methylester (F 108 - 109 C (Methanol); 20°C = -15,1° (c = 1 [α]D20°C = -15,1° ( c = 1,Methanol) (D)-3-Methal-3-(3,4-dimethoxybenzyl)-4-benzyl-piperazinon-(2) (F 181 - 183°C (Methanol) [α]D20°C = + 24,1°8c = 1, Methanol) B) (L)-3,4-Dimethoxybenzyl-α-alanin-methylester über (L)-N-Benzyl-3,k4-dimethoxy-α-qalanin-methylester (FHC1 197 - 1990C (H20); FBase 54 - 560C, HCl 2 Base [α]D20°C = -82° ( c= 1, methanol) (L)-N-Benzyl-N-cyanomethyl-3,4-dimethoxybenzyl-a-alaninmethylester (F 109°C (methanol) [α]D20°C =+15,2° (c = 1, Methanol) (L)-3-methyl-3-(3,4-dimethoxybenzyl)-4-benzyl-piperazi non-(2) (F 181 -183°C (Methanol) [α]D20°C = - 24,1° (c = 1, Methanol) C) (L)-3,4-Dihydroxy-phenyl-α-alanin über (L)-N-Benzyl-3,4-dibenzyloxyphenyl-α-alanin-methylester (FHCl = 152°C (Essigester); [α]D20°C = +55,5° (c = 1, Methanol und (L)-N-Benzyl-N-cyanomethyl-3,4-dibenzyloxyphenyl-ocalanin-methylester (F 119 C (Isopropanol) [α]36520°C = -4° (c = 1, Methanol) (L)-3-Methyl-3-(3,4-dibenzyloxyphenyl)-4-benzyl-pipera zinon-(2) (FHC1 188 - 190°C (Äthanol); [α]D20°C = +5,5° (c = 1, Methanol) D) (D)-3,4-Dihydroxy-phenyl-a-alanin über (D)-N-Benzyl-3,4-dibenzyloxyphenyl-α-alaninmethylester (FHCl = 1500 (Essigester); o [α]D20 C = ~ 55,8° (c = 1, Methanol) und (D)-N-Benzyl-N-cyanomethyl-3,4-dibenzyloxyphenyl-aalanin-methylester (F 1180C (Isopropanol); [α]D20°C = + 4,1° (c = 1; Methanol) (D)-3-Methyl-3-(3,4-dibenyloxyphenyl)-4-benzyl-pi perazinon- (2) (FHCl 186-188°C (Äthanol) [α]D20°C= -5,4 ( c = 1 Me [α]D20 C = - 5ß4° (c = 1, Methanol) E) 3,4-Dimethoxy-glycin-methylester über N-Benzyl-3,4-dimethoxybenzylglycin-methylester (Kp 180 - 185°C; 10-2 Torr) und N-Benzyl-cyanomethyl-3,4-dimethoxyphenyl-glycin-methylester (Kp 180 -182°C (5 x 10-2 Torr) 3-(3,4-Dimethoxybenzyl)-4-benzyl-piperazinon-(2) (FHCl 207 - 209 0C (Isopropanol) Similarly, from A) (D) -3, 4-dimethoxy-a-alanine methyl ester were prepared via (D) -N-benzyl-3, 4-dimethoxybenzyl-a-alanine methyl ester (FHCl197 - 199 ° C (H2O); FBase 53-55 ° C; [cc3D0 C = 81.60 (c = 1, methanol)) and (D) -N -benzyl-N -cyanomethyl-3,4-dimethoxybenzyl-α-alanine methyl ester (F 108 - 109 C (methanol); 20 ° C = -15.1 ° (c = 1 [α] D20 ° C = -15.1 ° (c = 1, methanol) (D) -3-Methal-3- (3,4-dimethoxybenzyl) -4-benzyl-piperazinone- (2) (F 181 - 183 ° C (methanol) [α] 20 ° C = + 24.1 ° 8c = 1, methanol) B) (L) -3,4-dimethoxybenzyl-α-alanine methyl ester via (L) -N-benzyl-3, k4-dimethoxy-α-qalanine methyl ester (FHC1 197-1990C (H20); FBase 54-560C, HCl 2 base [α] D20 ° C = -82 ° (c = 1, methanol) (L) -N-Benzyl-N-cyanomethyl-3,4-dimethoxybenzyl-α-alanine methyl ester (F 109 ° C (methanol) [α] 20 ° C = + 15.2 ° (c = 1, methanol) (L) -3-methyl-3- (3,4-dimethoxybenzyl) -4-benzyl-piperazi non- (2) (F 181 -183 ° C (methanol) [α] D20 ° C = - 24.1 ° (c = 1, methanol) C) (L) -3,4-dihydroxyphenyl-α-alanine via (L) -N-benzyl-3,4-dibenzyloxyphenyl-α-alanine methyl ester (FHCl = 152 ° C (ethyl acetate); [α] D20 ° C = + 55.5 ° (c = 1, methanol and (L) -N-benzyl-N-cyanomethyl-3,4-dibenzyloxyphenyl-ocalanine methyl ester (Mp 119 C (isopropanol) [α] 36520 ° C = -4 ° (c = 1, methanol) (L) -3-methyl-3- (3,4-dibenzyloxyphenyl) -4-benzyl-pipera zinon- (2) (FHC1 188 - 190 ° C (ethanol); [α] D20 ° C = + 5.5 ° (c = 1, methanol) D) (D) -3,4-dihydroxyphenyl-a-alanine via (D) -N-benzyl-3,4-dibenzyloxyphenyl-α-alanine methyl ester (FHCl = 1500 (ethyl acetate); o [α] D20 C = ~ 55.8 ° (c = 1, methanol) and (D) -N-benzyl-N-cyanomethyl-3,4-dibenzyloxyphenyl-aalanine methyl ester (F 1180C (isopropanol); [α] D20 ° C = + 4.1 ° (c = 1; methanol) (D) -3-methyl-3- (3,4-dibenyloxyphenyl) -4-benzyl-pi perazinone- (2) (FHCl 186-188 ° C (ethanol) [α] D20 ° C = -5.4 (c = 1 Me [α] D20 C = -534 ° (c = 1, methanol) E) 3,4-dimethoxy-glycine methyl ester via N-benzyl-3,4-dimethoxybenzylglycine methyl ester (Bp 180-185 ° C; 10-2 Torr) and N-benzyl-cyanomethyl-3,4-dimethoxyphenyl-glycine methyl ester (Bp 180-182 ° C (5 x 10-2 Torr) 3- (3,4-Dimethoxybenzyl) -4-benzyl-piperazinone- (2) (FHCl 207 - 209 0C (isopropanol)
Claims (3)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE2438619A DE2438619A1 (en) | 1974-08-12 | 1974-08-12 | Substd. 2-ketopiperazine deriv. prepn. - from amino acid esters by aralkylation, cyanomethylation, catalytic reductive cyclosation and use as cardaic remedy inter. |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE2438619A DE2438619A1 (en) | 1974-08-12 | 1974-08-12 | Substd. 2-ketopiperazine deriv. prepn. - from amino acid esters by aralkylation, cyanomethylation, catalytic reductive cyclosation and use as cardaic remedy inter. |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DE2438619A1 true DE2438619A1 (en) | 1976-02-26 |
Family
ID=5922985
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE2438619A Withdrawn DE2438619A1 (en) | 1974-08-12 | 1974-08-12 | Substd. 2-ketopiperazine deriv. prepn. - from amino acid esters by aralkylation, cyanomethylation, catalytic reductive cyclosation and use as cardaic remedy inter. |
Country Status (1)
| Country | Link |
|---|---|
| DE (1) | DE2438619A1 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0072932A2 (en) * | 1981-08-20 | 1983-03-02 | CASSELLA Aktiengesellschaft | Piperazinones, their preparation and use |
| US4483988A (en) * | 1980-03-14 | 1984-11-20 | Richardson Merrell Inc. | Substituted derivatives of 4-t-alkoxycarbonyl-piperazin-2-ones |
| EP0546868A1 (en) * | 1991-12-12 | 1993-06-16 | Hampshire Chemical Corp. | 1-Cyanomethyl-4-carboxymethyl-3-ketopiperazine, salts thereof, and process for their preparation |
-
1974
- 1974-08-12 DE DE2438619A patent/DE2438619A1/en not_active Withdrawn
Non-Patent Citations (1)
| Title |
|---|
| NICHTS-ERMITTELT * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4483988A (en) * | 1980-03-14 | 1984-11-20 | Richardson Merrell Inc. | Substituted derivatives of 4-t-alkoxycarbonyl-piperazin-2-ones |
| EP0072932A2 (en) * | 1981-08-20 | 1983-03-02 | CASSELLA Aktiengesellschaft | Piperazinones, their preparation and use |
| EP0072932A3 (en) * | 1981-08-20 | 1984-03-21 | Cassella Aktiengesellschaft | Piperazinones, their preparation and use |
| EP0546868A1 (en) * | 1991-12-12 | 1993-06-16 | Hampshire Chemical Corp. | 1-Cyanomethyl-4-carboxymethyl-3-ketopiperazine, salts thereof, and process for their preparation |
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