CH385808A - Process for the production of basic substituted esters of hydracrylic acid - Google Patents

Process for the production of basic substituted esters of hydracrylic acid

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Publication number
CH385808A
CH385808A CH156660A CH156660A CH385808A CH 385808 A CH385808 A CH 385808A CH 156660 A CH156660 A CH 156660A CH 156660 A CH156660 A CH 156660A CH 385808 A CH385808 A CH 385808A
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Switzerland
Prior art keywords
isopropyl
hydracrylic acid
acid
phenyl
radical
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CH156660A
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German (de)
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Hartmund Dr Wollweber
Rudolf Dr Hiltmann
Georg Dr Kimmerle
Horst Dr Kreiskott
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Bayer Ag
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Publication of CH385808A publication Critical patent/CH385808A/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/60—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Description

  

  



  Verfahren zur Herstellung basisch substituierter Ester der   Hydracrylsäure   
Es ist bekannt, dass man basische Ester von Car  bonsäuren    erhält, wenn man die freien Säuren oder ihre funktionellen Säurederivate mit Aminoalkoholen oder deren Derivaten, die unter   Esterbildung    mit den Säuren oder Säurederivaten reagieren, umsetzt.



   Es wurde nun gefunden, dass man therapeutisch wertvolle, insbesondere bei Morbus Parkinson hochwirksame Verbindungen erhält, wenn man als Car  bonsäuren      ss-substituierte      Hydracrylsäuren    der Formel I oder ihre funktionellen Säurederivate verwendet.
EMI1.1     




   Hierin bedeutet   R1    Wasserstoff oder einen Acylrest und R einen gegebenenfalls gesättigten oder ungesättigten Bicyclo- (2, 2,   1)-heptylrest,    den Nortricyclyl-, den Isopropyl-, den Isopropenyl-oder den tert.-Butylrest ; der Phenylkern kann gegebenenfalls durch eine oder mehrere Alkoxy-, Methylendioxyoder Alkylmercaptogruppen substituiert sein.

   Durch Umsetzung mit Aminoalkoholen oder deren funktionellen Derivaten entstehen daraus die noch nicht beschriebenen Verbindungen der Formel
EMI1.2     
 worin X einen   Alkylenrest    mit gerader oder verzweigter Kette oder einen Cycloalkylenrest und   R2    und   Rs    Wasserstoff oder ein Alkylrest bedeuten, wobei   R2    und   R3    gemeinsam mit dem Stickstoffatom oder mit einem Kohlenstoffatom der Gruppe X einen mono-oder bicyclischen Heterocyclus bilden können, der ausserdem noch weitere Heteroatome oder heteroatomhaltige Gruppen enthalten kann.



   Die Herstellung der genannten basisch substituierten   Ester ss-substituierter Hydracrylsäuren    erfolgt nach an sich bekannten Arbeitsverfahren.



   So können die freien Carbonsäuren oder deren Alkalisalze mit reaktionsfähigen Estern von Aminoalkoholen, zweckmässig in Gegenwart inerter   Lösungs-    mittel, z. B. Isopropanol, vorzugsweise bei erhöhter Temperatur, umgesetzt werden. In manchen Fällen kann es dabei auch vorteilhaft sein, in Gegenwart eines halogenwasserstoffbindenden Mittels, wie   Al-    kalialkoholat, zu arbeiten.



   Ferner   können ss-substituierte    nichtbasische Hy  dracrylsäureester    mit Aminoalkoholen   umgeestert wer-    den. Die Umsetzung wird dabei zweckmässig so ausgeführt, dass man den   ss-substituierten    nichtbasischen   Hydracrylsäureester    mit Aminoalkohol in Gegenwart eines basischen Katalysators, vorzugsweise eines Alkalimetalls, in An-oder Abwesenheit von   Lösungs-    mitteln, z. B. Toluol oder Xylol, bei Temperaturen bis zu   150 ,    gegebenenfalls auch unter vermindertem Druck, umestert. Anschliessend kann die Hydroxylgruppe mit Carbonsäureanhydriden oder Carbonsäurechloriden bei normaler oder erhöhter Temperatur verestert werden.

   Die so erhaltenen Verbindungen können in ihre optisch aktiven Komponenten zerlegt werden.



   Soweit nach den beschriebenen Verfahren ungesättigte Verbindungen entstehen, können sie durch 
Hydrierung in die entsprechenden gesättigten Verbin dungen übergeführt werden.



   Es sind zwar schon basische   ss-Diphenylhydracryl-    säureester beschrieben [Ann. Rept. Tohuku Coll.



   Pharm. Nr. 2, (1955)   42-49      ;      Journ.    Am. Chem. Soc.



   65 (1943) 1967], die eine mässige   analgetische,    lokal    anästhetische    und mydriatische Wirkung besitzen.



  Durch die Einführung des Bicyclo- (2, 2,   1)-heptenyl-,      Nortricyclyl-,    Isopropyl-oder tert.-Butylrestes an Stelle einer   PhenyIgruppe,    werden nun Verbindungen erhalten, die gegenüber den genannten   fl-Diphenyl-      hydracrylsäureestern    eine andersartige pharmakologische Wirkung entfalten.



   Sie zeigen nämlich im Tierversuch eine starke Antiparkinsonwirkung, die z. B. den bekannten basischen   Diphenylhydracrylsäureestern    völlig fehlt. Ge    genüber    bekannten, zur Behandlung des Morbus Par kinson verwendeten Mitteln, wie etwa dem   
1-Phenylcyclopentan-l-carbonsäurediäthyl- aminoäthylester    zeichnen sich die erfindungsgemäss hergestellten Stoffe durch zum Teil erheblich höhere Wirksamkeit bei durchweg geringer Giftigkeit aus. Diese   Überlegen-    heit der neuen Verbindungen kommt besonders bei einem Vergleich der therapeutischen Indices zum Ausdruck.



   Die nachstehende Tabelle enthält eine Zusammenfassung der   tierexperimentellen    Versuchsergebnisse.



  Zur Testung auf   Antiparkinsonwirkung    wurde eine Modifikation der Versuchsanordnung von Everett (Science   177,      [1956],    S. 1238) benutzt.



      ED50 LDso       mg/kg mg/kg    Therap. Ind.



   Maus   i.    v. Maus i. v. a) bekannte Stoffe
EMI2.1     
 b) erfindungsgemäss hergestellte neue Stoffe
EMI2.2     
 
ED50 LD50 mg/kgmg/kg Therap. Ind.



  Maus i. v. Maus i. v.
EMI3.1     




   Die in den Beispielen als Ausgangsmaterialien verwendeten disubstituierten Hydracrylsäureester kann man durch Umsetzung eines entsprechenden Ketons mit Bromessigester nach Reformatzki erhalten.



  Durch Verseifung kann man daraus die freien Car  bonsäuren    erhalten. Nach diesem Verfahren wurden folgende Verbindungen hergestellt :    ss-Phenyl-ss-{2-bicyclo-[2,    2,   l]-hepten- (5)-yI}-       hydracrylsäure,   
F.   124-126     ; ¯thylester Kp.   0. 2 140     ;

    ¯-Phenyl-¯-(2-nortricyclyl)-hydracrylsÏure    äthylester,      Kpv o 140     ;    ss-Phenyl-ss-isopropyl-hydracrylsäure,   
F.   118-119o    ; ¯thylester Kp.0,7 108-110¯ ;    fl-Phenyl-ss-tert.-butyl-hydracrylsäure,   
F.   114-115     ; Äthylester Kp. 0,2 100¯ ;    ss-(p-Methoxyphenyl)-ss-isopropyl-       hydracrylsäure,    F.   115     ;  ¯-(p-¯thoxyphenyl)-¯-isopropyl-hydracrylsÏure,
F.   115-116     ;

    ¯-(3,4-Dimethoxyphenyl)-¯-isopropyl    hydracrylsäure,    F.   113-114     ;    ss- (3, 4-Methylendioxyphenyl)-ss-isopropyl-       hydracrylsäure,    F.   133-134 .   



   Beispiel 1
40 g   ss-Phenyl-ss-2-bicyclo- [2,    2,   1]-heptan- (5)-yl}-      hydracrylsäureäthylester    werden mit 38 g 2-N, N-Di äthylaminoäthanol und 0, 5 g Natrium so lange im Ölbad auf   110-120     erhitzt, bis das bei der Umsetzung freiwerdende Äthanol über eine 20 cm lange Vigreuxkolonne abdestilliert ist. Man destilliert das überschüssige Diäthylaminoäthanol im Vakuum ab, nimmt den Rückstand in verdünnter Salzsäure auf, wäscht mit Äther und macht mit   Pottaschelösung    alkalisch. Das ausgeschiedene Íl wird in Äther aufgenommen und nach dem Trocknen über Pottasche der Destillation im Vakuum unterworfen.

   Man erhält
33   g      ss-Phenyl-ss-{2-bicyclo-[2,    2,   1]-hepten-       (5)-yl}-hydracrylsäure-2-N, N-diäthylamino-  äthylester    vom   Kp. 015 180-184 .    Das Citrat wird aus dem Ester durch Zugabe eines Mols Citronensäure in Isopro  panollösung    hergestellt, F.   86-87@.   



   In analoger Arbeitsweise wird aus   ss-Phenyl-ss-      (2-nortricyclyl)-hydracrylsäureäthylester    und 2-N, N Diäthylaminoäthanol der   ss-Phenyl-ss-(2-nortricyclyl-      hydracrylsäure-2-N,      N-diäthylamino-äthylester,    Kp. 1   190 ,    erhalten. Citrat F. 92-93¯.



   Beispiel 2
22, 2 g   ss-Phenyl-ss-tert.-butyl-hydracrylsäure    werden zu einer Lösung von 2, 3 g Natrium in 100 cm3 Isopropanol gefügt, 18 g 2-N, N-DiÏthylaminoÏthylchlorid eingetragen und 6 Stunden unter Rückfluss erhitzt. Man destilliert anschliessend das   Lösungsmit-    tel im Vakuum ab, nimmt in verdünnter Salzsäure auf, äthert nicht umgesetztes Ausgangsmaterial aus und macht die salzsaure Phase alkalisch. Das abgeschiedene   bd    wird nach der Extraktion mit Äther der Destillation unterworfen. Man erhält 22 g    ss-Phenyl-ss-tert.-butyl-hydracrylsäure-2-N,    N   diäthylaminoäthylester    vom   Kp.", 146-1480.    Citrat F.   101-102 .   



   Beispiel 3
15 g ¯-Phenyl-¯-isopropyl-hydracrylsÏure werden mit 13 g 3-N-Pyrrolidinopropylchlorid in 100   cm3    Isopropanol über Nacht unter Rückfluss erhitzt. Nach dem Abfiltrieren der heissen Lösung dampft man das Lösungsmittel im Vakuum ein, nimmt den Rückstand in Äther auf und setzt die Base durch Zusatz von Pottasche in Freiheit. Aus der ätherischen Lösung erhält man nach dem Trocknen über Kaliumkarbonat und Abdestillieren des Lösungsmittels den    p-Phenylff-isopropyl-hydracrylsäure-3-N-    pyrrolidinopropylester vom Kp.   0,      s 158-16po    in einer Menge von 20 g als fast farbloses Öl.

   Zur Überführung in das Citrat wird eine alkoholische Lösung des Esters mit der berechneten Menge (1 Mol) Citronensäure versetzt, worauf sich beim Abkühlen das Citrat in farblosen Kristallen abscheidet. F.   107-108 .   



   In der gleichen Arbeitsweise können aus entsprechenden   ss-disubstituierten      Hydracrylsäuren    und entsprechenden   Aminoalkylhalogeniden    folgende Verbindungen erhalten werden :    ss-Phenyl-ss-isopropyl-hydracrylsäure-3-N,    N   dimethylaminopropylester,       Kp. 0, 3 140     ; Citrat F. 63-65" ;  ¯-Phenyl-¯-isopropyl-hydracrylsÏure-2-N, N dimethylaminopropylester,
Kp.0,6 134¯; Hydrochlorid F. 104-105¯;  ¯-Phenyl-¯-isopropyl-hydracrylsÏure-2-N, N   dimethylaminoäthylester,   
Kp.0,3 128¯ ; Citrat F.   74-75     ;    ss-Phenyl-ss-isopropyl-hydracrylsäure-2-N-    pyrrolidinoisopropylester,
Kp.   zig    6 162¯ ; Citrat F.   78-80     ;

    ¯-Phenyl-¯-isopropyl-hydracrylsÏure-2-N   pyrrolidinoäthylester,       Kp. 0, 3 158  ;    Citrat F.   75-76     ;  ¯-Phenyl-¯-isopropyl-hydracrylsÏure-3-N, N   diäthylaminopropylester,       Kp. 164     ; Citrat F.   77-78     ;    ss-Phenyl-ss-isopropyl-hydracrylsäure-2-N,    N   diäthylaminoäthylester,   
Kp. 0,1 144¯; Citrat F.   77     ;    ss-Phenyl-ss-isopropyl-hydracrylsäure-2-  (2-piperidino-N-methyl)-äthylester,   
Kp. 0,3 180¯ ;     ss-(p-Methoxyphenyl)-ss-isopropyl-hydracryl- säure-2-N-pyrrolidinoäthylester,   
Kp. 0,5 185¯; Citrat F.   69-70     ;

    ¯-(p-Methoxyphenyl)-¯-isopropyl-hydracryl   säure-2-N, N-diäthylaminoäthylester,       Kp.      0, 3 1750    ; Citrat F.   85-87     ;    ss- (3, 4-Dimethoxyphenyl)-ss-isopropyl)-       hydracrylsäure-2-N,    N-diäthylamino   äthylester,       Kp. 03 190     ; Citrat F.   98-99     ;    ss- (3, 4-Methylendioxyphenyl)-ss-isopropyl- hydracrylsäure-2-N, N-diäthylamino-  äthylester,   
Kp. 0.5 186-188¯ ; Citrat F.   54-55     ;  ¯-(p-¯thoxyphenyl)-¯-isopropyl-hydracryl   säure-2-N, N-diäthylamino-äthylester,   
Kp.   o 3 1800,    F.   89 .   



   Beispiel 4
22, 2   g      ss-Phenyl-ss-isopropyl-hydracrylSäure    werden in 100 cm3 Isopropanol mit 14, 7 g   2-N-Piperi-    dinoäthylchlorid über Nacht unter Rückfluss erhitzt.



  Die Lösung wird heiss abfiltriert, auf 45 cm3 eingeengt und mit Äther verrieben. Man erhält 30 g  ¯-Phenyl-¯-isopropyl-hydracrylsÏure-2-N   piperidinoäthylester-hydrochlorid,    F.   122-123 .   



   Nach der gleichen Arbeitsweise erhält man aus ¯-Phenyl-¯-isopropyl-hydracrylsÏure und 2-N-Morpholinoäthylchlorid das  ¯-Phenyl-¯-isopropyl-hydracrylsÏure-2-N   morpholinoäthylester-hydrochlorid.   



  F.   125-126 .  



  



  Process for the production of basic substituted esters of hydracrylic acid
It is known that basic esters of carboxylic acids are obtained if the free acids or their functional acid derivatives are reacted with amino alcohols or their derivatives which react with the acids or acid derivatives to form esters.



   It has now been found that therapeutically valuable compounds, especially highly effective in Parkinson's disease, are obtained if ß-substituted hydracrylic acids of the formula I or their functional acid derivatives are used as the carboxylic acids.
EMI1.1




   Here, R1 denotes hydrogen or an acyl radical and R denotes an optionally saturated or unsaturated bicyclo- (2, 2, 1) -heptyl radical, the nortricyclyl, the isopropyl, the isopropenyl or the tert-butyl radical; the phenyl nucleus can optionally be substituted by one or more alkoxy, methylenedioxy or alkyl mercapto groups.

   Reaction with amino alcohols or their functional derivatives results in the compounds of the formula not yet described
EMI1.2
 wherein X is an alkylene radical with a straight or branched chain or a cycloalkylene radical and R2 and Rs are hydrogen or an alkyl radical, where R2 and R3 together with the nitrogen atom or with a carbon atom of group X can form a mono- or bicyclic heterocycle, which also further May contain heteroatoms or groups containing heteroatoms.



   The basic substituted esters of β-substituted hydracrylic acids mentioned are prepared by working processes known per se.



   For example, the free carboxylic acids or their alkali metal salts can be mixed with reactive esters of amino alcohols, advantageously in the presence of inert solvents, e.g. B. isopropanol, preferably at elevated temperature, are implemented. In some cases it can also be advantageous to work in the presence of an agent that binds hydrogen halide, such as alkali alcoholate.



   In addition, β-substituted non-basic hydracrylic acid esters can be transesterified with amino alcohols. The reaction is expediently carried out in such a way that the β-substituted non-basic hydracrylic acid ester is mixed with amino alcohol in the presence of a basic catalyst, preferably an alkali metal, in the presence or absence of solvents, e.g. B. toluene or xylene, transesterified at temperatures up to 150, optionally also under reduced pressure. The hydroxyl group can then be esterified with carboxylic acid anhydrides or carboxylic acid chlorides at normal or elevated temperature.

   The compounds obtained in this way can be broken down into their optically active components.



   As far as unsaturated compounds are formed by the processes described, they can through
Hydrogenation can be converted into the corresponding saturated compounds.



   Basic β-diphenylhydracrylic acid esters have already been described [Ann. Rept. Tohuku Coll.



   Pharm. No. 2, (1955) 42-49; Journ. At the. Chem. Soc.



   65 (1943) 1967], which have a moderate analgesic, local anesthetic and mydriatic effect.



  By introducing the bicyclo- (2, 2, 1) -heptenyl, nortricyclyl, isopropyl or tert-butyl radical in place of a phenyl group, compounds are now obtained which have a different pharmacological effect compared to the mentioned fl-diphenylhydracrylic acid esters unfold.



   Namely, they show in animal experiments a strong anti-Parkinsonian effect, which z. B. the known basic Diphenylhydracryläureestern completely absent. Ge compared to known agents used to treat Par kinson’s disease, such as the
1-Phenylcyclopentane-1-carboxylic acid diethylaminoethyl ester is distinguished by the substances prepared according to the invention, in some cases considerably greater effectiveness with consistently low toxicity. This superiority of the new compounds is particularly evident when comparing the therapeutic indices.



   The table below contains a summary of the animal experiment results.



  A modification of the test arrangement by Everett (Science 177, [1956], p. 1238) was used to test for the antiparkinsonian effect.



      ED50 LDso mg / kg mg / kg Therap. Ind.



   Mouse i. v. Mouse i. v. a) known substances
EMI2.1
 b) new substances produced according to the invention
EMI2.2
 
ED50 LD50 mg / kgmg / kg Therap. Ind.



  Mouse i. v. Mouse i. v.
EMI3.1




   The disubstituted hydracrylic acid esters used as starting materials in the examples can be obtained by reacting a corresponding ketone with bromoacetic ester according to Reformatzki.



  The free carboxylic acids can be obtained from them by saponification. The following compounds were prepared according to this process: ss-phenyl-ss- {2-bicyclo- [2, 2, l] -hepten- (5) -yI} - hydracrylic acid,
F. 124-126; Ethyl ester bp 0.2140;

    ¯-Phenyl-¯- (2-nortricyclyl) -hydracrylsÏure äthylester, bp o 140; ss-phenyl-ss-isopropyl-hydracrylic acid,
F. 118-119o; Ethyl ester b.p. 0.7 108-110¯; fl-phenyl-ss-tert-butyl-hydracrylic acid,
F. 114-115; Ethyl ester b.p. 0.2 100¯; ss- (p-methoxyphenyl) -ss-isopropyl-hydracrylic acid, mp 115; ¯- (p-¯thoxyphenyl) -¯-isopropyl-hydracrylic acid,
F. 115-116;

    ¯- (3,4-Dimethoxyphenyl) -¯-isopropyl hydracrylic acid, m.p. 113-114; ss- (3, 4-methylenedioxyphenyl) -ss-isopropyl-hydracrylic acid, m.p. 133-134.



   example 1
40 g of ss-phenyl-ss-2-bicyclo- [2, 2, 1] -heptan-(5) -yl} - hydracrylic acid ethyl ester are mixed with 38 g of 2-N, N-diethylaminoethanol and 0.5 g of sodium for so long heated in an oil bath to 110-120 until the ethanol released during the reaction has been distilled off via a 20 cm long Vigreux column. The excess diethylaminoethanol is distilled off in vacuo, the residue is taken up in dilute hydrochloric acid, washed with ether and made alkaline with potash solution. The precipitated oil is taken up in ether and, after drying over potash, is subjected to vacuum distillation.

   You get
33 g of ss-phenyl-ss- {2-bicyclo- [2, 2, 1] -hepten- (5) -yl} -hydracrylic acid-2-N, N-diethylamino-ethyl ester of bp 015 180-184. The citrate is prepared from the ester by adding one mole of citric acid in isopropanol solution, F. 86-87®.



   In an analogous procedure, ß-phenyl-ss- (2-nortricyclyl-hydracrylic acid-2-N, N-diethylamino-ethyl ester, Kp 1 190. Citrate F. 92-93¯.



   Example 2
22.2 g of ß-phenyl-ß-tert-butyl-hydracrylic acid are added to a solution of 2.3 g of sodium in 100 cm3 of isopropanol, 18 g of 2-N, N-diethylaminoethyl chloride are added and the mixture is refluxed for 6 hours. The solvent is then distilled off in vacuo, taken up in dilute hydrochloric acid, unreacted starting material is etherified and the hydrochloric acid phase is made alkaline. The deposited iodine is subjected to distillation after extraction with ether. 22 g of β-phenyl-β-tert-butyl-hydracrylic acid-2-N, N diethylaminoethyl ester of bp 146-1480 are obtained. Citrate F. 101-102.



   Example 3
15 g of ¯-phenyl-¯-isopropyl-hydracrylsÏure are refluxed with 13 g of 3-N-pyrrolidinopropyl chloride in 100 cm3 of isopropanol overnight. After the hot solution has been filtered off, the solvent is evaporated in vacuo, the residue is taken up in ether and the base is released by adding potash. From the ethereal solution, after drying over potassium carbonate and distilling off the solvent, the p-phenylff-isopropyl-hydracrylic acid-3-N-pyrrolidinopropyl ester of boiling point 0, s 158-16po is obtained in an amount of 20 g as an almost colorless oil.

   To convert it into the citrate, the calculated amount (1 mol) of citric acid is added to an alcoholic solution of the ester, whereupon the citrate separates in colorless crystals on cooling. F. 107-108.



   In the same procedure, the following compounds can be obtained from corresponding ß-disubstituted hydracrylic acids and corresponding aminoalkyl halides: ß-phenyl-ß-isopropyl-hydracrylic acid-3-N, N dimethylaminopropyl ester, b.p. 0.3 140; Citrate F. 63-65 "; ¯-phenyl-¯-isopropyl-hydracrylic acid-2-N, N dimethylaminopropyl ester,
B.p. 0.6 134¯; Hydrochloride F. 104-105¯; ¯-Phenyl-¯-isopropyl-hydracrylsÏure-2-N, N dimethylaminoethyl ester,
B.p. 0.3 128¯; Citrate F. 74-75; ss-phenyl-ss-isopropyl-hydracrylic acid-2-N-pyrrolidinoisopropyl ester,
Kp. Tens of 6 162¯; Citrate F. 78-80;

    ¯-Phenyl-¯-isopropyl-hydracrylsÏure-2-N pyrrolidinoethylester, boiling point 0.3158; Citrate F. 75-76; ¯-Phenyl-¯-isopropyl-hydracrylsÏure-3-N, N diethylaminopropyl ester, bp 164; Citrate F. 77-78; ss-phenyl-ss-isopropyl-hydracrylic acid-2-N, N diethylaminoethyl ester,
Bp 0.1 144¯; Citrate F. 77; ss-phenyl-ss-isopropyl-hydracrylic acid-2- (2-piperidino-N-methyl) -ethyl ester,
B.p. 0.3 180¯; ss- (p-methoxyphenyl) -ss-isopropyl-hydracrylic acid-2-N-pyrrolidinoethyl ester,
Bp 0.5 185¯; Citrate F. 69-70;

    ¯- (p-Methoxyphenyl) -¯-isopropyl-hydracrylic acid-2-N, N-diethylaminoethyl ester, boiling point 0.31750; Citrate F. 85-87; ss- (3, 4-dimethoxyphenyl) -ss-isopropyl) - hydracrylic acid-2-N, N-diethylamino ethyl ester, bp 03 190; Citrate F. 98-99; ss- (3, 4-methylenedioxyphenyl) -ss-isopropyl-hydracrylic acid-2-N, N-diethylamino-ethyl ester,
B.p. 0.5 186-188¯; Citrate F. 54-55; ¯- (p-¯thoxyphenyl) -¯-isopropyl-hydracrylic acid-2-N, N-diethylamino-ethyl ester,
Kp. O 3 1800, F. 89.



   Example 4
22.2 g of ss-phenyl-ss-isopropyl-hydracrylic acid are refluxed overnight with 14.7 g of 2-N-piperidinoethyl chloride in 100 cm3 of isopropanol.



  The solution is filtered off while hot, concentrated to 45 cm3 and triturated with ether. 30 g of ¯-phenyl-¯-isopropyl-hydracrylsÏure-2-N-piperidinoethylester-hydrochloride, mp 122-123 are obtained.



   Using the same procedure, ¯-phenyl-¯-isopropyl-hydracrylic acid and 2-N-morpholinoethyl chloride give ¯-phenyl-¯-isopropyl-hydracrylic acid-2-N-morpholinoethyl ester hydrochloride.



  F. 125-126.

Claims (1)

PATENTANSPRUCH Verfahren zur Herstellung basisch substituierter Ester der Hydracrylsäure, dadurch gekennzeichnet, dass man Verbindungen der Formel EMI4.1 in der R, Wasserstoff oder einen Acylrest bedeutet, in der R einen gesättigten oder ungesättigten Bicyclo [2, 2, 1]-heptyl-, einen Nortricyclyl-, einen Isopropyl-, einen Isopropenyl-oder einen tert.-Butylrest bedeutet und wobei der Phenylkern durch eine oder mehrere Alkoxy-, Alkylmercapto-oder Methylendioxygruppen substituiert sein kann, oder ihre funktionellen Car bonsäurederivate mit Aminoalkoholen folgender Formel EMI4.2 oder deren funktionellen Derivate umsetzt, PATENT CLAIM Process for the preparation of basic substituted esters of hydracrylic acid, characterized in that compounds of the formula EMI4.1 in which R, is hydrogen or an acyl radical, in which R is a saturated or unsaturated bicyclo [2, 2, 1] -heptyl, a nortricyclyl, an isopropyl, an isopropenyl or a tert-butyl radical and where the Phenyl nucleus can be substituted by one or more alkoxy, alkyl mercapto or methylenedioxy groups, or their functional carboxylic acid derivatives with amino alcohols of the formula EMI4.2 or implements their functional derivatives, worin X einen Alkylenrest mit gerader oder verzweigter Kette oder einen Cycloalkylenrest und R2 und R3 Wasserstoff oder einen Alkylenrest bedeuten, wobei R2 und R3 gemeinsam mit dem Stickstoffatom oder mit einem Kohlenstoffatom der Gruppe X einen mono-oder bicyclischen Heterocyclus bilden können, der ausser- dem noch weitere Heteroatome oder heteroatomhaltige Gruppen enthalten kann. wherein X is an alkylene radical with a straight or branched chain or a cycloalkylene radical and R2 and R3 are hydrogen or an alkylene radical, where R2 and R3 together with the nitrogen atom or with a carbon atom of the group X can form a mono- or bicyclic heterocycle, which also may contain further heteroatoms or groups containing heteroatoms.
CH156660A 1959-02-27 1960-02-12 Process for the production of basic substituted esters of hydracrylic acid CH385808A (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2017501A1 (en) * 1968-09-06 1970-05-22 Asta Werke Ag Chemische

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2017501A1 (en) * 1968-09-06 1970-05-22 Asta Werke Ag Chemische

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