CH510662A - Cinnamic acid amides antiinflammatory antipyretic - Google Patents

Cinnamic acid amides antiinflammatory antipyretic

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Publication number
CH510662A
CH510662A CH1780868A CH1780868A CH510662A CH 510662 A CH510662 A CH 510662A CH 1780868 A CH1780868 A CH 1780868A CH 1780868 A CH1780868 A CH 1780868A CH 510662 A CH510662 A CH 510662A
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Switzerland
Prior art keywords
cinnamic acid
formula
piperidide
bromo
produced
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Application number
CH1780868A
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German (de)
Inventor
Manfred Dr Kleemann
Wolfgang Dr Grell
Gerhard Dr Dahms
Hans Dr Machleidt
Albrecht Dr Eckenfels
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Thomae Gmbh Dr K
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Publication date
Priority claimed from AT1091167A external-priority patent/AT280283B/en
Priority claimed from AT1075768A external-priority patent/AT285606B/en
Priority claimed from AT1075568A external-priority patent/AT281821B/en
Priority to CH342571A priority Critical patent/CH513857A/en
Priority to CH343071A priority patent/CH510019A/en
Priority to CH343571A priority patent/CH510022A/en
Application filed by Thomae Gmbh Dr K filed Critical Thomae Gmbh Dr K
Priority to CH343471A priority patent/CH516554A/en
Priority to CH342771A priority patent/CH510018A/en
Priority to CH343171A priority patent/CH510020A/en
Priority to CH343271A priority patent/CH510021A/en
Priority to CH342971A priority patent/CH519499A/en
Priority to CH342471A priority patent/CH515235A/en
Priority to CH342871A priority patent/CH513163A/en
Publication of CH510662A publication Critical patent/CH510662A/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
    • C07D295/16—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 acylated on ring nitrogen atoms
    • C07D295/18—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 acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/52—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing halogen
    • C07C57/58—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing halogen containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/64—Acyl halides
    • C07C57/72—Acyl halides containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/42—Unsaturated compounds containing hydroxy or O-metal groups
    • C07C59/56—Unsaturated compounds containing hydroxy or O-metal groups containing halogen
    • 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
    • C07D211/36—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/22—Amides of acids of phosphorus
    • C07F9/224—Phosphorus triamides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/40—Esters thereof
    • C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/4056—Esters of arylalkanephosphonic acids
    • C—CHEMISTRY; METALLURGY
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    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/535—Organo-phosphoranes
    • C07F9/5352—Phosphoranes containing the structure P=C-
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/54—Quaternary phosphonium compounds
    • C07F9/5407—Acyclic saturated phosphonium compounds
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/54—Quaternary phosphonium compounds
    • C07F9/5456—Arylalkanephosphonium compounds
    • C—CHEMISTRY; METALLURGY
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/576—Six-membered rings
    • C07F9/58—Pyridine rings

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Hydrogenated Pyridines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Method for the preparation of cinnamic acid amides - (I) where R1 = bromine or iodine and - R2 = piperidino, 4-hydroxypiperidino or morpholino - The compounds show antiinflammatory and antipyretic activity. - A suspension of 30.0 g. 4-bromocinnamic acid chloride in absolute ether is added slowly to a solution of 31.5 g. piperidine in absolute ether at 20 deg.C. and the solution is stirred for 3 hrs. Water is added and the main product is filtered off, a further quantity is isolated from the ether phase. Recrystallisation from petrol gives 23.9 g. 4-bromocinnamic acid piperidide, mp. 134 deg.C.

Description

  

  Verfahren zur Herstellung neuer Zimtsäureamide         Die    vorliegende Erfindung betrifft ein     Verfahren    zur  Herstellung neuer Zimtsäureamide der Formel I  
EMI0001.0002     
    worin R1 ein Brom- oder Jodatom und R2 einen     Piperi-          dino-    oder Morpholinorest bedeuten, das dadurch ge  kennzeichnet ist, dass man ein Zimtsäurederivat der  Formel II  
EMI0001.0005     
  
EMI0001.0006     
  
     eines Alkalihydroxids oder eines Alkalicarbonats, zweck-    mässigerweise bei Temperaturen zwischen 0 und 160  C  durchgeführt. Ein teritäres Amin und/oder ein Amin der  Formel     HI    können auch gleichzeitig als     Lösungsmittel     dienen.

   Die     Umsetzung    kann auch ohne Lösungsmittel       durchgeführt    werden.  



  Bedeutet X eine Hydroxylgruppe oder eine freie  durch niedere Alkylgruppen mono- oder disubstituierte  Aminogruppe, so wird die Reaktion zweckmässigerweise  bei 200 bis 250  C durchgeführt, gegebenenfalls in einem  Druckgefäss.  



  Die     Umsetzung    kann auch in der Weise durchgeführt  werden, dass ein gegebenenfalls in situ erzeugtes reak  tionsfähiges Derivat einer Verbindung der Formel II,  z. B. mittels Carbonyldiimidazol,     Thiocarbonyl-diimid-          azol    oder eines Carbodiimids, mit einem Amin der For  mel III oder eine Verbindung der Formel II mit einem  gegebenenfalls in situ hergestellten reaktionsfähigen De  rivat eines Amins der Formel HI, z. B. mittels     Phosphor-          trichlorid    [Lit.: Liebigs Ann. Chem. 580, 68 (l953)], zur  Reaktion gebracht wird.  



  Die bei diesem Verfahren verwendeten Ausgangsstoffe  sind teilweise neu und lassen sich nach bekannten Metho  den darstellen. So lässt sich beispielsweise eine Verbin  dung der Formel Il über ihr Säurehalogenid oder durch  Olefinierung herstellen.  



  Die     erfindungsgemäss    hergestellten neuen     Zimtsäure-          amide    der Formel I besitzen     wertvolle    pharmakologische  Eigenschaften, insbesondere eine antiphlogistische und  antipyretische Wirkung.  



  Im Kaolin- und Carrageenin-Oedem-Test an der Ratte  sind die Verbindungen der Formel I dem     Phenylbutazon     bezüglich der therapeutischen Breite     überlegen.     



  Die nachstehenden Beispiele dienen zur näheren Er  läuterung der Erfindung:      Beispiel 1  4-Brom-zimtsäurepiperidid  Zu einer Lösung von 31,5 g (0,37 Mol) Piperidin in  abs. Äther wird bei 20  C langsam die Suspension von  30,0 g (0,12 Mol) 4-Brom-zimtsäurechlorid in abs. Äther  gegeben. Man rührt zur Vervollständigung der Reaktion  noch 3 Stunden bei 20  C, gibt Wasser zum Reaktions  gemisch und     filtriert    die Hauptmenge des Produkts ab.  Ein weiterer Anteil wird aus der Ätherphase isoliert. Man ,  kristallisiert aus Petroläther um und erhält 23,9 g (68%  der Theorie) farblose Kristalle vom Smp. 134  C.  



  <I>Beispiel 2</I>  3-Brom-zimtsäurepiperidid  Aus 3-Brom-zimtsäurechlorid und Piperidin analog  Beispiel 1. Ausbeute: 84% d.Th., Smp.: 98-99  C (aus  Petroläther).  



  <I>Beispiel 3</I>  3-Jod-zimtsäuremorpholid  Aus 3-Jod-zimtsäurechlorid und Morpholin analog  Beispiel 1. Ausbeute: 33% d.Th., Smp.: 100-101  C (aus  Essigester). ,  <I>Beispiel 4</I>  4-Jod-zimtsäurepiperidid  Aus 4-Jod-zimtsäurechlorid und Piperidin analog Bei  spiel 1. Ausbeute: 83% d.Th., Smp.: 134-135  C (aus  Methanol).  



  <I>Beispiel</I>     S     4-Brom-zimtsäurepiperidid  Eine Suspension von 6,5 g (0,015 Mol)     4-Brom-zimt-          säureanhydrid    in 200 ml Benzol versetzt man bei 2007C  mit 2,5 g (0,03 Mol) Piperidin. Anschliessend wird 2 Stun  den unter Rückfluss     erhitzt,    wobei eine klare Lösung  entsteht. Man entfernt das     Lösungsmittel    im Vakuum,  nimmt den Rückstand in Essigester auf und     gibt    ver  dünnte Natronlauge hinzu. Nach dem Abfiltrieren des  entstandenen Niederschlages     engt    man das Filtrat im  Vakuum ein und     kristallisiert    den Rückstand aus Essig  ester um. Ausbeute: 3,0 g (68% d.Th.), Smp. 134  C.  



  <I>Beispiel 6</I>  4-Brom-zimtsäurepiperidid  Zu einer Lösung von 0,75b (0,032 Mol) Natrium in  Äthanol werden 7,5 g (0,029 Mol)     4-Brom-zimtsäure-          äthylester    und 2,7 g (0,032 Mol) Piperidin gegeben. Man  lässt 2 Tage stehen, erhitzt dann 4 Stunden unter     Rück-          fluss,    nach dem Abkühlen wird abfiltriert und das Fil  trat im Vakuum eingeengt. Den Rückstand versetzt man  mit Wasser und Chloroform, trennt die organische Phase  ab und trocknet sie über Natriumsulfat. Man     entfernt     das Lösungsmittel im Vakuum und erhält beim Umkri  stallisieren aus Essigester 1,0 g (12% d.Th.) farblose Kri  stalle vom Smp. 134  C.  



  <I>Beispiel 7</I>  4-Brom-zimtsäurepiperidid  8,9 g,0,035 Mol) 4-Brom-zimtsäuredimethylamid und  16,0 g (0,19 Mol) Piperidin werden in 200 ml Benzol    16 Stunden im Autoklaven auf 200  C erhitzt: Durch  Säulenchromatographie des Rohproduktes an Kieselgel  (Benzol/Aceton = 3/1) lassen sich 0,3 g (3% d.Th.)  4-Brom-zimtsäurepiperidid vom Sing. 134  C isolieren.  <I>Beispiel 8</I>  4-Brom-zimtsäurepiperidid  Eine Mischung aus 11,3 g (0,05 Mol)     4-Brom-zimt-          säure    und 4,3 g (0;05 Mol) Piperidin wird 5 Stunden  auf 200  C erhitzt. Nach dem Abkühlen versetzt     man    mit  2n Natronlauge, filtriert den Niederschlag ab und löst  ihn in Chloroform.

   Durch Waschen der Chloroform-Lö  sung mit 2n Natronlauge wird die nicht umgesetzte     4-          -Brom-zimtsä.ure    entfernt. Aus der organischen     Phase     erhält man 6,2 g (42% d.Th.) weisse Kristalle vom  Smp. 134  C (aus Isopropanol).  



  <I>Beispiel 9</I>  4-Brom-zimtsäurepiperidid  Unter Eiskühlung tropft man 2,75 g (0,02 Mol)     Phos-          phortrichlorid    zur Lösung von 5,1 g (0,06 Mol) Piperidin  in 50 ml trockenem Pyridin. Man rührt noch 30 Minuten  bei Raumtemperatur, gibt in Portionen 11,4 g (0,05 Mol)  4-Brom-zimtsäure zu und erwärmt das Gemisch 2V2  Stunden auf 50  C. Man dampft im Vakuum ein, löst  den Rückstand in Chloroform und wäscht die Lösung  mit Wasser, verdünnter Natronlauge und verdünnter     Salz-          säure.    Das aus der     Chloroform-Phase    gewonnene Pro  dukt wird aus Isopropanol umkristallisiert. Ausbeute:  4,6g (31% d.Th.), Smp.: 134  C.  



       Beispiel   <I>10</I>  4-Bronz-zimtsäurepiperidid  Eine Lösung von 7,2 g (0,06 Mol) Thionylchlorid in       Chloroform    tropft man bei Raumtemperatur zu 7,6 g  (0,033 Mol) 4-Brom-zimtsäure und 6,4 g (0,075 Mol)     Pi-          peridin    in Chloroform. Dabei entsteht in exothermer Re  aktion eine klare Lösung. Nach 7stündigem Stehen gibt  man Wasser zu, trennt die     Chloroform    Phase ab, wäscht  n     -it    verdünnter Natronlauge und mit Wasser, trocknet  über Natriumsulfat und dampft im Vakuum ein. Der  Rückstand wird aus Methanol und aus Essigester umkri  stallisiert.

   Ausbeute: 3,1 g     (32%        d.Th.),        Smp.    134  C.  



  <I>Beispiel 11</I>       4-Jod-zimtsäuremorpholid     
EMI0002.0035     
  
       <I>Beispiel 12</I>  3-Brom-zimtsäurepiperidid  Eine Lösung von 4,55 g (0,020 Mol)     3-Brom-zimt-          säure    und 1,9 g (0,022 Mol) Piperidin in absolutem     Di-          methylformamid    wird bei 0  C mit einer Lösung von  4,5 g (0,022 Mol) Dicyclohexylcarbodiimid in     Dimethyl-          formamid    versetzt. Nach Stehen über Nacht wird 8 Stun  den auf 40  C erwärmt. Man giesst das Reaktionsgemisch  in Wasser und     extrahiert    mit Chloroform. Das aus der  Chloroform-Lösung erhaltene Rohprodukt wird durch  Säulenchromatographie an Kieselgel gereinigt.

   Ausbeute:  0,41 g (7% d.Th.), Smp. 98-99  C.  



  <I>Beispiel 13</I>  4-Brom-zimtsäurepiperidid  7,93 g ,0,028 Mol) Trispiperidinophosphin werden in  200 ml abs. Toluol gelöst und mit 19,07 g (0,084 Mol)  4-Brom-zimtsäure versetzt. Man erhitzt 1 Stunde unter  Rückfluss, säugt heiss durch Celite, gibt nach dem Ab  kühlen 300 ml Petroläther zu und filtriert den gebildeten  Niederschlag (18,8 g) ab. Beim Eindampfen der Mutter  lauge werden weitere 3,4 g farblose Kristalle erhalten.  Die vereinigten Kristallfraktionen werden mit 300 ml  Benzol digeriert. Man filtriert 3,15 g ungelöste     4-Brom-          -zimtsäure    ab, dampft das Filtrat im Vakuum ein und  kristallisiert den Rückstand aus Benzol-Petroläther um.  Ausbeute: 17,5 g (71% d.Th.) 4-Brom-zimtsäurepiperidid  vom Smp.: 130-l32  C. Misch-Smp. mit Originalsubstanz  131-132  C.  



  <I>Beispiel 14</I>  4-Brom-zimtsäuremorpholid  Aus 4-Brom-zimtsäurechlorid und Morpholin analog  Beispiel 1. Ausbeute: 73% d.Th., Smp. 142-144  C.  <I>Beispiel 15</I>  3-Brom-zimtsäuremorpholid  Aus 3-Brom-zimtsäurechlorid -und Morpholin analog  Beispiel 1. Ausbeute: 69% d.Th., Smp. 80-81  C.  <I>Beispiel 16</I>  3-Jod-zimtsäurepiperidid  Aus 3-Brom-zimtsäurechlorid und Piperidin analog  Beispiel 1. Ausbeute: 74% d.Th., Smp. l09-110  C.



  Process for the production of new cinnamic acid amides The present invention relates to a process for the production of new cinnamic acid amides of the formula I.
EMI0001.0002
    where R1 is a bromine or iodine atom and R2 is a piperidino or morpholino radical, which is characterized in that a cinnamic acid derivative of the formula II
EMI0001.0005
  
EMI0001.0006
  
     an alkali hydroxide or an alkali carbonate, expediently carried out at temperatures between 0 and 160.degree. A tertiary amine and / or an amine of the formula HI can also serve as a solvent at the same time.

   The reaction can also be carried out without a solvent.



  If X is a hydroxyl group or a free amino group mono- or disubstituted by lower alkyl groups, the reaction is expediently carried out at 200 to 250 ° C., if appropriate in a pressure vessel.



  The reaction can also be carried out in such a way that an optionally generated in situ reactive derivative of a compound of formula II, eg. B. by means of carbonyldiimidazole, thiocarbonyl-diimidazole or a carbodiimide, with an amine of the formula III or a compound of the formula II with an optionally prepared in situ reactive De rivat of an amine of the formula HI, z. B. by means of phosphorus trichloride [Lit .: Liebigs Ann. Chem. 580, 68 (1953)], is reacted.



  The starting materials used in this process are partly new and can be represented by known methods. For example, a compound of the formula II can be produced via its acid halide or by olefination.



  The new cinnamic acid amides of the formula I prepared according to the invention have valuable pharmacological properties, in particular an anti-inflammatory and anti-pyretic effect.



  In the kaolin and carrageenin edema test on rats, the compounds of the formula I are superior to phenylbutazone with regard to the therapeutic range.



  The following examples serve to explain the invention in greater detail: Example 1 4-Bromo-cinnamic acid piperidide To a solution of 31.5 g (0.37 mol) of piperidine in abs. Ether is slowly at 20 C, the suspension of 30.0 g (0.12 mol) of 4-bromo-cinnamic acid chloride in abs. Ether given. To complete the reaction, the mixture is stirred for a further 3 hours at 20 ° C., water is added to the reaction mixture and most of the product is filtered off. Another part is isolated from the ether phase. It is recrystallized from petroleum ether and 23.9 g (68% of theory) of colorless crystals with a melting point of 134 ° C. are obtained.



  <I> Example 2 </I> 3-Bromo-cinnamic acid piperidide From 3-bromo-cinnamic acid chloride and piperidine as in Example 1. Yield: 84% of theory, melting point: 98-99 ° C. (from petroleum ether).



  <I> Example 3 </I> 3-iodo-cinnamic acid morpholide From 3-iodo-cinnamic acid chloride and morpholine as in Example 1. Yield: 33% of theory, melting point: 100-101 ° C. (from ethyl acetate). , <I> Example 4 </I> 4-iodo-cinnamic acid piperidide From 4-iodo-cinnamic acid chloride and piperidine analogously to Example 1. Yield: 83% of theory, melting point: 134-135 ° C. (from methanol).



  <I> Example </I> S 4-bromo-cinnamic acid piperidide A suspension of 6.5 g (0.015 mol) 4-bromo-cinnamic acid anhydride in 200 ml benzene is mixed with 2.5 g (0.03 mol ) Piperidine. The mixture is then refluxed for 2 hours, a clear solution being formed. The solvent is removed in vacuo, the residue is taken up in ethyl acetate and dilute sodium hydroxide solution is added. After the resulting precipitate has been filtered off, the filtrate is concentrated in vacuo and the residue is recrystallized from ethyl acetate. Yield: 3.0 g (68% of theory), melting point 134 C.



  <I> Example 6 </I> 4-Bromo-cinnamic acid piperidide To a solution of 0.75b (0.032 mol) sodium in ethanol are 7.5 g (0.029 mol) ethyl 4-bromo-cinnamate and 2.7 g ( 0.032 mol) of piperidine. The mixture is left to stand for 2 days, then heated under reflux for 4 hours, after cooling it is filtered off and the filtrate is concentrated in vacuo. Water and chloroform are added to the residue, and the organic phase is separated off and dried over sodium sulfate. The solvent is removed in vacuo and, when recrystallized from ethyl acetate, 1.0 g (12% of theory) of colorless crystals with a melting point of 134 ° C. are obtained.



  <I> Example 7 </I> 4-Bromo-cinnamic acid piperidide 8.9 g, 0.035 mol) 4-bromo-cinnamic acid dimethylamide and 16.0 g (0.19 mol) piperidine are heated to 200 in 200 ml benzene for 16 hours in an autoclave C. Heated: By column chromatography of the crude product on silica gel (benzene / acetone = 3/1), 0.3 g (3% of theory) of 4-bromocinnamic acid piperidide from Sing. 134 C can be isolated. <I> Example 8 </I> 4-Bromo-cinnamic acid piperidide A mixture of 11.3 g (0.05 mol) 4-bromo-cinnamic acid and 4.3 g (0.05 mol) piperidine is for 5 hours 200 C heated. After cooling, 2N sodium hydroxide solution is added, the precipitate is filtered off and dissolved in chloroform.

   The unreacted 4-bromocinnamic acid is removed by washing the chloroform solution with 2N sodium hydroxide solution. 6.2 g (42% of theory) of white crystals with a melting point of 134 ° C. (from isopropanol) are obtained from the organic phase.



  Example 9 4-Bromo-cinnamic acid piperidide While cooling with ice, 2.75 g (0.02 mol) phosphorus trichloride are added dropwise to a solution of 5.1 g (0.06 mol) piperidine in 50 ml dry pyridine . The mixture is stirred for a further 30 minutes at room temperature, 11.4 g (0.05 mol) of 4-bromocinnamic acid are added in portions and the mixture is heated to 50 ° C. for 2½ hours. It is evaporated in vacuo, the residue is dissolved in chloroform and washed the solution with water, dilute sodium hydroxide solution and dilute hydrochloric acid. The product obtained from the chloroform phase is recrystallized from isopropanol. Yield: 4.6 g (31% of theory), m.p .: 134 C.



       Example <I> 10 </I> 4-bronzecinnamic acid piperidide A solution of 7.2 g (0.06 mol) of thionyl chloride in chloroform is added dropwise at room temperature to 7.6 g (0.033 mol) of 4-bromocinnamic acid and 6 , 4 g (0.075 mol) of peridine in chloroform. This creates a clear solution in an exothermic reaction. After standing for 7 hours, water is added, the chloroform phase is separated off, washed n -with dilute sodium hydroxide solution and with water, dried over sodium sulfate and evaporated in vacuo. The residue is crystallized from methanol and from ethyl acetate.

   Yield: 3.1 g (32% of theory), melting point 134 C.



  <I> Example 11 </I> 4-iodo-cinnamic acid morpholide
EMI0002.0035
  
       <I> Example 12 </I> 3-Bromo-cinnamic acid piperidide A solution of 4.55 g (0.020 mol) 3-bromo-cinnamic acid and 1.9 g (0.022 mol) piperidine in absolute dimethylformamide is at 0 C. A solution of 4.5 g (0.022 mol) of dicyclohexylcarbodiimide in dimethylformamide is added. After standing overnight, it is heated to 40 ° C. for 8 hours. The reaction mixture is poured into water and extracted with chloroform. The crude product obtained from the chloroform solution is purified by column chromatography on silica gel.

   Yield: 0.41 g (7% of theory), melting point 98-99 C.



  <I> Example 13 </I> 4-Bromo-cinnamic acid piperidide 7.93 g, 0.028 mol) trispiperidinophosphine are dissolved in 200 ml abs. Dissolved toluene and mixed with 19.07 g (0.084 mol) of 4-bromo-cinnamic acid. The mixture is heated under reflux for 1 hour, sucked hot through Celite, 300 ml of petroleum ether are added after cooling and the precipitate formed (18.8 g) is filtered off. When the mother liquor is evaporated, a further 3.4 g of colorless crystals are obtained. The combined crystal fractions are digested with 300 ml of benzene. 3.15 g of undissolved 4-bromo-cinnamic acid are filtered off, the filtrate is evaporated in vacuo and the residue is recrystallized from benzene-petroleum ether. Yield: 17.5 g (71% of theory) of 4-bromo-cinnamic acid piperidide with a melting point of 130-132 C. Mixed melting point. with original substance 131-132 C.



  <I> Example 14 </I> 4-Bromo-cinnamic acid morpholide From 4-bromo-cinnamic acid chloride and morpholine analogously to Example 1. Yield: 73% of theory, melting point 142-144 ° C. <I> Example 15 </ I > 3-Bromo-cinnamic acid morpholide From 3-bromo-cinnamic acid chloride and morpholine as in Example 1. Yield: 69% of theory, melting point 80-81 ° C. <I> Example 16 </I> 3-iodocinnamic acid piperidide from 3-Bromo-cinnamic acid chloride and piperidine analogous to Example 1. Yield: 74% of theory, melting point 109-110 C.

Claims (1)

PATENTANSPRUCH Verfahren zur Herstellung neuer Zimtsäureamide der Formel I EMI0003.0010 worin R, ein Brom- oder Jodatom und R, einen Pipe- ridino- oder Morpholinorest bedeuten, dadurch gekenn zeichnet, dass man ein Zimtsäurederivat der Formel II EMI0003.0013 worin X einen reaktionsfähigen, abspaltbaren Rest be deutet, mit einem Amin der Formel III H-R2 (III) oder einem reaktionsfähigen, funktionellen Derivat davon umsetzt. UNTERANSPRÜCHE 1. Verfahren nach Patentanspruch, dadurch gekenn zeichnet, dass man eine Verbindung der Formel II ver wendet, worin X eine Hydroxylgruppen bedeutet. 2. PATENT CLAIM Process for the production of new cinnamic acid amides of the formula I. EMI0003.0010 where R, a bromine or iodine atom and R, a piperidino or morpholino, characterized in that a cinnamic acid derivative of the formula II EMI0003.0013 wherein X is a reactive, cleavable radical be, with an amine of the formula III H-R2 (III) or a reactive, functional derivative thereof. SUBClaims 1. Process according to patent claim, characterized in that a compound of the formula II is used in which X is a hydroxyl group. 2. Verfahren nach Patentanspruch, dadurch gekenn zeichnet, dass man eine Verbindung der Formel II ver- wedet, worin X eine freie oder durch niedere Alkylreste mono- oder disubstituierte Aminogruppe bedeutet. 3. Verfahren nach Patentanspruch, dadurch gekenn zeichnet, dass man die Umsetzung in einem Lösungs mittel durchführt. 4. Verfahren nach Patentanspruch, dadurch gekenn zeichnet, dass man einen Ausgangsstoff in Form eines unter den Reaktionsbedingungen erhältlichen rohen Re aktionsgemisches einsetzt. 5. Verfahren nach Patentanspruch, dadurch gekenn zeichnet, dass man 4-Bromzimtsäurepiperidid herstellt. Process according to patent claim, characterized in that a compound of the formula II is used in which X is an amino group which is free or mono- or disubstituted by lower alkyl radicals. 3. The method according to claim, characterized in that the reaction is carried out in a solvent medium. 4. The method according to claim, characterized in that a starting material is used in the form of a raw reaction mixture obtainable under the reaction conditions. 5. The method according to claim, characterized in that 4-bromocinnamic acid piperidide is produced. 6. Verfahren nach Patentanspruch, dadurch gekenn zeichnet, dass man 3-Bromzimtsäurepiperidid herstellt. 7. Verfahren nach Patentanspruch, dadurch gekenn zeichnet, dass man 4-Jodzimtsäurepiperidid herstellt. B. Verfahren nach Patentanspruch, dadurch gekenn zeichnet, dass man 4-Jodzimtsäuremorpholin herstellt. 6. The method according to claim, characterized in that 3-bromocinnamic acid piperidide is produced. 7. The method according to claim, characterized in that 4-iodocinnamic acid piperidide is produced. B. The method according to claim, characterized in that 4-iodocinnamic acid morpholine is produced. <I>Anmerkung des</I> Eidg. <I>Amtes für geistiges</I> Eigentum: Sollten Teile der Beschreibung mit der im Patentan spruch gegebenen Definition der Erfindung nicht in Ein- klang stehen, so sei daran erinnert, dass gemäss Art .51 des Patentgesetzes der Patentanspruch für den sachlichen Geltungsbereich des Patentes massgebend ist. <I> Note from the </I> Federal <I> Office for Intellectual Property </I>: If parts of the description do not match the definition of the invention given in the patent claim, it should be remembered that according to Art. 51 of the Patent Act, the patent claim is decisive for the material scope of the patent.
CH1780868A 1967-12-01 1968-11-29 Cinnamic acid amides antiinflammatory antipyretic CH510662A (en)

Priority Applications (10)

Application Number Priority Date Filing Date Title
CH342871A CH513163A (en) 1968-11-05 1968-11-29 Process for the production of new cinnamic acid amides
CH342471A CH515235A (en) 1967-12-01 1968-11-29 Process for the production of new cinnamic acid amides
CH342971A CH519499A (en) 1968-11-05 1968-11-29 Process for the production of new cinnamic acid amides
CH343071A CH510019A (en) 1968-11-05 1968-11-29 Antiphlogistic, antipyretic halo-cinnama-mides
CH343571A CH510022A (en) 1968-11-05 1968-11-29 Process for the production of new cinnamic acid amides
CH342571A CH513857A (en) 1967-12-01 1968-11-29 Cinnamic acid amides antiinflammatory antipyretic
CH343471A CH516554A (en) 1968-11-05 1968-11-29 Process for the production of new cinnamic acid amides
CH342771A CH510018A (en) 1967-12-01 1968-11-29 Antiphlogistic, antipyretic halo-cinnamamides
CH343171A CH510020A (en) 1968-11-05 1968-11-29 Process for the production of new cinnamic acid amides
CH343271A CH510021A (en) 1968-11-05 1968-11-29 Process for the production of new cinnamic acid amides

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
AT1091167A AT280283B (en) 1967-12-01 1967-12-01 Process for the preparation of new cinnamic acid amides
AT1075568A AT281821B (en) 1968-11-05 1968-11-05 Process for the production of new cinnamic acid amides
AT1075768A AT285606B (en) 1968-11-05 1968-11-05 Process for the production of new cinnamic acid amides

Publications (1)

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CH510662A true CH510662A (en) 1971-07-31

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