CH310985A - Process for the preparation of a sulfur-containing pyridone. - Google Patents

Process for the preparation of a sulfur-containing pyridone.

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Publication number
CH310985A
CH310985A CH310985DA CH310985A CH 310985 A CH310985 A CH 310985A CH 310985D A CH310985D A CH 310985DA CH 310985 A CH310985 A CH 310985A
Authority
CH
Switzerland
Prior art keywords
compound
parts
sulfur
ethyl
methyl
Prior art date
Application number
Other languages
German (de)
Inventor
F Hoffmann- Aktiengesellschaft
Original Assignee
Hoffmann La Roche
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Hoffmann La Roche filed Critical Hoffmann La Roche
Publication of CH310985A publication Critical patent/CH310985A/en

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Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D213/00Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/62Oxygen or sulfur atoms
    • C07D213/70Sulfur atoms

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pyridine Compounds (AREA)
  • Hydrogenated Pyridines (AREA)

Description

  

  verfahren zur Herstellung eines     schwefelhaltigen        Pyridons.       Es wurde gefunden, dass die Verbindungen  der     alleemeinen    Formel  
EMI0001.0004     
    worin     R.1    und R2 niedere     Alkyl-    oder     Alkenyl-          reste    mit 1 bis 4     Kohlenstoffatomen    darstellen,  sich durch tiefe, kurz dauernde Schlafwirkung       auszeiehnen.     



  Gemäss der vorliegenden Erfindung wer  den die bisher unbekannten     2-Thio-3,3-dialkyl-          4-oxo-1,2,3,4-tetrahydropyridine    dadurch ge  ,vonnen,     da.ss    man ein     a,a-Dialkyl-acetaceto-          nit.ril    mit. einem     Ameisensäureester    in Gegen  wart eines alkalischen Kondensationsmittels  in die     y-Oxymethylenverbindung    und diese  mit Ammoniak in die     y-Aminomethylenverbin-          dung    umwandelt, diese mit einem alkalischen  Kondensationsmittel     cyclisiert    und mit Schwe  felwasserstoff oder einem Schwefelwasser  stoff abspaltenden Mittel behandelt.  



  Die     a,a   <I>-</I>     Dialkylacetacetonitrile    werden  durch     Alkylierung    der von E. Mohr (Journal  für praktische Chemie (2), Band 75 [1907],  Seite 749, und (2), Band 90 [1914], Seite  <B>189)</B> dargestellten     a-Alkyl-acetacetonitrile    er  halten, Die     Alkylierung    kann mit     Alkenyl-          oder        Alkylhalogeniden    mit den für     a-Alkyl-          acetessigester    üblichen Methoden ausgeführt  werden.

   Die a,a-Dialkyl-y-oxymethylen-acet-         acetonitrile    werden vorteilhaft durch Umset  zen der entsprechenden     Nitrile    mit einem       Ameisensäureester    in einem indifferenten or  ganischen Lösungsmittel, wie z. B. Benzol, To  luol oder     Diäthylkohlensäureester,    in Gegen  wart eines alkalischen Kondensationsmittels,  wie z. B. Natrium, Kalium oder     Natriumalko-          holat,    dargestellt.  



  Die in Wasser schwer löslichen     a,a-Dialkyl-          acetacetonitrile    bilden mit wässerigen Laugen  keine Salze und sind leicht von den in wäs  serigen     Alkalilaugen    gut löslichen     a,a-Dialkyl-          y-oxymethylen-acetacetonitrilen    zu trennen.  Diese     Alkalisalzlösungen        können    mit Ammo  niak und     Ammoniumchlorid        in    die in wässeri  ger Lösung schwer löslichen     a,a-Dialkyl-y-          aminomethylen    - Verbindungen übergeführt  werden.  



  Mit     alkalischen    Kondensationsmitteln, wie  z. B.     Alkalialkoholate,    vorteilhaft in einem or  ganischen Lösungsmittel, wie z. B. Methanol,  lassen sich die     a,a-Dialkyl-y-aminomethylen-          acetacetonitrile        cyclisieren.    Durch Umsetzen  des Kondensationsproduktes mit Schwefelwas  serstoff oder mit Schwefelwasserstoff abgeben  den Mitteln,     wie    z. B.     Phosphorpentasulfid,     entstehen die     2-Thio-3,3-dialkyl-4-oxo-1,2,3,4-          tetrahydropyridine.     



  Die neuen Verbindungen sind gelblich, in  Wasser schwer und in den gebräuchlichen or  ganischen Lösungsmitteln leicht löslich. In  Laugen lösen sie sich     unter    Farbvertiefung  und fallen auf Zusatz von Säuren     unter    Farb-           aufhellung    unverändert wieder aus. Sie, sollen  als Schlafmittel Verwendung finden.  



  Gegenstand des vorliegenden Patentes ist  ein Verfahren zur Herstellung eines schwefel  haltigen     Pyridons,    das dadurch     gekennzeich-          riet    ist, dass man     a-Äthyl-a-methyl-acetaceto-          nitril    mit einem     Ameisensäureester    in Gegen  wart eines alkalischen Kondensationsmittels in  die     y-Oxymethylenverbindung    und diese mit  Ammoniak in die     y-Aminomethylenverbindung     umwandelt, diese mit einem alkalischen Kon  densationsmittel     cyclisiert    und mit Schwefel  wasserstoff oder einem Schwefelwasserstoff       abgebenden    Mittel behandelt.  



  Das so erhältliche, neue     2-Thio-3-äthyl-3-          methyl-4-oxo-1,2,3,4-tetrahydropyridin    bildet  gelbe Kristalle mit einem Schmelzpunkt von  113-114 C. Die Verbindung ist schwer lös  lich in Wasser, in den gebräuchlichen organi  schen Lösungsmitteln dagegen leicht löslich.  <I>Beispiel:</I>  Eine Lösung von 23 Gewichtsteilen Na  trium in 500 Raumteilen trockenem Alkohol  wird mit einem Gemisch von 97 Gewichtsteilen       2-Cyanobutanon-3    (E.

   Mohr, Journal für  praktische Chemie (2), Band 90 [1914], Seite  189     [Kp.19        n,.    78  C]) und 109 Gewichtsteilen       Äthylbromid    versetzt und 16 Stunden bei  50  C     verrührt.    Nachdem die Hauptmenge des  Alkohols im Vakuum     abdestilliert    worden ist,  wird der Rückstand mit Wasser versetzt     und     das oben schwimmende     a-Äthyl-a-methyl-acet-          acetonitril    abgetrennt. Das in Alkalien unlös  liche Öl siedet uniersetzt     zwischen    80 und  82  C unter 1.4 mm Druck.  



  125     Gewiehtsteile    des     a-Äthyl-a-methyl-          acetacetonitrils    werden mit 90 Gewichtstei  len     Ameisensäure-methylester    in eine Su  spension von 24 Gewichtsteilen Natrium  in 800 Raumteilen     Toluol    zugegeben und  16 Stunden bei 20  C verrührt.

   Das ent  stehende     a-Äthyl-a-methyl-y-oxymethylen-aeet-          acetonitril    wird mit Wasser als     Natriumsalz     gelöst, abgetrennt und direkt mit Ammonium-         ehlorid    und Ammoniak in die     Aminomet.hy        -          lenv        erbindung    übergeführt. Das in verdünn  ter     Ammoniaklösung    schwer     lösliehe        a-Äthyl-          a.-methyl-y-aminometh@-len-acetacetonitril    wird  mit Benzol ausgezogen, getrocknet und im Va  kuum eingeengt.

   Das verbleibende Öl kann im  Hochvakuum rektifiziert werden     (Kp.0,05        Inn"     106  C).  



  152 Gewichtsteile     a-Äthyl-a-methyl-y-amino-          methylen-acetacetonitrilwerden    mit einer aus  3<B><I>'0</I></B> Gewichtsteilen Natrium in 500 Raumteilen  Alkohol     zubereiteten        Natriumalkoholatlösung     umgesetzt und 12 Stunden stehengelassen.  Dann werden 80     Gewiehtsteile    Schwefelwas  serstoff eingeleitet, wobei sich die Lösung er  wärmt. Nach dem Abklingen der Reaktion  wird mit 125 Raumteilen     37o/oiger    Salzsäure  tropfenweise versetzt, wobei Schwefelwasser  stoff entweicht.

   Das dunkel gefärbte Reak  tionsgut wird durch Tierkohle filtriert und  mit 500 Raumteilen Wasser tropfenweise ver  setzt, wobei das     2-Thio-3-äthyl-3-methyl-4-oxo.          1,2,3,4-tetrahydropyridin    in gelben Kristallen  ausfällt. Nach     Umlösen    aus Methanol schmel  zen die Kristalle bei 113-11.4  C.



  process for the production of a sulfur-containing pyridone. It has been found that the compounds of the general formula
EMI0001.0004
    in which R.1 and R2 represent lower alkyl or alkenyl radicals with 1 to 4 carbon atoms, are drawn out by deep, short-lasting sleep effect.



  According to the present invention, the hitherto unknown 2-thio-3,3-dialkyl-4-oxo-1,2,3,4-tetrahydropyridines are given that an a, a-dialkyl-acetaceto- nit.ril with. a formic acid ester in the presence of an alkaline condensing agent into the γ-oxymethylene compound and converting this with ammonia into the γ-aminomethylene compound, cyclizing this with an alkaline condensing agent and treating it with hydrogen sulfide or a hydrogen sulfide-releasing agent.



  The a, a <I> - </I> Dialkylacetacetonitrile are by alkylation of E. Mohr (Journal for practical chemistry (2), volume 75 [1907], page 749, and (2), volume 90 [1914], Page 189) shown a-alkyl-acetacetonitrile, the alkylation can be carried out with alkenyl or alkyl halides using the methods customary for a-alkyl acetic esters.

   The a, a-dialkyl-y-oxymethylene-acet-acetonitrile are advantageous by converting the corresponding nitriles with a formic acid ester in an inert or ganic solvent, such as. B. benzene, To luene or diethyl carbonate, in the presence of an alkaline condensing agent such. B. sodium, potassium or sodium alcoholate shown.



  The a, a-dialkyl acetacetonitriles, which are sparingly soluble in water, do not form any salts with aqueous alkaline solutions and can be easily separated from the a, a-dialkyl y-oxymethylene acetacetonitriles, which are readily soluble in aqueous alkaline solutions. These alkali salt solutions can be converted with ammonia and ammonium chloride into the a, a-dialkyl-y-aminomethylene compounds, which are sparingly soluble in aqueous solution.



  With alkaline condensing agents, such as. B. alkali metal, advantageously in an or ganic solvent, such as. B. methanol, the a, a-dialkyl-y-aminomethylene acetacetonitrile can be cyclized. By reacting the condensation product with hydrogen sulfide or hydrogen sulfide give off the means such. B. phosphorus pentasulfide, the 2-thio-3,3-dialkyl-4-oxo-1,2,3,4-tetrahydropyridines arise.



  The new compounds are yellowish, heavy in water and easily soluble in the common organic solvents. In alkaline solutions they dissolve with a deepening of the color, and when acids are added they precipitate again with a lightening of the color. They should be used as a sleeping aid.



  The subject of the present patent is a process for the production of a sulfur-containing pyridone, which is characterized by converting α-ethyl-α-methyl-acetacetonitrile with a formic acid ester in the presence of an alkaline condensing agent into the γ-oxymethylene compound and this converted with ammonia into the γ-aminomethylene compound, cyclized this with an alkaline condensation agent and treated with hydrogen sulfide or a hydrogen sulfide releasing agent.



  The new 2-thio-3-ethyl-3-methyl-4-oxo-1,2,3,4-tetrahydropyridine obtainable in this way forms yellow crystals with a melting point of 113-114 C. The compound is sparingly soluble in water , however, easily soluble in common organic solvents. <I> Example: </I> A solution of 23 parts by weight of sodium in 500 parts by volume of dry alcohol is mixed with a mixture of 97 parts by weight of 2-cyanobutanone-3 (E.

   Mohr, Journal for practical chemistry (2), Volume 90 [1914], page 189 [Kp.19 n ,. 78 C]) and 109 parts by weight of ethyl bromide are added and the mixture is stirred at 50 C for 16 hours. After the bulk of the alcohol has been distilled off in vacuo, the residue is mixed with water and the floating α-ethyl-α-methyl-acet-acetonitrile is separated off. The oil, which is insoluble in alkalis, boils between 80 and 82 C under 1.4 mm pressure.



  125 parts by weight of the a-ethyl-a-methyl-acetacetonitrile are added with 90 parts by weight of methyl formate in a suspension of 24 parts by weight of sodium in 800 parts by volume of toluene and the mixture is stirred at 20 ° C. for 16 hours.

   The resulting α-ethyl-α-methyl-γ-oxymethylene-aeet-acetonitrile is dissolved as the sodium salt with water, separated off and converted directly into the aminometric hydrogen compound with ammonium chloride and ammonia. The a-ethyl- a.-methyl-y-aminometh@-len-acetacetonitrile, which is poorly soluble in dilute ammonia solution, is extracted with benzene, dried and concentrated in vacuo.

   The remaining oil can be rectified in a high vacuum (boiling point 0.05 Inn "106 C).



  152 parts by weight of a-ethyl-a-methyl-y-aminomethylene acetacetonitrile are reacted with a sodium alcoholate solution prepared from 3 parts by weight of sodium in 500 parts by volume of alcohol and left to stand for 12 hours . Then 80 parts by weight of hydrogen sulfide are introduced, whereby the solution warms up. After the reaction has subsided, 125 parts by volume of 37% hydrochloric acid are added dropwise, with hydrogen sulphide escaping.

   The dark-colored reac tion material is filtered through animal charcoal and added dropwise ver with 500 parts by volume of water, the 2-thio-3-ethyl-3-methyl-4-oxo. 1,2,3,4-tetrahydropyridine precipitates in yellow crystals. After redissolving from methanol, the crystals melt at 113-11.4 C.

 

Claims (1)

PATENTANSPRUCH Verfahren zur Herstellung eines schwefel haltigen Pyridons, dadurch gekennzeichnet, dass man a-=3thyl-a-methyl-acetacetonitril mit einem AmeiserLsäureester in Gegenwart eines alkalischen Kondensationsmittels in die y-Oxy- methylenverbindung und diese mit Ammo niak in die 7,-Aminomethylenverbindung um wandelt, diese mit einem alkalischen Konden sationsmittel cyclisieri.und mit Schwefelwas serstoff oder einem Sehziefelwasserstoff ab gebenden Mittel behandelt. PATENT CLAIM Process for the production of a sulfur-containing pyridone, characterized in that a- = 3-ethyl-a-methyl-acetacetonitrile is converted into the γ-oxymethylene compound with a formic acid ester in the presence of an alkaline condensing agent and this with ammonia into the 7-aminomethylene compound converts, these cyclisieri.and treated with an alkaline condensation agent with hydrogen sulfide or a hydrogen-releasing agent. Das neue 2-Thio-3-äthy 1-3-metbyl-4-oxo-1,2, 3,4-tetrahydropyridin bildet gelbe Kristalle mit einem Schmelzpunkt von 113-114 C. Die Verbindung ist in Wasser schwer löslich und in den gebräuchlichen organischen Lö sungsmitteln leicht löslich. The new 2-thio-3-ethy 1-3-metbyl-4-oxo-1,2,3,4-tetrahydropyridine forms yellow crystals with a melting point of 113-114 C. The compound is sparingly soluble in water and in the Common organic solvents easily soluble.
CH310985D 1952-12-04 1952-12-04 Process for the preparation of a sulfur-containing pyridone. CH310985A (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CH310985T 1952-12-04

Publications (1)

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CH310985A true CH310985A (en) 1955-11-15

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ID=4494383

Family Applications (1)

Application Number Title Priority Date Filing Date
CH310985D CH310985A (en) 1952-12-04 1952-12-04 Process for the preparation of a sulfur-containing pyridone.

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Country Link
BE (1) BE524609A (en)
CH (1) CH310985A (en)
DE (1) DE1000381C2 (en)
GB (1) GB735686A (en)

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE634284C (en) * 1935-06-18 1936-08-25 Hoffmann La Roche & Co Akt Ges Process for the preparation of 2, 4-dioxo-3, 3-dialkyltetrahydropyridines

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Publication number Publication date
BE524609A (en)
GB735686A (en) 1955-08-24
DE1000381B (en) 1957-01-10
DE1000381C2 (en) 1957-06-19

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