[go: up one dir, main page]

CH436287A - Process for the preparation of new pharmaceutically active pyridine derivatives - Google Patents

Process for the preparation of new pharmaceutically active pyridine derivatives

Info

Publication number
CH436287A
CH436287A CH238363A CH238363A CH436287A CH 436287 A CH436287 A CH 436287A CH 238363 A CH238363 A CH 238363A CH 238363 A CH238363 A CH 238363A CH 436287 A CH436287 A CH 436287A
Authority
CH
Switzerland
Prior art keywords
parts
general formula
group
pharmaceutically active
pyridine derivatives
Prior art date
Application number
CH238363A
Other languages
German (de)
Inventor
Alfons Dr Schuler Wilhelm
Beschke Helmut
Original Assignee
Degussa
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 Degussa filed Critical Degussa
Publication of CH436287A publication Critical patent/CH436287A/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic 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
    • C07D213/02—Heterocyclic 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
    • C07D213/04—Heterocyclic 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
    • C07D213/60—Heterocyclic 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
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic 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
    • C07D213/02—Heterocyclic 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
    • C07D213/04—Heterocyclic 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
    • C07D213/60—Heterocyclic 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
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/70—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic 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
    • C07D213/02—Heterocyclic 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
    • C07D213/04—Heterocyclic 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
    • C07D213/60—Heterocyclic 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic 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
    • C07D213/02—Heterocyclic 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
    • C07D213/04—Heterocyclic 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
    • C07D213/60—Heterocyclic 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic 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
    • C07D213/02—Heterocyclic 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
    • C07D213/04—Heterocyclic 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
    • C07D213/60—Heterocyclic 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/84—Nitriles

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pyridine Compounds (AREA)

Description

  

  Verfahren zur Herstellung neuer pharmazeutisch wirksamer Pyridinderivate    Das vorliegende Patent betrifft ein Verfahren zur  Herstellung neuer Pyridinderivate der allgemeinen For  mel:  
EMI0001.0000     
    und gegebenenfalls ihrer Salze und die Verwendung die  ser Verbindungen zur Herstellung ihrer quartären Am  moniumverbindungen.  



  In dieser Formel bedeuten R1 und R2 Alkylreste,  vorzugsweise solche, die zu einem Ring geschlossen sind,  der ein weiteres Heteroatom, insbesondere Sauerstoff,  enthalten kann. Alk bedeutet eine gerade oder ver  zweigte niedere Alkylenkette mit höchstens 4 C-Atomen,  X bedeutet Schwefel, Sauerstoff oder die NH-Gruppe.  Y kann ein Halogen, vorzugsweise in 3-Stellung, aber  auch eine Trihalogenmethyl-, z. B. eine Trifluormethyl-,  Alkyl-, vorzugsweise Methyl-, oder Alkoxy-, vorzugs  weise Methoxygruppe, ferner den Rest -CN, -COORs  oder -CONR4R5, worin R3, R4 und R5 gleich oder ver      schieden sein können udn Wasserstoff oder niedere Alk  ylgruppen sind, bedeuten.  



  Die genannten Verbindungen haben gute pharmako  logische Eigenschaften, insbesondere analgetische bzw.  antiphlogische Wirkungen.  



  Diese Verbindungen werden erfindungsgemäss da  durch erhalten, dass man eine Verbindung der allgemei  nen Formel:  
EMI0001.0001     
    mit einer Verbindung der allgemeinen Formel:  
EMI0001.0002     
    in welchen Formeln der eine der beiden Reste A und Z  Chlor oder Brom und der andere Rest die Gruppe -XH  bedeutet, umsetzt.  



  Im Falle, dass A Chlor oder Brom bedeutet, erfolgt  die Umsetzung vorzugsweise bei erhöhter Temperatur  und unter Verwendung von basischen Kondensations  mitteln, wie Pottasche, Natriumäthylat oder anderer ba  sischer Stoffe, z. B. tertiärer Amine.  



  Wenn aber A die Gruppe -XH bedeutet, so wird die  Kondensation vorzugsweise in Gegenwart basischer  Stoffe, wie Natriummethylat oder Natriumamid, bei er  höhter Temperatur vorgenommen. Die erhaltenen Ba  sen können in ihre Salze oder quartären Ammoniumver  bindungen übergeführt werden.  



  Beispiel 1  32 Teile Morpholinoäthylmercaptan, in 300 Teilen  Xylol gelöst, werden unter Sieden am Rückfluss mit  20 Teilen einer 50%igen Suspension von Natriumamid      in Toluol versetzt. Nach beendeter Gasentwicklung wer  den 33 Teile 2,3-Dichlorpyridin, in 200 Teilen Xylol ge  löst, zugetropft und das Gemisch 1 Stunde am     Rück-          fluss    gekocht. Nach dem Abkühlen wird der Ansatz mit  Wasser zersetzt, die Xylolschicht mit verdünnter Salz  säure bei einem pH-Wert von 4 extrahiert und hierauf  die saure wässrige Phase mit Natronlauge und Äther  aufgearbeitet. Der Ätherextrakt wird getrocknet und im  Vakuum destilliert. Bei 0,5 mm Druck und l64-168   Celsius gehen 32 g     2-(Morpholinoäthylmercapto)-3-          chlor-pyridin    über.

   Das salzsaure Salz, aus Isopropanol    gefällt und umkristallisiert, schmilzt bei 181 C  Beispiel 2  75 Teile 2-Oxy-6-chlor-pyridin, in 750 Teilen Toluol       /oigen    Suspension  gelöst, werden mit 43 Teilen einer 50  von     Natriumamid    in     Toluol    unter Sieden am     Rückfluss         versetzt. Anschliessend tropft man 70 Teile     Dimethyl-          aminoäthylchlorid    zu und kocht noch 3 Stunden weiter.  Nach Aufarbeitung entsprechend Beispiel 1 werden bei  Kp11: 115-122  C 53 Teile     2-(Dimethylaminoäthoxy)-          6-chlorpyridin    erhalten. Das Hydrochlorid schmilzt bei  146-148  C.  



  Beispiel 3  Entsprechend Beispiel 2, aber unter Verwendung  von Dimethylaminopropylchlorid, wird     2-(Dimethyl-          aminopropyloxy-)-6-chlorpyridin    vom Kp10: 134-138   Celsius erhalten. Das Hydrochlorid schmilzt bei 181 bis  183  C.  



  Beispiel 4  74 Teile 2,6-Dichlorpyridin und 102 Teile     1-Dimeth-          ylaminopropylamin    3 werden auf dem Ölbad vorsich  tig erhitzt. Bei etwa 90  C setzt eine heftige Reaktion  ein. Nach dem Abkühlen wird in einem Gemisch von  Wasser und Äther gelöst, mit Pottasche alkalisch ge  macht und die Ätherlösung aufgearbeitet. Bei Kp11: 176  bis 182 C werden 58 g     2-(Dimethylaminopropylamino)-          6-chlorpyridin    erhalten. Das Hydrochlorid schmilzt bei  83-85  C.  



  Beispiel 5  Entsprechend Beispiel 1, aber unter Verwendung  von 2,6-Dichlorpyridin anstelle von 2,3-Dichlorpyridin,  wird 2-(Morpholino-äthyhnercapto-)-6-chlor-pyridin er  halten, dessen Hydrochlorid bei 163-165  C schmilzt.    Beispiel 6  Zu einer Lösung von 44 Teilen Morpholinopropanol  in 300 Teilen Toluol werden unter Sieden am Rückfluss  24 Teile einer 50%igen Natriumamid-Suspension in  Toluol zugetropft. Nach beendeter Reaktion werden  45 Teile 2,3-Dichlorpyridin, gelöst in 200 Teilen Toluol,  zugetropft. Anschliessend wird 2 Stunden nachgekocht.  Das Reaktionsgemisch wird auf Wasser gegossen, die  Toluolschicht bei einem pH-Wert von 4 mit verdünnter  Salzsäure extrahiert, der saure wässrige Extrakt alka  lisch mit Äther aufgearbeitet und destilliert.

   Bei Kp1:  149-151 C gehen 63 g     2-(Morpholinopropyloxy-)-3-          chlor-pyridin    über. Das Hydrochlorid wird in     Isopro-          panol    mit isopropanolischer Salzsäure gewonnen; es  schmilzt bei 151-162  C.    Beispiel 7  Entsprechend Beispiel 1, aber unter Verwendung  von 2-Brom-3-methyl-pyridin anstatt 2,3-Dichlorpyridin,  wird 2-(Morpholinoäthyl-mercapto-)-3-methyl-pyridin  erhalten, dessen Hydrochlorid bei 169-171'C schmilzt.  Beispiel 8  Entsprechend Beispiel 6 wird 2,6-Dichlorpyridin  statt 2,3-Dichlorpyridin verwendet und     2-(Morpholino-          propyloxy-)-6-chlor-pyridin    erhalten; das Hydrochlorid  schmilzt bei 164-167  C.  



  Beispiel 9  Entsprechend Beispiel 1, aber unter Verwendung  von Piperidinoäthylmercaptan anstatt     Morpholinoäthyl-          mercaptan,    wird     2-(Piperidinoäthylmercapto-)-3-chlor-          pyridin    erhalten. Das Hydrochlorid schmilzt bei 181 bis  183  C.  



  Beispiel 10  38 Teile 2-Amino-5-chlorpyridin werden mit 300  Teilen Toluol zum Sieden erhitzt. Dann lässt man 23  Teile einer 50%igen Natriumamid-Toluol-Suspension  zutropfen und kocht 1 Stunde nach. Anschliessend wer-    den 45 Teile Morpholino-äthylchlorid zugegeben, da  nach wird nochmals 1 Stunde gekocht. Das Reaktions  gemisch wird anschliessend auf Wasser gegossen, die  Toluolschicht abgetrennt, getrocknet und destilliert. Bei  Kp1: 164-170  C gehen 46 Teile     2-(Morpholinoäthyl-          amino-)-5-chlor-pyridin    über. Das Dihydrochlorid wird  in Isopropanol gefällt; es schmilzt bei 223-225  C.    Beispiel 11  9 Teile Natrium werden in 60 Teilen     Morpholino-          propanol    und 50 Teilen Xylol gelöst.

   Dann werden 57  Teile 6-Methoxy-2-chlor-pyridin zugegeben. Nach guter  Durchmischung wird langsam angeheizt. Bei einer In  nentemperatur von 140  C ist der Beginn der Reaktion  zu beobachten. 1 Stunde lang wird danach die Badtem  peratur auf 240  C gehalten. Anschliessend wird der  Ansatz auf Wasser gegossen und mit Äther aufgearbei  tet. Bei Kp1: 151-163  C werden 35 Teile     2-(Morpho-          linopropyloxy-)-6-methoxy-pyridin    erhalten. Das     Hydro-          chlorid    wird aus Isopropanol gefällt; es schmilzt bei 154  bis 156  C.    Beispiel 12  3 Teile Natrium werden in 120 Teilen Äthanol ge  löst.

   Es werden nacheinander 19 Teile     Morpholinoäthyl-          mercaptan    und 18 Teile 2-Chlor-3-cyanopyridin zugege  ben. Anschliessend wird der Alkohol abdestilliert und  1 Stunde lang eine Temperatur von 140  C eingehalten.  Nach dem Abkühlen löst man in Äther und Wasser,  extrahiert mit verdünnter Salzsäure und arbeitet die  wässrige Phase alkalisch auf. Bei Kp, 185-190  C ge  hen 23 Teile     2-(Morpholinoäthylmereapto-)-3-cyan-          pyridin    über. Das Hydrochlorid schmilzt bei 197 bis  200  C.  



  Beispiel 13  6 Teile Natrium werden in 250 Teilen Äthanol ge  löst. Nacheinander werden 19 Teile     Morpholinoäthyl-          mercaptan    und 20 Teile 2-Chlor-nicotinsäure zugegeben,  der Alkohol abdestilliert und der Rückstand 1 Stunde  auf 160  C erhitzt. Danach wird in 100 Teilen Wasser  gelöst, mit 50 Teilen 48%iger Bromwasserstoffsäure ver  setzt, bis zur klaren Lösung erhitzt und dann gekühlt.  Es werden 15 Teile     2-(Morpholinoäthylmercapto-)-nico-          tinsäurehydrobromid    vom Schmelzpunkt 210-213  C  erhalten.  



  Beispiel 14  2,5 Teile Natrium werden in 100 Teilen Äthanol  gelöst, danach 15 Teile Morpholinoäthylmercaptan und  19 Teile 2-Chlor-nicotinsäureäthylester zugegeben, der  Alkohol abdestilliert und der Rückstand 1 Stunde auf  150  C erhitzt. Anschliessend wird eiskalt mit verdünn  ter Salzsäure extrahiert und alkalisch mit Äther aufge  arbeitet. Der Ätherrückstand ist     2-(Morpholinoäthyl-          mercapto-)-nicotinsäureäthylester,    dessen Hydrobromid  bei 176  C schmilzt.  



  Beispiel 15  Analog Beispiel 14, unter Verwendung von     2-Chlor-          nicotinsäureamid,    wird     2-(Morpholinoäthylmercapto-)-          nicotinsäureamid    erhalten.



  Process for the preparation of new pharmaceutically active pyridine derivatives The present patent relates to a process for the preparation of new pyridine derivatives of the general formula:
EMI0001.0000
    and optionally their salts and the use of these compounds for the preparation of their quaternary ammonium compounds.



  In this formula, R1 and R2 denote alkyl radicals, preferably those which are closed to form a ring which can contain a further heteroatom, in particular oxygen. Alk denotes a straight or branched lower alkylene chain with at most 4 carbon atoms, X denotes sulfur, oxygen or the NH group. Y can be a halogen, preferably in the 3-position, but also a trihalomethyl, e.g. B. a trifluoromethyl, alkyl, preferably methyl, or alkoxy, preferably methoxy group, also the radical -CN, -COORs or -CONR4R5, wherein R3, R4 and R5 can be identical or different udn hydrogen or lower alk are yl groups, mean.



  The compounds mentioned have good pharmacological properties, in particular analgesic and anti-inflammatory effects.



  According to the invention, these compounds are obtained by using a compound of the general formula:
EMI0001.0001
    with a compound of the general formula:
EMI0001.0002
    in which formulas one of the two radicals A and Z is chlorine or bromine and the other radical is the group -XH.



  In the event that A is chlorine or bromine, the reaction is preferably carried out at an elevated temperature and using basic condensation agents, such as potash, sodium ethylate or other basic substances such. B. tertiary amines.



  But if A is the group -XH, the condensation is preferably carried out in the presence of basic substances, such as sodium methylate or sodium amide, at an elevated temperature. The bases obtained can be converted into their salts or quaternary ammonium compounds.



  Example 1 32 parts of morpholinoethyl mercaptan, dissolved in 300 parts of xylene, are mixed with 20 parts of a 50% strength suspension of sodium amide in toluene while boiling under reflux. After the evolution of gas has ceased, 33 parts of 2,3-dichloropyridine, dissolved in 200 parts of xylene, are added dropwise and the mixture is refluxed for 1 hour. After cooling, the batch is decomposed with water, the xylene layer is extracted with dilute hydrochloric acid at a pH of 4 and the acidic aqueous phase is then worked up with sodium hydroxide solution and ether. The ether extract is dried and distilled in vacuo. At 0.5 mm pressure and 164-168 Celsius, 32 g of 2- (morpholinoethylmercapto) -3-chloropyridine pass over.

   The hydrochloric acid salt, precipitated from isopropanol and recrystallized, melts at 181 ° C. Example 2 75 parts of 2-oxy-6-chloropyridine, dissolved in 750 parts of toluene / oigen suspension, are boiled with 43 parts of sodium amide in toluene Reflux added. Then 70 parts of dimethylaminoethyl chloride are added dropwise and the mixture is boiled for a further 3 hours. After working up as in Example 1, 53 parts of 2- (dimethylaminoethoxy) -6-chloropyridine are obtained at boiling point 11: 115-122 C. The hydrochloride melts at 146-148 C.



  Example 3 As in Example 2, but using dimethylaminopropyl chloride, 2- (dimethylaminopropyloxy -) - 6-chloropyridine with a boiling point of 134-138 Celsius is obtained. The hydrochloride melts at 181 to 183 C.



  Example 4 74 parts of 2,6-dichloropyridine and 102 parts of 1-dimethylaminopropylamine 3 are carefully heated on an oil bath. A violent reaction sets in at around 90 ° C. After cooling, it is dissolved in a mixture of water and ether, made alkaline with potash and the ethereal solution is worked up. At bp11: 176 to 182 ° C., 58 g of 2- (dimethylaminopropylamino) - 6-chloropyridine are obtained. The hydrochloride melts at 83-85 C.



  Example 5 As in Example 1, but using 2,6-dichloropyridine instead of 2,3-dichloropyridine, 2- (morpholino-ethyhnercapto) - 6-chloro-pyridine, the hydrochloride of which melts at 163-165 ° C., is obtained. EXAMPLE 6 To a solution of 44 parts of morpholinopropanol in 300 parts of toluene, 24 parts of a 50% strength sodium amide suspension in toluene are added dropwise with refluxing. When the reaction has ended, 45 parts of 2,3-dichloropyridine, dissolved in 200 parts of toluene, are added dropwise. It is then boiled for 2 hours. The reaction mixture is poured into water, the toluene layer is extracted at pH 4 with dilute hydrochloric acid, the acidic aqueous extract is worked up alkaline with ether and distilled.

   At boiling point: 149-151 ° C., 63 g of 2- (morpholinopropyloxy -) - 3- chloropyridine pass over. The hydrochloride is obtained in isopropanol with isopropanolic hydrochloric acid; it melts at 151-162 ° C. Example 7 As in Example 1, but using 2-bromo-3-methyl-pyridine instead of 2,3-dichloropyridine, 2- (morpholinoethyl-mercapto) -3-methyl-pyridine is obtained whose hydrochloride melts at 169-171'C. Example 8 As in Example 6, 2,6-dichloropyridine is used instead of 2,3-dichloropyridine and 2- (morpholinopropyloxy -) - 6-chloropyridine is obtained; the hydrochloride melts at 164-167 C.



  Example 9 As in Example 1, but using piperidinoethyl mercaptan instead of morpholino ethyl mercaptan, 2- (piperidino ethyl mercapto) -3-chloropyridine is obtained. The hydrochloride melts at 181 to 183 C.



  Example 10 38 parts of 2-amino-5-chloropyridine are heated to the boil with 300 parts of toluene. Then 23 parts of a 50% sodium amide-toluene suspension are added dropwise and the mixture is boiled for 1 hour. Then 45 parts of morpholino-ethyl chloride are added, after which the mixture is boiled for another hour. The reaction mixture is then poured into water, the toluene layer is separated off, dried and distilled. At bp1: 164-170 ° C., 46 parts of 2- (morpholinoethylamino) -5-chloropyridine pass over. The dihydrochloride is precipitated in isopropanol; it melts at 223-225 ° C. Example 11 9 parts of sodium are dissolved in 60 parts of morpholinopropanol and 50 parts of xylene.

   Then 57 parts of 6-methoxy-2-chloropyridine are added. After thorough mixing, heating is started slowly. The beginning of the reaction can be observed at an internal temperature of 140.degree. The bath temperature is then kept at 240 ° C. for 1 hour. The batch is then poured into water and worked up with ether. At bp1: 151-163 ° C., 35 parts of 2- (morpholinopropyloxy) - 6-methoxypyridine are obtained. The hydrochloride is precipitated from isopropanol; it melts at 154 to 156 ° C. Example 12 3 parts of sodium are dissolved in 120 parts of ethanol.

   19 parts of morpholinoethyl mercaptan and 18 parts of 2-chloro-3-cyanopyridine are added one after the other. The alcohol is then distilled off and a temperature of 140 ° C. is maintained for 1 hour. After cooling, it is dissolved in ether and water, extracted with dilute hydrochloric acid and the aqueous phase is worked up in an alkaline manner. At b.p. 185-190 C, 23 parts of 2- (morpholinoethylmereapto) -3-cyanopyridine go over. The hydrochloride melts at 197 to 200 C.



  Example 13 6 parts of sodium are dissolved in 250 parts of ethanol. 19 parts of morpholinoethyl mercaptan and 20 parts of 2-chloro-nicotinic acid are added one after the other, the alcohol is distilled off and the residue is heated to 160 ° C. for 1 hour. It is then dissolved in 100 parts of water, 50 parts of 48% strength hydrobromic acid are added, the mixture is heated until the solution is clear and then cooled. 15 parts of 2- (morpholinoethylmercapto) - nicotinic acid hydrobromide with a melting point of 210-213 ° C. are obtained.



  Example 14 2.5 parts of sodium are dissolved in 100 parts of ethanol, then 15 parts of morpholinoethyl mercaptan and 19 parts of 2-chloro-nicotinic acid ethyl ester are added, the alcohol is distilled off and the residue is heated to 150 ° C. for 1 hour. It is then extracted ice-cold with dilute hydrochloric acid and worked up alkaline with ether. The ether residue is 2- (Morpholinoäthyl- mercapto-) - nicotinic acid ethyl ester, the hydrobromide of which melts at 176 ° C.



  Example 15 Analogously to Example 14, using 2-chloronicotinic acid amide, 2- (morpholinoethylmercapto) - nicotinic acid amide is obtained.

Claims (1)

PATENTANSPRUCH I Verfahren zur Herstellung von neuen pharmazeu tisch wirksamen Pyridinderivaten der allgemeinen For mel: EMI0003.0000 wobei R1 und R2 Alkylreste, die zu einem Ring geschlos sen sein können, der ein weiteres Heteroatom enthalten kann, Alk eine gerade oder verzweigte Alkylengruppe mit höchstens 4 C-Atomen, X Schwefel, Sauerstoff oder die NH-Gruppe und Y Halogen, Alkyl-, Trihalogen- methyl- oder Alkoxygruppe, ferner den Rest -CN, -COORg oder -CONR4R5, worin. PATENT CLAIM I Process for the production of new pharmaceutically active pyridine derivatives of the general formula: EMI0003.0000 where R1 and R2 are alkyl radicals that can be closed to form a ring that may contain a further heteroatom, Alk is a straight or branched alkylene group with at most 4 carbon atoms, X is sulfur, oxygen or the NH group and Y is halogen, alkyl , Trihalomethyl or alkoxy group, also the radical -CN, -COORg or -CONR4R5, in which. R3, R4 und R5 gleich oder verschieden sein können und Wasserstoff oder nie dere Alkylgruppen sind, bedeuten, dadurch gekennzeich net, dass man eine Verbindung der allgemeinen Formel: EMI0003.0003 mit einer Verbindung der allgemeinen Formel: EMI0003.0004 in welchen Formeln der eine der beiden Reste A und Z Chlor oder Brom und der andere Rest die Gruppe -XH bedeutet, umsetzt. UNTERANSPRÜCHE 1. Verfahren nach Patentanspruch, dadurch gekenn zeichnet, dass die Basen in ihre Säureadditionssalze über geführt werden. 2. Verfahren nach Patentanspruch I, dadurch ge kennzeichnet, dass R1 und R2 über einen Ring geschlos sen sind, der als weiteres Heteroatom Sauerstoff enthält. PATENTANSPRUCH II Verwendung der nach Patentanspruch I hergestell ten Basen zur Herstellung ihrer quartären Ammonium verbindungen. R3, R4 and R5 can be the same or different and are hydrogen or lower alkyl groups, are characterized in that a compound of the general formula: EMI0003.0003 with a compound of the general formula: EMI0003.0004 in which formulas one of the two radicals A and Z is chlorine or bromine and the other radical is the group -XH. SUBClaims 1. The method according to claim, characterized in that the bases are converted into their acid addition salts. 2. The method according to claim I, characterized in that R1 and R2 are closed over a ring which contains oxygen as a further heteroatom. PATENT CLAIM II Use of the bases produced according to claim I for the production of their quaternary ammonium compounds.
CH238363A 1962-03-27 1963-02-25 Process for the preparation of new pharmaceutically active pyridine derivatives CH436287A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DED0038499 1962-03-27
DED0040747 1963-01-23

Publications (1)

Publication Number Publication Date
CH436287A true CH436287A (en) 1967-05-31

Family

ID=25971408

Family Applications (1)

Application Number Title Priority Date Filing Date
CH238363A CH436287A (en) 1962-03-27 1963-02-25 Process for the preparation of new pharmaceutically active pyridine derivatives

Country Status (5)

Country Link
CH (1) CH436287A (en)
DK (2) DK106848C (en)
FI (1) FI44120C (en)
IT (1) IT1062005B (en)
SE (1) SE308312B (en)

Also Published As

Publication number Publication date
DK107611C (en) 1967-06-19
FI44120C (en) 1971-09-10
DK106848C (en) 1967-03-28
FI44120B (en) 1971-06-01
SE308312B (en) 1969-02-10
IT1062005B (en) 1983-06-25

Similar Documents

Publication Publication Date Title
DE897405C (en) Process for the preparation of substituted piperazines
DE69109871T2 (en) PYRIDINE AND PYRIDINE-N-OXIDE DERIVATIVES OF DIARYLMETHYL PIPERIDINES OR PIPERAZINES, THEIR COMPOSITIONS AND USE.
DE3244594A1 (en) 1-PHENYLISOCHINOLINE DERIVATIVES AND METHOD FOR THE PRODUCTION THEREOF, PHARMACEUTICAL PREPARATIONS CONTAINING THIS COMPOUND AND THE USE THEREOF
DE1946172A1 (en) New heterocyclic ethers and methods for their preparation
DE1518489A1 (en) Substituted N-Cyclopropylaethylene diamines and processes for their preparation
DE2009408A1 (en) 5-pyridyl-2-imidazolone
DE60203820T2 (en) Pyridine derivatives as NMDA receptor ligands
DE1445580A1 (en) New aminopyrazoles
AT238200B (en) Process for the preparation of new pyridine derivatives
DE2118315C3 (en) 2- (1H) -quinazolinone derivatives, processes for their preparation and pharmaceuticals containing these compounds
CH436287A (en) Process for the preparation of new pharmaceutically active pyridine derivatives
DE2123784A1 (en) Thienobenzothiazepine derivatives
CH440292A (en) Process for the preparation of new aminopyrazoles
DE2349493A1 (en) 2- (2-PYRIDYL) - OMEGA-PHENYLALKYLAMINE AND THE METHOD FOR THEIR PRODUCTION
DE922825C (en) Process for the production of antihistamines
DE2345422C2 (en) Substituted isoquinolyl-arylpiperazines containing these drugs and processes for their preparation
DE551029C (en) Process for the preparation of N-substituted compounds of the pyridone series
DE831696C (en) Process for the production of antihistamines
DE2643671A1 (en) 4-PHENYLPIPERIDINYL- AND 4-PHENYLTETRAHYDROPYRIDINYL-ALKYLAMINO-KETOALKANECARBONIC ACIDS AND THEIR SALT WITH ACIDS AND BASES
DE1445649C (en) Pyridine derivatives and processes for their preparation
AT330372B (en) PROCESS FOR THE PREPARATION OF NEW 2- (HETEROARYL-METHYL) -5,9BETA-DIALKYL -6,7- BENZOMORPHANES
AT240373B (en) Process for the preparation of benzodiazepine derivatives
DE895903C (en) Process for the production of new basic substituted haloaryl-pyridyl-alkanones
AT251596B (en) Process for the preparation of new 5,6-dihydro-5-oxo-11H-pyrido [2,3-b] [1,5] benzodiazepines
DE1445665C (en) Derivatives of 2 (2 Morpholinoathylmer capto) pyridine compounds