CH376512A - Process for the preparation of new pyrazole derivatives - Google Patents

Process for the preparation of new pyrazole derivatives

Info

Publication number
CH376512A
CH376512A CH260960A CH260960A CH376512A CH 376512 A CH376512 A CH 376512A CH 260960 A CH260960 A CH 260960A CH 260960 A CH260960 A CH 260960A CH 376512 A CH376512 A CH 376512A
Authority
CH
Switzerland
Prior art keywords
piperidyl
methyl
acetic acid
benzyl
benzene
Prior art date
Application number
CH260960A
Other languages
German (de)
Inventor
Ernst Dr Jucker
J Dr Lindenmann Adolf
Erwin Dr Rissi
Original Assignee
Sandoz Ag
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
Priority to NL253320D priority Critical patent/NL253320A/xx
Priority to LU38903D priority patent/LU38903A1/xx
Priority to CH7527959A priority patent/CH373391A/en
Application filed by Sandoz Ag filed Critical Sandoz Ag
Priority to CH260960A priority patent/CH376512A/en
Priority to GB30802/61A priority patent/GB939901A/en
Priority to GB2123160A priority patent/GB932812A/en
Priority to US38769A priority patent/US3041342A/en
Priority to FR831821A priority patent/FR1295363A/en
Priority to BE592550A priority patent/BE592550A/en
Priority to DES69209A priority patent/DE1150989B/en
Publication of CH376512A publication Critical patent/CH376512A/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three 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
    • C07D231/38—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)

Description

  

  Verfahren zur Herstellung von neuen Pyrazol-Derivaten    Es wurde gefunden, dass man zu neuen     Pyrazol-          Derivaten    der allgemeinen Formel 1,  
EMI0001.0002     
    worin R1 den n-Butylrest oder eine Aralkylgruppe be  deutet und     R2    für ein Wasserstoff-, Chlor- oder Fluor  atom steht, gelangen kann, indem man     N-Methyl-          piperidyl-4-hydrazin    mit einem Acylessigsäurenitril  der allgemeinen Formel II,  
EMI0001.0006     
    kondensiert.

    Die als Ausgangsmaterialien verwendeten     Acyl-          essigsäurenitrile    der Formel II, worin R1 den     n-Butyl-          rest    oder eine Aralkylgruppe und R2 ein Fluoratom  bedeuten, werden hergestellt, indem man     4-Fluor-          benzylcyanid    in Gegenwart eines alkalischen Konden  sationsmittels mit Arylessigsäureäthylestern resp.     Va-          leriansäureestern    umsetzt.  



  <I>Beispiel 1</I>       1-(N-Methyl-piperidyl-4')-3-benzyl-4-phenyl-          5-amino-pyrazol     Zu einer Lösung von 9,4 g     &alpha;-(Phenyl-acetyl)-ben-          zylcyanid    in 25 cm3 Eisessig lässt man unter Rühren    eine Lösung von 5,6 g N-Methyl-piperidyl-4-hydrazin  in 8 cm3 Eisessig so zutropfen, dass die Temperatur  50  nicht übersteigt. Anschliessend wird das Reak  tionsgemisch noch 2 Std. bei Zimmertemperatur     wei-          tergerührt    und darauf der Eisessig im Vakuum bei  40-50  abdestilliert.

   Der Rückstand wird in 120 cm3  Wasser aufgenommen, die wässerige Lösung mit     Na-          triumcarbonat    alkalisch gestellt und gesättigt und mit  total 300 cm3 Benzol ausgeschüttelt. Nach Trocknen  über Magnesiumsulfat wird das Benzol im Vakuum  entfernt und der Rückstand im Hochvakuum destil  liert, wobei das     1-(N-Methyl-piperidyl-4')-3-benzyl-          4-phenyl-5-amino-pyrazol    zwischen 201-210  über  destilliert und in der Vorlage zu einer glasartigen  Masse erstarrt.  



  Durch Versetzen einer äthanolischen Lösung die  ser Pyrazol-Base mit der berechneten Menge einer  äthanolischen Lösung von Maleinsäure im Mol-Ver  hältnis 1 :2 und anschliessende Zugabe von Äther  scheidet sich das     1-(N-Methyl-piperidyl-4')-3-benzyl-          4-phenyl-5-amino-pyrazol-bis-maleinat    kristallin aus.  Nach zweimaligem Umkristallisieren aus Äthanol       schmilzt    das     Salz    bei l44-145 .

      <I>Beispiel 2</I>       1-(N-Methyl-piperidyl-4')-3-benzyl-4-(4''-fluor-          phenyl)-5-amino-pyrazol     Zu einer Lösung von 5,1 g     &alpha;-(Phenyl-acetyl)-          4-fluor-benzylcyanid    in 75 cm3 Eisessig lässt man un  ter Rühren eine Lösung von 2,6 g     N-Methyl-piperidyl-          4-hydrazin    in 3 cm3 Eisessig so zutropfen, dass die  Temperatur 50  nicht übersteigt.     Anschliessend        rührt     man das Reaktionsgemisch noch 2 Std. bei Zimmer  temperatur,     filtriert    von etwas ausgeschiedenem  &alpha;-(Phenyl-acetyl)-4-fluor-benzylcyanid ab, und dampft  das Filtrat im Vakuum bei 40-50  ein.

   Der Rück  stand wird in 100     cm3    Wasser aufgenommen, die wäs-      serige Lösung mit Natriumcarbonat alkalisch gestellt  und gesättigt und mit total 200 cm3 Benzol ausge  schüttelt. Nach Trocknen über Magnesiumsulfat wird  das Benzol im Vakuum entfernt und der kristalline  Rückstand, das     1-(N-Methyl-piperidyl-4')-3-benzyl-          4-(4''-fluor-phenyl)-5-amino-pyrazol,    zweimal aus  Benzol umkristallisiert. Smp. l25-127 .  



  Das als Ausgangsmaterial zur Verwendung gelan  gende &alpha;-(Phenyl-acetyl)-4-fluor-benzylcyanid (Smp.  105-107 ) wird hergestellt, indem man     4-Fluorben-          zylcyanid    in Gegenwart von Natriumäthylat in     Ätha-          nol    mit Phenylessigsäureäthylester umsetzt.

      <I>Beispiel 3</I>       1-(N-Methyl-piperidyl-4')-3-benzyl-4-(4''-chlor-          phenyl)-5-amino-pyrazol     Zu einer Lösung von 5,4 g     &alpha;-(Phenyl-acetyl)-          4-chlorbenzylcyanid    in 120 cm3 Eisessig lässt man  unter Rühren eine Lösung von 2,6 g     N-Methyl-pipe-          ridyl-4-hydrazin    in 3 cm3 Eisessig so zutropfen, dass  die Temperatur 50  nicht übersteigt. Darauf wird das  Reaktionsgemisch noch 1 Std. bei Zimmertemperatur  und 2 Std. bei 45  weitergerührt und anschliessend  das Benzol im Vakuum abgedampft.

   Der Rückstand  wird in 150 cm3 Wasser aufgenommen, mit Benzol  gewaschen, die wässerige Lösung mit     Natriumcarbo-          nat    alkalisch gestellt und gesättigt und mit total  200 cm3 Benzol extrahiert. Nach Trocknen über Ma  gnesiumsulfat wird das Benzol im Vakuum entfernt  und der Rückstand im Hochvakuum destilliert, wobei  das     1-(N-Methyl-piperidyl-4')-3-benzyl-4-(4''-chlor-          phenyl)-5-amino-pyrazol    unter einem Druck von  0,06 mm Hg bei l90-210  überdestilliert.

   Durch Ver  setzen einer äthanolischen Lösung von 1-(N-Methyl       piperidyl-4')-3-benzyl-4-(4''-chlorphenyl)-5-amino-          pyrazol    mit einer äthanolischen Lösung von Malein  säure im Molverhältnis 1: 2 wird das Bis-maleinat  hergestellt. Durch Zugabe von Äther     kristallisiert    das  Salz aus und schmilzt nach zweimaligem Umkristalli  sieren aus Äthanol/Äther bei 108-110 .

      <I>Beispiel 4</I>       1-(N-Methyl-piperidyl-4')-3-n-butyl-4-(4''-fluor-          phenyl)-5-amino-pyrazol     Zu einer Lösung von 11,0 g     &alpha;-Valeroyl-4-fluor-          benzylcyanid    in 50 cm3 Eisessig lässt man unter Rüh  ren eine Lösung von 6,45g     N-Methyl-piperidyl-4-          hydrazin    in 8 cm3 Eisessig so zutropfen, dass die Re-    aktionstemperatur 50  nicht übersteigt. Anschliessend  wird das Reaktionsgemisch noch 2 Std. bei Zimmer  temperatur     weitergerührt    und darauf der Eisessig im  Vakuum bei 40-50  abdestilliert.

   Der Rückstand wird  in 200 cm3 Wasser aufgenommen, mit total 150 cm3  Äther gewaschen, die wässerige Lösung mit     Natrium-          carbonat    alkalisch gestellt und gesättigt und mit total  350 cm3 Benzol extrahiert. Nach Trocknen über Ma  gnesiumsulfat wird das Benzol im Vakuum entfernt  und der Rückstand im Hochvakuum     fraktioniert,    wo  bei das     1-(N-Methyl-piperidyl-4')-3-n-butyl-4-(4''-          fluor-phenyl)-5-amino-pyrazol    unter einem Druck von  0,03 mm Hg bei 160-180  als dickflüssiges, gelbes  Öl überdestilliert. Beim Anreiben mit Benzol kristalli  siert das Pyrazol-Derivat, das anschliessend noch zwei  mal aus dem gleichen Lösungsmittel umkristallisiert  wird. Smp. 82-84 .  



  Das als Ausgangsmaterial zur Verwendung gelan  gende &alpha;-Valeroyl-4-fluor-benzylcyanid (Sdp. 138 bis  1410/0,1 mm Hg) wird hergestellt, indem man  4-Fluor-benzylcyanid in Gegenwart von     Natrium-          äthylat    in Äthanol mit Valeriansäureäthylester um  setzt.



  Process for the preparation of new pyrazole derivatives It has been found that new pyrazole derivatives of the general formula 1,
EMI0001.0002
    where R1 denotes the n-butyl radical or an aralkyl group and R2 denotes a hydrogen, chlorine or fluorine atom, can be obtained by N-methyl-piperidyl-4-hydrazine with an acyl acetic acid nitrile of the general formula II,
EMI0001.0006
    condensed.

    The acyl acetic acid nitriles of the formula II used as starting materials, where R1 is the n-butyl radical or an aralkyl group and R2 is a fluorine atom, are prepared by 4-fluorobenzyl cyanide in the presence of an alkaline condensation agent with aryl acetic acid ethyl esters, respectively. Valeric acid esters implemented.



  <I> Example 1 </I> 1- (N-methyl-piperidyl-4 ') -3-benzyl-4-phenyl-5-amino-pyrazole To a solution of 9.4 g of α- (phenyl-acetyl ) benzyl cyanide in 25 cm3 of glacial acetic acid, a solution of 5.6 g of N-methylpiperidyl-4-hydrazine in 8 cm3 of glacial acetic acid is added dropwise with stirring so that the temperature does not exceed 50. The reaction mixture is then stirred for a further 2 hours at room temperature and the glacial acetic acid is then distilled off in vacuo at 40-50.

   The residue is taken up in 120 cm3 of water, the aqueous solution is made alkaline with sodium carbonate and saturated and extracted with a total of 300 cm3 of benzene. After drying over magnesium sulfate, the benzene is removed in vacuo and the residue is distilled in a high vacuum, the 1- (N-methyl-piperidyl-4 ') -3-benzyl-4-phenyl-5-aminopyrazole between 201-210 distilled over and solidified in the template to a glass-like mass.



  By adding an ethanolic solution to this pyrazole base with the calculated amount of an ethanolic solution of maleic acid in the molar ratio 1: 2 and then adding ether, the 1- (N-methyl-piperidyl-4 ') - 3- benzyl-4-phenyl-5-aminopyrazole-bis-maleate crystalline out. After recrystallizing twice from ethanol, the salt melts at 144-145.

      <I> Example 2 </I> 1- (N-methyl-piperidyl-4 ') -3-benzyl-4- (4 "- fluorophenyl) -5-amino-pyrazole To a solution of 5.1 g of α- (phenyl-acetyl) -4-fluoro-benzyl cyanide in 75 cm3 of glacial acetic acid are allowed to drop in, with stirring, a solution of 2.6 g of N-methyl-piperidyl-4-hydrazine in 3 cm3 of glacial acetic acid so that the temperature Does not exceed 50. The reaction mixture is then stirred for a further 2 hours at room temperature, some of the α- (phenyl-acetyl) -4-fluoro-benzyl cyanide which has separated out is filtered off, and the filtrate is evaporated in vacuo at 40-50.

   The residue is taken up in 100 cm3 of water, the aqueous solution is made alkaline with sodium carbonate and saturated and shaken out with a total of 200 cm3 of benzene. After drying over magnesium sulfate, the benzene is removed in vacuo and the crystalline residue, 1- (N-methyl-piperidyl-4 ') -3-benzyl-4- (4 "- fluorophenyl) -5-aminopyrazole , recrystallized twice from benzene. M.p. l25-127.



  The α- (phenyl-acetyl) -4-fluoro-benzyl cyanide (melting point 105-107) which is used as starting material is prepared by reacting 4-fluorobenzyl cyanide in the presence of sodium ethylate in ethanol with phenylacetic acid ethyl ester.

      <I> Example 3 </I> 1- (N-methyl-piperidyl-4 ') -3-benzyl-4- (4 "- chlorophenyl) -5-aminopyrazole To a solution of 5.4 g of α- (phenyl-acetyl) -4-chlorobenzyl cyanide in 120 cm3 of glacial acetic acid is allowed to drop in a solution of 2.6 g of N-methylpiridyl-4-hydrazine in 3 cm3 of glacial acetic acid with stirring so that the temperature is 50% does not exceed. The reaction mixture is then stirred for a further 1 hour at room temperature and 2 hours at 45 and the benzene is then evaporated off in vacuo.

   The residue is taken up in 150 cm3 of water, washed with benzene, the aqueous solution is made alkaline with sodium carbonate and saturated and extracted with a total of 200 cm3 of benzene. After drying over magnesium sulfate, the benzene is removed in vacuo and the residue is distilled in a high vacuum, the 1- (N-methyl-piperidyl-4 ') -3-benzyl-4- (4' '- chlorophenyl) -5 -amino-pyrazole distilled over under a pressure of 0.06 mm Hg at 190-210.

   By Ver put an ethanolic solution of 1- (N-methyl piperidyl-4 ') -3-benzyl-4- (4' '- chlorophenyl) -5-aminopyrazole with an ethanolic solution of maleic acid in a molar ratio of 1: 2 Bis-maleinat is produced. The salt crystallizes out by adding ether and melts after recrystallizing twice from ethanol / ether at 108-110.

      <I> Example 4 </I> 1- (N-methyl-piperidyl-4 ') -3-n-butyl-4- (4 "- fluorophenyl) -5-amino-pyrazole To a solution of 11 , 0 g of α-valeroyl-4-fluorobenzyl cyanide in 50 cm3 of glacial acetic acid, a solution of 6.45 g of N-methyl-piperidyl-4-hydrazine in 8 cm3 of glacial acetic acid is added dropwise with stirring so that the reaction temperature is 50% does not exceed. The reaction mixture is then stirred for a further 2 hours at room temperature and the glacial acetic acid is then distilled off in vacuo at 40-50.

   The residue is taken up in 200 cm3 of water, washed with a total of 150 cm3 of ether, the aqueous solution is made alkaline with sodium carbonate and saturated and extracted with a total of 350 cm3 of benzene. After drying over magnesium sulfate, the benzene is removed in vacuo and the residue is fractionated in a high vacuum, where the 1- (N-methyl-piperidyl-4 ') -3-n-butyl-4- (4' '- fluorophenyl ) -5-amino-pyrazole distilled over under a pressure of 0.03 mm Hg at 160-180 as a thick, yellow oil. When rubbed with benzene, the pyrazole derivative crystallizes, which is then recrystallized two more times from the same solvent. M.p. 82-84.



  The α-valeroyl-4-fluoro-benzyl cyanide (b.p. 138 to 1410 / 0.1 mm Hg), which is used as the starting material, is prepared by treating 4-fluoro-benzyl cyanide in the presence of sodium ethylate in ethanol with ethyl valerate implements.

Claims (1)

PATENTANSPRUCH Verfahren zur Herstellung von neuen Pyrazol- Derivaten der allgemeinen Formel I, EMI0002.0035 worin R1 den n-Butylrest oder eine Aralkylgruppe be deutet und R., für ein Wasserstoff-, Chlor- oder Fluor atom steht, y dadurch gekennzeichnet, dass man N-Methyl-piperidyl-4-hydrazin mit einem Acylessig- säurenitril der allgemeinen Formel II, EMI0002.0041 kondensiert. PATENT CLAIM Process for the preparation of new pyrazole derivatives of the general formula I, EMI0002.0035 where R1 denotes the n-butyl radical or an aralkyl group and R. denotes a hydrogen, chlorine or fluorine atom, y is characterized in that N-methyl-piperidyl-4-hydrazine is mixed with an acyl acetic acid nitrile of the general formula II, EMI0002.0041 condensed.
CH260960A 1959-07-03 1960-03-08 Process for the preparation of new pyrazole derivatives CH376512A (en)

Priority Applications (10)

Application Number Priority Date Filing Date Title
NL253320D NL253320A (en) 1959-07-03
LU38903D LU38903A1 (en) 1959-07-03
CH7527959A CH373391A (en) 1959-07-03 1959-07-03 Process for the preparation of new pyrazole derivatives
CH260960A CH376512A (en) 1960-03-08 1960-03-08 Process for the preparation of new pyrazole derivatives
GB30802/61A GB939901A (en) 1959-07-03 1960-06-16 Improvements in or relating to amino pyrazoles
GB2123160A GB932812A (en) 1959-07-03 1960-06-16 Improvements in or relating to amino pyrazoles
US38769A US3041342A (en) 1959-07-03 1960-06-27 Amino-pyrazoles
FR831821A FR1295363A (en) 1959-07-03 1960-07-01 New pyrazole derivatives and their preparation
BE592550A BE592550A (en) 1959-07-03 1960-07-01 New derivatives of pyrazole and their preparation
DES69209A DE1150989B (en) 1959-07-03 1960-07-01 Process for the preparation of 5-amino-pyrazole derivatives

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CH260960A CH376512A (en) 1960-03-08 1960-03-08 Process for the preparation of new pyrazole derivatives
CH373046T 1960-03-08

Publications (1)

Publication Number Publication Date
CH376512A true CH376512A (en) 1964-04-15

Family

ID=25690928

Family Applications (1)

Application Number Title Priority Date Filing Date
CH260960A CH376512A (en) 1959-07-03 1960-03-08 Process for the preparation of new pyrazole derivatives

Country Status (1)

Country Link
CH (1) CH376512A (en)

Similar Documents

Publication Publication Date Title
DE2404113A1 (en) 4-PHENYLPIPERIDINE AND THEIR SALT WITH PHARMACEUTICAL ACIDS, METHOD OF MANUFACTURING THEIR PRODUCTS AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS
DE1795587A1 (en) New nitroso compounds and processes for their preparation
CH376512A (en) Process for the preparation of new pyrazole derivatives
DE1160443B (en) Process for the production of tetrahydro-oxathiazine-dioxides
DE1111208B (en) Process for the production of cough-relieving, basic substituted diphenylcarbinol esters
CH500982A (en) 3 phenyl-7-amino carbostyriles as brightening agents
CH484070A (en) Process for the preparation of basic substituted phenylacetonitriles
CH374071A (en) Process for the preparation of new isoindoline derivatives
DE745314C (en) Process for the preparation of 1-oxyphenyl-3-aminoalkyl compounds with an analgesic effect
DE826133C (en) Process for the preparation of dihydroresorcinol carbamic acid esters
CH437354A (en) Process for the preparation of 1- (acylphenyl) -2-amino-1,3-propanediols
AT206892B (en) Process for the preparation of new tertiary amines
AT300785B (en) Process for the preparation of new 1-Β-phenylpropioloyl-3-indolylacetic acid derivatives
DE1620189C (en) 4 (2 Carbo alpha glyceryloxy phenyl amino) chloroquinoline acetomde and a process for their preparation
DE959015C (en) Process for the preparation of new pharmacologically active basic esters and their salts
AT235831B (en) Process for the preparation of new esters of basic carbinols and their acid addition salts
AT331804B (en) PROCESS FOR THE PREPARATION OF NEW 6-AZA-3H-1,4-BENZODIAZEPINES, THEIR OPTICAL ISOMERS AND THEIR SALTS
AT203496B (en) Process for the preparation of new tertiary amines
DE871761C (en) Process for the preparation of basic esters
AT273940B (en) Process for the preparation of new ω- (2-amino-5-halobenzylamino) alkanoic acids, their esters, amides and / or salts
AT201582B (en) Process for the preparation of new dimethylaminopropoxybenzenes
CH359703A (en) Process for the production of new piperidines
DE1088484B (en) Process for the production of bicyclically substituted carbinamines or their non-toxic salts with an effect on blood pressure
AT223204B (en) Process for the production of new azepine derivatives
DE1470428C (en) 5- (beta-dimethylaminoethyl) -5,6dihydro-6-oxomorphanthridines