CH291677A

CH291677A - Process for preparing 1-phenyl-2,3-dimethyl-5-pyrazolone aldehyde.

Info

Publication number: CH291677A
Authority: CH
Inventors: Anonyme Luxema Societe
Original assignee: Anonyme Luxema Societe
Priority date: 1949-07-30
Filing date: 1950-07-20
Publication date: 1953-06-30

Description

  

  Procédé de préparation de l'aldéhyde de 1-phényl-2,3-diméthyl-5-pyrazolone-    La présente invention, due à     M..        .1.        Ledrut,     est relative à un procédé de préparation de       l'aldélivde    de 7-phényl=?,3-diméthvl-5-pyrazo-         lone    ou     aldéhvde    d'antipyrine, une substance  connue correspondant à la formule suivante:

    
EMI0001.0007     
    On sait qu'en faisant réagir de la     diphényl-          formamidine    sur de la     1-phényl-3-méthyl-          pyrazolone,    on forme la base de     Schiff    de    cette     pyrazolone    selon le schéma de réaction  suivant:  
EMI0001.0014     
    La. même base de     Schiff    peut encore être  obtenue par action de     phénylisonitrile    sur la         1-phényl-3-méthyl-pyrazolone,    selon le schéma  de réaction suivant:

      
EMI0002.0001     
    On sait     aussi    qu'en faisant agir à 100  C  de l'iodure de méthyle sur la base de     Sehiff     précitée, en présence d'alcool méthylique, on  obtient     l'iodométhylate    correspondant:  
EMI0002.0005     
    Dans le procédé suivant l'invention, on  traite     l'iodométhylate    de la base de     Schif    f  susdite, à l'aide d'une solution aqueuse de car  bonate de     potassium,    de faon à obtenir la  base de     Schiff    de la     1-pliényl-2,3-diméthyl-5-          p-,#razolone,    de formule suivante:

    
EMI0002.0012     
    et on décompose cette dernière base de     Schiff,     par chauffage à l'ébullition, en présence d'une       solution    aqueuse d'un agent, d'hydrolyse qui  peut être une base telle que l'ammoniaque ou  le bicarbonate de potassium, ou un acide tel  que l'acide acétique.  



  L'aldéhyde de     1-phényl-2,3-diméthyl-5-          pyrazolone    se présente sous forme de cristaux  blanc jaunâtre fondant à 160-161  C. Elle  est soluble dans l'eau, l'alcool éthylique, le  chloroforme, l'acétate d'éthyle, l'acétone et le       dioxane.     



  Les     exemples    suivants illustrent l'inven  tion       Exemple        Z:     0,3 g de     1-phényl        2-iodo-2,3-diméthyl-4-          phényliminométhyl-5-pyrazolone    est préparé    selon la méthode de     Passerini    et     Loseo        [Gazz.          Chim.        Ital.    70, 412     (19401)]    et dissous dans  5 cm- d'eau chaude.

   A la solution obtenue, on       ajoute    5     cm?,        d'une        solution    à     25        %        de        car-          bonate    de potassium. Au moment de l'addition  de la solution de carbonate de     potassium,    on  observe la. formation d'un     trouble,    puis l'appa  rition d'une huile. On chauffe le mélange pen  dant une demi heure au bain-marie. On laisse       refroidir    et on extrait la solution obtenue au  chloroforme. Le     résidu    se prend en masse.

   On  purifie la base de     Schiff    obtenue par     recrus-          tallisa.tion        dans    le benzène. Cette base de     Schifî     fond à 152  C et possède la formule brute sui  vante:     C1sH170N3.     



  L'analyse     quantitative    de cette base de       Sehiff    a donné les résultats suivants, compa  rés aux résultats     théoriques:       Trouvé:       C=74)2211/o;    H =     6,081/o;        N=14,45%;     P. M. = 230.  



  Calculé       C=74>11/o;    H = 5,S8 0/0; N=14,43%;  P. M. = 291.    5     g,    de     1-phényl-2,3-dimét.hyl-4-phényl-          iniinométhyl-5-pyrazolone    sont dissous dans  100     cm3    d'eau bouillante. La solution obtenue  est additionnée de 5     em3    d'une solution     N,110     de soude     eaustique.    On fait. bouillir le mélange  pendant 15 secondes, puis on neutralise à  l'aide d'acide acétique dilué. On laisse refroi  dir, on extrait. l'aniline au moyen de benzène  et on sépare l'aldéhyde par extraction au  chloroforme.

   Cette aldéhyde, recristallisée  dans l'alcool     isopropylique,    fond à     7.60     C.         Exemple     2     g    de     1-phény        1-2,3-diméthyl-4-phényl-          iminométhyl-5-pyrazolone,    préparée comme dé  crit dans l'exemple 1, sont mis en suspension           dans        \?b        em3    d'eau bouillante. La solution  obtenue est additionnée de 2     cms    d'acide acé  tique à 80 /0. On chauffe le mélange pendant  5 minutes à l'ébullition.

   Après ce chauffage,  on neutralise à l'aide de bicarbonate de     so-          dium,    on laisse refroidir, on extrait l'aniline  formée à l'aide d'éther de pétrole et on sépare  (le la solution aqueuse restante l'aldéhyde de       l-pliényl2,3-dimétliyl-5-pyrazoloiie    au moyen  de chloroforme.  



  Cette aldéhyde, purifiée par sublimation  à l60  C sous une pression de 0,01 mm de  mercure, se présente sous forme de cristaux       incolores    fondant à 160  C.  



  L'aldéhyde de     1-phényl-2,3-diméthyl-5-          pyrazolone    ou aldéhyde d'antipyrine, obte  nue par le procédé décrit dans les exemples  ci-dessus, peut     avantageusement    être purifiée.  A cette fin, on peut, de manière connue en  soi, transformer l'aldéhyde brute en un dé  rivé de la fonction carbonyle, tel que     l'oxyme,          l'hy        drazone    éventuellement substituée ou la.       semiearbazone,    et décomposer ensuite ce dé  rivé, de manière à récupérer l'aldéhyde sous  forme pure.  



       L'aldéhyde    de     1-phényl-2,3-diméthyl-5-          pyrazolone    ou aldéhyde d'antipyrine préparée  par les procédés décrits dans l'un ou l'autre  des exemples précédents se caractérise par une  forte activité     hypothermisante.    Des essais com  paratifs ont montré que les propriétés     hypo-          thermisantes    de cette aldéhyde sont beaucoup  plus marquées que celles de l'antipyrine,     tan-           < lis    que la toxicité de l'aldéhyde précitée n'est  que faiblement     plus    sensible que celle de  l'antipyrine.

   La dose mortelle     d'aldéhyde     d'antipyrine     est    de 2,04     gjkg    chez le cobaye,  tandis que celle de l'antipyrine est de  2,85     g/kg.     



  L'aldéhyde de     1-phényl-2,3-diméthyl-5-          pyrazolone,    obtenue suivant l'invention, est  employée comme médicament dans les cas  oui une activité antithermique est souhaitée.



  Process for the preparation of 1-phenyl-2,3-dimethyl-5-pyrazolone aldehyde- The present invention, due to M .. .1. Ledrut, relates to a process for preparing the aldehyde of 7-phenyl = ?, 3-dimethyl-5-pyrazolone or antipyrine aldehyde, a known substance corresponding to the following formula:

    
EMI0001.0007
    It is known that by reacting diphenylformamidine with 1-phenyl-3-methyl-pyrazolone, the Schiff's base of this pyrazolone is formed according to the following reaction scheme:
EMI0001.0014
    The same Schiff base can also be obtained by the action of phenylisonitrile on 1-phenyl-3-methyl-pyrazolone, according to the following reaction scheme:

      
EMI0002.0001
    It is also known that by allowing methyl iodide to act at 100 ° C. on the aforementioned Sehiff base, in the presence of methyl alcohol, the corresponding iodomethylate is obtained:
EMI0002.0005
    In the process according to the invention, the iodomethylate of the aforesaid Schiff base is treated with an aqueous solution of potassium carbonate, so as to obtain the Schiff base of 1-plienyl- 2,3-dimethyl-5- p -, # razolone, of the following formula:

    
EMI0002.0012
    and this latter Schiff's base is decomposed by heating to boiling in the presence of an aqueous solution of a hydrolysis agent which can be a base such as ammonia or potassium bicarbonate, or an acid such as acetic acid.



  1-Phenyl-2,3-dimethyl-5-pyrazolone aldehyde occurs as yellowish-white crystals melting at 160-161 C. It is soluble in water, ethyl alcohol, chloroform, ethyl acetate, acetone and dioxane.



  The following examples illustrate the invention. Example Z: 0.3 g of 1-phenyl 2-iodo-2,3-dimethyl-4-phenyliminomethyl-5-pyrazolone is prepared according to the method of Passerini and Loseo [Gazz. Chim. Ital. 70, 412 (19401)] and dissolved in 5 cc of hot water.

   To the resulting solution is added 5 cc of a 25% solution of potassium carbonate. At the time of addition of the potassium carbonate solution, the. cloudiness, followed by the appearance of an oil. The mixture is heated for half an hour in a water bath. Allowed to cool and the resulting solution was extracted with chloroform. The residue solidifies.

   The Schiff base obtained is purified by recrystallization from benzene. This Schifl base melts at 152 C and has the following crude formula: C1sH170N3.



  Quantitative analysis of this Sehiff basis gave the following results, compared to theoretical results: Found: C = 74) 2211 / o; H = 6.081 / o; N, 14.45%; P. M. = 230.



  Calculated C = 74> 11 / o; H = 5, S80 / 0; N, 14.43%; P. M. = 291. 5 g of 1-phenyl-2,3-dimét.hyl-4-phenyl-eniinométhyl-5-pyrazolone are dissolved in 100 cm3 of boiling water. To the solution obtained is added 5 em3 of a N, 110 solution of water soda. We do. boil the mixture for 15 seconds, then neutralize with dilute acetic acid. We let cool say, we extract. aniline with benzene and the aldehyde separated by extraction with chloroform.

   This aldehyde, recrystallized from isopropyl alcohol, melts at 7.60 C. Example 2 g of 1-pheny 1-2,3-dimethyl-4-phenyl-iminomethyl-5-pyrazolone, prepared as described in example 1, are suspended in \? b em3 of boiling water. The solution obtained is added with 2 cms of acetic acid at 80/0. The mixture is heated for 5 minutes at the boil.

   After this heating, the mixture is neutralized with sodium bicarbonate, allowed to cool, the aniline formed is extracted with petroleum ether and the remaining aqueous solution is separated from the aldehyde of l -plienyl2,3-dimethyl-5-pyrazoloiie by means of chloroform.



  This aldehyde, purified by sublimation at 160 C. under a pressure of 0.01 mm of mercury, is in the form of colorless crystals melting at 160 C.



  The aldehyde of 1-phenyl-2,3-dimethyl-5-pyrazolone or antipyrine aldehyde, obtained by the process described in the examples above, can advantageously be purified. To this end, it is possible, in a manner known per se, to convert the crude aldehyde into a derivative of the carbonyl function, such as the oxym, optionally substituted hy drazone or Ia. semiearbazone, and then decompose this derivatized, so as to recover the aldehyde in pure form.



       The aldehyde of 1-phenyl-2,3-dimethyl-5-pyrazolone or antipyrine aldehyde prepared by the methods described in either of the preceding examples is characterized by a strong hypothermic activity. Comparative tests have shown that the hypothermic properties of this aldehyde are much more marked than those of antipyrine, while the toxicity of the aforementioned aldehyde is only slightly more sensitive than that of the. antipyrine.

   The lethal dose of antipyrine aldehyde is 2.04 g / kg in guinea pigs, while that of antipyrine is 2.85 g / kg.



  The aldehyde of 1-phenyl-2,3-dimethyl-5-pyrazolone, obtained according to the invention, is employed as a medicament in cases where antithermic activity is desired.

Claims

CLAIM: Process for preparing 1-phenyl-2,3-diniethyl-5-pyrazolone aldehyde, of the following formula: EMI0003.0032 starting from the iodomethylate of the 1-phenyl-3-methyl-5-pyrazolone Schiff base, of the following formula EMI0003.0036 characterized in that the iodomethylate of the aforesaid Schiff's base is treated with an aqueous solution of potassium carbonate, so as to obtain the Schiff's base of 1-phenyl-2,3 -dimethyl-5-pyrazolone, of formula:

EMI0003.0043 and the latter Schiff's base is decomposed by heating to boiling in the presence of an aqueous solution of a hydrolysis agent. SUB-CLAIMS 1. A method according to claim, characterized in that the hydrolysis agent is ammonia. 2. Method according to claim, charac terized in that the hydrolysis agent is sodium bicarbonate. 3. Process according to claim, charac terized in that the hydrolysis agent is acetic acid. 4.

Process according to Claim, characterized in that the above-mentioned iodomethylate is dissolved in hot water, and to the solution obtained is added a substantially equivalent volume of a 25% solution of potassium carbonate. , the mixture is heated in a water bath for.

a few minutes, it is left to cool again, it is extracted with chloroform, the Schiff base obtained is crystallized in a suitable solvent, this base is dissolved in hot water, a small volume of an aqueous solution of caustic soda is added . it is boiled for less than a minute, neutralized with acetic acid, allowed to cool, the aniline formed is extracted with an organic solvent and the remaining solution is extracted by means of chloroform. 5.

Process according to claim and sub-claim 3, characterized in that the aforementioned iodomethylate is dissolved in hot water and added to the. solution obtained Him volume substantially equivalent to a _5% solution of potassium carbonate, the melanve is heated in a water bath for some;

minutes, allowed to cool, extracted with chloroform, crystallized in a suitable solvent the Schiff base obtained, said ,, out. this base in hot water, add a small volume of acetic acid, boil for 5 minutes, neutralize with sodium bicarbonate, allow to cool, extract the aniline formed by means of a organic solvent and the remaining solution is subjected to extraction with eliloroform.