A new synthesis of 3-amino-4-arylpyrazoles involving the acetic acid catalyzed reaction of hydrazine with aformylarylacetonitriles is described. Seventeen new pyrazoles in this series are reported, as well as thirteen new N-substituted derivatives of 3-amino-4-phenylpyrazole. While a number of these compounds exhibited muscle relaxant activity, 3-amino-4-phenylpyrazole was the most active. Structure-activity relationships are discussed.In connection with an investigation of the synthesis and pharmacologic action of muscle relaxants, it was necessary to prepare a number of 3-aminopyrazoles unsubstituted in the 1-position. Although numerous synthetic routes for the formation of the pyrazole ring system have been described in the literature,2 relatively few convenient methods for the preparation of 3-aminopyrazoles are described. Thus, reduction of 3-phenyl-azopyrazoles3 and 3-nitropyrazoles,4 hydrolysis of bispyrazolyl formamidines,5 and modification of a carboxylic acid derivative in the 3-position via the Curtius or Hoffman rearrangements43•6 have been used.A more direct route to 3-aminopyrazoles was suggested by the reaction of hydrazine with an a-substituted-/3-ketonitrile to give a 3-amino-4,5-disubstituted derivative.7 When the enol ether of an a-cyanoketone8 or an -cyanoaldehyde9 was used, similar products were obtained. The preparation of 3aminopyrazoles by the direct reaction of hydrazine with an -cyanoaldehyde has not been reported, presumably because of the well known reaction between aldehydes and hydrazine to give excellent yields of azine. Treatment of -formylphenylacetonitrile (B) with hydrazine did, in fact, generate the azide (D). However, small yields of 3-amino-4-phenylpyrazole (C) could be obtained by using excess hydrazine. Furthermore, yields of up to 88% of the pyrazole (C) could be obtained by adding an amount of acetic acid in excess of that required to neutralize the hydrazine. This was found to be a quite general reaction, and the compounds in Table I were prepared using the same procedure and the appropriate a-formylarylacetonitriles.The -formylarylacetonitriles were prepared by a modification of the method of Walther and Schickler10 in which the corresponding arylacetonitriles wrere (1) To whom all inquires concerning pharmacology should be sent.(2) T. L.

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