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times cortisol. The isomeric 1’- and 2’-methylpyrazoles X X I and X X were, however, of more comparable potency (1.5and 5.9times cortisol, respectively). Thus the 2’-p-fluorophenylpyrazole function is the most powerful activity enhancing group yet reported in the anti-inflammatory field. The application of these findings to the 6-dehydro-6-methylcortisol series is described in a separate communication. 17.18
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nitrogens are readily interconvertible, is that the isotopic rearrangement, reaction (l), should accornpany the solvolysis of a labelled diazonium salt. We now show evidence for this reaction. Ar+S*-N
+Ar+N=N*
(1)
Benzenediazonium-ar-Ni5 fluoroborate was prepared from aniline-Nlj (99yo “5) by diazotization with norH2C-0, mal sodium nitrite. Decomposition in water a t 35’ to the extent of 80% (assuming the rate to be the same as that of normal diazonium salt2) left a solution of residual diazonium salt which was degassed and then degraded by treatment with sodium azide.3 The “primary nitrogen” derived only from the azide ion, was discarded, except in one experiment in which it was shown to have normal isotopic abundance of N16. The R‘ “secondary nitrogen,” 1/4 of which is derived via phenylpentazole from the @-nitrogen of the diazonium salt, Ri R2 X Ri Ra H CH3 F I V” SYII CsHj CHI was collected for analysis. A second sample of nitroH CH, F XVIII = with free side v gen was obtained by arsenite reduction of the total V I = 1- with free side chain XVII chain phenyl azide; this contained the remainder of the pV11= 6-CaHdF CH,< F XIX CH, CHq VI11 ‘p-C6H;F CH; F XXI = with free s i d e nitrogen and none of the a-nitrogen. Mass spectrofree side chain 21XIX chain 21-acetate metric analysis of these samples then gives the NI5 acetate XXY C6Hs H content of the @-nitrogen: i t was found to have 2.6% XI H CH3 H 4,5a-dihydro nil6 (natural abundance 0.3673. The value calculated XI1 C+s CH3 H from the phenyl azide nitrogen agreed with that from XI11 = with free side XI1 chain the “secondary nitrogen” if the literature value3 for XIV P-C6H4F CI-13 H the relative amounts of reaction by the two routes XV = with free side (which we confirm more roughly) was used. XIV chain 21-acetate The quantitative specificity of labelling and the XXVII CHI CH3 H XX = with free side degradation were both checked by repeating the same XXVII chain 21-acetate process omitting only the prior 80% decomposition. XXIV CsH6 H H All samples had only natural abundance of N15, showing 4,ja-dihydro that N15 appears in the p position only after extensive XXVI = with 4,Scu-dihydro XXIY free side chain 21decomposition. Reaction (1) therefore occurs during acetate the solvolysis reaction. 11-keto rather than 11-p-hydroxyl. If reaction (1) follows a first-order course, with the rate constant k , , accompanying the solvolysis with rate (17) J. H. Fried, H. Mrozik, G. E. Arth, T. S.Bry, S . G. Steinherg, 11. Tishler, R. Hirschmann a n d S. L. Steelman, J . .4m. Chenz. SOC.,86, Jan. constant k,, it can be shown that k t = 0.014k,. This 20 (1963). result is consistent with the existence of an intermediate (IS) It is noteworthy t h a t in the androgen series, the Ga-methyl and the which can return to diazonium ion, as well as going on Sa-F-substituents decrease the activity of the pyrazoles,eb to phenol; in this intermediate the initial C-N bond is MERCKSHARP 8r DOHME RALPHHIRSCHMASN RESEARCH LABORATORIES N.G. STEIXBERC nearly or totally broken. PAULBUCHSCHACHER The reaction ( 2 ) is a possible return reaction of DIVISIONOF MERCK& Co., ISC. RAHWAY, KEWJERSEY J . H . FRIED interest in connection with nitrogen fixation. Although ”
G. J . KEST MAXTISHLER
MERCKISslITUTE ITOR THERAPEUTIC l
