alnal. Found: C, 63.25; H, 7.34; C1, 8.44, prepared from the corresponding 21-mesylate with lithium chloride in acetic acid was inactive in the liver glycogen assay a t 10 times the minimum effective dose of cortisone acetate.
keto-A4 and ll-keto-A%ystems), 8.0s p (acetate) ; Found: C, 71.69; H, 7.17) in contrast t o 111, gave a positive tetrazolium test, it is formulated as 21acetoxy-l'TP-methyl-18-nor-9{, 1A{-1 7a-S4>'?-pregn:tdiene-3,11,20-trione. Structure VI, an unlikely alternative for the ' r H E SQUIBB IVSTITUTE FOR JOSEF E HERZ acid product on mechanistic XIEDICAL RESEARCH JOSEF FRIED methanol-sulfuric YFII R R I T \ I \ \ ICK, N. J. PAUL GRABOIVICHgrounds, is ruled out further by the U . V . spectruiii EMILYI: SARO of V,and because the reaction sequel I V can bc. paralleled in the (la-fluorohydrocortisone series. RECEIVED JVLY 20, 19.56 The conversion of I1 to I11 resembles the conversion of 33-acetoxy-16a,l7a-epoxy-lj-pregnene20-one to 3/3-acetoxy-l6@-forniyloxy-l75-methylwith formic A CONTRIBUTION TO T H E CHEMISTRY OF STEROID lS-n0r-17a-A~~~~-pregnadiene-20-orie 17,21-OXIDES acid in the presence of sulfuric acid.j The stabilization of the intermediate carbonium ion a t C-13 Sir: by ring closure rather than by formation of an Treatment of 1lp, 17a-dihydroxy-21-iodo-.l--preg- olefin had, however, not been previously described. T1-e have also prepared 17a,21-epoxy-Ocu-fluoronene-3,20-dione1 (I) with silver dihydrogen phosphate afforded, in addition to the steroid 21-phos- I l@-hydroxy-A4-pregnene-3,20-dione(VIII), m.p, phate, a water-insoluble by-product, m.p. 237-243" 236" (dec.), [a]E"' +192"; A::,"" 237 nip ( E = 3.0 p, 5 . 5 p , 6.07 p , sh 6.17 p ; Found. (dec.), [.]Ehf +246"; AZEl;'" 240.5mp (E = 16,300); 16,900) ; :;A!: 2.72 p , 2.8-2.38 p (OH), 5.54 p (20-ketone), C, 69.18; H, 7.47.6 It is of considerable interest that whereas compounds 11-V are essentially (i.0 p (3-ketone), 6.15 p (A4-double bond); 2.95 p , 3.55 p, 6.0-6.05 p , sh 6.12 p ; Found: C, inactive7 in the systemic granuloma inhibition and 73.49; H, 8.15. The mobility of the compound liver glycogen tests, VI11 exhibited anti-inflammaby paper strip chromatography is nearly identical tory activity of the same order of magnitude as with that of 110-hydroxyprogesterone. The prod- hydrocortisone in these tests7 uct was formulated as 17a,21-epoxy-ll/3-hydroxy?.. A4-pregnene-3,20-dione (11). The same structure has been assigned? to a different product VI1 [alp:' +69"; ::A: 5.72 p , (m.p. 198.5-201"; 6.02 p, 6.16 p) which Allen, et al., obtained by treating 17,21-epoxy-1lp-hydroxy-A4-pregnene3,20-dione 3,20-bisethplene ketal with aqueous methanolic sulfuric acid. However, the infrared spectrum of VI1 is inconsistent with structure 11, since 3-oxetanones generally absorb a t 5.j5 p . 3 The properties of VI1 are, however, in fair agreement with a substance I11 (m.p. 201-206" ; [a]ghf +.52O; ":A:: 240 mp ( E = 16,400); A$:, 2.79 p , 11, R = H 2.95 p , 5.72 p, 6.03 p , 6.17 p ; Found: C, 73.37; H, 7.96) which resulted from treating I1 with i-111, R = F CH~OAC methanolic sulfuric acid. I11 was shown to be 1 13 a,2 1-epoxy-11/?-hydroxy-17b-methyl-l 8-nor- 17aA4-pregnene-3,20 - dione by relating the position of the oxide-bridge to the hydroxyl function a t C-11. Oxidation of I11 with chromium trioxide-pyridine4 gave the 1 1-ketone IV (m.p. lt57-138"; At:" 236 mp (E = 15,200); 5.70 5.70 p , 3.83 p, 3.97 p, 6.16 p (no OH); : : A: p, 3.82 p , 5.99 p, 6.16 1.1; Found: C, 73.49; H, 7.56). When the latter was refluxed with pyridine and acetic anhydride, a large increment in the extinction a t 238 m p occurred, demonstrating the OF THE RALPHHIRSCHMANX formation of a second a,@-unsaturated ketone CONTRIBUTION MERCK-SHARP & DOHME GEORGE A. BAILEY group. Since the product (V) (m.p. 185-186", RESEARCH LABORATORIES GEORGE I. POOS 238 mp ( E = 26,200); A:,' 5.72 p and 5.83 DIVISIONO F MERCK& C O . , ISC. ROBERTWALKER RAHWAY, NEW JERSEY JOHS M. CHEMERDA p (21-acetate, 20-ketone), 6.02 p and 6.18 p (3( I ) C. T. Bergstrom, U . S . P a t e n t 2,ti84.OF8, July 27, 1954. (2) W, S. Allen, S . Bernstein, LZ. Heller a n d R . Littell, T H I S 77, 4784 (1955). D r . Bernstein, whom we advised of our
RECEIVED JULY 27, 1956
JOURNAL,
results. informed us t h a t he, too, h a s come to question t h e correctness uf his structural assignment and t h a t he is pursuing t h e m a t t e r himself. (3) G. B Hoey, D. 0. Dean a n d C . T. Lester, ibid., 7 7 , 391 (1955); B, L. Rfurr, G. R . Hoey a n d C. T. Lester, ibid., 77,4130 (1955). (4) G. I. Poos, G . A . A r t h , R . E. Bey!er a n d L. H. S a r e t t , ibid., 7 6 , 421" [1953),
(5) K. Heusler a n d A. WetLstein, B e y . , 87, 1301 (1954). (6) T h e 11-keto-analog of I1 was first isolated b y Dr. R . E. Beyler a n d Miss F. Hoffman in anothei connection a n d independently assigned a 17,21-oxide structure (7) W e are very much inriehted t i , D;. C .A W i n t e r ani1 n r . C C Porter f u r t h e animal acsayr
