4722
IC. P. GRABER,A. C . HAVEN, JR.,
AND
N . L. WENDLER
VOl. 75
A8(14)-Cholestene-3~-ol-7-one (VI) from VIIa (I(.N.).-A product that separated as a solid on dilution of the cooled solution of 400mg. of VIIa and 1cc. of 36% hydrochloric acid reaction mixture. This material absorbed at 248 mp and in 20 cc. of 95% ethanol was refluxed for 3 hr. and diluted to the infrared spectrum indicated the absence of a carbonyl saturation. The product separated as colorless needles and group; it was acetylated and the acetate chromatoafter recrystallization from methanol melted at 129-130' graphed. Fractions eluted by petroleum ether-benzene (7:3 and 1:l) crystallized from ether-methanol to give (240 rng.), hEtoH 261 mp (8,800),XChf 3.0, 6.03, 6.31 p . Anal. Calcd. for C2,Ha402 (400.62): C, 80.94; H, 11.07. elongated prisms melting in the range 90-95". The combined crystallizate (300 mg.) on two recrystallizations from Found: C, 80.91; H, 10.97. afforded A*J4-cholestadiene-3p-y1acetate The acetate, m.p. 141-142', CYD -53.3" Chf (c 1.25), did ether-methanol (x), m.p. loo-lolo, XEtoH 249 mp (19,800), CYD -19.3' not depress the m.p. of an authentic ample.^ Chf (c 2.22), no depression in m.p. on admixture with an Wolff-Kishner Reduction of AsJ4-Cholestadiene-3~-01-'7m.p. 99-99.4'. one 3-Acetate (IX)(W.-Y. H.1.-Reduction of 1 E. of di- authentic enone by the Huang-Minlon procedure a t 200" gavea crude CAMBRIDGE, MASSACHUSETTS
[CONTRIBUTION FROM T H E
RESEARCH LABORATORIES O F MERCK 82 e o . ,
INC.]
Ag~('l)-Dehydro Cortical Steroids. Synthesis of AY~~"~-Anhydro-17-hydroxycorticosterone Acetate B Y K. P. GTC4BER, A.
c. HAVEN,JR.,
4ND
N. L.
WENDLEK
RECEIVED MAY28, 1953
The formation of several functionally substituted ~l~~(~~)-dehydrosteroids including the synthesis of A9j(11)-anhydro-17hydroxycorticosterone acetate is described
The conversion of 1lp-hydroxylated cortical rivative (VI) could also be prepared smoothly and steroids t o their Ag,(l1)-anhydroderivatives has in good yield by the direct dehydration of 4,5been variously described by Reichstein and his dihydro-17-hydroxycorticosterone acetate (11)3 associates' employing conditions of room tempera- again employing phosphorus oxychloride in pyriture dehydration with phosphorus oxychloride in dine a t room temperature. The relative ease and pyridinele as well as with refluxing acetic-hydro- freedom from side reactions with which the dechloric acid mixtures.la-d By the latter technique hydration of I1 proceeded is noteworthy in view of Shoppee and ReichsteinId were able to convert the recognized lability of the cortical steroid side corticosterone acetate to A9~(11)-anhydrocortico-chain.5 Bromination of VI followed by dehydrosterone acetate. We wish to report the conversion bromination with semicarbazide acetate completed of certain 110-hydroxylated steroids and particu- the synthesis of As~~11~-anhydro-17-hydroxycorticolarly those bearing the 17-hydroxycortical side chain sterone acetate (VIII) .6 This substance was also into their respective ~l~r(~')-anhydro derivatives. formed in low yield by the direct dehydration of 17These conversions have made possible several hydroxycorticosterone acetate (IV) with phosroutes culminating in the synthesis of Ag,(ll)-anhy- phorus oxychloride in pyridine. The low yield of dro- 17-hydroxycorticosterone acetate (VIII) . anhydro derivative obtained from IV in the latter Treatment of 20-cyano-17-pregnene-11~,21-diol- manner suggests involvement of the A-ring un:%one 2 1-acetate (I) with phosphorus oxychloride saturated ketone, possibly by way of formation in in pyridine a t room temperature afforded the part of a phosphorylated enolate. ilg*('l)-anhydrocyanopregnene(V) in 50-60% yield. It had been our earlier experience3that the hydroSomewhat lower yields of this compound were ob- gen bromide catalyzed bromination of 4,5-dihydrotained under dehydration conditions employing 17-hydroxycorticosterone acetate (11) gave variable refluxing 1: 4 hydrochloric-acetic acid. Id Hydroxy- results. It was subsequently observed that I1 in lation of V employing a slight excess over one mole acetic acid containing catalytic amounts of hyof osmium tetroxide afforded VI in good yield, drogen bromide underwent a fairly rapid loss of with no apparent evidence of involvement of the rotation which after several hours became nearly Lg*(")-doublebond in the hydroxylation reaction. constant and approached the value for the anhydro In this regard i t has previously been reported that derivative VI (Fig. 1). The latter could, in fact, ~ I ~ ~ ( ~ ~ ) - dbonds o u b l ein the normal (E@) steroid be isolated from such an experiment in good yield. series are essentially unreactive to osmium tetrox- The same room temperature dehydration of I1 -+ d e S in contrast to the ullo series ( s a ) where hy- VI was also observed to occur in chloroform as droxylation proceeds readily. The anhydro de- well as acetonitrile in the presence of small amounts of hydrogen bromide. By employing Q-toluene(1) See for example (a) C. W. Shoppee, H e l a . Chim. Acta, 23, 740 sulfonic acid as the catalyst in acetic acid solution, (1940); (bj C. W. Shoppee and T. Reichstein, i b i d . , 24, 3.51 (1941); ( c ) P. Hegner and T. Reichstein. ibid., 26, 715 (1943); (d) C. T V however, no substantial change in rotation correShoppee and T. Reichstein. i b i d . , 26, 1316 (1843); (e) E. Seebeck and sponding to dehydration was observable even when T. Reichstein. ibid., 26, 536 (1943). ( 2 ) N.L. Wendler, R. P . Graber, R. E. Jones and A4. Tishler, THIS the concentration of p-toluenesulfonic acid was 72, 5793 flSS0); 74, 3G30 (1052). ( 3 ) I,, H. Sarett in 1,. F. Fieser and M . I'ieser, "Natural Products Related to Phenanthrene," Rcinhold Pub1 C o r p , X e w York. N. Y., 3rd JOURXAL,
4 ) R. Hirgchniaun, C S. S n < x I d v , J r , nnrl h' 1.. Wmcller, THIS
, I ( ~ I ~ R K 76, ~ I , ,:32.?,? ( l ! l X + )
(5) See for example, L. F . Fieser and M. Fieser, "Natural Products Related t o Phenanthrene," Reinhold Puhl. Co., Xew York, N. Y., 1849, Chapt 3; V. R. Mattox, Trirs J O U R N A L , 74, 4340 (19.52). (0) Since the completion o f this work J. Fried and 15. Sabo ( i b i d . , 76, 2273 (1953)) have described the conversion of 11-epi-17or-hydroxgm11 ~ i ~ o s ~ c i r r ~,\'',[l''-:inhvtll-r,on~ l ~ ~ - l i s ~ l r ~ ~ ~ ~ acetnle ~ ~ ~ ~ . l i ~ . ~ s l ~ i -
Oct. 5 , 1953
gOr
SYNTHESIS OF hg~(11)-L4NHYDRO-17-HYDROXYCORTICOSTERONE ACETATE
increased to the one mole level. Recently the acetylation of an llp-hydroxy steroid has been reported' whereby strong acid catalysis (inter alia HCI04) was employed for effecting this conversion. In view of these observations there would appear to be a critical though obscure association between the ease of dehydration of 1Ip-hydroxy steroids and the nature of the acid employed as a catalyst. CHzOCOCHs
CHzOCOCH3
c-cn-
C-CK
I
4723
80
I
-,d2 70' N
v
I
Joso4
JOsOa
CHLOCOCH,
CHzOCOCHs
c=o
c=o
1
60 '
1
50
0 4 812
I1
&
VI
4
Bn
Brz
I11
3.
VI1 CHzOCOCH3
CHzOCOCHa
I
I
c=o
p,'\"" O A Y IV
VI11
Experimental* 20-Cyan0-A~(~~)J~-pregnadiene-2 1-01-3-one 2 1-Acetate (V). Method A.-To a solution of 2.0 g. of 20-cyano-17pregnene-ll~,21-diol-3-one 21-acetate ( I ) in 10.0 ml. of pyridine containing one drop of water was added 1.0 ml. of phosphorus oxychloride and the mixture allowed to stand a t room temperature for three days. At the end of this time, 50 ml. of water was added and the organic material extracted with three portions of chloroform. The combined chloroform extracts were washed with 2.5 N hydrochloric acid until free of pyridine, then with water and finally the solvent was removed in vacuo. The partly crystalline residue was chromatographed over acid-washed alumina and eluted with benzene. The fractions which gave crystalline residues melting in the range 120-129' were combined and recrystallized from ethyl acetate-petroleum ether (b.p. 3060") to give 1.01 g . (53%) of the A9(11)J7-pregnadiene(V), m.p. 124.5-126'. A sample prepared for analysis by re(7) E. P. Oliveto, C. Gerold, I,, Weber, H. E. Jorgensen and E. B . Hershberg, Abstr. of the Meeting-in-miniature, North Jersey Section of the American Chemical Society, Newark, N. J., Jan. 20, 1953; also A ~ c h Biochein. . Biophys., 48, 234 (1953). ((I) All melting ~ i n i n t swere taken o n R ruiri-
