\
h,l6-Diinethylated Steroids. l \ ' . &+Dimethyl A4nalogs'
01.
7
6, 16-DIMETHPLATED STEROIDS.IT'
,July, 1961
glycol (7) was then oxidized in good yield with either 8 N chromic acid-sulfuric acid reagent1* or with Kbromosuccinimide in acetone3 l 3 to 4,4,6,16a-tetramethyl-5-pregnen-17a-ol-3,20-dione(4b). Acetylation of the tetramethyl-&pregnene afforded the 17aacetate ( 4 ~ identical ) with that prepared cia alkylation of the enamine. COCH3
COCH,
0
(y+Y
CH3
CH3
la, R - H b, R = O H c, R-OAC
2a, R = H b, R - O H C, R-OAC
I
COCH3
-0
COCH3
0 % H3C CH3 CH3
Ro CH3
la, R - H
3a, R - H
b,R=OH C, R = OAc
b, R = A c
CH3
H3C CH3CH3
5
lb
-
&ogH3 0 H3C CH3CH3 1
The oral progestational activity of 4c was estimated by the Clauberg method on immature estrogen-primed rabbits.I4 The data obtained are as follows. Level, mg.
0.075 0.75 7.5
Response
O.X+
15+ 3.8+
Since the data do not give the normal response curve, no meaningful comparison of the activity of 4c with (12) K. Bowden, I. 11. Heilbron. E. R . H. Jones, and B. C. L. Weedon, J . Chem. S O L . .39 (1946); A . Bowers, T . G. Halsall, E. R. H. Jones, and A. J. Lemin, ibid.. 2548 (1Y53). (13) E. W. Cantrall and S. Bernstein, U. S. Patent 3,019,219 (Jan. 30, 1962). (14) Bioassays by Endocrine Laboratories, Madison 1, Wis.
55 3
any standard substance, e.g., ethisterone, can be given. The response at the 0.075-mg. level, however, is particularly interesting for a compound of this structure.
Experimental'" 3-(N-Pyrrolidyl)-6~,16~-dimethylpregna-3,5-dien-2O-one (2a). (la) -A solution of 3.42 g. of 6~~,16~~-dimethylprogesterone in 20 ml. of absolute methanol containing 1 drop of pyrrolidine was heated to boiling and t,hen 1.5 ml. of pyrrolidine was added. The mixture was boiled gently for 5 min. during which a crystalline solid separated. The mixture was cooled in ice: the solid was separated by filtration, washed with cold methanol, and dried in ziaczio a t room temperature to give 3.665 g. (92.'ic;C), m.p. 144-146" dec., [ m I z 5 -24.9'; ~ AEf:5.87, 6.11, and 6.23 p.16 A n a l . Calcd. for C2,H41?i0: C, 81.97; H, 10.45; S , 3.54. Found: C, 81.25; H, 10.22; X,3.14. 4,4,6,16a-Tetramethy1-5-pregnene-3,20-dione(4a).-The enamine (2a) (2.85 g.) in 250 ml. of absolute methanol vias treated with 50 ml. of methyl iodide and the solution heated under reflux for 40 hr. The mixture was concentrated in z"xo to ca. one-half the original volume, 10 ml. of 10% aqueous sodium hydroxide solution added, and this mixture heated under reflux for 10 min. The solution was then concentrated in ~ z c z i oto about 50 ml. and diluted with water (2000 ml.). The crystalline solid which separated was removed by filtration, washed to neutrality with water, and dried in uacuo to give 2.15 g.,m.p. 78-84'. -41.84-g. port,ion was chromatographed over 60 g. of Florisil (column prepared in hexane). The fractions eluted with methylene chloride were combined, 450 nig., m.p. 112-115', no selective absorption in the ultraviolet. Recrystallization from methanol afforded ~ : :A: 5.84 and 5.87 p. 223 mg., m.p. 114-115°, [ a ]z j+lo', Anal. Calcd. for CzjHZE02: C, 81.03; H , 10.34. Found: C, 80.12; H, 10.03. Further elution of the column with methvlene chloride-ether ( 8 : 2 ) gave 9 i 2 mg. of solid, m.p. i0-86", A,, 250-251 mp ( e 900). Attempts to separate the 4,6a,lB~~-trimethylprogesterone from this mixture failed. 3 4 N-PyrrolidyI)-6a,l6a-dimethylpregna-3,5-dien-l7a-ol-20one (2b) -A suspension of 5 g. of 6p,l6~-dimethylpregnane5,) 17a-diol-3,20-dione (3a) in 30 ml. of absolute methanol was heated to boiling and 1.5 ml. of pyrrolidine added. The solid quickly dissolved. The mixt,ure was heated for 2 min., then quickly cooled in ice, and the crystalline solid separated by filtration. After washing with cold methanol and drying in vacuo the product weighed 5.726 g., m.p. 151-160' dec. Recrystallization from absolute methanol afforded 3.102 g. (56.8%), m.p. ~ : :A: 2.86, 5.89, 6.08, and 6.22 p. 188-190' dec., [ a ]2 6 -148'; A n a l . Calcd. for C27H41X02: C , 78.78; H, 10.04; T,3.40. Found: C, 78.24; H, 9.95; S,3.50. Treatment of the 5,-acetate (3b) with pyrrolidine in methanol under the above conditions gave material identical in all respects with that prepared above. Treatment of l b with pyrrolidine in benzene in the presence of p-toluenesulfonic acids gave only recovered starting material. Treatment of 6a,16adimethyl-l7a-acetoxyprogesterone(IC)with pyrrolidine in methanol also gave a mixture of the 3-enamine 17-acetate (2c) and starting material. 4,4,6,16or-Tetramethyl-5-pregnen-l7,-ol-3,2O-dione 17-Acetate (412). A . From the Enamine 2b.-A solution of 3.0 g. of the enamine (2b) in 250 ml. of absolute methanol and 50 ml. of methyl iodide was heated under reflux for 64 hr. The solution was evaporated in Vacuo to ca. 100 ml., poured into ice-water, and the resulting suspension acidified to pH 2 with hydrochloric acid. After standing for 1.5 hr., the product was extracted 11-ith methylene chloride. The extracts were washed to neutrality with water, dried, and evaporated to dryness in vaciio t'o give 2.510 g. (89%), m.p. 135-148'; A,, 250-251 mp ( E 300); : :A: 2.98, 5.88, 6.04, and 6.18 p. The crude product (2.5 g.) was dissolved in 20 ml. of glacial acetic acid and the solution treated with 4 ml. of acetic anhydride (15) A11 melting points were determined in capillaries on a Hershberg apparatus (Eck and Krebs, Inc., New York) using Anschutz thermometers. Rotations were observed in chloroform a t ca. 17, concentration. ultraviolet spectra in 9570 ethanol. Infrared spectra were determined using a Beckmann Model IR-5 spectrophotometer. (16) Attempts t o recrystallize this material resulted in partial decomposition. Therefore, the physical d a t a above are on the "crude" product. T h e material was also carried on without further purification.
7s.u; H, 9.39. B. From the 17a.20B-Diol ( 7 L T o
a solutiori of 1.0
t[. (if
