September 1067
7s9
ether gave the mixture of XXT? and X X T I I (4.2 g): mp 110120'; IIV, ,,A, 237 (sh), 242.5, 231 (sh) mp ( E 18,832, 19!820, 13,070); nnir, :&proton triplet 6 0.92, J = 6.3 cps (1%-H). :;-prototi riiiglet 6 2.08 (acetate CI l a ) j 1-prolon niiiltiplel (hroad) 6 :3.92 (&[I), I-proton triplet, 6 4.X0, .f = 8 "1)s ( l i a - H ) , I-proton doublet, J = 3.3 cps (11-H). An aliquot (166 mg) of the foregoing mixtiire was shaken a t atmospheric pressure with H1 in methanol (10 ml) containing 5cc Pd-C (100 mg) until 12 ml of gas had been absorbed (30 min). Recrystallization of the product from ether-pentane gave a mixture containing I11 and 11-,mp 109-112', having a closely similar infrared abmrption spectrum to a mixtiire of I11 and IV obtained from the NaBHl reduction of 11, and shown by tlc to coiitain ea. 80'; of I11 and 20'5 of 11.. The mother liquors of this material were shown by tlc to cwiitaiii the same mixtiire. The mixture of Xi17 and XST'II ( 2 g ) was treated with 211-Cn coiiple (10 g) and CHJs (20 g ) in ether (130 nil) for 1 hr as previously described, and the mixture wa.* heated in an autoclave for 3 hr a t 90". Trituration of the criide product with ether gave crystals formulated as X X I S (0.12 g): mp 170-180" (after preliminary softening a t 150'); iimr, 2-proton singlet 6 0.iO (19-H), 3-proton triplet 6 0.93, J = 6.3 cps (18a-H), 3-proton singlet 6 2.04 (acetate CH,), 1proton multiplet 6 3.63 (broad), half-height width 30 cps (3-H), 1-proton triplet 6 4.82, J = 8 cps ( l i a - H ) , 1-proton doublet, 6 5.43, J = ,5.3 cps (11-H). The residue in the mother liquors was chromatographed on neutral alumina (60 g), benzene-hexane ( 1: 1 ) eliitiiig iniideritified material (0.72 g), possibly 3-alkosy steroids," and benzeiie-ethyl acetate ( 9 : 1 ) eluting a gum (0.31 R ) t'oimulated as S S J T I I : nmr, 2-proton singlet 6 0.53 (19-H),
3-proton triplet 6 0.97, J = 6.5 cps (18a-H), 3-proton singlet 6 2.10 (acetate CH,), 1-proton multiplet 6 3.63 (broad), halfheight width 30 cps (8-11), 1-proton triplet 6 4,!11, J = 8 cps (lia-H), 1-proton doliblet 6 5.72, J = 5.3 cps (11-11). Benzeiieethyl acetate ( 8 : 2 ) eluted further X X I S (0.04 g). SXT'III (0.04 g ) was oxidized with 8 l\. H2CrOI (0.04 ml) in acetone (10 ml) and the product was n-orked up as usual to give an oily ketone (0.032 g) uniform by tlc; nmr, 2-proton AB system pair of doublets 6 0.55 and 0.80, J = 3.3 cps (19-H), 3-proton triplet 6 0.97, J = 6.5 cps (18a-H), 3-proton singlet 6 2.08 (acetate CH,), 2-proton singlet, 6 2.32 (4-H), 1-proton triplet 6 4.80, J = S cps ( l i a - H ) , 1-proton doublet 6 5.70, J = 6 cps (11-H), The ketone (20 mg) was kept for 1.3 hr a t room temperature in CHCI,HC1. The product was recrystallized successively from ether and acetone t o give XSS (16 mg): mp 161-164": Amax 342 mp ( E 13,100); nnir, 3-proton triplet 6 0.98, J = 6.3 cps (18a-H), 3-proton singlet 6 2.04 (acetate CH,), 2-proton AB system, pair of doublets 6 3.42 and 3.68, J = 11 cps (9a-H), 1-proton broad singlet 6 5.95, half-height width 3 cps (4-H). Anal. Calcd for C2?HalC103: C1, 9.35; 111, 8i8.0. Foriiitl: C1, 9.9; 31 - 36 (by mass spectroscopy), 342.
Acknowledgments.-We t,hank Mr. R. E. Bright for the preparation of key intermediates, Dr. R. -4. Edgren and his associates, Endocrinological Department, Wyet'h Laboratories Inc., for the biological data, and Dr. D. DeJongh, Chemistry Departmelit, Wayne State University, for the mass spectra.
The Synthesis of Certain 17a-Alkyl Corticoids ROBERT E. SCHAUB ASD 01
RIARTIN
J.
ITEISS
(Ian?( C h e m c a l RPveaich Section, Leclerle T,aboratorzes Divasaon, .Inzerican Cyananiztl Cornpanil, Pearl River, .Vex I'ork Received February 6 , 1Y67 Reoised lllanuscrzpt Recezved M a y 18, 1967 The preparation of several 17-alkyl-17-deoxy steroids of the corticoid series is described. The 17-alkyl group TTas introduced via Li-liquid ammonia treatment of 3p-acetoxy-3a-pregna-9( 11), 16-dien-20-one (I ) followed by appropriate alkylation. Methyl groups a t the 16a and l i a positions were introduced by a procedure involving 1,4 addition of methylmagnesiiim iodide t o the A16-20-keto system of I, or its corresponding 3-tetrahydropyranyl derivative, followed by methylation of t,he 16a-methyl-17-enolate anion thiis generat>ed. Farther elsboratiou of the resiilting li-alkyl derivatives was carried orit by standard procediires. Of particiilsr interest is the synthesis of the li-methyl and li-ethyl derivatives of li-deos~-~)a-flut,roprediiisoloiie 21-ttcetiite and of 17-deoxy17-methyldesamethasone 21-acetate.
In this paper we report t8hesynthesis of a variety of l'ia-methyl and ethyl derivatives of the corticoid type. Previous reports'* from this laboratory have described a useful procedure for the preparation of 17-alkylpregnan-20-ones, which involves the alkylation of an intermediate 17-enolate anion developed by treatment of a 16-pregnen-2O-one with a solution of Li, Ca, or Ra in liquid ammonia. The application of this method to the synthesis of a series of orally effective 17-alkylprogesterone derivatives has also been described.',* 1."- the present study we have utilized this method and also have developed a convenient process for the simultaneous introduction of met'hyl groups a,t the 16a: and 17a positions involving Grignard 1,4 a,ddition to a A1620-ketone followed by methylation of the intermediate enolate anion. Some years prior to this investigation Engel described the synthesis of 17-methylcorticosterone3 and its 11f l ) (a) 31. J . \\-eiss. R. E. Srhaiih, G . R. Allen, J r . , J. F. Poletto, C. I'idarks. R. 1.C'onrotv. ani1 C . .J. Coscia. T e t r n i r d r o n , 20, H R i (1964); ( b ) w? also H. I)wIienglii, C . RPvein, a n d R. Baildry, J . .Mri/. C i i r m . . 6 , :301 (I'Jii8). ( 2 ) AI. .J. \Veisn, It. I,:, Scliaiih. .I. 1:. l'oli-ttu, (;. I f . : \ l l ~ r ! , .Jr.. : I I ! ~(', l'iilwks, S t r r o i d s , 1, 608 (19tk3).
dehydro d e r i v a t i ~ e . ~ From the results reported at that time it appeared that replacement of the hydroxy group at CI7with a methyl group results in a decrease in glucocorticoid and antiinflammatory activity as measured by liver glycogen and local granuloma assays, respectively. On the other hand, the possible effect of this modification on mineralocorticoid activity aroused our interest since it appeared that, with regard t o this important parameter of biological activity, there was a qualitative difference between 17methyl-1 1-dehydrocorticosterone acetate and cortisone a ~ e t a t e . ~We have been unable to find any further reports concerning this preliminary observation nor, to our knowledge, has there been an application of the possibilities thus raised to a Sa-fluoro-substituted corticoid. With the hope that 17-alkylation in the corticoid series might in fact result in a favorable separatio:i of certain of the parameters of corticoid activity arid encouraged by our own observations? in the progesterone series that at least in some instuncc:, ly-ethyl ;mtl R. Engel, Con J C h e m , 86, 131 (1967). c7. R. F,ng?l .r 4 ,,I C ' h a n ~ ,hL , 78, 4727 (1956).
(3) C (4)
7!10
17-prop) 1 derivatives \~ercl 111orcl eff wtivc 111:11i t h c cwxspoiiding 17-methyl derivntivcs. we uiic1erti)oli the hyiithesis of vertaiii 17-all;> 1 corticoids, i n p:wt i c u lar those cont aiiiirig the :L(’tivit!.-ellhall(’illg !?a-fluori 1 principle. As L: starting point fur our \yiitliese+, l i e taliow 3@:~c~etoxy-.ia-pregna-9(1l),lti-c1ien-~OO-oiie (I), :L ( * o i ~ i pound having the requisite l~-deh\-dro-‘lO-l~rtc 1 tem for 17-all;) Intion, thc 9(11) tlouhle bond tor 5ubsequent ring C e1abor:ttioil :mcl the 3-ox> func*tioi~ :is an entry for ring development. The prepltratioii (Jf this substance from hecogellin ha. been described.” l$-Alethylation of I by the Iithiuni-liquid ammonia procedure’ mas achieved in fair yield (see Scheme I). For the preparation of analogs in the 21-deoxy seriei, the resulting 17-methyl-3 a-pregn-9 (1l)-eii-3p-ol-%O-ollc.~ii~~ (Ha) was oxidized (Joneb’ reagent) t o the 3-ketone I*:i, 1vhic.h on dehydrogenation with 2,:3-dichloro-3,6-dic.ysnobenzoquinone (DDQ)’ aforded the intermediate
\‘ill.
IO
1,8)J. Fried and L . 1‘. h b o , .I. A m . C k m . Soic., 79, 11.30 ( I Y , i i ) : I
