108
Vol. 7
SOTES
cqstalline inaterial which wis filtered, washed well with water, -C,.i-unsaturated $ketosteroids piovides :t w i i \ y > t i i ( i i i t and dried to give I11 (8.56 g., 9-1':1), r1i.p. 98-107". Chromatogiiiethod for the iiitroductioii of a fluorine substituclit r:iphy on silicx gel and recryst,allization from methanol gave an adjacent or vinylogous to the carhoiiyl group. .\p:inalytic*:tl sxmple having m.p. 142-143', X K R r 2.8.5, 5.88, 6.83, plication of these reactions to li-ketosteroids l i a h I)WII 7 . 2 2 , 0.00, 9.75, 9.98, and 10.23 [.]I) -41' (c I , CHC:Il). I 1 I eshihited no distinct ultraviolet absorption. limited by the reluctance of t l i ~17-ketoiic t o f o ~ x ci. i i o l . I n n / . C:~KI. for G ; H d ) J : C, 7 7 . 2 7 : H, 10.38. Found: (%hers1or eliamines.l 77.10: H, 10.31. ]Ye h a r t fouiid that acetylated 17-ainiiio-1 lh-sttioitls 4,4,6,16cu-Tetramethyl-5-sndrostene-3,17-dione [IV).-4,4,6,(riiamides), conveniently prepared' 1)y the I3wkniaiIii 1 (ia-Tetrainethyl-j-pregnene-1 ia,20p-diol-3-one (111) (300 rng. 1 rearraiigeiiieiit of tht oxime of 20-keto-1 'fi-steroids, W:IS diesolved in 30 nil. of methanol and treated with an aqueous tolution of 2jO mg. of periodic acid in 3 nil. of water at rooni ieact sinoothly a i d stereospecifically with pt~i~liloryl temperature for 1 7 hr. On dilution with water, the resultnnt flrioride to furiiish tlic correspoiidiiig I(ia-flriol.o-1 Tvryst:ils were cwllected hy filtration, washed well with water. ketosteroids in high yield. I :ind dried to give 262 nig. of crystals, 1n.p. lt5S-1600. IievrystalI'resuniably, t h e reactloll proceeds hy elect~~opliilic 1iz:rtion from hexane-acetone gave 240 nig. of I \ - , ii1.p. 160-161 '. 5.80, and 5.88 W , [ a ] ? %-6" (c 1: CHC1:j). 31:iss spectruiii attack of the fluoriiie at the negative center at positioii showed a strong t n / e 342 peak. ("-l(i (I) fol1on.e~~hy loss of a protoii to pi.oduct ii .Inn/. C:~lrd. for C23H340?:C, 80.65: H , 1 0 . ~ 0 . F~irlrltl: (', SO,5!): H, 9.96. 4,4,6,16a-Totramethyl-5-androstene-17p-ol-3-one (V).--4,4.f i , 1 ti~-'l'etr:~riiethyl-:',-androstene-~3,17-diiinc(I\.) ( 175 mg.) wis tlissc~lvedin 80 nil. of absolute niethanol :tnd the systein was fluslitd u.it.h nitrogen gas for 3 min. Sodium borohydride (40 nig.) XIS thcn :itided and the niixture stirred for 30 min. :it room temperature. A frn- drops of acetic arid were added and the mixturc. diluted with water. The resulting crystals were cdlerted Iiy filir:ttion, w:rshed well with water, and dried to give 17-1 mg. of c,rystals, ni.p, 06-99". Recrystallization froin aqueous niet,hanr~l fiirnished pure 4,4,6>1 6 ~ t e t r : t i nthyl-5-~~ndr[istene-l e 7p-ol-3-one I ( \ 1, 162 n i g . of crystals, ni.p. 101L102°, hKR' 2.!)0, :inti 5 . S 5 p . l a ] 11 --t2' ( c I , CHCI,,). \ - exhiiiited no signific,:int nltr:ivi~~lc~t d:~lis~irpti~in. A 1 7 ~ n I . Calid. for CraHa6O2:( ' , 80.IS: H, 10.53. Found: (', 80.12; H, 10.47. IX 4,4,6,16a-TetramethyI-5-androstene-3i3,17~-dioI (VI).-A S C I ~ I I t ion of 4,4,6,16~-tetrariiethy1-~5-:~ndrostene-3,1 7-dione ( I \ ' I ing.) in 30 nil. of anhydrous ether was added at anihienr eratiire during it period of 15 niin. t o a stirred solution of Iitliiuin :iluniinum hydride (300 nig. ) in 30 nil. o f anhydrous t ~ t h e r . 'The mixture was thcn refluxed for 30 niin., miled to O", :ind cx(*esslithiurn :rluniinurn hydride decoriipiised with watcr. The iiiisture ans further diluted with w t e r and extracted with (,thy1 :ic.etate. The organic layer wts washed well with water, R It clrid ovcr magnesium sulfate, filtered, itnd concentrated to givr> IIa, R = C H i , R ' = H I I I a , R = C H i,R' = H 2% nig. of carystals, 1n.p. 105-1 I % " , w1iic.h was put on :i 5 g. I). R = H , R ' = C H i b, R = H , R ' =CH, 1~'lorisil uilunin. 1':lntions with hexane gave (*rude crystals Iiec,ryst:tllization of 156 nig. of crudc t I f i 4 r11g.) 11i.p. 1X-12I0. 0 0 prodii(,t froin hexane-acetone g:~ve a first crop of 62 nig. of F rryst:ils, ni,p, 120-121 ', AK"' 3.00, no c.:rrhonyl al)sorptior~~ R !I. &j, :ind !).8S p . There was no significmt ultraviolet absorption. R--+ TIIP ni:iss spertruni show-rd :i parent peak (-orresponding t o / iiiolecrilar weight of 346, :in6 31 - CH:,,3I - H?O, 11 - ( C H I 0 I I z o ) :rnd strong 31 - 83 peaks have h e m ohservetl. HO Ii Ii ir C r u H d) > : C', 79.71 ; H, I 1.05. I.'oiiniI: Va, R = CHJ,R' = H IVa R = C H 3 , R ' = H b, R = H R'=C'Hj b R=H,R'=CHI :I
5
+
1 6 ~Fluorinated Steroids from the Reaction of Perchloryl Fluoride with Enamides'
eF 0
0H
sl~5rMlS A I C A X I b I l I
I'eritrccl 1ic.seorch I,ciburutoricjs, Gc'riercil .I1 ills, Iric.>Jliruicupcdis,
Illinncsotn Neceiilerl
./til!!
12, 1:Jfi.j
VI11
-
January, 1964
NOTES
fluorinated acetyl amine. Subsequent addition of water results in rapid hydrolysis to the fluorinated ketone as illustrated in Chart I. In direct contrast, the fluorination reaction of perchloryl fluoride with the enol acetate (IX) of a 17-ketosteroid is very slow and is accompanied by side reactions of ch1orination.l The greatly enhanced reactivity of the acetylamino compound (I) as compared to the enol ester (IX) is consistent with the greater ability of the nitrogen atom to donate electrons to the double bond for interaction with the electrophilic fluorine of perchloryl fluoride. A brief treatment of enamides I1 in pyridine with perchloryl fluoride at room temperature furnished 16afluoro-3p-acetoxy-3-androstene-17-one derivatives (111) in 70% yield. Acidic methanolysis of I11 gave the corresponding 3p-hydroxy compounds (IV) in quantitative yield. Oxidation of IV by chromic acid in acetone gave rise to 71% of 16a-fluoro-4-androstene3,17-dione derivatives (V). Configuration assignment of a-fluorine and p-methyl groups for 16a-fluoro-16Pmethyl-4-androstene-3,17-dione (Vb) has been performed by infrared spectrumga as well as by n.m.r. studygb which is in agreement with the observations of Cross and Landis.'O Vb was further converted to its 3-ethoxy enol ether (VI) and reduced with sodium borohydride to 16a-fluoro-l6/3-methyltestosterone (VII). Direct partial reduction" of Vb gave rather poor yield, due to 3,17-diol formation in spite of the expected difference in the reactivity between 17-ketone and the 4-en-3-one. l1 Reduction of VI with either sodium borohydride or lithium aluminum hydride produced VI1 with retention of configuration a t C-16. Catalytic hydrogenation of VI1 gave 16a-fluoro-16p-methyldihydrotestosterone (VIII). In both compounds, VI1 and VIII, androgenic propertjesl* (ventral prostate) were of a low order at both 0.14 and 1.4 mg. total dose levels, being about 10% that of testosterone and similar to the control, while the seminal vesicles weight increase was only about three times the control, and almost no change of levator ani was observed. Similar observations have been described recently by Hoffman and his c o - ~ o r k e r s ' ~ on 16-disubstituted progesterone and deoxycorticosterone derivatives.
-The Beckmann rearrangement8 of the above 20-oxime furnished slightly orange colored crystals of IIa, 4.67 g. (88'j$), m.p. 196-198" dec., [CY]~'D -45.7', XKBr 3.02, 3.41, 5.78, 6.04, 6.49, 7.28, 8.00, and 12.22 p. Anal. Calcd. for C24HasN03: C, 74.65; H, 9.31; X, 3.75. Found: C, 74.76; H, 9.15; K,3.63. 6-Methyl-l6~~-fluoro-5-androsten-3p-ol-l7~one 3-Acetate (IIIa).-The enamide I I a ( 4 g.) was dissolved in 250 ml. of dry pyridine and treated with perchloryl fluoride a t room temperature for 4 min. After removal of excess perchloryl fluoride by water pump suction, the reaction mixture was poured into ice-water, acidified with concentrated hydrochloric acid t'o pH 2, and the acidic suspension was kept a t room temperature for 1 5 hr. to complete the hydrolysis. The cryst'alline solids were filtered, well washed with water, and dried in ~ C U overnight O to give 3.58 g., m.p. 99-106". Purification by Florisil column chromatography (elutions with methylene chloride) gave 2.708 g. (72c;C of crystals, m.p. 199-213". Recrystallization from hexaneacetone gave 70% of IIIa, m.p. 214-215', [ o L ] ~ ~+8", D XKBr5.70, 5.81, and 8.02 p . Anal. Calcd. for Cz2H31F03: C, 72.89; H, 8.62; F, 5.24. Found: C, 72.83; H, 8.46; F, 5.20. 6-Methyl-16a-fluor0-5-androsten-3p-ol-17-one (IVa).-A mixture of I I I a (1.4 9.) in 200 ml. of absolute methanol and 1 ml. of concentrated hydrochloric acid was kept a t room temperature overnight. After concentration to about 10 ml., it was diluted with H20, filtered, washed, dried, and concentrated to give 1.233 g. of crystals, m.p. 134-140". Two recrystallizations from hexane-acetone gave IF'a, (1.185 g., 96Cj,), n1.p. 169-170.5", [ c Y ] ~ % I +24", XKBr 2.86 and 5.70 p. Anal. Calcd. for C ~ O H ~ ~ FC, O ?74.96; : H, 9.12; F, 5.93. Found: C,74.84; H, 9.56; F, 5.97. 6a-Methyl-16a-fluoro-4-androstene-3,17-dione(Va).-The chromic acid oxidation8 of IVa (730 mg.) in acet,one at lo", followed by a purification on 15 g. of Florisil (elution with methylene chloride), gave 490 mg. of crystals, m.p. 178-184". Recrystallization from hexane-acetone gave 370 mg. of crystals, m.p. 184-188'. Another recrystallization from the same solvent mixture furniRhed Va monohydrate (364 mg.), m.p. 227-228", [ a ] ' 8 +119", ~ hKBr5.69,5.98, and6.22p, XEL:H241 mp ( e 16,680). -4nal. Calcd. for C2oH?'FO2: C, 71.40; H, 8.69; F, 5.65. Found: C, 71.60; H,8.09; F, 5.58. 16-Methyl-5,16-pregnadiene-3p-o1-2O-one3-Acetate 20Oxime.-16-Methyl-16-dehydropregnenolone acetate ( 5 9 , ) was converted t o 16-methyl-5,16-pregnadiene-3p-o1-20-one 3-acetate 20-oxime (4.84 g., 92%), m.p. 176-177" (from hexane-acetone), [CY]%D -90.7", XKBr2.84,5.82,5.86, 6.16,and6.27p. -4nal. Calcd. for C24H3SN03: C, 74.76; H, 9.15; N, 3.63. Found: C, 74.65; H, 9.07; S,3.66. 16-Methyl-17-acetylamino-5,16-androstadiene-3p-o~ 3-Acetate (IIb).-The Reckmann rearrangement8 of the above oxime (4.5 g.) gave I I b (3.395 g., 745(,), m.p. 193-195' dec. (from hexane-acetone), XKBr 3.02, 5.76, 5.94, 6.52, 8.00, and 1 2 . 2 2 ~ ; -33.2'. Anal. Calcd. for C21H35K-03: C, 74.76; H, 9.15; K, 3.63. Found: C, 74.71; H,9.04; K , 3.85. 16~-Fluoro-16p-methyI-5-androsten-3p-ol-l7-one 3-Acetate (IIIb).-The enamide ( I I b ) (3.3 g.) was dissolved in 250 ml. of pyridine and h a t e d with perchloryl fluoride a t room temperature for 4 min. After removal of excess perchloryl fluoride by waterpump suction it was diluted with ice-water, acidified with concentrated hydrochloric acid to pH 2, and kept a t room temperature for 5 hr. The crystals formed were filtered, washed with water to neutrality, and dried to give 3.019 g. of crystals, m.p. 94-102'. Purification by Florisil column chromatography (elutions with methylene chloride) gave 2.547 g. (80.5%) of crystals, 1n.p. 162-168". Recrystallization from hexane-acet,one gave I I I b (2.03 g.), m.p. 168-169", [ a I 3 ' D +37.1", XKBr 5.69, 5.79, and 8.04 p . Anal. Calcd. for C22H31F03: C, 72.89; H, 8.62; F, 5.24. Found: C, 73.18; H, 8.58; F, 5.01. 16~-Fluoro-16p-methyl-5-androsten-3p-ol-l7-one (lVb).-A solution of I I I b (1.88 g.) in a mixture of 200 ml. of methanol and I ml. of concentrated hydrochloric acid was kept at' room temperature overnight. Then it was diluted with water and the resulting crystals were filtered, washed, and dried to give 1.695 g. of crystals, m.p. 170-177'. The crude product 1.62 g. was purified by Florisil (60 g.) Chromatography. Elution with methylene chloride containing 5% ether gave 1.07 p. of rrystals,
E~perimental'~
6-Methylpregna-5,16-dien-3p-ol-20-one 3-Acetate 20-Oxime. -6-hIethyl-pregna-5,16-diene-3/3-ol-20-one 3 acetate was converted t o its 20-oxime in quantitative yield according to the method of Rosenkranz, et a1.* The analytical sample was recrystallized from hexane-acetone and melted a t 202-203", [ a ]2 5 -53.0", XKBr2.90,5.79, 6.20, 6.29, 7.85, and 1 2 . 1 9 ~ . Anal. Calcd. for C~H35N03: C, 74.76; H, 9.15; N, 3.63. Found: C, 74.69; H, 9.21; X, 3.62. 6-Methyl-3p-acetoxy-17-acetamino-5,16-androstadiene (lla). (9) (a) S. Nakanishi. J . .Wed. C h e n . , in press; fb) N.m.r. study by Dr. L. Peterson and L. Hickman. Central Research Laboratoriee. General Mills, Inc. (10) A. D.Cross and P. 'X. Landis. J . Am. C h e n . SoL..,84, 3785 (1962). (11) J. K. Norymberski a n d G . F. Woods, J . Chem. Sac., 3426 (1955). f 12) Androgenic-myotrophic test performed by the Endocrine Laboratories, Madison. Wis. Subcutaneous administration with CRlC solution as diluent. (13) A. R. Hoffman, H . M. Kissman, and RI. J. Weies. J. M e d . PhaTm. Chem.. 6 , 962 (1962). (14) All melting points were determined in capillaries on a Hershberg apparatus lEck and Krebs, Inc., New York) using Anschutz thermometers end are corrected. Rotations u-ere observed in CHCla a t ca. lYo concentration
~
109
110
SOTEY
ii1.p. 175.5-l'iS.3". Recrystallization from acetone-liexane furnishedIVb (1.05g.), m.p. l'i6-178.5", [LY]D+43", hKBr2.93,5.GSp. A n d . Calcd. for C2oHrgFOr: C , i 4 . ! ) 6 ; H, !).12: F, 5.93. Fvunid: C, 74.79; H, 9.14; F, 5 . 3 . 16~-Fluoro-16p-methyI-4-androstene-3,17-dione (Vb).--Thc chromic acid oxidation8 of 1Ybj 1 g., in acetone at 5" yielded !)SO mg. of crystals, m.p. 198-202". Recrystallization from ether gave Vb, 950 mg., ni.p. 2O4-2o.jo, AE,~P," 241 m p ( e I ~ , N I O ) , [a111+203", XKB' 5.69, 6.01, 6.20 p . .l?iai. Calrd. for Cr6HziFOn: c', 75.43; H, S . 5 5 ; F, >.!J7. Follon iiig the d i m n w y of tlic high estrogenic poFound: C, 75.66; H, 8.40; F, 5.7;. 16a-Fluoro-16p-methyI-3-ethoxyandrost-3,5-diene-l7-on~ tency of diethylstilhestrol,~ iiuiiim" related coiii(VI) and 16or-Fluoro-16p-methyl-androst-4-ene-17p-ol-3-onepounds \vew prepared for horinonal assay.4 l l o r c (VII). (a)--A mixture of Vb (950 mg.), 10 ml. of dry tetrahydrorecently the search has turiwd toward the developmciit furan and 0.6 ml. of t,riethyl orthoformate was heated to reflux. of compounds I\ hich might possess antihormonal Then 0.4 nil. of absolute ethanol containing 2 drops of concenactioiij: relatively few of these compounds ha\-e intrated sulfuric acid was added. After refluxing for 30 inin., an d d i t i o n a l 0.4 nil. of triethyl orthoforninte was added, then t l i ~ cluded Iieterocyclic groupingh. However, se\.ri-al stilmixture was refluxed for an additiond hr. Tlie mixture was t h t n hestrol-like conipouiid~hearing tlie tliiophene nucleus diluted with water, extracted with ethyl acetate, the organic1 in place of oiic or h t l i of the hciizciic rings ha1.c h e t i layer was washed with water, dried over magnesium sulfate, 1eportcd.6 filtered, snd concentrated to give 1.1 g. of oil, AC':14 2.78, 6.04, In ail attempt to prepare a. 2-thienol analog of stiland 6.13 p . This crude oil was dissolved in 25 inl. of anhydrous tetrahydrofuran and then 8.2 nil. of water, 0.125 inl. of 2.5 .\ticstrol, n-c hare iiow succeeded in synthesizing its sodium hydroxide, and 520 mg. sodium borohydride were added moi*e stablr tautomeric a,p-unsaturated thiolactone with stirring, and the mixture was refluxed for 5 hr. After coolform as the crystalline acetate, (IId). Preliminary ing t,o room temperature, the mixture was extracted with ethyl work, i.esultiiig iii tlie synthesis of the ielated methyl acetate, and the organic layer was washed to neutrality, dried, and ethers (11%and IIb), was also conducted. ,I recently concentrated to give 900 my. of :t foamy glaze. This crude product was dissolved in 30 nil. of allsolute etlimol and 5.2 nil. of drreloped syiithesis7 of 5-siihstituted ?((.SH)-thiowater. Then 10.5 nil. of 0.12 S hydrochloric. acid W L ~ Sadded and pliciioiica has t w i i utilized. tlie mixture was kept a t room temperature overnight. Thc mixture was further diluted with 300 rnl. of m t e r and extract( Fvitli ethyl acetate. The organic 1:tyer W E washed with .j sodium bicarlxmate solution :tnd w:ttrr t o neut,ralit>-,dried, :I concentrated to give SO0 mg. of fo:trn, X I C R ~2.!)1, 6.0, :tn I+;niploying :I 30 g. Florisil column. c>lutions with 1Or, niethylene chloride yielded 485 nix. of crystals, r n . p . ltec.r~.st:~.lliz;ttion from ether gave :L first, cmp of TI1 ( 11i.p. l;%&l:
