-ILAN H. NATHAN, JOHN C. BABCOCK AND
1436
[CONTRIBUTION FROM
THE
JOHX
-1. HOGG
1'01.
s-'
RESEARCH LABORATORIES OF TIIEUPJOHS Co. I
The Adrenal Hormones and Related Compounds. VI. Fluorinated Derivatives of Testosterone and Progesterone BY ALAN H . h
T
~JOHN ~ C.~ BABCOCK ~ ~ AND ,
JOHN
A. HOGG
RECEIVED AUGUST27, 1959 Preparation of 2-fluorotestostcrone and several of its derivatives, and of 2-fluoroprogesterone is described. logical acti\ it? of 2-fluorotestosterone is briefly discussed.
The physio-
The technique of fluorinating carbanions with fibroadenomasa which had grown resistant to the perchloryl fluoride' has made accessible a number action of testosterone propionate.Sb I n the male of a-fluoro ketosteroids2 The present paper rat, 2-fluorotestosterone exhibited very little, if reports some further results of our experiences with any, androgenic activity. this technique. Testosterone, l7a-methyltestosterone, 11P-hyExperimental9 droxy-17-methyltest~sterone,~ 9(11)-dehydro-172-Fluorotestosterone (I).--*% solution of 5.76 g. (0.02 methyltestosterone3 and Scr-fluoro-llP-hydroxy-17- mole) of testosterone in 100 ml. of t-butyl alcohol was stirred methyltestosterone3 were fluorinated successfully while heating t o 65" with exclusion of air and moisture by a gentle flow of dry nitrogen above the surface. in the 2-position by the reaction of perchloryl maintaining Heating was stopped and 5.45 ml. (0.04 mole) of ethyl oxafluoride with the sodium salts of their 2-ethoxy- late was added all at once, and then sufficient commercial oxalyl derivatives followed by base-catalyzed 25yc sodium methoxide in methanol10 t o contain 0.03 mole of cleavage of the ethoxyoxalyl groups. The yields sodium methoxide (approximately 6.7 ml.). After stirring were good in all cases except in that of the 2,9cr-di- for one-half hour under nitrogen (without further heating), the solution, which was deep green, was cooled to 25-30', fluoro compound which was prepared in better and 300 ml. of dry ether was added. The sodium salt of the yield from 2-fluoro-9(1l)-dehydro-17-methyltestos- 2-ethoxyoxalyl derivative which precipitated was collected terone by reaction of hydrofluoric acid with the on a biichner funnel in as dry a n atmosphere as possible (it was exceedingly hygroscopic) and dried in a vacuum desiccorresponding 9p, 1 lfl-oxide. over calcium chloride for three hours. 2-Fluoroprogesterone was prepared by appli- cator The dried salt then was dissolved in 170 ml. of methanol, cation of the perchloryl fluoride-glyoxalate pro- the solution was cooled in an ice-salt-bath to - l o o , and an P)-hydroxy-4-pregnen-3-one4ice-cold solution of 3.2 g. of perchloryl fluoride in 100 ml. of cedure to 20(a (obtained from lithium aluminum hydride re- methanol was added at such a rate as to raise the temperature no higher than -5'; about 10 minutes was required for thc tluctionj" of the 3-pyrrolidinyl enamine of proges- addition. Then a volume of 25yc methanolic sodium methteroneSb) and then by oxidation of the 20-hydroxyl oxide was added equal to 2.19 times the number of grams o f group. perchloryl fluoride added (7.0 ml. in this case) and stirring The configuration of the 2-fluorine atom, by was continued for 0.5 hour while the flask remained in the analogy, would seem to be alpha. The infrared cooling bath. solution was evaporated under reduced pressure a t 50" absorptions of the 3-keto groups in all cases are t o The about 50 ml. and diluted with one liter of cold water. displaced by about 25 ern.-' toward higher wave The precipitated product was collected, washed thoroughly numbers which is in the direction predicted for with water, dried arid recrystallized from 9.iyo ethanol. equatorial a-bromoketosteroids6 and as was indeed The yield was 4.3 g. (70yo),n1.p. l58-16Oo. Thecompound solvent of crystallization, which was driven off a t observed for the 2-fluorocholestan-3-one reported retained 105" in a vacuum oven. The analytical sample, obtained by by Gabbard and Jensen,?" to which they assigned one further recrystallization, melted a t 1.59.5-161 '. the a-configuration. However, since the axial The acetate I1 and the propionate 111 were prepared from a-fluoro isomer may exert an effect upon the in- 2-fluorotestosterone ( I ) by reaction with acetic anhydride propionic anhydride, respectively, in pyridine for 16 frared absorption of a carbonyl group similar t o and hours a t room temperature (see Table I). that of the equatorial isomer, this evidence does The other compounds listed in Table I were prepared from not preclude the possibility that the configuration the corresponding steroids by the same procedure given above for 2-fluorotestosterone ( I ) . In addition, 2,9m-diof the 2-fluorine atom is beta. Bioassays performed in these laboratories' indi- fluoro-110-hydroxy-17-methyltestosterone ( V I I ) was prefrom 3.0 g. of 2-fluoro-9( 1l)-dehydro-l7-methyltestoscate that 2-fluorotestosterone, in the female rat, pared terone aia the bromohydrin and 95,11,8-oxide by making produced a marked increase in body weight, yet use of the procedures of Fried and Sabo." These two interaffected nearly 10070 inhibition of the mammary mediates were not purified or characterized except for the
+
(1) C. 13. Inman, E . A. Tyczkomski, R. E . Oesterling and F. L. Scott, E r p e r i e n t i a , 14, 355 (1'258); C. E . Inman, R . E. Oesterling and E. .4. Tyczkowski, THISJ O U R N A L , 80, 6533 (1958). ( 2 ) (a) K . R . Gabbard and E. V . Jensen, J . O i g . Chem., 23, 1400 (1058); (b) H. lf. Kissman, A. M Small and RZ. J. Weiss, THIS J o ~ R K . ~81, L , 1262 (1929); fc) A . 11. N a t h a n , 13. J , lfagerlein and J. A . Iiopg, J . OYR.Chem., 24, 1217 (1950). (3) XI. E. Herr, J. A . Hogg and R. H Levin, THISJ O U R N A L , 78, ,500 [1ile, W. Charney. P . I, Pcrlman, H . 1,. Herzog. C . C. ]'dyne. hl I
