3,629,301 United States Patent Office Patented Dec. 21, 1971 3,629,301 3,3-DIFLUORO-2-SUBSTITUTED STEROIDS AND THER PREPARATION William C. Ripka, Wilmington, Del, assignor to E. I. du Pont de Nemours and Company, Wilmington, Del. 5 where R is hydrogen, methyl, or ethynyl, and R2 is hydro No Drawing. Filed Oct. 24, 1969, Ser. No. 869,352 gen or an alkanoyl having no more than 8 carbon atoms, Int, C. C07c 169/20 Such as formyl, acetyl, propionyl, butyryl, valleryl and U.S. C. 260-397.3 10 Claims caproyl. These compounds are prepared from 3-fluoro-A2-steroids 10 by a reaction with nitrosyl fluoride and subsequent conver ABSTRACT OF THE DISCLOSURE sion of the 3,3-difluoro-2-nitrimino steroid products to the New steroids of the formula corresponding 3,3-difluoro-2-keto steroids with alumina CE containing Water, as shown in the reaction scheme below X involving the steroid A-ring: R NO R R ? NOF N= A. AlO3.H2O Os R - A. l -3 F2 Fs! N Z-F 20 The 2-keto group can be converted to the 2-hydroxy F= group by conventional techniques, including, for example, wherein Z is oxygen or reduction with sodium borohydrides. DETALED DESCRIPTION OF THE INVENTION The first step of the reaction sequence, the reaction of a .O 3-fluoro-Asteroid with nitrosyl fluoride is carried out in R is hydrogen or methyl; and X is oxygen or an inert Solvent such as methylene chloride, chloroform, OR2 carbon tetrachloride, fluorodichloromethane, and ethylene 30 dichloride. Potassium fluoride or sodium fluoride some times are added to absorb hydrogen fluoride which is 6. formed. The reaction takes place at moderate tempera where R is hydrogen, methyl or ethynyl, and R2 is hydro tures, but a temperature of up to about 100° C. can be gen or an alkanoyl of no more than 8 carbon atoms can be used. The preferred temperature range is about -10° to made in two steps from 3-fluoro-A-steroids. These hor 30 C., where the reaction rates are satisfactory and can be mone-active 3,3-difluoro steroids primarily have antiandro readily controlled. Atmospheric pressure usually is suffi genic activity, although some exhibit androgenic properties. cient, although higher pressures may be sometimes required to maintain a sufficient concentration of the reactants at the temperature used. BACKGROUND OF THE INVENTION 40 The nitrosyl fluoride adduct obtained in the first step, This invention relates to new steroid compounds having the 2-nitrimino-3,3-difluoro steroid, can be determined two fluorine atoms in the 3-position and a ketone or a spectrometrically; but it is unnecessary to isolate and purify hydroxyl in the 2-position. These compounds possess anti the adduct. The crude solution is treated with an alkali androgenic activity. Some of them also have androgenic bicarbonate or another weak base to remove excess nitro properties. Certain steroids having fluorine atoms in C-2, 45 Syl fluoride and/or acidic products formed. The adduct is C-3, or C-4 positions were disclosed in U.S. Pats. 3,055,- then contacted with neutral alumina containing 5-15% by 916; 3,257,424; and 3,232,960; respectively. However, weight of water (activity grade III). This is most conven neither 3,3-difluoro-2-keto steroids nor 3,3-difluoro-2-hy iently done by chromatographic technique, eluting the droxy steroids have been heretofore reported. desired 3,3-difluoro-2-keto steroid from the alumina with 50 an appropriate solvent or solvent combination. The prod SUMMARY uct then is purified by crystallization from usual solvents. The new compounds of this invention can be represented The starting 3-fluoro-A2-steroids can be prepared by a by the formula: reaction of 3-keto steroids with sulfur tetrafluoride to yield CE 55 the corresponding 3,3-difluoro steroids, which are then X dehydrofluorinated with neutral anhydrous alumina. This latter reaction is conducted essentially as described in U.S. 3,413,321. This sequence is illustrated by the following scheme involving the A ring: 60 AlO3 A. --> m N/ Oc Fs F. wherein Z is oxygen or one hydroxyl and one hydrogen; R 65 This invention is now illustrated by the following exam is hydrogen or methyl; and X is oxygen or ples of certain preferred embodiments thereof. 3,629,301 3 4 EXAMPLE 1 To a solution of 2.5 g. of 3-fluoro-2-androsten-17-one in 50 ml. of methanol and 50 ml. of tetrahydrofuran was 3,3-difluoroandrostan-2-17-dione added 0.175 g. of sodium borohydride and the mixture CH CH was stirred at 25 for 2 hours. The solution was then CH O 5 concentrated under vacuum and water was added. The solid residue was collected and dried to give 2.7 g. of 3-fluoro-17 (3-hydroxy-2-androstene. This was dissolved in 50 ml. of pyridine and 25 ml. of acetic anhydride and r stirred at 25 for 16 hours. The solution was then poured 1) NOF O= h O into water. The precipitate was collected, dried and crys al tallized from acetone-hexane to give 2.6 g. of 3-fluoro 2) AlO3.H2O F= 17,3-hydroxy-2-androstene 17-acetate. This compound OO O (2.6 g.) was dissolved in 50 ml. of methylene chloride and 1 g. of NOF was added. The reaction mixture was A solution of 1.4 g. of 3-fluoro-2-androstan-17-one 5 subsequently treated as in Example 1 to give, after chro in 25 ml. of methylene chloride was contacted with 10 g. matography on alumina activity grade III, 0.633 g of of nitrosyl fluoride at 25 for 16 hours. The mixture was white crystalline 3,3-difluoro-17 3-hydroxyandrostan-2- poured into water and the methylene chloride layer was one acetate, M.P. 165-167 (from acetone-hexane). separated, washed successively with water, Saturated So Infrared: dium bicarbonate, water and brine. It was dried over 20 NaSO4 and concentrated to give crude 3,3-difluoro-2- ASl 5.76 and 5.82a (acetate and C-2 C=O) nitriminoandrostan-17-one, 8.4, 8.5 and 8.7a, (C-F); NMR (H) (CDCl3); 4.65 Infrared: p.p.m.; triplet with J about 7 c.p.s. (H-17), 2.50 p.p.m.; triplet with J about 3 c.p.s. (H-1), 2.05 p.p.m. (acetate AE. 6.lu (C=N), 6.41 (No.2) CH), 0.833 and 0.800 p.p.m. (H-19 and H-18). The crude nitrimino steroid was chromatographed on Analysis.-Calcd. for C2H30O3F2 (percent): C, 68.44; 40 g. of alumina of activity III (containing about 6% H, 8.21. Found (percent): C, 68.49; H, 8.09. water) and eluted with hexane:benzene fractions to give EXAMPLE 3 3,3-difluoroandrostan-2,17-dione of which 0.8 g. was re crystallized from acetone-hexane to give long needles, 30 3,3-difluoro-2,17-dihydroxyandrostane 17-acetate M.P., 163-164.5. CE CH Infrared: OA.c Ac ASE 5.75 (C-2 and C-17 C=O) 35 8.50, 8.65 and 8.86 (C-F), NMR (H) tetramethylsilane as internal standard: H-18 (0.87 p.p.m.), H-19 (0.83 NaBH p.p.m.; doublet), H-1 (2.5 p.p.m.; triplet with J =3 c.p.s.); e-ass NMR (F-19) with trichlorofluoromethane as internal 40 standard: F-3ox and 36 at --5772, 6049, 6446 and -6683 C.P.S. To a cooled solution of 0.2 g of 3,3-difluoroandrostane Analysis.-Calcd. for C19H26FO2 (percent): C, 70,34; 2-one 17-acetate (see Example 2) in 15 ml. of methanol H, 8.08; F, 11.71. Found (percent): C, 70.72; H, 7.92; was added 0.023 g. of sodium borohydride. The solution F. 1.91. was stirred for 30 minutes and poured into water. The When ethylene glycol is added to 3,3-difluoroandrostan solid was collected and recrystallized in acetone-hexane 2,17-dione in benzene solution and heated in the presence to give 0.16 g. of crystalline 3,3-difluoro-2,3,176-dihy of p-toluenesulfonic acid, the monoketal, 3,3-difluoro-17 droxyandrostane 17-acetate, M.P. 158–160°. ethylenedioxyandrostan-2-one is formed as shown by Infrared: NMR spectrum. This is a useful compound for further 50 reactions involving the steroid. XSEC 2.77 and 2.90 (OH); 5.78. (C=O) Analysis.--Calcd. for CHOF (percent): C, 68.07; EXAMPLE 2 H, 8.71. Found (percent): C, 68.23; H, 8.61. When the general procedure of Example 1 is repeated 3,3-difluoro-17 3-hydroxyandrostan-2-one acetate except that 3 - fluoro - 170 - ethynyl - 17B - hydroxy 2-androstene 17-acetate is employed, there results from CH CH reaction with nitrosy fluoride and treatment with the Cs CH QA alumina, 3,3 - difluoro - 17o - ethynyl - 176 - hydroxy androstan-2-one acetate, according to the reaction 60 CH CHs OA OAc 1) NaBE 1) NOF CH3 r CH r F 2 F- V3 2 TN/r 2) AcO CO:N/ AlO3 . HO 65 CH 1) NOF =/ O -reel-ar CE QAe F- 2) AllO3H2O F= /N 70 The 3 - fluoro - 17 or - ethynyl - 17B - hydroxy - 2 - an drostene 17-acetate was prepared as follows: o/N/N/ Androstan-3,17-dione was reacted with sulfur tetra fluoride at 20 to yield 3,3-difluoroandrostan-17-one which was dissolved in Xylene and treated with neutral anhydrous 75 alumina of activity I (in the manner described in U.S.