4611
gff, 1Ifi-DIHA4LOGENOANDROSTANES
Sept. j , 1960
charcoal, and evaporated again under reduced pressure; yield 300 mg., m.p. 182-184', [LY]%D-31' (c 1 in water).
[COSTRIBUTIOS FROM THE
Anal. Calcd. for CloHlg06X: C, 48.17; H , 7.70; N, 5.62. Found: C, 48.01; H, 7.61; X, 5.52.
RESEARCH DIVISIOX OF
THE SCHERIXC CORP.]
New Anabolic Agents : 9a,11p-Dihalogenoandrostane Derivatives BY C. H. ROBINSON, L. E. FINCKENOR, R. TIBERI, M. EISLER,R. NERI, A. WATNICK, P. L. PEKIXAN, P. HOLROYD, \V. CHARNEY AND EUGENE P. OLIVETO' RECEIVED JANUARY 9, 1960
A number of Qa,llp-dihalogeno derivatives of testosterone, 1-dehydrotestosterone, methyltestosterone and 1-deli! dromethyltestosterone have been synthesized. Some of these compounds possess favorable anabolic-androgenic ratios.
The synthesis of 19-nortestosterone2in 1950 (and the subsequently recognized fact3 that this compound showed a favorable anabolic-androgenic ratio relative to testosterone) marked the beginning of an intensive search4 for anabolic agents in both the androstane and estrane series.
CHARTI1 OCOC2HZ
0&o c:&
CHARTI CHPOH
V 0 &CH,i
VI
-
o&CH,l
',
Ia, R = H b, H=CH,
0
IIa, R = H b, IZ-CHi
-o&...R
@:.-R
'
X
f
g h i
Br Br
Y
C1 F
c1 c1
C1 C1 Br c1 Br Br
F
F
F
c1
OCOCH, OSO&~&
R
H H H H H CH3 CHa H H
R'
12 '
R
&' :&b, X = Y = C I
OR'
COClHb I I I a H COCZHS b H C O C I H ~ c CH3 COCzHj d CHs H COC~HS COCiHI COCzHs COCtH6
x
VIIIa, X=Br; Y = F
VI1
0 IVa b c d e
'
I1
COCtHs H COCA
In view of the physiological activity manifested and progestins,6 the by 9,11-dihalogenoc~rticoids~ preparation and biological evaluation of the corresponding androstane analogs were undertaken in these laboratories. As will be shown in the sequel, this new class of hormone analogs provides yet an(1) C . H Robinson, L. E. Finckenor, R . Tiberi a n d Eugene P. Oliveto ( S a t u r a l Products Research Dept.); M. Eisler, R . Neri, A Watnick and P. L. Perlman (Biochemistry Dept.); P. Holroyd a n d W. Charney (Industrial Microbiology Dept.), (2) A. J. Birch, J. Chein. Soc., 367 (19.50). (3) (a) I,. G. Hershberger, E. G. Shipley and R. K. Meyer, Proc. .Cor. E i p r v . .\fed., 8 5 , 17.5 (19.53): (b) R . S. Stafford, B. J. Bowman and K. J. Olsen. ihid., 86, 322 (1934); ( c ) F . J. Saunders and V . A. Drill, Esdocrinol., 68, 567 (19.56). ( 4 ) (a) For pertinent references see L. F. Fieser and h l . 1;ieser. "Steroids," Reinhold Publ. Corp., K e w York, N . Y.,1959. p . Ry2 et srq. (b) See also R . 0. Clinton, A. J. hlanson, F W. Stonner, A . I,. Reyler, (;, 0. Potts and A. Arnold, THISJOURNAI,, 81, 151:i [1%!)), ( 5 ) C. H. Robinson, L. I'inckenor, E. P. Oliveto and U. €1. Could, i b i d . , 81, 2191 (1959). (6) H. Reimann, E. P. Oliveto, R. Keri, M. Eisler and P . Perlman, ibid., 82, 2808 (1960)
OH CH3
OH CH.I
o
/
/
IX
Xa, X=Br; Y = F b, X = Y = C 1
other example of physiologicalIy active 9a,l I@-dihalogeno steroids. The androstatrienediones IIa and I I b served as starting materials for the key intermediates IIIb and IIId, which led to a series of 0,ll-disubstituted derivatives of 1-dehydrotestosterone propionate. Thus, enzymic reduction7** a t C-17 of 1,4,9(11)andr0statriene-3,17-dione~~~ proceeded uneventfully in 55% yield, to give 1,4,9(11)-androstatrien-liD01-3-one (IIIa) which was converted to the 17ppropionate IIIb. The preparation of I (ia-methyl-l,4,9(1])-androstatriene-3,17-dione (IIb) from lea-methyl1,4,9(11)-pregnatriene-1'7a,21-diol-3,20dione - 21acetatelofollowed conventional procedures (i.e., hydrolysis to the 21-alcohol followed by sodium bismuthate degradation), and reduction by yeast then afforded the desired 178-01 IIIc and thence the l i p propionate IITd. (7) L. Mamoli and A. Vercellone, B m , 7 0 , 470 (1937). ( 8 ) H. I,. Herzog, M. A . J e v n i k , P. I,. Perlman, A . Nobile and E , R . Ilershberg, T H I S J O U R N A L , 76, ?6f, (I95:j). (9) B. J. Magerlein and J. A. Hogg, ibid., 80, 2220 (19x3). (10) E. P. Oliveto, R . Rausser, L. Weber, A. L. Nussbarlm, W. Gebert, C. T. Coniglio, E. B. Hershberg, S. Tolksdorf, h f . Eisler, P. L. Perlman and hI. AI. Pechet, i b i d . , 81, 4431 (1959).
4612
ROBINSON, FINCKENOR, TIBERI,EISLER,NERI, HOLROYD, CIIARNEY AND OLIVETO
Vol. 82
The 9cr,11,R-dihalogenated derivatives of I I I b the case of saturated steroidal 12a-tosylatesI6 and and IIId were secured by procedures essentially the tosylated sugars.” same as those previously used5 in the cortical seIn steroids containing an a.p-unsaturated ketone ries, namely the use of N-haloamides in the presence grouping and a 12a-tosylate, the observed ultraof the appropriate anion. However, the addition violet absorption maxima are now similar to the of ClF to the 9(11)-double bond, while employing curves constructed by adding the absorptions of the N-chlorosuccinimide and hydrogen fluoride (thus two chromophors.16v18Specific examples are 120being analogous with the method of BrF addition tosyloxy-17a-methylprogesterone (Amax 229 mw, developed in these laboratories) was performed in e 17,800) and 12a-tosyloxyprogesterone (Amax 228 pyridine-carbon tetrachloride mixtures. l 1 m,u, e 25,000). The structures of ,compounds IVa-IVg are We therelore formulate 115 as 9a-bronio-1,4assigned on the bases of elemental analysis, spec- androstadiene-1lp,17/3-diol-X-one 1I@-tosylate17ptroscopic evidence and analogy with the additions propionate. The procedure described above thus to the 9(1l)-double bond reported ear1ier.j offers a route to the previously inaccessible steroidal The mildness of the N-chlorosuccinirnide-hydroSa-halo-1I@-tosylates and, possibly, to cyclic and gen fluoride system described above is worthy of acyclic a-halo-arylsulfonyl esters by a one-step note. Addition of C1F can be carried out in the process from olefins. presence of an unprotected secondary hydroxyl, as We finally turned our attention to the l i a exemplified by the conversion of 1,4,9(11)-androsta- methyltestosterone series, aiid the bromofluoro and trien-17fi-ol-3-one to the 9a-chloro-1 l,R-fluoro-l,4- dichloro analogs VIIIa and VIIIb of methyltestosandrostadien-17p-ol-3-one(IVe) in good yield. terone were prepared from 17a-methyl-4,9(11)Propionylation of IVe in pyridine with propionic androstadien-17p-ol-3-one (VII) .Ig anhydride gave the 17,R-propionate IVd, prepared Conversion of VI1 to the 1-dehydro compound also by addition of C1F to 1,4,9(11)-androstatrien- I X was accomplished microbiologically, using 17p-ol-3-one 170-propionate (IIIb). Bacillus sphaericus. 2o The 9,ll-dihalogenated deA 1,2-dihydro analog of the above compounds rivatives Xa and Xb of l-dehydromethyltestoswas also prepared, by the addition of BrF to 4,9- terone were then secured b y our standard pro(1l)-androstadien-17P-ol-3-one 17P-,propionate,12 to cedures. give 9a-bromo-ll~-fluoro-4-androsten-l7/3-ol-3-one Finally it may be noted that the assumption 17p-propionate (VI). that no inversion had occurred a t C-16 in the prepSince the Sa-bromo-1ID-fluoro- and Sa-bromo- aration of 16a-methyl-1,4,9(1l)-androstatriene-3,1ID-chloro-1-dehydrotestosterone derivatives (IVb 17-dione (IIb) has been confirmed in the following and IVa, respectively) displayed similar activities, way. Sodium bismuthate degradation of 1GPwe were led to speculate whether the nature of the methyl-l,4,9(1l)-pregnatriene-l7a,21-diol-3,20-di11-substituentwas critical. To test this hypothesis, onez1 furnished a methylandrostatrienedione d$we prepared Sa-bromo-1lp-acetoxy-l-dehydrotes-fering from IIb. This 17-ketone, which is thus tosterone propionate (IVh) by the N-haloamide the 16p-methyl analog of IIh, has been reduced procedure,13 and attempted to prepare the 9a- to the corresponding lip-alcohol, which differs bromo-1 lp-methoxy analog. Treatment of the from 16a-methyl-l,4,9(11)-androstatrien-1’7/3-01-31,4,9(11)-triene I I I b with N-bromoacetamide in one (IIc). The 16a-configuration for IIc is thereby methanol14 gave very poor yields of solid bromine- confirmed. A preliminary screening test for androgenic containing product. However, addition of 1.1 equivalents of p-toluenesulfonic acid to the reac- and myotrophic activity of the compounds was tion mixture resulted in the isolation of a crystalline done using the immature male rat weighing 5060 g. Androgenic activity was revealed by the product, IVi, in excellent yield. Elemental analysis indicated that we have in increase in weight of the seminal vesicles and hand a compound resulting from the addition of prostate over the controls. Alyotrophic activity Br-C6H6S03 to IITb. The infrared spectrum was determined by the increase in the levator showed bands a t 7.32 and 7.44 ,u and a very strong ani muscle. If the compound was inactive as an band a t 8.54 ,u (the latter being a summation band androgen or in the myotrophic test no further due partly to the 17-propionate group) character- tests were performed. If, however, the comistic of p-toluenesulfonate esters. l5 The ultraviolet pound showed either androgenic or anabolic (myoabsorption maximum appeared a t 230 mw (24,300) trophic) activity, a 6-point bioassay was carried and is consistent with the presence of the A ring out to determine the dose response curve. The chromophor and a p-toluenesulfonate ester. The assay used was the response of the castrate r a t ultraviolet absorption due to an isolated tosylate seminal vesicle and growth of the levator ani, ac10,000) in grouping appears a t 224-226 mp ( e (16) C. R. Engel, K. F.Jennings and ( > Just, l ’ r m J O W R C A L , 78,
-
(11) Dr. M. Tanabe (Stanford Research Institute, Menlo Park, Calif.) has also independently observed t h e addition of chlorine fluoride to a Ag(ll)-steroid, using h--chlorosuccinimide and hydrogen fluoride in dimethylformamide. We wish t o thank D r . Tanabe for communicating his results to us, prior t o publication. (12) F . W. Hey1 and M. E. Herr, THISJ O U R N A L , 7 7 , 488 (1955). (13) C. H. Robinson, L. Finckenor, M Kirtley, D. Gould and E. p. Oliveto, ibid., SI, 2195 (1999). (14) Cf. W. H . Puterbaugh and M S. h-errrnan, i b i J . 79, 3409 (1957). (15) Cf.1,. J. Bellam). “ T h e Infrared Spectra of Com!,le\ l l u l e John Wiley and Sons, Inc., S P WI‘ork, S.I-.,1958, p. 364.
6153 (1956). (17) A. L. Bernoulli xnd €1. Stxuffcr, A?rlz,. i Jiiirz. Acto, 23, 015 (1940). (18) G. Just and C. R . Engel, J. OPE.Chem., 23, 12 (1958). (19) M. E, Herr, J. A. Hogg and R . H. Levin, THISJOURNAL,7 8 , 500 (1956) (20) T. H. Stoudt, W. J. hIcAleer, J. M. Chemerda, 11. A. Kozlowski, R . F. Hirschmann, V. M a r l a t t and R. Miller, Arch. Biochent. aiid Riophys.. 59, 304 (1955). (21) A detailed account of the preparation of these 16g-methyl compounds, and of some subsequent transformations, will be given shortly.
Sept. 3, 1960
CY, 110-DIHALOGENOANDROSTANES
4613
16a-Methyl-1,4,9( ll)-androstatriene-3,17-dione ( I I b ) .T o a solution of 16a-methy1-1,4,9( 1l)-pregnatriene-l7a,21diol-3,ZO-dione ( I b , 5.0 9.) in 50% aqueous acetic acid (300 ml.) a t 90-700" was added sodium bismuthate (25 g.) and the suspension was stirred at 90-100" for 0.5 hour. The reaction mixture was filtered and extracted with niethylene chloride. The methylene chloride was washed successively with water, 107h aqueous sodium hydroxide and water, dried (MgS04) and evaporated in z'acuo to yield oil ( 2 . 5 g.). The oil was filtered through Florisil ( 7 5 g.) in ether-hexane (1: 1) giving solid which was crystallized from acetonehexane t o yield IIb, (1.5 g.), 1n.p. 138-139", [ a ] ~ %", 238 mp (15,500); A&': 5.78, 6.00, 6.15, 6.23 p . Anal. Calcd. for C2&402: C, 81.04; H , S.16. Found: C, 81.31; H, 8.13. 1,4,9( 1l)-Androstatrien-l7p-ol-3-one(IIIa) by Enzymic Reduction of 1,4,9( 1l)-Andro~tatriene-3,17-dione.~~~-The inoculum consisted of a 24-hour culture of Saccharoinyce\ cereaisiae I.4.T.T.C. Xo. 4125) erown on a shaker at 28'. A 6% level was used for inoculuG. For both the inoculum and the fermentor the following medium was used: Difco yeast extract (1%), K H z P 0 4 (0.455%), Sa2HPOI (0.475i), dextrose (670),$H6.8. The fermentor was made up, the medium (10 liters) w:is poured in, and the entire assembly was autoclaved at 121' for 30 minutes. After inoculation the air-flow was adjusted t o 1 volume of air per volume of medium per minute. After 25 hours growth, n solution of 1,4,9(11)-androstatriene3,17-dioiie (1.0 g.) in ethanol (20 tnl.) was added, and the air-rate was increased to 1.5 volumes of air per volume of medium per minute. Fermentation was continued until a chromatographic sample showed that all the starting rnaterial had been converted. (This usually took ca. 120 TABLE I hours after addition of the steroid.) Fresh sterile medium The SUMMARY OF ASSAYS OF L~YOTROPHIC ASD ANDROGENIC was added daily to make up loss due to evaporation. steroid was extracted from the broth by adsorption upon ACTIVITI"~ Bentonite, and was then eluted with methanol, the methanol ComSI/A Ref. pound Androgenic M yotropic ratio b cmpd. C eluates being evaporated to dryness in Z'UCUO. Paper chromatography (toluene-propylene glycol system) confirmed i . i TP 0.044 0.340 IVa conversion of the starting niaterhl to a more polar product. (0.029-0.054) (0.220-0.570) The crudc residue was now exhaustively extracted with 1 2 . 8 TP 0.06 0.7; IVb ether, and the ethereal extract was filtered through a column of Florisil. The solids thereby obtained were crystallized (0.04-0.11) (0.47-1.34) from acetone-hexane to Five I I I a (550 mg.). m.0. 1400.84 1 . 6 TP IVd 0.51 145'. The analytical sample, prepared b?; 'recristalliza(0.40-0.64) (0.54-1.86) tion from acetone-hexane had m.p. 1 4 5 1 4 8 " , [ a ] -28", ~ 4.2 M T 0.04 0.17 VIIJa A&:?" 238 mw (15,300); Xi:?' 2.92,6.02,6.16,6.24 p . (0.03-0.05) (0.04-0.30) Anal. Calcd. for C&z402: C, 80.24; H, 8.51. Found: C, 79.91; H, 8.90. 3.0 5.0 M T Xb 0.60 1,4,9( 11)-Androstatriene- 17p-ol-3-one 17p-Propionate (0.45-0.80) (1,7-7.8) (IIIb).-The foregoing compound ( I I I a , 450 mg.) was Xa 0.12 0.23 1 . 9 MT treated with propionic anhydride ( 5 i d . ) in pyridine (10 (0.07-0.18) (0.11-0.37) ml.) and the solution was left a t room temperature for 17 hours. Water was then added, and the mixture, after 3 a Six point assay. * Myotrophic/androgenic = potency ratio. C T P = Testosterone propionate; MT = inethl-1- hours, was extracted with methylene chloride. The extract was washed successively with 2 iY hydrochloric acid testosterone; figures in parentheses indicate ranges. and water, evaporated i n tsacuo, and the crude residue was filtered through a short Florisil column in ether solution. Experimental Evaporation of the eluate and crystallization from acetonc16a-M ethyl- 1,4,9( 11)-pregnatriene- 170,2 1-diol-3,20-dione hexane furnished pure I I I b , m.p. 137-138", [ a ! --12', ~ (Ib).-A solution of 16a-methyl-1,4,9( 11)-pregnatriene238 m p (15,600); '";A:: 5.TS, 6.02, 6.16, 6.24, 8.40 17~,21-diol-3,20-dione21-acetateIo (10 9.) in 0.27 N methP. anolic perchloric acidz3 (70 ml.) was allowed t o stand a t Anal. Calcd. for CT2Hg803: C, iT.61; 13, 8.29. Found: room temperature for 17 hours. The reaction mixture was C, 77.94; H , 8.46. poured into water (3.0 1.) and extracted with methylene chloride. The methylene chloride was washed with water, 16a-Methyl-l,4,9(1l)-androstatrien-17p-ol-3-one(IIIc) by 10% aqueous sodium carbonate and water, dried (MgSOI) Enzymic Reduction of 16a-Methyl-l,4,9(11)-androstatrieneand concentrated to dryness zn tlacuo. The crude product 3,17-dione (IIb).-The 16a-methyl-l,4~9( 11)-androstatrienewas crystallized from acetone-hexane and yielded, in two 3,17-dione was reduced enz)-mically by exactly the same crops, I b (5.4 g.). The analytical sample had m . p . 228procedure described for the preparation of I I I a . The crude 231°, [a]D go, ktz:H 238 IIlp (16,100); ';A:: 2.04, product was filtered through a column o f Florisil, i n ether, 5.80, 6.03, 6.24 p . and the solids thereby obtained were crh-stallized from *4nal. Calcd. for C22H2804: C, 74.13; H, 7.92. Found: acetone-hexane t o give pure IIIc, m.p. 1i2-174', [ a ] ~ -46", " : : :A 238 111p (15,400); A:2" 2.92, 6.03, 6.18, C, 74.39; H , 8.03. 6.24~. (22) Melting points were obtained o n the Kofler block. Rotations Anal. Calcd. for C2,H,,Oa: C, 80.49; 11, X.7X. Fouiid: were measured a t 2 5 O in dioxane solution a t about 1% concentration. C, 80.71; H, 8.56. We are indebted to the Physical Chemistry Department, Schering 16~-Methyl-l,4,9(1l)-androstatrien-17p-ol-3-one 176Corp., for measurement of ultraviolet and infrared spectra. MicroPropionate (1IIdj.-To a stirred solution o f lfju-methylanalyses were carried o u t by M r . E. Conner (Microanalytical Labora1,4,9(11 )-aiidrostatrien-li~-ol-3-one( I I I c , 3.0 9.) in pyritory, Schering Corp.), and by the Schwarzkopf Microanalytical I.abdine (30 ml.) was added propionic anhydride (3.0 tnl.) and oratory, Woodside, K.Y . the solution \vas left a t room temperature for 18 hours. (23) J. Fried and E. F. Sabo, THISJ O U R N A L , 1 9 , 1130 (1957).
cording to the method of Hershberger, Shipley and Meyer.3a Compounds IVc and IVe were found t o have strong androgenic activity and no estimation was made of the myotrophic-androgenic activity ratio. Table I summarizes the myotrophic-androgenic activity of compounds IVa, IVb, IVd, VIIIa, Xa and Xb. Compound IVb has high myotrophic (anabolic) activity, and low androgenic activity. In comparing compounds IVa and IVd to compound IVb, interesting biological results are noted. The substitution of a chlorine atom for fluorine a t C-11 reduces the myotrophic activity, while the substitution of a chlorine a t C-9 instead of bromine further reduces the myotrophic-androgenic ratio when compared to the standard, testosterone propionate. In compound VIIIa in which methyltestosterone has been modified by the insertion of a Sa-bromo1ID-fluoro grouping, the myotrophic ratio is increased. Dehydrogenation of compound VIIIa a t C-1 and C-2, resulting in compound Xa, lowers the ratio appreciably. Compound X b which is the CY, 1I@-dichloroanalog of compound Xa, shows an appreciable increase in the myotrophic-androgenic ratio (Table I).
--
+
+
4614 ROBINSON, FINCKENOR, TIBERI, iv:ATNICK,
PERLLiS,
HOLROYD, CHARNEY
.iKD O L I V E T O
VOl. 82
Water (3.0 ml.) was added and the mixture allowed t o stand tuting N-chlorosuccinimide (345 mg.) for S-bromoacetamfor 15 minutes before being poured into cold 5% aqueous ide. The crude product was chromatographed on Florisil, sulfuric acid (300 ml.). T h e crude solid was filtered, dried elution with ether-hesane ( 4 : 1) yielding solid which was and crystallized from acetone-hesane t o yield I I I d (1.6 g.), crystallized from ether-pentane t o give 11-c (188 mg.), m.p. 140-143', [ a ]- ~2 i 0" ,: : :A 238 mp (15,600); ?':A: m.p. 170-173', "";:A: 237 m p (14,600). The infrared 5.75,5.98,6.14,6.22,8.38p. spectrum ( S u j o l ) was identical with t h e spectrum of IVc Anal. Calcd. for C23H3003: C , 77.93; H, 8.53. Found: prepared as in (A) above. 9~-Chloro-l1~-fluoro-l,4-androstadien-17p-ol-3-one 170C, 77.68; H, 8.80. a stirred suspension of 1,4,9( 11)9~-Bromo-l1~-chloro-l,4-androstadien-l7p-ol-3-one 178- Propionate (IVd).-To Propionate (IVa).-To a stirred solution of 1,4,9( 11)- androstatrien-17P-ol-3-one 178-propionate ( I I I b , 1 .O g.) androstatrien-17fJ-ol-3-0ne 176-propionate ( I I I b , 800 mg.) in carbon tetrachloride 130 nil.) and Dvridine (4 m l . ) chloroform-tetraand lithium chloride (4.0 g.) in glacial acetic acid (30 ml.) added hydrogen fluoride (588 'mg.) was added N-bromoacetamide (367 mg.) followed imme- hydrofuran ( 3 : l ; 1.5 ml.) and freshly crystallized Kdiately by an anhydrous solution of hydrogen chloride (92 chlorosucciniinide (432 mg.). Stirring was continued for mg.) iii tetrahydrofuran (0.5 m l , ) . Stirring was continued 20 hours, and the reaction mixture was poured into 5'jC for 3 hours, after which t h e reaction mixture was poured aqueous sodium carbonate solution (300 1111.) and extracted into cold water (300 ml.) and filtered. T h e crude product with methylene chloride. The methylene chloride extract was dried i n vacuo and crystallized from ether-pentane t o mas washed successively with water, 5Ljb aqueous sulfuric yield pure IVa (530 mg.), m.p. 128-130" dec., [a]D f acid, N sodium thiosulfate and water, dried ( h l g S O ~ j 116O, A&@;"" 239 mp (13,800); k:tri 5.76, 5.96, 6.12, 6.18, and evaporated in Z'QCUO. Trituration with ether gave a solid, which was crystallized from acetone-hesane t o yield 8.40 p . I\'d (330 mg.), m.p. 171-175', [ a ] $~. 63", hE;?.,O" 237 Anal. Calcd. for C22H2*O3BrCI: C, 57.96; H , 6.19; mp(15,000); h;~~'5.80,6.02,6.14,6.22,8.40p. Br, 17.5.3; Cl, 7.78. Found: C, 58.01; H, 6.30; B r , Anal. Calcd. for C22H?803C1F: C, 66.91; H , 7.15; 17.50;c1,7.95. C1, 8.98;F, 4.81. Found: C, 66.55; H, 7 . l i ; C1, 9.15; 9~-Bromo-ll3-fluoro-l,4-androstadien-17p-ol-3-one 178- F, 4.64. Propionate (IVb).-To a stirred solution of 1,4,9( 11)9~-Chloro-ll~-fluoro-l,4-androstadien-!7~-ol-3-one 17$nndrostatrien-17~-01-3-one lip-propionate ( I I I b , 600 mg.) Propionate (IVd) from 9~-Chloro-llp-fluoro-1,4-androstain diethylacetic acid (25 ml.) was added S-bromoacetamide dien-17p-ol-3-one (IVe).-A solution of IVe (80 m g . ) in (267 mg.) followed immediately by a solution of hydrogen pyridine (0.80 ml.) and propionic anhydride (0.16 nil.) fluoride (570 nig.) in tetrahydrofuran ( 2 ml.). Stirring was left a t room temperature for 17 hours. II'ater ( 0 '1 was continued a t room temperature for 24 hours aiid t h e ml.) was added and the mixture was poured into cold 10 reaction mixture was then poured into cold lo'?, aqueous aqueous sulfuric acid (10 ml.). T h e precipitated solid w sodium carbonate solution (300 ml.) a n d extracted with filtered, dried and crystallized from acetone-hesaue t o methylene chloride. The extract was washed successively yield IVd (65 mg.), m . p . 170-173", ( m . p . undepressed 011 with 10%; aqueous sodium carbonate solution, A' sodium admixture with authentic 11-d); infrared spectrum ( S u j o l ) thiosulfate solution and water, dried (MgS04) and evapo- identical with t h a t of authentic IVd. rated in ~ a c u o . T h e crude residue was crystallized from 9a-Chloro-1 lp-fluoro-l,4-androstadien-17~-ol-3-one (IVe 1. ether-pentane twice t o give 1Vb (240 mg.), m.p. 164- -To a stirred solution of 1,4,9(11)-androstatrien-l7$165O, [ a ] ~ 64", G :"' 239 mp (14,400); "'::A; 5.80, 01-3-one (1113, 1.0 g.) and N-chlorosuccinimide (000 rng.) G.02,6.15, 6.22, 8.40~. in carbon tetrachloride (30 m l . ) and pyridine (4 1111.)TKLS Anal. Calcd. for Cx2H2SOSBrF:C, 60.14; H,6 .42; Br, added hydrogen fluoride (338 mg.) in chloroforn-tetr>t1S.19; F, 4.32. Found: C , 60.22; H, 6.55; Br, 18.43; hydrofuran ( 3 : 1 , 1.5 ml.). Stirring was continued for 20 F , 4.13. hours. The reaction mixture was poured into lo',, 1,4,9( 1l)-Androstatrien-l7p-ol-3-one 170-Propionate aqueous sodium carbonate (300 ml.), extracted with methylene chloride, washed with 5% aqueous sulfuric acid (IIIb) from 9~~-Bromo-l1~-fluoro-l,4-androstadien-17p-ol3-011'5 178-Propionate (IVb).-To a solution of IVb (300 and water, dried (h!IgS04) and concentrated t o yield a mg.) in acetone (20 ml.) was added chromous chloride solu- yellow solid. Crystallization from acetone-hexane affordctl tion2' (20 ml., 5-ml. portions every 5 minutes). The re- IVe (650 mg.), m.p. 210-215' dec. Kecrystnliizatiolt action mixture was poured into water, extracted with from acetone-hexane afforded the analytical sample, n ~ " : : : :A 237 nip, (14,900); h methylene chloride, dried (MgSOa) and concentrated t o 212-215' dec., [ a ]+73", dryness to yield a colorless oil (200 mg.). Crystallization 2.94, 3.02, 6.02, 6.14,6.20p. from acetone-liesane ( b . p . 65") yielded I I I b (50 mg.), Anal. Calcd. for C1SH2402C1F: C, 67.34; 1 1 , 7.14; in .p. 133-135', undepressed on admixture with authentlc C1, 10.47; F, 5.61. Found: C, 67.76; 13, 6.82; CI, Ii.b, infrared spectrum (Nujol) identical with that of au- 10.78; F, 5.46. thentic I I I b . 9a-Bromo- 1lB-fluoro-l6a-methyl-l,4-androstadien17d9a,11P-Dichloro-l,4-androstadien-17p-ol-3-one 17p-PrO- ol-3-0ne 178-Propionate (IVf).-To a solution of 16ea stirred, cooled (-20 to -25') pionate (IVc). A.-To xnethy1-1,4,9( 1 ~)-antirostatriexi-l;3-~1-3-one 178-propioii;itc solution of 1,4,9(1l)-androstatrien-17P-ol-3-one 173-pro- ( I I I d , TOO m g . ) i n diethylacetic acid ( 2 8 n i l . ) was added Spionate ( I I I b , 800 mg.) in carbon tetrachloride ( 3 0 ml.) bromoacetamide (300 m g . ) followed immediatt,ly by hydroand pyridine (0.7 m l . ) was added chlorine (183 nig.) in gen fluoride (395 mg.) in a solution of cliloroform-letrallycarbon tetrachloride (3.0 nil.). Stirring mas continued for drofuran ( 3 : 1 , 1.5 ml ) and stirring was continucd for 18 15 minutes at -20 t o -25', and then a t room tempera- hours. ( T h e reaction was carried out in a polyetli)-leiic ture for 1 hour. T h e reaction mixture was then poured into bottle using magnetic stirring.) T h e reaction mixture KLS water (300 m l . ) and the carbon tetrachloride layer x a s sep:i- poured into 107' aqueous sodium c a r h i l a t e (300 nil.), rated, washed successively with :V-aqueous sodium thio- extracted with niethylene chloride, and tlie extract w:ts sulfate, 107; aqueous sulfuric acid, 1Oyoaqueous sodium washed with 5',:6 aqueous sodiuln hydrnuide a n d water, bicarbonate and water, dried ( M g S 0 4 ) and evaporated dried (MgSO1) and concentrated t o dryness. T h e rr-uctc in vacuo. The crude residue was crystallized from ether- product was triturated with ether and the residual h o l i t l pentane, t o furnish IVc (186 mg.), m.p. 1Tl)-173°, [a]D recrystallized from aqueous methanol to !.icld I Y f (:38U 105", A":t 237 111p (14,600); "::A: 5.82, 6.04, 6.14, l l l g . ) , 1ll.p. 163-165', [a]D 35" h:$" 239 Inp (14,.kl)o); 6.22, 8.40 p . h;Z"l5.78, F.OO,G.1-',6.18,8.40p. 4naZ. Calcd. for C22H280sC12: C, 64.23; H, 6.86; Cl, Anal. Calcd. for C23H3003BrF:C, G0.93; 11, 6.67; Iir, 17.24. Found: C,64.24; H, 7.15; C1, 17.04. 17.63; F, 4.19. Found: C, 61.21; H , 6.79; Br, 17.01; X second crop of IVco(l95 mg.) was obtained from ether- F, 3.89. pentane, m . p . 166-170 ; this material was identical with ~ C Y1 , 10-Dichloro- 16a-methyl-1,4-androstadien- 17B-01-3the analytical sample a s judged b y infrared comparison. one 17p-Propionate (IVg).-To a stirred solution of I GaB.-Compound I i - c was also prepared from I I I b (800 meth!-l-l ,4,9( 1~)-antlrostatrier~-l73-ol-3-o11e l 7P-~-,ropiotiate mg.) by the procedure described earlier for IXTa,substi- ( I I I d , 700 tng.), lithium chloride ( 3 g.) and ?;-chlorosuccitiimide (290 mg.) in acetic acid (30 tnl.) was added a q u w u s (21) , . G Rosenkranz. 0. AIancera, J. Gatica and C. Djerassi, THIS .V hydrochloric acid (2.23 m l . ) and stirring YWIS continued for :ihours. The rcaction mixture MYIS poured into water J O U R N A L , 72, 4077 (1950).
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Sept. 5 , 1960
YO(, 1~~-DIHALOGENOXNDROSTANES
(300 ml.), filtered and dried t o yield 700 mg. of crude product. Crystallization from acetone-hexane afforded IVg (280 mg.), m.?. 188-192" dec., [ a ] ~ Soo, 237 mp (15,000); k 2 2 5.80,6.02,6.14,6.20,8.40p. Anal. Calcd. for C23H3~03C12:C, 64.94; H , 7.11; C1, 16.67. Found: C,65.02; H,7.41; C1,16.81. 9a-Bromo-1,4-androstadiene-l lp,l7P-diol-3-one l l p Acetate 178-Propionate (In).--To a stirred solution of 1,4,9( 1l)-androstatrien-li~-ol-3-one176-propionate ( I I I b , 750 mg.) and lithium acetate (3.0 9.) in glacial acetic acid (30 ml.) was added N-bromoacetamide (335 mg.). T h e mixture was stirred for 24 hours a t room temperature and was then poured into water (300 ml.), and filtered. The dried residue was crystallized from ether-pentane t o give IVh (526 mg.), m.p. 161-166' dec., [ a ] D 99", $A": 239 mp (13,600); ' : : :A 5.75, 5.78, 6.02, 6.14, 6.22, 8.15, 8.36 p . Anal. Calcd. for Ct4Ha10jBr: C, 60.12; H, 6.52; Br, 16.67. Found: C,60.28; H , 6 . 4 4 ; Br, 16.94. Pa-Bromo-l,4-androstadiene-l l p , 178-diol-3-one 11p-pToluenesulfonate 17p-Propionate (IVi) .-To a stirred solution of 1,4,9( ll)-androstatrien-17~-ol-3-one17P-propionate ( I I I b , 1.0 g . ) and 9-toluenesulfonic acid monohydrate (615 mg.) in methanol (40 ml.) was added N-bromoacetamide (455 mg.). The solution immediately turned yellow, but after 15 minutes had decolorized and a crystalline solid had been deposited. The reaction mixture was chilled in the refrigerator for 0.5 hour and then filtered t o yield IVi (780 mg.), m.p. 125-127' dec., [a]D 50°," : : :A 230 mp (24,300); A%Y' 5.78, 5.98, 6.12, 6.18, 6.24, 6.7, 7.32, 7.44,S.M p . Anal. Calcd. for C2gH3506BrS:C, 58.88; H , 5.96; Br, 13.51; S, 5.42. Found: C, 59.00; H , 6.03; Br, 14.29; S, 5.40. 9a-Bromo- 118-fluoro-4-androsten- 17P-ol-3-one 170-Propionate (VI).-By the procedure used for IVb, 4,9(11)androstadien-lib-01-3-one l7p-propionate (V, 1.0 9.) was converted to the Sa-bromo-118-fluoro derivative VI which after two crystallizations from ether-pentane (yield 255 mg.) had m.p. 170-175°, [ a ] ~ 80°, A$": 239 tnp (16,200); ~.18,6.02,6.18,8.08p. Anal. Calcd. for CP2H3003BrF: C, 59.86; H, 6.85; Br, 18.11; F , 4.30. Found: C, 59.82; H , 6.68; Br, 18.16; F , 4.05.
461.5
Oa,11~-Dichloro-l7a-methyl-4-androsten-l7~-ol-3-one
(VIIIb).-Chlorine gas was bubbled a t a slow rate for 30 seconds into a solution of 17a-methy1-4,9( 11)-androstadien17@-01-3-one (VII, 1.0 g.) in methylene chloride (40 ml.) and pyridine (20 ml.). T h e mixture was stirred a t room temperature for 1 hour, diluted with methylene chloride (100 ml.), washed with cold 10% aqueous sulfuric acid, N sodium thiosulfate and water, dried (MgS04) and concentrated t o dryness. The residue was triturated with ether and the solid residue was then crystallized from acetone-hexane t o yield VIIIb, (285 mg.), m.p. 228-234' dec., [ a ] ~ 152', Ag$" 238 mp (16,800); ?A': 2.94, 6.01,6.16p. Anal. Calcd. for C20H280ZC12:C, 64.69; H, 7.60; Cl, 19.10. Found: C,64.47; H , 7 . 5 2 ; C1, 19.24. 17a-Methyl-1,4,9( ll)-androstatrien-17~-01-3-one(IX).17a-Methy1-4,9( 1l)-androstadien-17/3-ol-3-one1@( 5 .O g.) was subjected to the action of Bacillus sphaericus following the procedure of Stoudt et al.zo The crude extracts were adsorbed onto Florisil (10 g.), dried and chromatographed on Florisil (150 g.). The fractions eluted with ether-hexane ( 3 : 1) were crystallized with difficulty from ether-hexane to yield I x (2.1 g.), n1.p. 136-139", [a]D - 5 2 O ," : ; :A 239 mp (16,900 as l / 2 ether solvate): ?':A; 3.05, 6.01, 6.20, 6.24 p . Anal. Calcd. for C20H2602.1/2 C4HloO: C, '78.76; H, 9.31. Found: C, 79.01; H , 8.97. I n one experiment this compound was isolated with m.p. 68-70', O ;X :":: 239 mp (17,100 as ether solvate); XZtr'2.95, 6.00, 6.16,6.22p. Anal. Calcd. for C20H2602.C4H~00:C, 77.37; H, 9.74. Found: C, 76.56; H , 9.31. 9a-Bromo-1 lp-fluoro-l7~-methyl-l,4-androstadien-l7p01-3-one (Xa).-To a solution of 17a-methyl-1,4,9( 11)androstatrien-17b-ol-3-one( I X , 1.0 g . ) in diethylacetic acid (50 ml.) was added hydrogen fluoride (1.3 9.) in chloroformtetrahydrofuran ( 3 : 1, 12 ml.) followed immediately by Nbromoacetamide (509 mg.). The reaction mixture was stirred for 1 hour a t room temperature, then poured into water (500 ml.) containing sodium carbonate (50 9.) and extracted with methylene chloride. The methylene chloride was washed with 10% aqueous potassium hydroxide and water, dried (MgSOd) and concentrated zn vacuo t o yield white solid. Crystallization from acetone-hexane afforded X a (525 mg.), m.p. 192-197' dec., [ a ]f ~5 5 O , A$": 239 mp (14,500); A&'?' 3.0, 6.02, 6.15, 6.22 p . 9~-Bromo-l1p-fluoro-l7~-methyl-4-androsten-17p-ol-3-Anal. Calcd. for C20H2602BrF:C, 60.45; H , 6.60; one (VIIIa).-To a stirred solution of 17a-methyl-4,9(11)- Br, 20.11; F , 4.78. Found: C, 60.96; H , 6.42; Br, androstadien-lip-ol-3-one ( V I I , 2.0 g.) in diethylacetic 20.00; F , 5.05. acid (120 ml.) was added hydrogen fluoride (5.8 g.) in chloro9a, 11~-Dichloro-l7~-methyl-l,4-androstadien-178-ol-3form-tetrahydrofuran (20.8 m l . ) followed immediately by one (Xb).-To a solution of 17a-methyl-1,4,9(11)-androstaX-bromoacetamide (1.42 g.). The reaction mixture was trien-17P-ol-3-one (IX, 800 mg.) in methylene chloride stirred at room temperature for 2 hours, poured into water (22 ml.) and pyridine (16 ml.) was added chlorine (285 mg.) (1.2 1.) containing sodium carbonate (120 9.) and extracted in carbon tetrachloride (10 ml.). The mixture was stirred with methylene chloride. T h e methylene chloride was a t room temperature for 1 hour, diluted with methylene washed with 5'% aqueous sodium hydroxide and water, chloride (100 ml.) and washed with 10% aqueous sulfuric dried (MgS04) and concentrated to dryness to yield a yellow acid, N sodium thiosulfate and water, dried (MgSO4) oil. T h e oil was chromatographed on silica gel (60 g., and concentrated t o dryness in vacuo. The solid residue Davison Chem. Co., 100-200 mesh) and the product eluted was crystallized from acetone-hexane to yield X b (475 mg.), with ether-hexane (3 :2). Crystallization from acetone121",":1 ;: 237 mp (14,600); h2:r1 hexane gave VIIIa, (500 mg.), m.p. 190-195" dec., [ a ] ~ m.p. 210-215', [ a ] D 2.98,6.00,6.18,6.22p. 84O, A% ": 240 mp (15,400); A2:p12.92, 5.98, 6.14 p . Anal. Calcd. for C Z O H Z ~ O ~c C , ~65.04; ~: H, 7.10; C1, Anal. Calcd. for CnnHqaOlBrF: C. 60.15: H . 7.07: 19.20. Found: C,64.85; H , 7 . 2 5 ; C1,19.03. Br, 20.01; F, 4.76. F o i n d : C, 61.'00; H,' 7 . 2 5 ; - Br; 19.82; F , 4.41. BLOOMFIELD, N. J.
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