Jan. 1962
STEROIDKETALS
133
and l / [ H + ] = [OH-]/K,
(22)
so that in substitution of (21) and (22) into (20) 0 d[Ester] /dt = kK, K,[OH-] [RO&CH&!-OH]
0
(23)
Thus, intramolecular catalysis (equation 20) need not necessarily be favored over its kinetic equivalent (equation 23).
Acknowledgments are made to Dr. A. R. Hanze for the synthesis of most of the hemiesters and Mrs. L. G. Snyder and Mr. Max Royer for excellent technical assistance.
Certain Steroid Ketals and Their Biological Activity WILLIAM S. ALLEN,HENHYM. KISSMAN, SIDNEY MAUEB, IRARINGLER, AND MARTIN J. WEISS' Lederle Laboratories Division, American Cyanamid Company, Pearl River, NEW York Received August 25, 1961 By straightforwsrd procedures the 20-ketals of 6a-methylhydrocortisone, 6amethylprednisolone, 6a-methylprednisone, 9a-fluoro-6a-methylprednisone, 21deoxy-9a-fluoro-6a-methylprednisone,prednisone, Sa-fluorocortisone, Sa-fluoroprednisone, 9a-fluoro-l6a-hydroxycortisone, triamcinolone, 2a-methylhydrocortisone, 2a,6a-dimethylhydrocortisone, and 2,6a-dimethylprednisolone have been prepared. These ketal derivatives, although less active than the parent 20ones, showed substantial glucocorticoid activity.
The observation made i n the course of -routine screening of steroic' intermediates, that 6a-methylhydrocortisone 20-ethylene ketal (11), prepared as a substrate for ethoxalylation studies at C-2 of the steroid nucleus, possesses substantial glucocorticoid activity, prompted the study which is the subject of this paper. To our knowledge biolog(1) To whom inquiries concerning this paper should be addressed.
134
ALLEN,KISSMAN, MAUER,RINGLER AND WEISS
Vol. 5
ical activity for 20-ketal derivat,ives of st'eroid hormones had not been observed2previously and we therefore undertook the preparation of the 20-ket'als of various 11-oxygenated corticoid derivatives. The lead compound, 6a-methylhydrocortisone 20-ketal (11),had been prepared3 in excellent yield by preferential hydrolysis4 of the 3-ketal group in bisketal I, followed by base-catalyzed elimination of the &-hydroxy group and concomitant epimerizat'ion of the 6gmethyl gr0up.j The starting compound I for this sequence is available from 3,20-bisethylenedioxy-5 a,6a-epoxy-l lp, 17&2l-trihydroxypregnane by reaction with methylmagnesium bromide followed by 21-a~etylation.~Conversion of I1 to the 1-dehydro derivat,ive (V) was accomplished in poor yield by a selenium dioxide dehydrogenat.ion. Subsequently, a more satisfactory dehydrogenation was effect,ed from the 21-acetate I11 by treatment, with 2,3-dichloro-3,Fdicyanobenzoquinone (DCBQ).: In addit'ion. t h e I -dehydro-1 1keto analog VI was prepared b y ketalization of Ga-methylprednisone (ITr).8 Similarly, ket,alization of 9a-fluoro-6a-methylprednisone (VII)g followed by acetylation gave the 20-ketal IX. ,4 preliminary attempt to prepare a 20-ket,al in the 9a-fluoro-6a-methyl series via the ketalization of 17~~,2l-dihydroxy-6a-methyl-l,4,9(11)-pregna(2) S . Bernstein of these Laboratories and R. Dorfman of the Worcester Foundation and their associates have noted corticoid activity for the 20-ethylene ketal and t.he 3,20-bisethylene ketal of hydrocortisone, private communication. (3) Experiments carried out by J. F. Poletto of these Laboratories. (4) R. Antonucci, S . Bernstein, &f, Heller, R. Lenhard, R. Littell and J. H. Williams, J. Org. Chem., 18, 70 (1953). ( 5 ) Based on the procedure recently reported for the synthesis of the corresponding 11-keto derivatives.6 (6) S. Bernstein and R. Littell, J . Am. Chem. Soc., 82, 1235 (1960). (7) D. Burn, D. N. Kirk and V. Petrow, Proc. Chem. Soc., 14 (1960). (8) G. B. Spero, J. L. Thompson, B. J. Magerlein, A. R. Hanae, H. C. Murray, 0. R.Sebek and J. A. Hogg, J . An. Chem. Soc., 78, 6213 (1956). Details for the preparation of I V from 6a-methylprednisolone ma 21-acetylation (97%), oxidation with chromic oxide (65%) and de@acetylation (88%)are given in the experimental section. (9) 9a-Fluoro-Ga-methylprednisone (VII) was obtained from Sa-fluoro-6a-methylprednisolone acetate, the preparation of which from 6a-methylprednisolone acetate has been reported previously without details.10 Procedures for this transformation are given in the experimental section. One point worthy of comment is the apparent relative inactivity of the intermediate 9B,ll@-oxideto hydrogen fluoride. Thus, using the same conditions [R. F. Hirschmann, et al., J . A m . Chem. Soc., 18, 4956 (1956)l whereby 21-acetoxy-17a-bydroxy-9B,ll~-oxido-1,4-~regnadiene-3,aO-dione afforded 73% of fluorohydrin, '1 the corresponding 6a-methyl derivative gave mixtures contsining substantial amounts of unreacted oxide. (10) G. B. Spero, J. L. Thompson, F. H. Lincoln, W. P. Schneider and J. A. Hogg, J . Am. Chem. Soc., 19, 1515 (1957). (11) Experiment by Mrs. Bernice Kliebard of the Chemical Process Improvement Departiiient of these Laboratories.
STEROIDKETALS
Jan. 1962
I
II,R=H 111, R-AC
135
V VI, 11-C=t
t
VII, R = O H VUI,R - H
IX,R=OAc X,R = H CH~OAC
CHZOAC
kl
XI
El
XI1
triene-3,N-dione was unsuccessful, possibly as a result of interaction between the ring A dienone and ethylene glycol. Also unsuccessful was an approach involving treatment with hydrogen fluoride of the 20-ketal-9/3,11P-oxide XII, prepared as indicated from 6a-methylhydrocortisone 20-ketal21-acetate (111). Here the attempted transformation of XI1 to the correspondmg ring C fluorohydrin gave complex mixtures containing much blue tetrazolium-positive material. Apparently the 20-ethylenedioxy grouping was not stable to the experimental conditions from which it is difficult to exclude moisture.
136
ALLEIV, KISSMAN, MAUER,RINGLER A N D WEISS
VOl. 5
The 6a-methyl series was completed with the preparation of the 21deoxy-20-ketal X by ketalization of 9a-fluoro-17cr-hydroxy-6amethy1-1,4-pregnadiene-3,11,20-trione (VIII), available by oxidation with the chromic oxide-pyridine complex of the corresponding 11p-01.12 In order to evaluate the effect on biological activity of structural variations in the 20-alkylenedioxy moiety, the preparation of a series of prednisone 20-ketal derivatives was undertaken. Thus, treatment of prednisone in the usual manner with the appropriate glycol gave the ethylene ketal XI11 and the lJ2-propylene ketal XIV. Satisfactory analyses could not be obtained for these two ketals, presumably because of solvation difficulties. However, conversion to the 21-acetates gave products which afforded satisfactory analytical values. Methanolic-sulfuric acid hydrolysis of the ethylene ketal XI11 regenerated prednisone, indicating that XI11 is not the ketal of a rearrangement product. With I ,3-propanediolJ the desired ketal was not obtained but instead there was isolated in 45% yield a substance which is apparently a Mattox-rearrangement13 product (XV). The assignment of structure XV to this product is based on combustion analyses and the infrared spectrum which showed no appreciable hydroxy absorption, the apparent presence of a 20-carbonyl band and its shift14to a lower wave length, and heavy C-0-C absorption. The isolation of analogous products has been observed previously from the ethylene glycol ketalization of cortisone14 and of compound S.15 Although Tsuda et aZ.15 reported that the 21-ethylene acetal from compound S could undergo acid hydrolysis, an attempt t o hydrolyze XV by heating with 8% methanolic-sulfuric acid failed and starting material was recovered. However, resistance to hydrolysis by an 11-keto-21-ethylenedioxy steroid has been noted. l 4 Attempts to effect the condensation of prednisone with 2-mercaptoethanol and with lJ2-ethanedithiol were essentially unsuccessful. These experiments gave complex mixtures which could not be resolved even after extensive chromatography. Continuing our exploration of this field, the 20-ethylene ketal (XVII) of 9a-fluorocortisone was prepared by 3,20-bisketalization (12) (13) (14) (15)
German Patent 1,056,605 (May 6 , 1959). V. R. Mattox, J . A m . Chem. SOC.,74, 4340 (1952). S. Bernstein. M. Heller and W. 8. Allen, J. Ore. Chem., 2 6 , 1338 (1961). K. Tsuda, N. Ikekawa and S. Noroe, Chem. and Pharm. Bullatin (Tokyo), 1, 519 (1959).
STEROID KETALS
Jan. 1962
137
-F
,
&,& \
--OH
-F
,
' XVI
XIX, R = A c XX, R = H
--OH
--OH
/F
HOAc
___,
e o
lo
xv
XIII, R = H XIV, R = CHs
DCBQ
,-F
* /
/
/
0
0 XVII, R = H XVIII, R = A c
XXI
of 9a-fluorocortisone16 followed by preferential4 3-ketal hydrolysis. This sequence also afforded an example of a 3,20-bisketal, the intermediate XVI.17 For the preparation of a 3-monoketal, 9a-fluorocortisone 21-acetate was submitted to an exchange reaction with 2-ethyl-2-methyl-l,3-dioxolane1* and the desired XIX was obtained in 87% yieldlg; de-0-acetylation then gave the 21-01 XX. Acetylation of 20-ketal XVII and treatment of the resulting XVIII with the 1,Zdehydrogenating agent DCBQ' with subsequent de-0-acetylation, afforded Sa-fluoroprednisone 20-ethylene ketal (XXI). For the synthesis of 20-ketal derivatives in the 9a-fluoro-16ahydroxy series,17 Sa-fluorocortisone bisethylene ketal 21-acetate (XVI 21-acetate) was treated with phosphorus oxychloride to give the 16-dehydro derivative XXII which was converted to the 16a,17a-diol XXIII by reaction with osmium tetroxide. Preferential 3-ketal hydrolysis of XXIII afforded 16a-hydroxy-9a-fluoroc~-+* ,:sone 20-ethylene ketal 21-acetate (XXV). Reduction of the 11-carbonyl (16) J. Fried and E. F. Sabo, J . Am. Chem. Soc., IS, 1130 (1957). (17) J. Fried and G. H. Thomas (U.5. Patent 2,963,496, Dec. 6, 1960) after the conclusion of our work, described the preparation by similar procedures of compounds XVI and XXII and in U. S. Patent 2,929,496 (March 2 2 , 1960) the preparation of XXIII and the 16-acetate of XXV. (18) H. J. Dauben, Jr., B. L6ken and H. J. Ringold, J . Am. Chem. Soc., 76, 1359 (1954). (19) Experiment carried out by Mrs. Arlene Small Hoffman of these Laboratories.
ALLEN,KISSMAN,MAUER,KINGLERA N D WEISS
138
Vol. 5
in bisketal XXIII wit290' dec. (combined yield 51%). Recrystallization of a portion changed the melting point to 268' dec. Analysis for this product indicated the probable formation of a cycloborate ester.'' The product WM used as such for acetylation to the 16,21-di-O-acetate. Anal. Calcd. for CgaHgsBFOg: C, 58.83; H,7.11; F, 3.72. Found: C, 58.49; H,7.44; F, 3.79; ash 4.1. 3,~-Bis-ethylenedioxy-9a-fluoro-11~,21-dihydroxy-5,16-pregnadiene,-Lithium borohydride reduction of XXII (4.9 g.) in tetrahydrofuran-benzene (5:I ) was carried out by the procedure described directly above for the preparation of the corresponding Ma, 17a-diol-presumed cyeloborate ester. Solvent evaporation afforded a semi-solid substance which was crystallized from acetone-petroleum ether to give 1.58 g. of product, m,p. 202' dec. The mother liquor yielded s n additional 1.00 g., m.p. 199' dec. (combined yield 57%). A portion W ~ Z Rrecrystallized from the same solvent pair, raising the melting point to 215-217'; [(Y]*)D 31'; XmX. none; urnax.3440, 1622,1034 cm.-l. Anal. Calcd. for CtsHd'Os: C,66.65; H, 7.83; F, 4.22. Found: C, 66.87; H,7.96; F, 4.53. 3,20-Bls-ethylenedioxy-9a-fluoro-11@,16a,l7~,21-tetrahydroxy-L-pregnene.Osmylation of 3,20-bis-ethylenodioxy-9a-ffuoro-l1@,21-dihydroxy-5,16-pregnadicne (1.26 g.) was effected by the procedure described above for the preparation of XXIII. Evaporstion of the chloroform extracts gave 0.75 g. of product, m.p.
.
-
S ~ R O IKETALS D
Jan. 1962
lS2
23S-236'. The water layer then waa mxtracted with chloroform, the extract wsahed with water, dried and evaporated to give an additional 0.03 g. of product, m.p. 230-231 ' (wmbined yield 100%). Crystallization from acetone-petroleum ether raised the melting point to 245-247'; [ C Y ] ~ D-28' (methanol); Y-., 35.00,105.0 cm. -I. C, 61.97; H,7.70; F, 3.92. Found: C, 62.12; A d . Calcd. for CUHWFO~: H,7.97; F, 3.62,
3,20-Bie-ethylenedioxy-l6t~,21 -diacetoxg-9a-fluoro-ll~,17~-ilihydroxy-5~pre~ nene (XXIV). A.-A solution of 3,!2O-bis-ethylenedioxy-9a-fl~oro-l1b,16a,17a,21-tetrahydroxy-&pregnene (1.06 g.) was acetylated in the usual manner with acetic anhydride in pyridine solution to give 1.11 g. (90%) of product, map. 170-216' (dec. a t 216'). The infrared spectrum was identical with that of the material prepared by procedure B (below). B.-A solution of 3,2O-bis-ethylenedioxy-9a-fluoro-l1/3,16a, 17a,2l-tetrahydroxy-&pregnene presumed 16,17-cycloborate ester (0.5 g.) in pyridine was treated with acetic anhydride in the usual manner to give 0.42 g. (72%) of XXIV, m.p. 166234' (dec. at 234'). Crystallization from acetone-petroleum ether gave a gelatin-like precipitate, m.p. 147-183'. This material waR dissolved in acetone, treated with decolorizing charcoal, filtered and evaporated; m.p. 147235' (dec. at 235'); [ a ] " D -46'; Xmhr. none; Ymax. 3460, 1748, 1244, 1050 c m . '. Anal. Calcd. for C~H,IFOIO:C, 61.25; H, 7.29; F, 3.34. Found: C, 61.48; H, 7.67; F, 3.54. 9~~-Fluoro-16~-hydroxyhydrocorti~ne 20-Ethylene Ketal 16,21-Diacetate (16a,21 Diacetoxy 20 ethylenedioxy S a fluoro 11&17a dihydroxy 4pregnen3-0ne, XXVI).-A solution of 16a,2ldiacetoxy-3,20-bis-ethylenedioxy9a-fluoro-l1~,17adihydroxy-5-pregnene (XXIV)(1.0 g.) in aqueous acetic acid (750J0, 40 ml.) was heated on the steam bath for 1 hr., water was added and the mixture extracted with chloroform. The extract was washed with saturated sodium bicarbonate solution and then to neutrality with water, dried m d evaporated to give0.77 g. of XXVI,m.p. 158-250' (dec. at 250'); [a]*%4-23'. A d . Calcd. for CnHsdOo: C, 61.82; H, 7.11; F, 3.62. Found: C, 61.46; H, 7.45; F, 3.52. Triamcinolone 20-Ethylene Ketal 16,21-Diacetate (16a,21-DIacetoxy-9~ fluoro-20-ethylenedioxy-11~,17~~-dihydroxy-1,4-pregnadien-3-one).-A solution of 16a,2l-diacetoxy-20-ethylenedioxy-9a-fluoro-l1/3,17a-dihydroxy-4-pregn-3one (XXVI)(0.51 g.) in dioxane (200 ml.) was refluxed with 2,3-dichloro-5,6dicyano-l,4benzoquinone% (350 mg.)for 50 hr. The mixture was evaporated to dryness and the residue taken up in benzene. The benzene solution was washed to neutrality with water, 1% potassium hydroxide (cold) and again with water. The extract was then evaporated to dryness to give 0.46 g. of dienone; m.p. 232' dec.; XmX. 238 mp ( CE 3,100); vmX. 3510,1754,1668,1614,1244,1062 cm.-1. Anal. Calcd. for CnHlsFOo: F, 3.64. Found: F, 3.19. Triamcinolone-20-ethylene Ketal (20-Ethylenedioxy-9~-fluoro-l1/3,16~,17~,2l-tetrahydroxy-1,4-pregnadien-3-one,XXVII).-This compound was prepared by deacetylation of the corresponding 16,21-diacetate (0.45 g.) according to the procedure deecribed above for the preparation of IV. After neutralhation with
-
- -
- -
-
-
-
154
Ar,r,m, KIBBMAN, MAUER,RINCILER A N D WEIHK
Vcd. h
ylacid acctic acid, th(! solritioa WUH cvqmittcd 1 ( J r m r clrync~ws. Wtitcr \v:w added to effect cryt3tallisution und thc! product co1lcc:tcti by filtrut,ion to givc 6 3 mg. (14%) of X X i I I ; m.p. 224-230' (dco. at 258'); xwgutivc a-keto1 h l u d d m solitim test. Recryatalliaationof tho crystalline fraction froin aaetone-petrolcum ether raiscd the melting point to 235-236'; [a]3% + 3 8 O (methanol); vlrlPX. 3448 (s), 1675 (a), 1631(in), 1612 (ah.) cm.''; X, 239 nip ( e 15,1148). Anal. Calcd. for C33Ha1F01*Wd):C, 60.52; H 7.39; F, 4.26. l h m d : C , (i0.90; 33, 7.28; F,4.01. 2a-Methylhydrocortisne 20-Ethylene Ketal (20-Ethylenedioxy-ll8,17cu,21trihydro ly16, 1961 A number of aralkylsulfonylhydrazine derivatives were prepared as possible inhibitors of monoamine oxidase. In vitro results, as well ns in vivo effects or1 mourn brain serotonin levels, are reported. Several I-sulfanyl-l..arrkylhydra.zines were strongly active in both tests. Methods of prepnrnt,ion of l-suhstit,iited~iilfonyl-1 -aralkylhydrazines are described.
Thr disrovery of the cliirically
iiwcfril
nntitlcprcswnt, ncbtivily of
