J. ROMOAND A. Ro,tlo DE VIVAR
1118
g. (12.17&) of 3a-acetoxybisnor-17(20)-cholen-22-al, m.p. 1735 (acetate), 1655 (conj. 140-148', A$254 mp; ald.), 1620 cm.-' (conj. C=C). The resinous residue (3.06 g.) was a mixture containing much 3-hydroxy compound, probably resulting from hydrolysis of the 3-acetate, A%x 256 m p . D. Dehydrobromination with -pCollidine.-A solution of 2.27 g. (5 mmoles) of 3a-acetoxy-20-bromobisnorcholan22-a1 in 5 ml. of ycollidine was heated 2 hours (iTz atm.) on a steam-bath. The mixture was diluted with 25 ml. of ether and filtered. The yield of collidine hydrobroniide
Ac':
[ C \ O N l R I B U T I O N F R O M THE
INSTI'ITJTO D E
Yol. 79
was 0.82 g. (82%). The filtrate was diluted with 75 1111. of ether and was washed with two 25-1111. portions of ice-cold 10% hydrochloric acid, and two 25-1111. portions of water. The solution was dried, concentrated t o 5 ml., diluted with 5 ml. of Skellysolve A, and refrigerated. The first crop of crystals (0.29 g.) was 3a-acetoxybisnor-17(20)-cholen-22-al, m.p. 130-137', ,:A: 253.5 m p . The gummy residue (1.35 g.) was a mixture of the desired A17(")-aldehyde and a large amount of the saturated aldehyde, probably from reductive removal of bromine. KALAMAZOO, MICHIGAX
Q U ~ M I C A D E L A t j N I V E R S I D A D S A C I O N A L A u r 6 X O h I A DE
MI~XICO]
The Favorskii Rearrangement in the Pregnane Series. cis-trans Isomerism in Some 17,20-Dehydro Derivatives BY J. ROMO AND A.
RO&IoDE VI\'.IR
RECEIVED SEPTEMBER 5, 1936 Treatment of 17~-bromo-21-iodo-A6-pregnen-3p-ol-20-one acetate (11) with methanolic potassium hydroxide under the conditions of the Favorskii rearrangement yielded two isomeric acids, cis-A5,17(20) -pregnadien-3P-ol-21-oic acid ( I I I a ) and trans-A6,17(20)-pregnadien-3P-ol-2l-oic acid (Ia), as well as the corresponding methyl esters IIIc and Ib. 2 0 - B r o m 0 - A ~ ~ ~ ~ ( ~ 0 ~ pregnadien-3&01-21-oic acid (Xa) was obtained from the 17a,21,21-tribromo-A5-pregnen-3~-ol-20-one acetate which accompanies the iodinated ketone I1 as an impurity. The structure of Xa was proved definitely by zinc debromination. Various experiments with lithium aluminum hydride are described which afforded derivatives of the cis series. The trans configuration is assigned to various homologs of the pregnane series that were prepared by a new method.
Marker, et aL,I carried out a Favorskii rearrange- rose to a constant value of 252-234", and these aument on the crude product obtained by treatment t h o r ~assumed ~ that the low n1.p. of the crude acid of 5,6,17a,2l-tetrabromo-pregnan-3~-ol-20-one ace- was due to the presence of the P,y-unsaturated tate with sodium iodide and obtained A5,17(20)-preg-acid. nadien-3P-ol-21-oic acid (Ia) . Julian and Karpe12 When we carried out the Favorskii reaction with reported a quantitative yield of this acid using the iodinated derivative I1 (m.p. 133-157" dec.) pure 17a-bromo-21-iodo-~5-pregnen-3/3-ol-20-one in methanolic potassium hydroxide, we obtained acetate (11) but gave no experimental data. Sond- approximately 70y0yield of an acidic fraction with heimer, et ~ l . also , ~ carried out the reaction with m.p. 211-218", which gave a positive Beilstein test the halogenated derivative I1 and these authors and about 20Yc yield of a partially crystalline neuobtained an 8.57" yield of crude acid with m.p. tral fraction. By fractional crystallization of the 21.5-222'. By repeated crystallization the m.h. crude acid we could isolate three acids: A, B and C. The acid h (m.p. 253-255", Xmax 222 mp, log 0 // E 4.22) is identical with the one obtained preH C" CH2I v i o ~ s l y , ' Ia. ~ ~ The methyl ester prepared by I \c/ \R ' treatment with diazomethane and the methyl ester acetate have physical constants in good agreement with those reported by Plattner and Schrecki for I b and IC. These authors prepared the acid (Ia) (n1.p. 249-230") by Reformatzky reaction between bromo acetic ester and A5-androstene-3fl-ol-17-one acetate followed by dehydration. The acid €3 (C21H&, m.p. 265-267", Xmax 224 mp, log e 4.10) is isomeric with A, since partial 0 hydrogenation of its methyl ester acetate afforded Ia, R = H, R' = OH I1 R'OC H H, R ' = OCHa b, R the same unconjugated methyl ester IVa that PlattC , R = Ac, R ' = OCHa \ / ner and Schreck4 obtained by selective hydroC d, R = H, R' = CH3 genation of the methyl ester IC. e, R = Ac, R ' = CH3 Xs both acids have the ultraviolet absorption for a,B-unsaturated carboxylic acids, they must be cis-trans isomers. IIIa, R = H, R ' = H Examination of models6 of the two isomers show b, R H, R ' CH8 very clearly that in the acid with the carboxyl C,
R = Ac, R'
CH,
( 1 ) R. E. Marker, H. M. Crooks, E. M . Jones and A. C. Shabica, THISJOURNAL, 64, 1276 (1942). (2) P. L. Julian and W . J. Karpel, zbid., 73, 362 (1950). (3) F. Sondheimer, 0. Mancera, hf. Urquiza and G. Rosenkranz, i b i d . , 77, 4145 (1955).
(4) P. A. Plattner and W. Schreck, H e h . Chim. Acta, 22, 1178 (1939). ( 5 ) T h e t e r m [vans is given t o t h e isomer with t h e carboxyl group opposite t o t h e angular methyl group, and the cis isomer has t h e n t h e reverse configuration. (6) hlolecular models, made b y Catalin Products, L t d . , Waltham 4 b b e y . Essex, England.
FAVORSKII REARRANGEMENT I N THE
March 5 , 1957
group on the side of the side chain opposite to the ring system there is no distortion of the side chain due to steric hindrance, whereas with the carboxyl group on the same side as the ring system, the side chain is distorted and this distortion affects the co-
bond alpha to the carboxyl group.12 This shift is observed also in the methyl ester X b and in the acetate Xc.
I
C=O
I/
COR
I
H
CH30C
I CHz
\ /
C
/'--
l
IVa, R = Ac, R' = OCHs b, R = H, R' = CHa C. R = Ac, R' = CH3
I
l
l
V
planarity between the double bond and the carboxyl group. Braude, et al.,' have pointed out that when this later situation occurs, there is an inhibition of resonance that reduces the intensity of absorption. The acid Bq and the derived methyl ester, methyl ester acetate, all have a lower extinction coefficient than those derived from acid A and must therefore belong to the cis series and have structures IIIa, I I I b and IIIc, respectively. Other cases of cis-trans isomerism in steroids about the double bond in the 17,20position are known. Marshall, et a1.,8 and Fieser and Huang-Minlong have separated the cis-trans isomers of the enol acetates of 20-ketones, and recently the Upjohn workerslO described some further cis-trans isomers. They assigned the configiirations by oxidative experiments and also converted the cis into the trans isomer by means of sodium methoxide in anhydrous methanol. When we applied this method to our isomers we recovered our trans isomer I b unchanged, whereas the cis I I I b was converted into the trans isomer Ib. Direct crystallization of the neutral fractions gave the trans-methyl ester Ib, and the mother liquors on acetylation yielded the cis-methyl ester acetate IIIc. Loftfieldll has pointed out that in most cases the Favorskii rearrangement involves the presence of a cyclopropanorie intermediate and as the base can remove either of the two a-hydrogen atoms in the iodo ketone 11, two cyclopropanone intermediates are possible, VI and VII. Further attack by base breaks the three-membered ring and gives the carbanions VI11 and IX, and these, by elimination of iodide ion, produce the acids I a and IIIa. The acid C (C21H290aBr) (m.p. 275-278', Xmax 248 mp, log E 3,80) is also a conjugated acid and must have the structure X a since the ultraviolet maximum shows a bathochromic shift of ca. 24 mp due to the bromine atom substituted on the double (7) E. A. Braude, E. R. H. Jones, H. P. Koch, R. W. Richardson, F. Sondheimer and J . B. Toogood, 1.Chcm. SOC., 1890 (1949). ( 8 ) Ch. Marshall, T. H . Kritchevsky, S. Liebermann and T. F. Gallagher, THIS JOURNAL, 70, 1837 (1948). (9) L. F. Fieser and Huang-Minlon. ibid., 71, 1840 (1949). (IO) J. A. Hogg, P. F. Beal, A. H. Nathan, F. H. Lincoln, W. P. Schneider, B. J. Magerlein, A. R. Hanze and R . W. Jackson, ibid.. 77, 4486 (1955). (11) R . B . Loftfield, rbid., 73, 4707 (1951).
/-
/'-
VI
l
COR I
I
H
0
R'
I
1119
PREGNANE SERIES
VI1
/I-
R- = Base VI11
IX
Wagner and Moore13 prepared 20-brom0-A'~(~~)pregnen-3P-ol-21-oic acid by rearrangement of the corresponding tribromo ketone with base. However, they did not report the ultraviolet spectrum. Zinc reduction of Xc afforded' a mixture of the two methyl esters IIIc and IC. Oppenauer oxidation of the methyl ester X b afforded the A4-3 keto derivative X I . Doubtless the acid X a must be produced by action of the base on the tribrominated derivative XI11 which occurs in small amounts as impurity in the iodo-ketone 11. When the Favorskii reaction was carried out with a very pure specimen of ketone 11, no brominated acid X a was isolated. COOR'
COOCHs
I
i
C-Br
C-Br
/I
Xa, R = R' = H b, R = H, R' = CHa C , R = Ac, R' = CH3 CHBr2
XI
I
CHBr2
c=o
I
i
c=o
Br XI1
AcO/ XI11
The same reaction on the tribrominated ketone X I I I , gives a very pure acid X a in 72% yield. This tribromo ketone XI11 was prepared by pentabromination of a chloroform solution of A6-pregnen-3P-ol-20-one acetate (if acetic acid is used, the 5,6,17a,21-tetrabromo derivative2 is precipitated). The pentabromo derivative XI1 on further treatment with sodium iodide using the conditions reported by Julian2 yielded XIII. The lithium aluminum hydride reduction of the methyl ester IIIc afforded the cis-diol XIVa. This on oxidation with manganese dioxide14 yielded the (12) A. L. Nussbaum, 0. Mancera, R . Daniels, G.Rosenkranz and C . Djerassi, ibid., 73, 3263 (1951). (13) R. B. Wagner and J. A. Moore, ibid., 72, 3655 (1950). (14) F. Sondheimer, C. Amendolla and G. Rosenkranz, ibid., 7 6 ,
5930 (1953).
1120
J. ROMOAND A. R'
\
/
I3
CI120R' I
CITY I
R O M O DE V I V h R
Vol. 79
Acknowledgments.-n'e are iiidebtecl to Dr. George Kosenkranz of Syntex. S. A, for a generous gift of steroids. I17e wish to express our thanks to Mr. Hector Macias for technical assistance. Experimental l9
Favorskii Rearrangement of 17a-Bromo-21-iodo-AK-pregnen-3P-ol-20-one Acetate (II),-A solution of the iodo ketone2 (60 g.) (m.p. 153-157' dec.) in methanol (2 1.) was 1 1 1 mixed with 100 g. of potassium hydroxide dissolved in 100 Ro/V'V ml. of water and refluxed for 2 hr., concentrated t o one-half S I V a , R = €I, R' = CH20H XVa, R = R ' = H its volume, then diluted and acidified with concentrated hyb, R = Ac, R' = CH~OAC b, R = R' = .4c drochloric acid. The precipitate was extracted with ethyl c, R = Xc, R' = CH=O acetate and washed with water. The organic layer was extracted with 5570 potassium hydroxide solution three times aldehyde, isolated as the acetate XIVc. The (the potassium salts were partially insoluble in water), the reduction with lithium aluminum hydride of the extracts were combined and made acid with hydrochloric acid, to precipitate the acidic fraction (23.85 g.). The methyl esters IVa and X c yielded the saturated ethyl acetate was washed with water, dried over anhydrous diol XVa and the bromo diol XVIa. sodium sulfate and evaporated to dryness, yielding 7.2 g. of semicrystalline residue. The acidic fraction gave a CH2OR' positive Beilstein test and by repeated crystallization from I R methanol-ether, 4.22 g. of the trans-acid Ia with m.p. 240245" was obtained. Further crystallization from meth~ (ethanol), anol yielded prisms, m.p. 253-255', [ a I z 3-83.4' Amax 222 mp, log B 4.22 (Marker, et d.=, report m.p. 252253"; Sondheimer, et ~ l . give , ~ m.p. 252-254', Plattner and Schreck4 report m.p. 249-250", [ a ] -82' ~ in dioxane), vmSl 1700, 1660 cm.-l and free hydroxyl band. Anal. Calcd. for C~lH8003: C, 76.32; H, 9.15. Found: C, 76.30; H , 9.57. The methyl ester I b was prepared by esterification, with diazomethane, following the directions of Plattner and \-IT1:i,R = R' = II S V I I a , R = CH2--C=CH Schre~k.~ In our hands the substance showed m.p. 185l), 11 = R ' = A4c b, I? = CHZ-COCHI 1F)Oo, [ a ] 2 3 D -83", Amsx 222 mg, log c 4.24; Ymax 1700, 1660 cm.-l and free hydroxyl band. (Flattner and 0 Schreck4 report m.p. 188-189", [a]D -73 in dioxane, Xmsx 222 mp, log E 4.22.) The methyl ester acetate IC showed m.p. l59", [ a ] Z 3 ~ -87', Xmax 222 mp, log E 4.23; vmax 1730, 1700, 1660 cm.-' (Plattner and Schreck4 reported m.p. 159", [ a ] D -69" it] chloroform, Xmsx 222 mp, log e 4.22). By crystallization of the mother liquors of the trans-acid I a from methanol, there was obtained 1.53 g. of the cis-acid IIIa, m.p. 25b260°, further crystallization from methanol vielded glistening plates, m.p. 265-267' (mixed m.p. with IZy treatment of the chloride of the trans-acid equal amount of the trans-acid Ia gave m.p. 218-222"), Ia with methyl-zinc-iodide, Plattner and Schreck [ a I z 3-36.7' ~ in ethanol, Xlnsx 224 m!.t, log E 4.04; ha. prepared the a,p-unsaturated ketone Id. This 1700,1660 cm.-land free hydroxyl band. A n d . Calcd. for C.1H,o03: C, 76.32; H, 9.15. Found: ketone also must have the trans configuration. H , 9.25. We have obtained this same ketone Id by dehydra- C, 76.51; cis-~~J7(20)-Pregnadien-3p-ol-21-oic Acid Methyl Ester tion with mineral acids of the acetonyl derivative (IIIc).-The cis-acid (2 g.) was dissolved in 150 ml. of methXVIIb prepared, in very good yield, by hydration anol, and an ethereal solution of diazomethane (prepared of the triple bond of 17a-propargyl-A5-andro- with 7 g. of N-nitrosomethylurea) was added; the mixture left overnight a t room temperature, then washed with stene-3/3,17P-diol-3 acetate (XVIIa)16,17 with mer- was water, dried and evaporated. The residue was crystallized curic chloride in presence of aniline.'* It is in- from acetone-hexane yielding 1.51 g . , m.p. 160-163" (the teresting to note that the acetonyl derivative substance frequently separates from the solution as a jelly). X\'IIb suffers a reverse aldol condensation with The analytical sample was obtained as needles, rn.p. 160171' (from acetone-hexane) (mixed m.p. with the fransalkalies, yielding i15-androsten-3/3-ol-17-one, and ester I b gives large depression), [ a l 2 --18", ~ ~ Xmaz 224 m ~ , this proves that no gross rearrangement took place log E 4.09; vmax 1700, 1660 cm.-' and free hydroxyl group. during the hydration of the triple bond. Anal. Calcd. for Cy21i3203: C, 76.70; H, 9.36. Found: I n Table I are recorded optical rotation data of C, 76.48; H, 9.37. the cis, trans and brominated acids and their derivThe acetate (acetic anhydride-pyridine, 1 hr. on the atives, as compared with the saturated analogs. steam-bath) after crystallization from acetone-hexane m.p. 165-167' (on admixture with the acetate IC It can be seen that in every case the cis and the showed gives depression), [ c Y ] ~ ~-47", D X,,,,, 224-22ffj m p , log E brominated acids and their derivatives have the 4.1OZ0;vmax 1730, 1700, 1660 an.-'. itlore positive rotation values than the saturated Anal. Calcd. for ClaHu04: C, 74.58; 11, 8.87. Found: derivatives, whereas the trans isomers all have c, 74.37; Ir, 8.98.
more negative rotations. (15) P . A. Plattner and W. Schreck, Helu. C h i m . Acta. 24, 472 (1941). (16) D. Magrath, V. Petrow a n d K. Royer, J. Cheni. Soc., 845 (1951). (17) C. W. Greenhalgh, H. B. Henbest a n d E . K. H. Jones, i b i d . .
1190 (1951). (18) H. E. Stnvely, THISTOIJRNAL,
63, 3127 (1941).
(19) Melting points are uncorrected. Rotations were determined in chloroform and ultraviolet absorption spectra in 9570 ethanol solution. T h e infrared spectra were measured o n a Perkin-Elmer double beam spectrophotometer with sodium chloride prisms using Sujol suspensions. T h e microanalyses were performed b y Dr. Franz Pascher, Bonn, Germany. (20) It is interesting t o note a small bathochromic shift in the civ series.
March 5, 1957
FAVORSKII REARRANGEMENT IN THE PREGNANE SERIES
1121
TABLE I MOLECULAR ROTATIONS OF SOME PREGNENOIC ACIDSAND DERIVATIVES5 MD -133.7' - 121 -186.5 -275.2 -173.4 -165.8 -219.7 -285.5 -227.85 -181.4 -260 -316.5 +429.4 +478.8 +289 $253.7 -151.8 -229.6 - 186 -240.5 $328 +293.4 4-90 These rotations were taken from the [mb
20-Bromo-A~~17-pregnadien-3~-ol-21-oic acid (Xa) ~is-A~~~~~~~~-Pregnadien-3B-ol-21-oic acid (IIIa) A5-Pregnen-38-ol-21-oic acid trans-A6~17(20)-Pregnadien-3B-ol-21-oic acid (Ia) 20-Bromo-A~~17~~~-pregnadien-3B-ol-21-oic acid, methyl ester (Xb) ~is-A~*~~(~)-Pregnadien-3P-ol-2l-oic acid, methyl ester (IIIb) A5-Pregnen-3P-ol-21-oic acid, methyl ester trans-A.6~~7(20)-Pregnadien-3P-ol-21-oic acid, methyl ester (Ib) 20-Bromo- A" 17(20)-pregnadien-3p-ol-21-oic acid, methyl ester acetate (Xc) ~~s-A~9~~(~~)-Pregnadien-3@-01-2l-oic acid methyl ester acetate (IIIc) A5-Pregnen-3B-ol-21-oicacid methyl ester acetat? (IVa) tf~ns-A~~~~~~)-Pregnadien-3p-ol-21-oic acid methyl ester acetate (IC) 20-Br0mo-A~~~7(20)-pregnadien-3-one-21-oic acid methyl ester (XI) cis-A4*17(20)-Pregnadien-3-one-21-oic acid, methyl ester (V) A4-Pregnen-3one-21-oic acid, methyl ester tran~-A~.~7(20)-Pregnadien-3-one-2l-oic acid, methyl ester 21-Methyl-A6-pregnen-3P-ol-21-one (IVc) 2l-Alethyl-A5~17(~)-pregnadien-3B-ol-21-one (Id) 21-Methyl-A6-pregnen-3P-ol-21-one acetate (IVb) 21-Methyl-A~~17(20)-pregnadien-3P-ol-21-one acetate (le) 21-Methyl-A4-pregnene-3,21-dione 21-1Llethyl-A4*~~(@)-pregnadiene-3,21-dione a Rotations were determined in chloroform solution unless otherwise indicated. paper of Plattner and Schreck.'
-32.7' (ethanol) -36.7 (ethanol) -56.4 (dioxane) -83.4 (ethanol) -41 -48 -63.5* (dioxane) -83 -49 -47 -67 -82 102 140 +84b (dioxane) 74 -46 - 70 -50 -65 +95
+ +
+
The mother liquors of the cis-acid IIIa by slow crys- 165O, and 3 g. of a mixture of the cis- and trans-acetates with tallization from methanol gave crystals of the brominated a constant m.p. of 116-117". acid Xa which on repeated crystallization from methanol Isomerization of the cis-Methyl Ester IIIb to the transyielded large needles (560 mg.), m.p. 269-270' dec. The 1b.-The cis-ester IIIb (175 mg.) was dissolved in a methaanalytical sample was obtained by recrystallization from nolic solution of sodium methixide prepared from sodium methanol, m.p. 274-276", with progressive decomposition, (1 9.) in methanol (50 ml.) and refluxed 3 hr. The solution was then diluted with water, acidified with hydrochloric [ a I z 3 -32.7' ~ (ethanol), Xmsx 248 mp, log e 3.80; vmsr 1700, 1680 cm.-' and free hydroxyl band. acid and extracted with ether. The ethereal extract was Anal. Calcd. for CZIHmOIBr: C, 61.61; H, 7.14; Br, washed with water and concentrated. On addition of hexane the trans isomer Ib crystallized (102 mg.), m.p. 18419.52. Found: C, 60.92; H , 7.47; Br,20.00. 187', [ c Y ] ~ ~-88" D (it was identified with an authentic 20-Bromo-A5J7~g~~-pregnadien-3@-ol-21-oic-acid Methyl Ester (Xb).-The bromo-acid Xa (1 g.) was esterified in 50 specimen by mixed m .p. and infrared comparison). A very pure sample of iodo ketone I1 was prepared by ml. of methanol with 150 ml. of an ethereal solution of dicrystallization of the 5,6,17,21-tetrabromo-A6-pregnenazomethane (prepared from 7 g. of N nitrosomethylurea). Crystallization from acetone-methanol furnished needles 3P-ol-20-one-acetate from chloroform-methanol and chloro(780 mg.), m.p. 149-151' methanol); the analytical sample form-ether (m.p. 177-178') and treatment with sodium ioshowed m.p. 156" (the substance very frequently melts in dide under the conditions described by Julian and Karpel.2 the 1030-140' range, resolidifies and melts again), [aIz3D The alkaline rearrangement (5 9.) afforded 90 mg. of the -41 ; Xmsx 222-224, 250 mp, log e 3.72, 3.85; vmsx 1700, trans-acid Ia, m.p. 249-%50', 80 mg. of the cis-acid IIIa, m.p. 259-262'; esterification with diazomethane furnished 1680 an.-' and free hydroxyl band. the trans-ester (200 mg.), m.p. 184-186'. Acetylation Anal. Calcd. for CzzHalOtBr: C, 62.41; H, 7.38; Br, yielded 325 mg. of the cis-acetate IIIc, m . p . 162-164", and 18.90. Found: C, 61.82; H, 7.44; Br, 18.37. 160 mg. of the trans-acetate, m.p. 148-151". No bromiThe acetate (prepared with acetic anhydride in pyridine nated derivatives were isolated. on the steam-bath) showed m.p. 0192-193' (small prisms from Selective Hydrogenation of A5,17(20)-Pregnadien-3~-ol-21chloroform-ether), [ a I a 3-49 ~ ; Xmsx 222-224, 248 m p , oic Acid Methyl Ester Acetate (IIIc).-A solution of 900 mg. log e 3.78, 3.84; Ymgx 1730, 1700 cm.-l. of IIIc in 70 ml. of ethyl acetate and 30 ml. of acetic acid Anal. Calcd. for C24H3304Br: C, 61.93; H , 7.14; Br, was hydrogenated with 100 mg. of prehydrogenated Adams catalyst until 1 mole of hydrogen was absorbed. The 17.17. Found: C, 61.89; H, 7.00; Br, 17.38. was filtered and the solution was washed with water, The last mother liquors of the acidic fractions (18.8 9.) catalyst diluted sodium carbonate and water again. The dried were dissolved in 200 ml. of methanol, 1 1. of an ethereal solution was evaporated. Crystallization of the residue solution of diazomethane (prepared from 40 g. of N-nitroso- from acetone-methanol afforded needles (815 mg.), m.p. methylurea) was added and the solution worked up as be127-130'. The analytical sample showed m.p. 131-132' fore. Crystallization from ether-hexane afforded the (from acetone-methanol), ] " D -67", vmax 1730 trans-methyl ester I b (2.4 g.), m.p. 184-186". One re- (Plattner and Schreck report[ a m.p. 128-129°, [a]n 4-57' in crystallization from acetone-hexane raised the m.p. to 189191' (mixed m.p. with an authentic specimen gavenodepres- dioxane). Anal. Calcd. for C24HsaOa: C, 74.19; H , 9.34. Found: D sion), [ c Y ] ~ ~-85'. Acetylation of the mother liquors (with acetic anhydride C, 74.19; H , 9.50. and pyridine on the steam-bath) yielded 15.5 g. of crude Hydrogenation of the trans isomer iu the same way afproduct. It was chromatographed on 340 g. of neutral forded 760 mg., m.p. 128-130°, [aIz3D -69", which was alumina. The first fractions were eluted with hexane fur- identical with the above substance by mixture m.p. and nishing 1.77 g. of the cis-methyl ester acetate IIIc, [ a I z 3 ~infrared comparison. -48". The second fractions afforded 1.19 g. of the cis-A4J~(z0)-Pregnadien-3-one-21-oic Acid Methyl Ester brominated acetate Xc, m.p. 185-187', [ a ] 2 3-52'. (V).-The free ester I I I b (300 mg.) was dissolved in a mix~ From the neutral fraction there was isolated 1.15 g. of the ture of 40 ml. of toluene and 10 ml. of cyclohexanone. Ten trans-ester Ib, m.p. 188-190'; acetylation of the mother ml. was distilled to eliminate moisture, and a solution of 300 mg. of aluminum isopropoxide in 8 ml. of toluene was added liquors yielded 800 mg. of the cis-acetate IIIc, m.p. 163-
1122
J. ROMOAND A. ROMODE VIVAR
Vol. 79
and the mixture refluxed for 1 hr. Water was then added tetrahydrofuran was added slowly t o a slurry of 300 mg. of and the volatile components were removed by steam distilla- lithium aluminum hydride in 80 ml. of ether; the mixture tion and the residue was extracted with ether. The dried was refluxed 15 min. The excess of lithium aluminum hyextract was evaporated and the residue dissolved in hexane dride was destroyed with a few drops of ethanol, and the and chromatographed on 10 g. of alumina. The fractions mixture was diluted with water and made acid with hydroeluted with hexane crystallized, affording brilliant plates (160 chloric acid. The precipitate was extracted with ethyl mg.), m.p. 136-137'. The analytical sample showed m.p. acetate, the organic layer was washed with water and the 139-140" (from hexane), [ c Y ] ~ ~+140", D A, 236-238 m p , dried solution evaporated. Crystallization of the residue log e 4.38; Ymax 1700, 1660 cm.-l. from acetone-ether afforded brilliant plates (320 mg.), m.pd Anal. Calcd. for C22H3003: C, 77.15; H , 8.83. Found: 196-202". The analytical sample showed m.p. 211-213 (from acetone-ether), -76.8O. C, 77.02; H , 8.84. Anal. Calcd. for C21H3202: C, 79.69; H , 10.19. Found: 5,6,17a,2 1,2l-Pentabromopregnan-3p-ol-2O-oneAcetate (XII).-To a solution of As-pregnen-3p-ol-20-one acetate (20 C, 79.66; H , 10.05. The diacetate showed m.p. 128-129' (from methanol), g.) in 300 ml. of chloroform 8.93 g. of bromine in 40 ml. of ia12$ -61". acetic acid was added rapidly. Decolorization took place immediately. A few drops of hydrobromic acid in acetic . Anal. Calcd. for C15H3604: C, 74.96; H, 9.06. Found: acid was added, followed by a solution of 26.67 g. of bromine C, 74.52; H , 9.14. in 70 ml. of acetic acid. After 2 hr. a t room temperature, czs-A5~~7(20)-Pregnadien-3p-ol-2l-al-acetate (XIVc).-The the solution was washed thoroughly with water, dried and cis-diol XIVa (1 9.) in 150 ml. of chloroform was shaken 8 concentrated in zmxn. On addition of methanol 34.5 g. hr. with IO g. of manganese dioxidez1; the residue after reof pentabromo derivative, m.p. 200-203" dec., crystallized. moval of the dioxide and the solvent was acetylated with The analytical sample showed m.p. 203-205' (brilliant acetic anhydride and pyridine overnight a t room temperaplates from chloroform-methanol), [CZ]'~D -61". ture. Crystallization from ether-hexane furnished needles Anal. Calcd. for C23H310aBr: C, 36.56; H , 4.13; Br, (250 mg.), m.p. 158-160"; further crystallization raised 52.94. Found: C, 36.35; H , 4.07; Br, 53.50. the m.p. to 178-180" (needles from ether-hexane), [CY]"D -106", Xmal 244 I I I ~ ,log E 4.25; Ymax 1730, 1700, 1660 17~~,21,21-Tribromo-A~-pregnen-3p-ol-2O-one Acetate (XIII).-The pentabromo derivative XI1 (13 9.) was dis- cm.-'. solved in a mixture of 250 ml. of benzene and 250 ml. of abAnal. Calcd. for C13H3203: C, 77.49; H , 9.05. Found: solute ethanol, 30 g. of sodium iodide was added, and the C, 77.65; H , 9.17. mixture was left 24 hr. a t room temperature. The dark AS-Pregnen-3p,Zl-diol (XVa).-The methyl ester acetate red solution was washed with water, dilute sodium bisulfite (1 6.) was reduced in the same conditions as the previous and water. The dried solution was concentrated i n Z I U C U O , example. Crystallization from ethyl acetate-ether yielded and the product crystallized from methanol as small prisms 680 mg., m.p. 203-205'. The analytical sample showed (6.8 g.), m.p. 180-182". The analytical sample showed m.p. 205-207' (plates from methanol), [a]"D -63". m.p. 185-187" (from chloroform-methanol), [ c Y ] ~ ~-70" D Anal. Calcd. for C21H3402: C, 79.19; H, 10.76. Found: (Julian and Karpel? report m.p. 190'). C, 79.13; H, 10.88. Anal. Calcd. for C~aHa103Br3:C, 46.38; H , 5.24; Br, The diacetate XVb showed m.p. 116-117" (needles from 40.30. Found: C, 46.09; H,5.37; Br,40.86. acetone-methanol), [CY]23D - 51.7". Favorskii Rearrangement of 17~~,21,21-Tribromo-A~Anal. Calcd. for C?jH3804: C, 74.59; IS, 9.51. Found: pregnen-3p-ol-20-one Acetate (XIII).-To a suspension of C , 74.92; H, 9.80. 4 g. of the tribromo derivative XI11 in 150 ml. of methanol, 20-Bromo-A5a~ 2 0-pregnadien-Jp ) ,21-diol (XVIa) .-Thc 4 g. of potassium hydroxide in 30 ml. of water is added; the mixture was refluxed 2 hr. Initially the tribromo de- brominated methyl ester X b (700 mg.) was reduced with rivative went into solution, but after 45 minutes a precipi- lithium aluminum hydride in the same way described before. tate of the potassium salt began to appear. The suspension Crystallization from methait01 furnished needles (500 mg.)> was diluted with water and acidified. The precipitate was m.p. 242-243', [ a I z 3 D -51 collected and washed thoroughly with water, and it was the Anal. Calcd. for C21H310zBr: C, 63.79; H, 7.90; Br, nearly pure bromo acid X a ( 2 g., 727,), m.p. 270-274" dec. 20.20. Found: C, 63.61; H , 7.72; Br, 20.33. One crystallization from methanol raised the m.p. t o 274The diacetate XVIboshowed m.p. 135-136" (plates from 276", [ a ] 2 3 ~-34O, A,, 246-248 m p , log E 3.81. It was methanol), [ a I z 3 D -31 . Anal. Calcd. for C2SH3504Br: C, identical by mixture m.p. and infrared comparison with the 62.62; H , 7.35; Br, 16.67. Found: C, 62.51; H , 7.50; acid obtained before. Br, 16.78. Zinc Dust Debromination of 20-Br0mo-A~~~~(~~)-pregnaThe 17cr-Acetonyl-A5-androstene-3p,17p-diol 3-Acetate dien-3p-ol-ZO-one Acetate (Xc).-To a solution of the acetate (XVIIb).-A solution of 3 g. of mercuric chloride in 15 ml. Xc (700 mg.) in 40 ml. of ethanol (heating is necessary to of water and 1.5 ml. of aniline were added t o 17~-propargyldissolve the substance) 10 g . of zinc dust was added and re- A5-androstene-3,9,17p-diol-3-acetate (XVIIa)ZZ(1.5 g.), disfluxed 9 hr. The zinc was filtered and the solvent evapo- solved in 90 ml. of benzene and 90 ml. of ethanol. The rated, the residue crystallized from Fther, yieldin530 mg. of mixture was refluxed 3 hr. (after a few minutes a pre~D , and the cipitate began t o form). I t was then diluted with water the trans-acetate IC, m.p. 154-156 , [ C Y ] ~ -79 mother liquors were chromatographed on 20 g. of neutral and ether was added. The organic layer was washed with alumina. The first fractious eluted with hexane, on re- mater several times, then with diluted sodium carbonate, crystallization, furnished 110 mg. of the &-acetate IIIc, dilute hydrochloric acid and water. The dried extract was m.p. 163-166', [ a I z 3-47'; ~ the second fractions afforded evaporated and the residue crystallized from acetone. 190 mg. more of the trans-acetate IC, m.p. 153-155'. There was obtained 1.12 g. of brilliant plates, m.p. 190(Both products were identified with the above cis- and 192"; further crystallization from acetone-ether raised the trans-diacetates through mixed m .p . and infrared compari- 1n.p. to 195-197", [ c Y ] ~ ~-71'; D vmgX 1718, 1700 cm." and son.) free hydroxyl band. 20-Brom0-A~~~7(20)-pregnadien-3-one-21-0ic Acid Methyl Anal. Calcd. for C2aHv,04: C, 74.19; H , 9.34. Found: Ester (XI).-The methyl ester X b (500 mg.) was dissolved C . 74.37; H , 9.37. i n a mixture of 70 ml. of toluene and 20 ml. of cyclohexaMineral Acid Treatment of the Ketone XVI1a.-To a solunone, 20 ml. was distilled off and 400 mg. of aluminum isotion of 660 mg. of the ketone XVIIa in 60 ml. of methanol, 1 propoxide in 15 ml. of toluene was added and the reaction carried out as above. Crystallization from acetone-meth(21) Prepared according t o t h e method of 0. Mancera, G. Rosen:mol furnished needles (330 mg.), m.p. 205-207", further crystallization from acetone-methanol raised the m.p. to kranz and F. Sondheimer, J . Chem. 5'06.. 2189 (1963). (22) This product was prepared using approximately the same 207-208O, [ a I z 3 D f87", Xm,, 244 mp, log e 4.37, Pmal 1700, conditions a n d in similar yield a s reported by Greenhalgh, Henbest liiii0 cm.-'. and Jones17 b u t tetrahydrofuran was used instead of dioxane as sol,lnnZ. Calcd. for CdlH2901Br:C, 62.70; €1, 6.93; Rr, vent in the Reformatzky. I n our hands the propargyl derivativr IX.00. Vound: C, 62.90; H,6.92; Br, 19.27. showed m . p . 148-150°, [ a 1 2 3 - a z o ; these authors reported m.p. 147148'. [ a ] 2 3 n - S l o in CHCls. hIagrath, Petrow and Royer" report cis-A5.17(20)-Pregnadien-3p,21-diol(XIVa).- -4 solution of the cis-methyl ester I I I b (500 mg.) in 20 mi. of anhydrous m.p. 149'.
.
March 5 , 1957
1123
17-ALKYL- 19-NORTESTOSTERONES
ml. of concentrated hydrochloric acid was added and refluxed 1 hr.; after dilution with water the precipitate was filtered. Crystallization from acetone-ether furnished prisms (500 mg.), m.p. 165-168'. The analytical sample showed m.p. 171-173" (from acetone-ether), [ a I a 3-70", ~ Amax 242 mp, log E 4.25, vmaL 1680 cm.-' and free hydroxyl band. (Plattner and SchreckI6 report m.p. 168-169', [ a ] -65' ~ in dioxane.) Anal. Calcd. for C22H3403: C, 80.44; H , 9.82. Found: C, 80.43; H , 9.38. The acetate showed m.p. 191-193" (needles from chloroform-methanol), [ o 1 I z 3 ~ -65", Amax 242 mp, log E 4.2z (Plattner and Schreck16 report m.p. 189-190", [ a ] D -63 , Amax 240 mp, log E 4.25). 21-Methyl-A5-pregnen-38-01-21-one Acetate (IVc).-A solution of the acetate Ie (1 8.) in 125 ml. of ethyl acetate was hydrogenated with 100 mg. of 570 palladium-on-charcoal until 1 mole of hydrogen was absorbed. The catalyst was filtered and the solution evaporated. Crystallization from ethyl acetate-methanol afforded long needles (780 mg.),
[CONTRIBUTION FROM
THE
m.p. 156-158', [ a I z 3-50" ~ (Plattner and Schreckl6 report m.p. 156-157', [ a ] D -49' in dioxane). Anal. Calcd. for CzlH3603: C, 77.37; H, 9.74. Found: C, 77.49; H, 9.53. Alkaline Treatment of the Ketone XVI1b.-To a solution of the ketone XVIIb ( 1 g.) in 50 ml. of methanol, 1 g. of potassium carbonate in 10 ml. of water was added and refluxed 1 hr. The solution was diluted with water and extracted with ether, the organic layer was washed with water and concentrated. On addition of hexane there crys. tallized 625 mg. of prisms, m.p. 147-1$3'. A second crop (200 mg.) was obtained, m.p. 143-145 , [o1Iz3D -3', vmaX 1736 cm.-' and free hydroxyl band (this material proved to be identical with A5-androstene-3p-ol-17-one by mixed m .]I. determination and infrared comparison). The acetate showed m.p. 169-171' (from ether-hexane), [a]2 3 ~ -1.3" (identical with A6-androstene-3p-ol-17-one acetate by mixed m.p. and infrared comparison). MEXICO,D.F.
RESEARCH LABORATORIES OF G. D. SEARLE AND Co.]
17-Alkyl-19-nortestosterones BY FRANK B. COLTON, LEONARD N. NYSTED,BYRONRIEGELAND ALBERTL RAYMOND RECEIVED OCTOBER 8, 1956
A series of 17-alkyl-19-nortestosterone derivatives was prepared for evaluation as anabolic and androgenic agents. the compounds studied, 17-ethyl-19-nortestosterone appears to be of greatest interest from a biological point of view.
A concerted effort has been made in our laboratory directed toward finding a substance with an anabolic potency of the order of testosterone but with a lower androgenic activity. To this end, a series of 17-alkyl-19-nortestosterone (l7a-alkyl17-hydroxy-4-estren-3-one)derivatives was prepared and biologically evaluated. 19-Nortestosterone was first synthesized by Birch' and was reported* to possess about 20y0of the androgenic activity of testosterone. Hershberger and co-workers recently reported3 that the substance I was a potent anabolic agent having a very favorable anabolic to androgenic ratio. This work has since been confirmed by Stafford and co-workers4as well as in our laboratories5 Djerassi and co-worker9 have prepared 17-methyl-19-nortestosterone and stated that this substance was a t least as potent an androgen as 17-methyltestosterone in the chick comb test but only weakly active in rats in so far as the increase in seminal vesicle weight was concerned. No mention was made of its anabolic activity. Recent publications' disclosed the preparation of several 11-oxygenated derivatives of 17-methyltestosterone possessing very marked activity as oral anabolic and androgenic agents. The most
A.
(1) J. Birch, J. Chem. S O C ,367 (1950); A. J. Birch and S. M . Mnkherji, Nature, 168, 766 (1949); J . Chem. Soc., 253 (1949). (2) A. J. Birch, Annual Reports on the Pyagress of Chemistry for 1950, T h e Chemical Society, London, 1951, p. 210. (3) L. G. Hershberger, E. G. Shipley and L. K. Meyer, Proc. Sac. E x p . B i d . and Med.. 83. 175 (1953). (4) R 0. Stafford, B. J. Bowman and K. J. Olson, ibid, 86, 322 (1954). (5) Private communication from our biology staff. (ti) C. Djerassi, L. Miramontes, G. Rosenkranz and F. Sondheimer, THIS JOURNAL, 76, 4092 (1954). (7) M. E. Hem, J. A. Hogg and R H Levin, ibid., 78, 500 (19.56); S. C. Lyster, G. H . Lund and R. 0. Stafford, E7tdrocrinology, 68, 781 (1956).
Of
active compound in this series, 17-methyl-9afluoro-11-oxotestosterone, is reported to possess 22 and 8.5 times the oral anabolic and androgenic activity, respectively, of 17-methyltestosterone. The 19-nortestosterone derivatives included in this study and their physical constants are recorded in Table I. TABLE I 17-ALKYL-19-NORTESTOSTERONEDERIVATIVES M.P.. ''2. l a l n (CHCIa)
19-Nortestosterone 17-Methyl-19-norte~tosterone~ 17-Ethyl-19-nortestosterone8 17-Propyl-19-nortesto~terone~ 17-Butyl-19-nortestoster~ne~ 17-0cty1-19-nortestosterone~ 17-Vinyl-19-nortestosterone~
123-124 156-158 136-139 122-123 126-127 120-122 169-171
17-Allyl-19-nortesto~terone~ 93-95 17-Ethynyl-19-nortestosterone5 202-204
55 O 31 25 21
2536 (CJLOH)
-22
The anabolic potency of the substances studied was determined by the levator ani method of Eisenberg and Gordan and the androgenic properties were ascertained by the increase in weight of the seminal vesicle and the ventral prostate.1° Of the compounds studied, 17-ethyl-19-nortestosterone (I)8v11appeared to be the most applicable for clinical use because of its high anabolic po(8) F. B. Colton, U. S. Patent 2,721,871 (1965). (9) A. Sandoval, L. Miramontes, G. Rosenkranz, C. Djerassi and F. Sondheimer. THIS J O U R N A L , 76, 4117 (1953); F. B. Colton, U. S. Patents 2,656,518 (1953), 2,704,768 (1955). (IO) F. J. Saunders and V. A. Drill, Endocrinology, 68, 567 (1956). (loa) V. A, Drill and F J . Saunders, "Hormones and the Aging Process." 1956, pp. 99-113. Academic Press Inc., New York, N. Y., ( 1 1 ) G. D. Searle and Co. has recently introduced this material under the trade name of Nilevar.
