Feb. 5, 1952
SELECTIVE
HYDROGENATION OF STEROID
The identity of this ester was confirmed by saponifying a small sample t o the parent hydroxy lactone. Isobisdehydroestrololactone Methyl Ether (IV).-The acetoxy lactone (193 mg.) was saponified with 10 ml. of 2% sodium hydroxide, and this solution at 60' was treated by the alternate, portionwise addition of dimethyl sulfate and sodium hydroxide solution. The warm mixture (containing some solid material) was acidified with excess hydrochloric acid, and the precipitate was collected, resaponified and again precipitated from hot solution with hydrochloric acid. The 140 mg. of product thus obtained melted at 183-186". After recrystallization from ethanol, it melted a t 189-191". Anal. Calcd. for ClgHaoOa: C, 77.00; H, 6.80. Found: C, 77.06; H, 6.71. A mixture-of the methoxy lactone of m.p. 189-191" and the acetoxy lactone of m.p. 187-188" melted a t 160-180°. Derivatives of Isobisdehydroestrolic Acid (V).-All aqueous media in this section were prepared from distilled water. The acetoxy lactone (173 mg.) was saponified and methylated, and the initially-precipitated methoxy lactone was resaponified with 10 ml. of 2 % sodium hydroxide. When this solution was concentrated to 5 ml. and cooled, the white, crystalline sodium salt (VI) separated. This could not be washed ion-free, as it dissolved almost immediately in water, methanol and ethanol, and no satisfactory solvent was found for recrystallization. It was collected on a filter, and repeatedly resuspended in and washed with portions of a solution prepared from 60 g. of sodium nitrate and 100 ml. of water, until the contaminating hydroxide ion was quantitatively replaced by nitrate ion. The organic
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POLYENES
sodium salt (with the adhering sodium nitrate) was dissolved in 15 ml. of warm water, and tHis solution was treated with dilute silver nitrate until precipitation was complete. The pale grey silver salt)I.!( weighed 162 mg. and melted with decomposition at 176 It is insoluble in water, organic solvents and sodium hydroxide solution, but it dissolves readily in aqueous ammonia. Analytical values indicate that it has the composition of a dihydrate. Anal. Calcd. for C I ~ H ~ ~ O ~ AAg, ~ ~23.59; H ~ OCH,O-, : 6.79. Found: Ag, 23.68; CHaO-, 6.73. The silver salt (90 mg.) was covered with 10 ml. of methyl iodide and allowed to stand a t 2 5 O , with occasional shaking, for 20 hours. When the mixture was boiled gently to dryness and the residue was extracted with several portions of warm methanol, a fraction of about 48 mg. remained undissolved (calculated for silver iodide = 46.2 mg., assuming the organic silver salt t o be a dihydrate). The methanol soluble fraction, after two recrystallizations from very small amounts of methanol, gave 6 mg. of a material, m.p. 107-108", tentatively formulated as the methyl ester (VIII),along, with a larger amount of less pure material. This compound is soluble in ethyl acetate, moderately soluble in methanol, slightly soluble in benzene, and almost insoluble in aliphatic hydrocarbon solvents and water. Although the material melted sharply and was thought to be the pure ester, a single carbon-hydrogen determination failed to substantiate the proposed formula. Confirmation of the identity of this compound must therefore be held in abeyance.
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CHICAGO 80, ILLINOIS
RECEIVED JULY 19, 1951
RESEARCH LABORATORIES OF CHAS.PFIZER AND Co., INC.]
Corticosteroid Intermediahs. A Selective Hydrogenation of Steroid Polyenes BY G. D. LAUBACH AND K. J. BRUNINGS Hydrogenation of several polyunsaturated sterols in the presence of Raney nickel catalyst a t room temperature and atmospheric pressure has been shown to proceed selectively without bond isomerization or saturation of non-conjugated side-chain double bonds. The important intermediate 5-dihydroergosterol has been prepared by this technique in quantitative yield from ergosterol. The method has been applied to four of the isomers of ergosterol, and in the course of this work A8(14)122ergostadien-3 8-01 acetate has been prepared and characterized.
Discussion sterol nucleus is rendered difficult by the reactivity The A7~s(11)-sterol dienes',* have long been con- of the side-chain function. Furthermore, the 7,Ssidered attractive intermediates for the synthesis of double bond generated in the reduction is extremely 11-oxygenated steroids, A key step in the prepa- labile and susceptible to migration to the S114-posiration of dienes of this type from readily available tion under certain catalytic hydrogenation condistarting materials involves the selective hydrogena- t i o n ~ . ~Despite the extensive study devoted to the no method tion of A6,7-steroldienes to A7-monounsaturated selective hydrogenation of erg~sterol,~ satisfactory for large-scale operation has been de("5-dihydro") derivatives. A typical example is the preparation of the important intermediate scribed. The best yields thus far reported have been of the order 30 to 357&4aand purification of (A7*9(11)~22-ergostatrien-3P-ol ergosterol-D-acetate acetate, which involves selective hydrogenation of the product (by fractional recrystallization) has ergosterol (I) to 5-dihydroergosterol (A7mz2-ergosta- been described as capricious and diffi~ult.~ A series of attempts to repeat in this Laboratory dien-3P-01) (111) followed by dehydrogenation a t the 9,ll-position. In all sterols possessing a syn- the hydrogenation of ergosterol acetate over platiwhich appeared to be the most thetically useful side-chain double bond, selective num in chlor~form,~a hydrogenation of ethylenic linkages within the straightforward of the published procedures, did not give consistent results, the product generally (1) W. Bergmann and J. Klacsman, J . Org. Chem., 13, 21 (1948). containing varying proportions of the monounsatu(2) Subsequent to the completion of this work M.Tishler and corated rearranged sterol, As(14)-ergosten-3 @-01aceworkers, THISJOURNAL, 73, 2396 (1951), and Fieser and co-workers, i b i d . , 73.2897 (1Q51),reported the first successful conversion of A78Q(l')tate. This product could in fact be obtained in exsterol dienes to 11-oxygenated corticosteroid intermediates. A cellent yields by allowing the hydrogenation to prosecond route was later announced by G . Stork, el a l . , ibid., 73, 3546 ceed to completion. Incorporation of solid calcium (3951). (3) A. Windaus and E. Auhagen, Ann., 472, 185 (1929); I. Heilcarbonate in an attempt to maintain the neutral bron, F. Johnstone and F. Spring, J . Chem. Soc., 22-28 (1929). (a) conditions essential for non-migration of steroid D. R . H. Barton and J. Cox,i b i d . , 219 (1949). (4) A . Windaus and J. Brunken, A n n . , 460, 225 (1927); I. Heilbron and W. Sexton, J . Chon. Soc.. 921 (1929); H. Wieland and W. Benend, Ann., S64 1 (1943). (a) D. R. H. Barton and J. Cox, J . Chrnr. Sac., 1354 (1948).
(5) A survey of bond migration on hydrogenation of steroids is given by.1,. P. aqd M. Fieoer, "Natural Products Related to Phenanthrene," 3rd Edition, Reinhold Publishing Corp., New York, N. Y . , 1948, p 240. See a b Wieland and Beneod, ref. 4.
706
G.D.LAUBACH AND K.J. BRUNINGS
VOl. 74
ditions adequate for rapid hydrogenation of ergosterol, a result in keeping with the reported resistance of the A6J4-dienicsystem to catalytic hydrog e n a t i ~ n . ~Ergosterol-D (the A7*g(11)J2isomer), of considerable interest because of its unsaturated center at the 11-position, similarly proved inert R d RO under the conditions of the hydrogena1,R-H 111, R = H tion, in contrast to results obtained 11, R CHaCS IV, R C H , C ~ with platinum in acidic medium.3a Ergosterol-B3 acetate (the A7*14122-isomer) was found to be equally resistant to hydrogenation. However, the A6v6(14)J2-triene (ergosterol-B2 acetate)a readily absorbed exactly one mole of hydrogen to afford in excellent yield an ergostadien-311-01 CHsCOO CHICOO acetate (VI). shown to be the A8(14)n22diene by quantitative conversion to the V VI known A8(14)-ergosten-3/3-01acetate double bonds over platinum in the presence of hy- over platinum catalyst in neutral medium. The drogens did not prove consistently successfd. The observed molecular rotation of the diene (MDobsd. use of alternate media in this hydrogenation was 117) is in fair agreement with the value calcufound to be somewhat limited by the poor solubility lated (MDcalcd. - 99) using the side-chain rotatory of ergosterol and its esters in most organic solvents. contribution derived by Barton in his study of These results led to a consideration of a variety of 8-dihydroergosterol acetate.10 other catalysts, with special emphasis on those not The reduction of dehydroergosterol acetate prone to attack isolated double bonds. A deacti- (Aa~7~e(11)~22-erg~~tatetraen-3~-ol acetate) seemed vated noble metal catalyst, palladium-lead on bar- of potential importance because selective hydroium carbonate in chloroform was investigated. Un- genation could conceivably lead directly to ergosder the conditions of the experiment, no hydrogen terol-n acetate by saturation of the 5,6-douhle uptake was observed a t ordinary conditions of tem- bond as in the case of ergosterol itself. However, perature and pressure. Similarly, hydrogenation under the conditions of the hydrogenation over of ergosterol over the same catalyst in dioxane re- Raney nickel an indefinite amount of hydrogen sulted in essentially no absorption of hydrogen and (approximating 1.3 moles) was absorbed to afford a afforded starting material of good purity. complex reaction mixture suggestive of attack a t However, when the hydrogenation was carried more than one of the double bonds of the conjuout in dioxane in the presence of a Raney nickel cat- gated trienic system. The ultraviolet spectrum of alysts a rapid uptake of exactly one mole of hydro- the crude product indicated the presence of about gen was observed, affording excellent yields of 5- 53% of ergosterol-D acetate, and suggested the presdihydroergesterol (111). The product was shown ence of ergosterol acetate. The spectrum appeared to be essentially uncontaminated by products of to be verysimilar to that observed by Bergmannlfor bond migration or side-chain saturation. The the crude product of the sodium+ilcohol reduction of rapidity of this hydrogenation when carried out at dehydroergosterol, indicating that the hydrogenaroom temperature and atmospheric pressure is par- tion had probably taken a similar course to the soticularly striking, since Raney nickel has not been diumalcohol reduction or platinum hydrogenaextensively used for saturation of carbon-carbon tions* of this compound. double bonds under these conditions.' The use of Experimentalll dioxane as solvent in this preparation was found to 5-Dihydroergosterol (III) (A).-A solution of 0.793 g. allow convenient operation in relatively concenmole) of ergosterol (m.p. 156.0-158.5°, [cU]*'D trated solution, and excellent results have been at- (0.002 --117.5O, c 1.99, chloroform) in 14 ml. of peroxide-free ditained with large runs a t atmospheric or slightly oxane was hydrogenated over about 1.2 g. of Raney nickel elevated pressures. catalyst which had previously been saturated with hydroIn order to investigate further the scope and gen- gen.' After three hours 51 .O ml. (105%) of the theoretical of hydrogen had been absorbed and hydrogen uperality of the method as applied to other conjugated quantity ceased. The reaction mixture was diluted with chlorosteroid dienes, several known isomers of ergosterol take form and the catalyst removed by filtration through a filterwere prepared and subjected to hydrogenation over aid. Concentration under reduced pressure afforded 0.749 Raney nickel. The A%14,22-isomer (ergosterol-B1 g. ( 9 4 p ) of nearly pure 111, m.p. 165.4-172.0°, [ Q } % ~ D - 18.3 (c 1.97, chloroform). Recrystallization from acetate) failed to adsorb hydrogen under the con- methylene chloride-methanol afforded material m.p. 173.0E
.
,I
-
(6) R. Mozingo Org Syn!hescs, 20, 15 (1941). (7) In a preliminary communication received subsequent to the completion of this work, Fleser and co-workers, ref. 2, have reported a similar case in the hydrogenation of 7-dehydrochlolesterol to ATcholesten-3&01. This work does not point up the specificity of the catalyst in non-attack of reactive side-chain double bonds. (8) A. Windaus, IC. Dithmar, H. Murke and F. Suckfull, Ann., 488, 91 (1981).
[cY]%'D -19.3' (c 2.06,chloroform) in 80% recovery. (B).-An efficient large-scale hydrogenation was carried out using an apparatus constructed from B standard Parr hydrogenator tank by attaching a magnetically stirred 2-
176.2O.
(9) D.R.H.Barton and J. Cor, 1.Ckm. Soc., 214 (1940). (10) D.R. H. Barton, J. Cor and W. Holnur, ibld., 1791 (ltt49). (11) All melting point8 corrected.
Feb. 5, 1952
ESTERIFICATION OF LACTATES WITH DIBASIC ACIDS
liter filter flask suitable for the large quantity of solvent required. In this apparatus a solution of 39.7 g. (0.1 mole) of ergosterol in 800 ml. of dioxane containing 50 g. of Raney nickel caused a pressure drop of 7.0 lb. (110% of the theory) of hydrogen when stirred for two hours under 10-15 Ib. pressure a t room temperature. At this time all hydrogen uptake ceased. From the filtered solution was isolated directly 40.1 g. (100%) of quite pure 111, m.p. 170.8-172.4". 5-Dihydroergosterol Acetate (N).-A solution of 0.199 g. (0.0005 mole) of 5-dihydroergosterol (111)in 5 ml. of acetic anhydride containing one drop of pyridine was refluxed for 20 minutes. On cooling, 0.182 g. (82.5%) of the acetate IV separated as large plates, m.p. 174.6-177.4", [ a ] * '-21.2" ~ (c 2.00, chloroform). The melting point on admixture with nn authentic sample prepared by the method of Barton," m.p. 176.0-180.6", was not depressed. A8(14)~z*-Ergostadien-3 8-01 Acetate (VI).-As8(14),*l-Erg~ statrien-38-01 acetate, m.p. 119.0-120.6°, [ ~ S D -94.0" (c 1.03, chloroform) was prepared essentially as described by Windauss who reported the physical constants as m.p. loo', [a]D -80.4".1a A solution of 0.700 g. (0.0016 mole) of the acetate (V)in 20 ml. of dioxane was hydrogenated over about 1.5 g. of Raney nickel catalyst as described in the preparation of I11 (A). After three hours nearly the theoretical quantity of hydrogen had been absorbed and hydrogen uptake ceased. The filtered reaction mixture on concentration to dryness under reduced pressure afforded 0.690 g. of crystalline product as small colorless platelets, m.p. 111.&114.0° (98%). Recrystallization from ethyl acetatemethanol afforded an 82% recovery of pure A8(14)~za-ergostadien-3/3-ol acetate (VI),m.p. 122.6-124.0", [ala6~ -26.5' (c 1.12, chloroform). The physical constants were not altered by further recrystallization. Anal. Calcd. for C30H4802: C, 81.76; H, 10.98. Found: C, 81.96; H, 10.89. Hydrogenation of A*(14)la*-Ergostadien-38slAcetate (VI).-A solution of 0.220 g. (0.0005 mole) of VI in 10 ml. of anhydrous peroxide-free dioxane was hydrogenated over 0.050 g. of prereduced platinum oxide catalyst. After 69 minutes, 12.4 ml. (100%) of the theoretical quantity of hydrogen required for saturation of one double bond had been absorbed. The filtered reaction mixture on conchration afforded quantitatively nearly pure A8(14)-ergosten-38-ol acetate, m.p. 101.5-110.0". Recrystallization from ethyl acetate afforded pure acetate as large glistening plates, (12) An alternate preparation of this triene will be the ;lubfect of a later communication.
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m.p. 109.0-110.5', [u]D +2.7' (c 1.11, chloroform). The melting point on admixture with an authentic sample, m.p. 109.0-110.5°, [ a ] D f 4 . 0 (C 1-01, chloroform), prepared by hydrogenation of ergosterol acetate over platinum in chloroform, was not depressed. Hydrogenation of As~14~zz-Ergostatrien-38-ol Acetate.A solution of 0.397 g. (0.001 mole) of A8.14*4z-ergostatrien38-01 acetate (ergosterol-B1 acetate),' m. p. 139.&142.O O, [.ID -57.9' ( c 1.04, chloroform) in 11 ml. of dioxane was stirred over prereduced Raney nickel catalyst (0.58 g.) in an atmosphere of hydrogen for several hours. No hydrogen absorption was observed, and the product isolated on filtration and concentration proved to be unchanged ergosterolB1 acetate, m.p. 139.0-144.4", not depressed on admixture with starting material. Hydrogenation of A7~e(11).*z-Ergostatrien-38-ol Acetate.A7,0(ll),*+Ergostatrien-38-ol acetate (ergosterol-D acetate) was prepared by the method of Barton,B.m.p. 165.&169.0°. Hydrogenation of a 0.175-g. portion over 0.43 g. of Raney nickel in 10 ml. of dioxane by the usual procedure resulted in no hydrogen uptake and quantitative recovery of starting material, m.p. 162.0-168.9O, [ a ]+26.7" ~ (c 0.98, chloroform), not depressed on admixture with an authentic sample. Hydrogenation of As~7~g(11)~B*-Ergostatetraen-3~-ol Acetate.-A6J~~(~~)~**-Ergostatetraen38-01 acetate (dehydroergosterol acetate) was prepared by mercuric acetate dehydrogenation of ergosterol acetate as described by Bergmann and Stevens," m.p. 146.2-151.0", [ a ] D $157" (c 2.03, chloroform). A solution of 0.437 g. (0.001 mole) of the tetraene acetate in I2 ml. of dioxane was hydrogenated over 0.63 g. of Raney nickel catalyst. Hydrogen uptake showed a sharp inflection after 1.33 moles had been absorbed, and only a slightjuther uptake was observed. Filtration and concentration $12 vacuo afforded a quantitative recovery of crystalline product as tiny platelets, m.p. 149.8-156.4", [a]%D f21.8' (c 1.97, chloroform), An ultraviolet spectrum measured in ether solution showed strong bands a t 235 and 242.5 m p (log c 3.82), indicating the presence of about 53% A7~oc11).zz-ergostatrienol acetate.
Acknowledgments.-We wish to express our appreciation to Mr. Robert Richter for technical assistance. We are indebted to Dr. John Means and his associates of these laboratories for the microanalyses. (13) W. Bergmann and P. G. Stevens, J . Org. Chsm., 13, 10 (1948).
BROOKLYN, N. Y.
RECEIVED AUGUST17,1951
EASTERN REGIONAL RESEARCH LABORATORY']
Diesters of Lactic Acid. Esterification of Lactates with Dibasic Acids BY C. E. REHBERGAND MARIONB. DIXON Twenty-six esters made by the esterification of lactate esters with dibasic acids are described. Boiling points, refractive indices, densities and viscosities of the esters at different temperatures are given. Potential usefulness of these compounds as plasticizers is suggested.
In the previous paper of this series,t the adipates of a number of esters of lactic acid were described, and their potential usefulness as plasticizers was suggested. The present paper reports work of the same general nature in which instead of adipic acid, various other dibasic acids were used to esterify the hydroxyl group of esters of lactic acid. These products may be represented by the formula X [-OCH( CH*)COOR]* (1) One of the laboratories of the Bureau of Agricultural and Industrial Chemistry, Agricultural Research Administration, U. 5. Department of Agriculture. Article not copyrighted. (2) Rehberg and Duon. T a I a JOVRNU, 71, 5767 (1960).
where X is the divalent acyl radical of a dibasic acid and R is the alcohol radical of the lactic ester. The dibasic acids used were phthalic, maleic, succinic, sebacic, carbonic and benzenephosphonic. Most attention was devoted to phthalic esters because of their importance in the plasticizer industry. The products obtained by the esterification of dicarboxylic acids with allyl lactate contain two allyl groups in the molecule and are polymerizable. Several such esters have been reported. Thus, allyl lactate has been treated with acid chlorides to produce the carbonate, succinate, fumarate, adipate, sebacate and phthalate.' The maleates of allyl' (3) Rowald and Jones,U. 5. Patent 3,463,043, Feb. 15, 1949. (4) Jonei, U.9. Patent 2,443,915, June 22, 1948.
