1720
VOL.
NOTES
Interconversion of crystal forms. (a) From phase 11 to phase I . To a hot saturated benzene solution of phase I1 was added a small crystal of phase I. On slow cooling to room temperature, fine colorless needles separated, m.p. 124-126'. (b) From phase 111 to phase I . To a hot saturated benzene solution of phase I11 was added a small crystal of phase I and the solution was cooled down slowly to room temperature. Colorless fine needles were formed, m.p. 124-126'. ( c ) From phase 1 to phase I I . The above crystals of phase I were dissolved in boiling benzene to make a saturated solution and a few small crystals of phase I1 were added, and then solvent was partially distilled off. Slightly yellowish plates of phase I1 were obtained, m.p. 126.5-128'. (d) From phase 11 to phase I I I . This conversion was accomplished by dissolving phase I or 11in hot chloroform, then allowing the solution to cool slowly. Large prisms of phase I11 separated, m.p. 127-129'. Ultraviolet spectra of samples of phase I, 11, and I11 in ethanol were identical, with Amnx 227, 251, and 286 miu. and log E 4.28, 4.15, and 3.96, respectively. DEPARTMENT OF CHEMISTRY OF PENNSYLVANIA UNIVERSITY PHILADELPHIA 4,PA.
4-Halogenated Derivatives of 1-Dehydrocortisone Acetate EUCEKEP. OLIVETO,LOIS WEBER, CORINNEGEROLD, M. M. PECHET, AND E. B. HERSHBERG
22
dioxide. We had observed independently the formation of l-dehydrocortisone acetate from cortisone acetate, 17a,2l-dihydroxypregnane-3,11,20trione 21-acetate or 17a,21-dihydroxyallopregnane3,11,2O-trione21-acetate using selenium dioxide, but since our results do not differ significantly from those of other investigator^,^^^ we shall not describe them. We should like t o report, however, on the extension of this reaction t o the preparation of 4-halogenated derivatives of l-dehydrocortisone acetate. When 4-bromo-l7a,21-dihydroxypregnane-3,11,20-trione 21-acetate (I) was refluxed for 4 hr. with selenium dioxide in xylene, a new compound was obtained with m.p. 235" (dec.), [.ID +213.7" (diox.), MeOR A,, 243 mp (e 9,700). This compound still contained one atom of bromine, which could not be removed by vigorous treatment with zinc. Based on these properties, and its non-identity with 4-bromocortisone acetate,6 the structure of 4-bromo-] dehydrocortisone acetate (111)is assigned. I n a similar fashion, 4-cl-iloro-17a,21-dihydroxypregnane-3,11,2O-trione 21-acetate (11) with selenium dioxide in chlorobenzene gave 4-chloro-l-dehydrocortisone acetate (IV), m.p. 254" (dec.), Ag:H 242 mp (e 10,600). This compound was not identical with 4-ehlorocortisone acetate5 and could not be dehalogenated with zinc. As further evidence for its structure, treatment with hydrogen and palladium in methanol gave only starting material. Clinical evaluation of IV indicates that the metabolic effects in man are considerably diminished by the substitution of a chlorine atom for a hydrogen atom a t C-4.
EXPERIMENTAL^
+&Bromo-l-dehydrocortisone acetate (111). A mixture of 40 g. of 4bromo-17ar,21-dihydroxypregnane-3,11,20-trione 21-acetate, 40 g. of selenium dioxide, and 2.01. of xylene was The increased antiinflammatory activity of 1- refluxed for 4 hr. The mixture was cooled to room temperadehydrocortisone as compared to cortisone' has ture and filtered, and the filtrate concentrated to a residue made the introduction of double bonds in a steroid under reduced pressure. This was taken up in 2 1. of methadjacent to a 3-keto group a problem of some impor- ylene chloride and washed with dilute sodium hydroxide and dilute hydrochloric acid, then with water to neutrality, tance. Chemically, this has been accomplished by dried, and concentrated to a residue of 30.3 g. This was only three different general methods: (a) dibromina- mixed with 100 ml. of ether and filtered to yield a residue of tion of a %keto saturated all0 or normal steroid, 12.43 g. (31%), m.p. 216" (dec.). Recrystallization from followed by dehydrobromination with collidine;2 methanol-Darco yielded 11.0 g. (28%), m.p. 235" (dec.), [CY]= +213.7' (diox.), 243 mp ( e 9,700).
Received April SO, 1957
(b) reaction of lead tetraacetate with a 3-keto-A4(4)(a) H. Ringold, G. Rosenkranz, and F. Sondheimer, steroid;a (c) reaction of a 3-keto-A4-steroid or 3keto saturated allo or normal steroid with selenium J. Org. Chem., 21, 239 (1956).(b) C. Meystre, H. Frey, W. Voser, and A. Wettstein, Helv. Chim. Acta, 39, 734 (1956). (c) K. Florey and A. Restivo, p. 45, Abstracts of Papers, (1)H. Herzog, A. h'obile, S. Tolksdorf, W. Charney, E. B. Hershbere. P. Perlman. and M. Pechet, Science., 121,. I76 (1955). (2) Cy. H.Herzog, C. Payne, M. Jevnik, D. Gould, E. Shaairo, E. Oliveto, and E. B. Hershberg, _. J . Am. Chem. sOc,77; 4781(1955j. (3) R. Clarke, K. Dobriner, A . Mooradian, and C. Martini, J . Am. Chem. SOC.,77, 661 (1955);s. Burstein and R. Dorfman, J . Am. Chem. SOC.,77,4668(1955). I ,
Delaware Valley Regional Meeting, Feb. 16, 1956,Philadelphia, Pa. (d) S. Szpilfogel, T. Posthumus, M. De Winter, and D. Van Dorp, Rec. trao. chim., 75,475 (1956). (5)E.Oliveto, C. Gerold, and E. B. Hershberg, J . Am. Chem. SOC.,79,3596(1957). (6) All melting points are corrected. All rotations were taken in a l-dm. tube a t a concentration of ca. 1% at 25". Analyses and optical data were obtained by the Microanalytical and Physical Chemistry Departments of these laboratories.
DECEMBER 1957
1721
NOTES
Anal. Calcd. for Cz3Hz7OeBr: C, 57.62; H, 5.68; Br, 16.67. C, 57.31; H, 5.54; Br, 16.26. Its 3-semicarbazone, prepared by refluxing I11 with semicarbazide acetate in aqueous methanol had m.p. ca. 250" (dec.), k:zE 275 mp ( e 21,000). Anal. Calcd. for Cz4H~~No06Br: N, 7.8; Found: N, 7.4. 4-Chloro-l-&hydrocortisone acetate (IV). A mixture of 8.0 g. of ~chloro-17a,21-dihydroxypregnane-3,11,2O-trione 21acetate, 8.0 g. of selenium dioxide, and 400 ml. of chlorobenzene was refluxed €or 4 hr.After cooling to room temperature and filtering, log. of sodium acetate and 100 ml. of water were added, and the solution steamdistilled. The aqueous residue was made slightly acid with dilute hydrochloric acid, extracted with methylene chloride, and the organic layer washed with dilute sodium hydroxide solution and water, dried, and evaporated to give 1.89 g. (24%), m.p. 248" (dec.), " : :A 241 IQI ( e 10,500).To remove residual selenium, this material was dissolved in 500 ml. of methanol and treated with hydrogen and 190 mg. 5% Pd-on-charcoal for 1 hr. After filtration and concentration, the residue was recrystallized from methanol to ield 1.06 g., m.p. 254" (dec.), [ a ]4-215.1' ~ (diox.), h:'"d;& lllp ( e 10,600). Anat. Calcd. for CZ&&CI: C1, 8.16. Found: c1, 8.09. Neither I11 nor IV, on refluxing with zinc in 80% EtOH20% HOAc for 3 hr., gave halogen-free products.
SCHERINQ GORP. BLOOMFIELD, N. 3. MASSACHUSETTS GENEW HOSPITAL BOSTON, MASS.
Thiazolidine Chemistry. IV. Alkylation of 2-Phenyl-3-n-alkyl-4-thiaxolidinones 21'
IRVINQ R.SCHMOLKAa AND PAUL E. SPOERRI' Received May 1, 1967
It was of interest to study the alkylation of some 2-phenyl-3-n-alkyl-4-thiazolidinones prepared in this laboratory. Erlenmeyer and Oberlin had reported6 that the two hydrogens on the 5-position of the thiazolidine ring of 2-phenyl-3pethoxyphenyl4-thiazolidinone had been replaced by two allyl groups. When this alkylation procedure was applied to 2-phenyl-3-n-butyl-4-thiazolidinone, the starting material was recovered unchanged. Alkylation with another agent was then attempted. The 2phenyl-3-n-octadecyl-4-thiazolidinonewas refluxed for 8 hr. with an equimolar quantity of methyl sulfate. The reaction mixture yielded a white waxy material with a faint pungent odor. A mixture melting point as well as ultraviolet and infrared absorption spectra indicated the product t o be entirely different from the starting material. The waxy nature (1) Part 111, I. R. Schmolka and P. E. Spoerri, J . Am. Chem.Soc., 79,4716 (1957). (2) Abstracted from the Ph.D. Thesis of Irving R. Schmolka, Polytechnic Institute of Brooklyn, June 1955. Presented before the qixth Meeting in Miniature of the Metropolitan Long Island Subsection of the New York Section, AMERICANCHMMICAL SOCIETY,Feb. 25, 1955. (3) Current address, Wyandotte Chemicals Gorp., Wyandotte, Mich. (4) To whom inquiries should be sent. (5) E. Erlenmeyer and V. Oberlin, Helv. Chim. Acta, 30, 1329 (1947).
of the product suggested that the n-octadecyl group had remained intact. Analytical results and an examination of the spectra suggested that the cleavage compound was N-(n-octadecy1)methylmercaptoacetamide, H&SCH&ONH(CHZ)~~CH~. This was proved by unequivocal synthesis, by condensing n-octadecyl amine with the chloride of Smethylmercaptoacetic acid, and the identity of the two compounds demonstrated in a conclusive way. The reproducibility of the cleavage with methyl sulfate was shown by repeated experiments not only on the 2-phenyl-3-n-octadecyl-4-thiazolidinone compound, but also on the n-butyl and n-tetradecyl homologs. The structure of these cleavage products was demonstrated by unequivocal synthesis of the postulated compounds. A literature search failed to show any reactions of a similar nature, although the rupture of the thiazolidine ring under various conditions has been r e p ~ r t e d . ~ ~ ~
EXPERIMENTAL^ N-(n-Tetr~cyl)meWlylmerca~toacetamide.I n a 100-ml. round-bottom flask were placed 10.4 g. (0.0277 mole) of 2-phenyl-3-n-tetradecyl-4-thiarolidinone, 3.5 g. (0.0278 mole) of methyl sulfate, and 8 ml. of benzene. The mixture was refluxed gently for 7 hr., during which the contents of the flask became red. After cooling, the contents were concentrated in vacuo. To the red viscous mam remaining, 50 ml. of methahol and 10 g. of finely divided barium carbonate were slowly added. After the carbon dioxide was evolved the mixture was gently warmedon the steam bath and filtered. The residue was warmed with a fresh 25-ml. portion of methanol and filtered. The combined filtrates were e v a p orated to dryness and the residue taken up in a minimum amount of hot acetone. Upon cooling and filtering, 4.5 g. of a tan waxy powder were obtained. This was recrystallized twice more from acetone, yielding 2.4 g. (29%) of white waxy crystals with a mild pungent odor; m.p. 64-65'. Anal.9 Calcd. for C I ~ H d O S :C, 67.71; H, 11.70; S, 10.63. Found: C, 67.79; H, 11.65; S, 10.93. N-(n-Octadecyl)methylmercaptoacetam&.This compound was similarly prepared from 0.03 mole of 2-phenyl-3-n-octadecyl-4-thiasolidinone and 0.03 mole of methyl sulfate in 10 ml. of benzene. Upon refluxing for 8 hr., there was subsequently obtained 4.1 g. (36%) of white waxy material with a weak pungent odor; m.p. 75.9-76.9'. After purification by vacuum sublimation it still retained a weak pungent odor. Anal. Calcd. for GHt3NOS: C, 70.53; H, 12.12; S, 8.97. Found: C, 70.83; HI 11.91; 5, 8.89. N-(n-ButyZ)methylmercuptoacetamide. This compound was similarly prepared from 0.06 mole of 2-phenyl-3-n-butyl-4thiazolidinone and 0.06 mole of methyl sulfate in 10 ml. of benzene. Upon refluxing for 2 hr., there was eventually obtained, after vacuum distillation, 2.5 g. (26%) of a pale red oil, ny 1.50289, with a strong pungent odor. SMethylmercaptoacetic acid. The alkylation of mercapto acids described (Method B) by Mooradian et aZ.10 was followed. From mercaptoacetic acid and methyl sulfate there (6) W. M. McLamore, W. D. Celmer, V. V. Bogert, F. C. Pennington, B. A. Sobin, and I A. Solomons, J. Am. Chem. Soc., 75,105 (1953). (7) H. T. Clarke, J. R. Johnson, and R. Robinson, The Chemktry of Penicillin, Princeton University Press, Princeton, N. J,, 1949, pp. 921-937. (8) Melting points are corrected, boiling points are not. (9) Analyses by Drs. Weiler and Straws, Oxford, England, and the Analytical Division of the Colgate Palmolive Go. Research Department.
