Synthesis of some new C ring steroidal derivatives

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In this paper, the synthesis of some new C ring steroidal derivatives from -pregnyne has been described. They are 9 -brom-17 -pregn-4-en-11 ,17 -diol-3-on-20-yne; 11 -formiat-9 - brom-17 -pregn-4-en-17 -ol-3-on-20-yne; 17 -pregn-11 ,17 -diol-4-en-3-on-20-yne; 9 ,11 - epoxy-17 -pregn-4-en-17 -ol-3-on-20-yne and 9 ,11 -epoxy-17 -pregn-4-en-17 -ol-3-on-20- yne. Structure of the products has been elucidated by IR, MS and 1 H-NMR methods.

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Nội dung Text: Synthesis of some new C ring steroidal derivatives

Journal of Chemistry, Vol. 43 (2), P. 250 - 252, 2005 synthesis of some new c ring steroidal derivatives Received 10th-April-2004 Luu duc Huy Institute of Chemistry,Vietnamese Academy of Science and Technology Summary In this paper, the synthesis of some new C ring steroidal derivatives from 9-pregnyne has been described. They are 9 -brom-17 -pregn-4-en-11 ,17 -diol-3-on-20-yne; 11 -formiat-9 - brom-17 -pregn-4-en-17 -ol-3-on-20-yne; 17 -pregn-11 ,17 -diol-4-en-3-on-20-yne; 9 ,11 - epoxy-17 -pregn-4-en-17 -ol-3-on-20-yne and 9 ,11 -epoxy-17 -pregn-4-en-17 -ol-3-on-20- yne. Structure of the products has been elucidated by IR, MS and 1H-NMR methods. I - Introduction the 9-pregnyne which is obtained from sterols via 17-ketosteroid (and- rostadiendion ADD) by Because the invention of microbial degra- the base-catalyzed condensation of the ADD dation of sterols which are recovered from a with acetylene [3, 4]. The C ring derivatives of waste of paper and soya industries provides an pregnyne are very valuable intermediates in the inexpensive source of 17-ketosteroids [1, 2], it synthesis of corticoidal medicines, such as is now a tendency to use plant sterols for cortisone and hydrocortisone. semisynthesis of steroidal medicines instead of old materials such as diosgenin and solasodin. II - Materials and methods This has a great signification for Vietnam, an agricultural and developing country. Starting material 9-pregnyne, all reagents, In Vietnam, now there are some large paper solvents, adsorbents were purchased from Aldrich factories and soybean is one of the most Co. (USA) and Merck Clevenot Co. (France). important agricultural produces (many hundreds Solvents were purified, distilled prior to use. thousand tons per year). Meanwhile, every year Melting points were determined on Boetius Vietnam must import a large quantity of apparatus. IR spectra were recorded on FT-IR- steroidal medicines because of lack the raw IMPACT-410 with KBr pellets. Optical rotations material necessary for synthesizing ones. were obtained on a Polartronic D (Schmidt + Besides the price of diosgenin and solasodin Haensch). 1H-NMR spectra were recorded on in the world market is very high because Bruker WM-250, Bruker AM 500 spectrometer in Dioscorea and Solanum plants are cultivated on CDCl3 with TMS as internal reference. MS spectra the agricultural land. were recorded on MS-5989B in CHCl3. Analytical thin-layer chromatography was performed using We have involved in the elaboration on Merck 60 GF254. some new methods for synthesis of corticoids from sterols via 17-ketosteroids and the 17 - III - Experimental, Results and hydroxy-17 -ethynylsteroids since 1988. discussion In this paper we presents the synthesis of some new C ring derivatives of pregnyne from The methods employed in this conversion 250 are summarized in the scheme 1. C CH RO OH O i MeONa ii Br O O O 9 Pregnyne (1) R = H (83%) (3) (50 - 70% ) - (2) R = COH (90%) MCPBA HO O O O (4) (60%) (5) (80%) i: CH3CONHBr (R = H); ii: H2NOC(CH2)2CONHBr (R = COH) Scheme 1 The first step in the present sequence is IR ( , cm-1): 1065, 1620, 1640, 1655, 2100, transformation of 9-pregnyne into bromhydrin 3255, 3370, 3590. (1) and bromformiat (2) by treatment with 1 H-NMR ( , ppm): 1.16s (18 Me), 1.77d (19 CH3CONHBr or H2NOC(CH2)2CONHBr corres- Me, j = 0.5 Hz), 2.67s (H21), 4.68q (H11, j = 5.75 pondingly in high yields [5, 6]. Then, (1) was and 3.5 Hz), 5.76d (H4, j = 2.25 Hz). debrominated by MeONa giving rise to 9,11 - epoxide (3) [5, 6]. The compound (2) was MS (m/z): 407 M+, 389 [M-H2O]+, 372[M- transformed into the ethynylalcohol (5) by H2O-OH]+,, 327 [M-Br]+, 309 [M-H2O- Br]+. treatment with HSnBu3 [7 - 9]. The compound Compound 2: 9,11 -epoxide (4) was synthesized from 9- 11 -formiat-9 -brom-17 -pregn-4-en-17 -ol- pregnyne by treatment with MCPBA (m- 3-on-20-yne chloroperbenzoic acid). The known route for the transformation of ADD into (5) follows Yield: 90%. Mp (Me2CO/C6H14): 179 - literature methods [10 - 12], involving brom- 180oC. hydroxylation of ADD, followed by debromi- IR( , cm-1): 1144, 1620, 1648, 1656, 1715, nation of the obtained bromohydrin and then 2105, 3290, 3390. 17 -ethynylation of obtained 17-ketosteroid .However, this sequence is limited by a low MS(m/z): 435M+, 389 [M-HCO2H]+,372 yield (30%) in the final step which also requires [M-HCO2H-OH]+, 355 [M-Br]+, 309 [M- HCO2H-Br]+, 291 [M-HCO2H-Br-H2O]+. protection of the 4-3-keto group. Yields, chem.-physical and spectral charac- Compound 3: teristics of obtained products as following: 9 ,11 -epoxy-17 -pregn-4-en-17 -ol-3-on-20- yne Compound 1: 9 -brom-17 -pregn-4-en-11 ,17 -diol-3-on- Yield: (63% from 1, 96% from 2). Mp 20-yne (Me2CO/C6H14): 219 - 222oC. Yield: 83%. Mp (MeOH/CHCl3): 184-7oC. IR ( , cm-1): 1615, 1650, 3290, 3370. 251 MS (m/z): 326 M+, 311 [M-Me]+, 308 [M- Acknowledgements: This research was H2O]+, 293 [M-Me-H2O]+, 283 [M-H2O- supported by Asia Research Centre, National C CH]+. Hanoi University, the International Foundation for Science, Stockholm, Sweden, and the Compound 4: Organization Prohibition of Chemical 9 ,11 -epoxy-17 -pregn-4-en-17 -ol-3-on- Weapons, the Netherlands, through a grant F/ 20-yne 2561 to Dr. Luu Duc Huy Yield: 60%. Mp (MeOH/CHCl3): 272 - 277oC. references Phæ IR ( , cm-1): 1612, 1635, 1655, 2100, 3260, 3390. 1. K. Fujimoto, Ch. -S. Chen, Z. Szeleezky, D. Tullio, C. J. Sih. J. Amer. Chem. Soc. Vol. Phæ MS (m/z): 326 M+, 311 [M-Me]+, 308 104, No. 17. P. 4718 (1972). [M-H2O]+, 293 [M-Me- H2O]+, 283 [M-H2O- 2. H. Westmijze, H. Kleijn, P. Vermeer, L. A. C CH]+. Van Dijck. Tetr. Lett. Vol. 21, No. 27, P. Compound 5: 2665 (1980). 17 -pregn-4-en-11 ,17 -diol-3-on-20-yne 3. Japan Pat. 57197299, CA (1983). Vol. 98. Yield: 95%. Mp (MeOH): 279 - 282oC (Lit. 215894d (1982). [10 - 12]: 280-2oC). 4. I. Nitta, S. Fujimori, H. Ueno. Bull. Chem. Soc. Japan. Vol. 58, P. 978 (1985). IR( , cm-1): 1063, 1620, 1642, 1655, 2100, 3253, 3373, 3590. 5. J. Fried, J. A. Edvards. Organic reactiones in Steroid Chemistry, N. Y. Vol. 2 (1972). MS(M/z): 328 M+, 313 [M-Me]+, 310 [M- H2O]+, 295 [M-Me-H2O]+, 277 [M-Me-2x 6. SU Pat. 937460 (1982), CA (1983). Vol. 98, 4714g. H2O]+, 252 [M-Me-2xH2O-C CH]+. 7. F. Germany Pat. 2320999, CA (1975). Vol Conclusion 82. 43657e (1974). 8. US Pat. 4304727 (1981), CA (1982). Vol. Some new C ring steroidal derivatives: 9 - 96. 163049u. brom-17 -pregn-4-en-11 ,17 -diol-3-on-20-yne; 9. H. Parnes, J. Pease. J. Org. Chem.Vol. 44, 11 -formiat-9 -brom-17 -pregn-4-en-17 -ol- No. 1, P. 151 (1979). 3-on-20-yne;17 -pregn-11 ,17 -diol-4-en-3- 10. US Pat. 2816121, CA (1958). Vol. 52. on-20-yne; 9 ,11 -epoxy-17 -pregn-4-en-17 - 6422a (1957). ol-3-on-20-yne and 9 ,11 -epoxy-17 -pregn- 11. C. W. Marshall, J. W. Ralls, F. J. Saunders, 4-en-17 -ol-3-on-20-yne were synthesized in B. Riegel. J. Biol. Chem. Vol. 228, No. 1, P. good yields. Their products were identified by 339 (1957). melting points as well as by IR, MS and 1H- 12. G. Muller, R. Jeguier, C. Plotka. J. Amer. NMR methods. Chem. Soc., Vol. 80, No. 8, P. 2026 (1958). 252