2. M. Ya. Fioshin and I. A. Avrutskaya, Khim.-farm. Zh., No. 12, 50 (1979). 3. V.P. Malyshev, Mathematical Planning of Metallurgical and Chemical Experiments [in

Russian], Alma-Ata (1977). 4. G. Charlot, Methods of Analytical Chemistry [Russian translation], Second edn., Vol.

2, Moscow (1969), p. 881. 5. V.V. Andosov, I. V. Kirilus, and G. A. Frangulyan, Khim.-farm. Zh., No. 4, 62 (1981).

SYNTHESIS OF ESTRADIOL ESTERS FROM ESTRONE

S. D. Shuvalova, N. I. Men'shova, and G. S. Grinenko

UDC 615.256.51.012.1

Estradiol esters are used in medical practice as effective estrogenic preparations [i]. Thus, estradiol dipropionate (IV) is widely used and has a strong and prolonged action in comparison with estradiol [2].

The synthesis of (IV) from estrone (I) is effected by the generally applicable scheme of [3], be reduction of the 17-keto group with one of the known methods to estradiol (III) and subsequent acylation of the 3 and 178 hydroxy groups with the formation of (IV).

When developing a method for obtaining (IV), particularly in the selection of conditions for the exhaustive propionylation of (III), it was necessary to obtain the 3 and 17 monopro- pionate esters of estradiol (V and VI) and to determine the conditions for chromatographing (IV-VI) by TLC. To obtain the 3 monopropionyl ester (V) acylation of the phenolic hydroxyl of (I) was effected with propionic anhydride in pyridine, the 17 keto group in (II), the propionate ester of (I), was then reduced with sodium borohydride in a medium of methyl al- cohol. The yield of (V) was 83.32% calculated on (I). To obtain the 17 monoester (VI) se- lective hydrolysis of the dipropionate ester (IV) at posis 3 of the steroid molecule was carried out under mild conditions using potassium carbonateJin methyl alcohol at room temper- ature. Monoester (VI) was obtained in quantitative;yield.

The behavior of (IV-VI) on Silufol was studied in various~solvent systems. Optimum sep- aration of the two monoesters and diester (IV) was achieved by dhrom~tography in the system ethyl--hexane (2:3) in which Rf values for (IV-VI) were ~i.0, 0.58, ~affd~O.134, respectively. A 10% solution of phosphomolybdic acid in alcohol with subsequent heating ~of the plates at I05~ for 2-3 min was used for visualizing chromatograms. The minimum determinable quantity of (IV-VI) was 0.I pg.

o o~ ~

I: R =H Z: i~=R =II

I: R=COCzH 5 /': R:t~= COC~H~ 7: R- coczgs, P,'=H E~ P,- H,' I~'= COC!tr 5

Conditions were selected for the propionylation ofeestradi01using the found conditions for TLC analysis. It was shown that an excess of not less than 0.5 mole propionic anhydride was necessary for completion of the reaction. On carrying out the reaction at room tempera- ture the process was complete after 24 h, on heating to I05-II0~ the starting material had disappeared completely after 15 min and according to TLC diester (IV) and the 3 monoester (V) were present in the reaction mixture. Compound (V) was converted into (IV) after 1.5 h. After recrystallization (IV) was obtained the quality of which corresponded to the require- ments of the State Pharmacopoeia. The yield of (IV) was 87% calculated in (I).

EXPERIMENTAL

PMR spectra were obtained on an XL-100 spectrometer (operating frequency i00 MHz) in S. Ordzhonikidze All-Union Scientific-Research Institute for Pharmaceutical Chemistry,

Moscow. Translated from Khimiko-farmatsevticheskii Zhurnal. Vol. 17, No. 9, pp. ii07rli08, September, 1983. Original article submitted October 21, 1982.

0091-150X/83/1709- 0663507.50 �9 1984 Plenum Publishing Corporation 663

CDCIs solution, internal standard was tetramethyl silane.

Estra-l,3,5(10)-trien-3-ol-17-one Propionate Ester (II). A mixture of (I) (2.5 g: 0.0092 mole) and propionic anhydride (3.25 ml, 3.26 g: 0.025 mole) in pyridine (7.5 ml) was heated for i h at I05-II0~ The reaction mixture was then cooled with ice water and 10% hydrochloric acid (16 ml) was poured in keeping the temperature 0-40C. The mixture was stir- red at this temperature for 2 h. The precipitated solid was filtered off, washed to neutral reaction, and dried. After crystallization of the crude product from a tenfold quantity of methyl alcohol with carbon, compound (II) (2.53 g: 83.83%) was obtained of mp 134-135~ [4].

Estra-l,3,5(10)-trien-3,17B-diol (III). An 18.8% aqueous solution (31 ml) of sodium hydroxide was added at 18-20~ during I0 min to a suspension of (I) (40 g: 0.148 mole) in methyl alcohol (280 ml). After complete solution of (I) as the sodium salt sodium borohy- dride (6 g: 5.7 g 100% solution, 0.158 mole) was added gradually to the reaction mixture at a temperature no greater than 200C. A 10% hydrochloric acid solution (ii0 ml) was added with stirring and cooling to the reaction mixture which was then stirred for I h. The pre- cipitated solid was filtered off and washed with water to neutral reaction. Compound (III) (40.25 g: 99.9%) was obtained of mp 175-177~ [a]~ ~ + 77 ~ (1% in dioxane) [3].

Estra-l,3,5(lO)-trien-3,178-diol Dipropionate Ester (IV). A mixture of (III) (20 g: 0.073 mole) and propionic anhydride (50 ml, 50.55 g: 0.388 mole) in pyridine (60 ml) was heated for i h at I05-II0~ The reaction mixture was then cooled to 40C and poured onto 10% hydrochloric acid (260 ml). Crude (IV) was obtained after working up analogously to the synthesis of (II) from (I). After crystallization from a tenfold quantity of methyl alcohol with carbon compound (IV) (24.85 g: 88.03%) was obtained of mp I06-I08~ [~]~o + 40 ~ (1% in dioxane) [4].

Estra-l,3,5(10)-trien-3~178-diol 3-Propionate Ester (V). Sodium borohydride (0.5 g: 0.013 mole) was added at a temperature no greater than 20~ to a suspension of (II) (3 g: 0.0092 mole) in methyl alcohol (21 ml). After working up analogously to the synthesis of (III) from (I) compound (V) (3 g: 99.4%) was obtained of mp 124-125~ [4]. PMR spectrum, ppm: 0.77 (18-CH3), 1.25, 2.52 (OCOC2H5), 3.72 (17-H), 6.80 (4-H), 6.84 (2-H), 7.3 (I-H).

Estra-1,3,5(10)-trien-3,178-diol 17-Propionate Ester (VI). A solution of (IV) (0.87 g) in 1% potassium carbonate in methyl alcohol solution (50 ml) was stirred for 1.5 h at room temperature. Water (i00 ml) was then added to the reaction mixture, which was stirred for i0 min, the precipitated solid was filtered off, and washed with water to neutral reaction. Compound (VI) (0.73 gf 99.8%) was obtained of mp 196-198~ [4]. PMR spectrum, ppm: 0.83 (18-CH3), 1.11, 2.34 (OCOC2H5), 4.72 (17-H), 6.58 (4-H), 6.64 (2-H), 7.16 (I-H).

LITERATURE CITED

i. J. Richter, L. Kny, and K. Cerecke, Pharmazie, 22, 97 (1967). 2. M.D. Mashkovskii, Drugs, 8th edn. [in Russian], Moscow (1978), Pt. i, p. 591. 3. L. Fieser and M. Fieser, Steroids, Van Nostrand Reinhold (1959). 4. K. Miescher and C. Scholz, Helv. Chim. Acta., 20, 263 (1937).

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