CS225014B1 - The 17ks-hydroxymethyl-3-methoxy-14beta-trimethylsilyloxy-8-alpha,9-alpha-1,3,5/10/estratriene and its preparation - Google Patents

Description

(54) 17ksi-Hydroxymethyl-3-methoxy-14beta-trimethylsilyloxy-8alpha, 9alpha-1,3,5 (10) estratriene and a process for its preparation

The present invention relates to 17α-hydroxymethyl-3-methoxy-14β-trimethylsilyloxy-8α, 9α-1,3,5 (10) -estratriene and a process for its preparation.

Substances of this type serve to synthesize a number of important biologically active compounds having cardiotonic activity, such as classical cardiotonics with a lactone ring at the 17-beta position (see, for example, V. Černý et al. Chemistry of Steroid Compounds, Nakladatelství ČSAV, Praha 1960, pp. 909- Cardio-active steroids in which the lactone ring is replaced by an acyclic system containing a double bond and an ester or nitrile group, as well as other derivatives such as guanylhydrazones, etc., or a heterocyclic nucleus (R. Thomas et al. J. Pharm. Sci. 63. 1649 (1974)).

The substance of the invention is of great interest as a precursor of highly active cardiotonic steroids, such as a cyclic 17-beta side chain cardiotonic (T. Godfraind, Récepteurs digitaliques, Pharmacologie moléculaire, Y. Cohen dir. Masson, Paris, 1978, 167 et al.), providing fully synthetic access to major drugs such as (20 E) -3-methoxy-21-alkoxycarbonyl-19-nor-14beta-trimethylsilyloxy-8alpha, 9alpha, 17ksi-1,3,5 - (10), 20-pregnatetraen (author's certificate No 225 013), which have so far been prepared solely by costly insulation from natural material, such as foxglove (Digitalis) or toad skin (Bufo), where they are contained only in very small quantities , which makes their preparation even more complicated.

In contrast, in the type of substances according to the invention, in addition to the ease of preparation and the possibility of fully synthetic preparation, independence from the natural sources of steroid substances is important.

The present invention provides 17-ksi-hydroxymethyl-3-methoxy-14beta-trimethylsilyloxy-8alpha, 9alpha-1,3,5- (1C) estratriene compound of formula I

in an organic solvent, preferably ether, at a temperature of -20 to 0 ° C and in the presence of boron trifluoride etherate with lithium aluminum hydride in a weight ratio of 1: 2 to 10 for 30 minutes to 4 hours and then at room temperature for a further half to 3 hours. Dissolve in an organic solvent, preferably tetrahydrofuran, and then treat the mixture with an alkali metal hydroxide and hydrogen peroxide in a weight ratio of 1: 1 to 4 in water at a temperature of -5 to +25 ° C for 15 to 100 minutes.

The following are examples of the process of the novel compound of the invention.

He did.

To a solution of 3-methoxy-17-methylene-14beta-trimethylsilyloxy-8alpha, 9alpha-1,3,5- (1 Oestratriene (100mg) and boron trifluoride etherate (0.5ml) in ether (3ml) cooled to -15 ° Lithium aluminum hydride (100 mg) in 4 mL of ether was added C. The mixture was stirred at -15 ° C for 1.5 hours and then for 30 minutes at room temperature, then a saturated sodium sulfate solution was added to the mixture, then diluted with water and extracted The extracts were dried over magnesium sulfate and evaporated.

The residue was dissolved in tetrahydrofuran (3 mL) and aqueous potassium hydroxide solution (10% solution, 2.5 mL) and 30% aqueous hydrogen peroxide solution (1.5 mL) were added to the mixture while cooling to 0 ° C. The mixture was stirred at this temperature for 30 minutes. It was then diluted with water and extracted with ether. The extract was dried over magnesium sulfate and evaporated. 90 mg of 17-ksi-hydroxymethyl-1,3-methoxy-14beta-trimethylsilyloxy-8alpha, 9alpha-1,3,5- (10) estratriene were obtained as an oil. 1 H-NMR spectrum (tetrachloride, external. Lock. Ppm., Δ scale):

6.2 to 6.9 m (3H, protons nuclei A), 3.57 s (3H, C H O), 0.84 s (3H, C ₍₃₎ -CH _3), 0.05 s (9H, -Si (CH3) _3). Mass spectrum (m / z): 388 (tI), 298 (M-H ₂ Si (CH ₃ ) ₃ ). For ^C 23 ^H 36 ° 3 ^Si (388.6) calculated: 71.08% C, 9.34% H and 7.23% Si, found 71.27% C, 9.56% H.

Example 2

The preparation was carried out as in Example 1 except that lithium aluminum hydride was added at -20 ° C and the mixture was stirred for 3 hours at -20 ° C.

Example 3

Preparation byle. as in Example 1, except that in the second part of the preparation, after dissolving the pre-purified intermediate in tetrahydrofuran, an aqueous solution of sodium hydroxide (10% solution, 3 ml) and a 30% aqueous solution of hydrogen peroxide ( 1.5 ml) with cooling to + 8.5 ° C, at which temperature the reaction mixture was stirred for 15 minutes.

Claims (2)

SUBJECT OF THE INVENTION. 1. 17-ksi-Hydroxymethyl-3-methoxy-14beta-trimethylsilyloxy-8alpha, 9alpha-1,3,5 (10) estratriene of formula I (I) 2. A process for the preparation of 17ksi-hydroxymethyl-3-niethoxy-14beta-trimethylsilyloxy-8alpha, 9alpha-1,3,5 (10) estratriene of formula I according to item 1, characterized in that the 17-methylenderivative of formula II is reacted in an organic solvent , preferably ether, at a temperature of -20 to 0 ° C and in the presence of boron trifluoride etherate with lithium aluminum hydride in a weight ratio of 1: 2 to 10 for 30 minutes to 4 hours and then at room temperature. hours, after which the intermediate is dissolved in an organic solvent, preferably tetrahydrofuran, and then the mixture is treated with an alkali metal hydroxide and hydrogen peroxide in a weight ratio of 1: 1 to 4 in water at a temperature of -5 to +25 ° C for 15 hours. and 100 minutes.