CS219765B1 - 3-methoxy-17-methylene-14beta-trimethylsilyloxy-8alpha,9alpha-1,3,5-/10/estratrien and method of making the same - Google Patents

Description

The invention relates to 3-methoxy-17-methylene-14/5-trimethylsilyloxy-8a, 9a-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 the lactone ring at the 17β position (see, for example, V. Černý et al., Chemistry of Steroid Compounds, Nakladatelství ČSAV, Praha 1960, p. 909 - 1110 is cardiotonically active steroids in which the lactone ring is replaced by an acyclic system containing a double bond and an ester or nitrile group and other derivatives such as guanylhydrazones, etc. (R. Thomas et al. J. Pharm. Sci. 63, 1649/1974) The compounds to which the invention relates are thus of great interest as precursors of highly active cardiotonic steroids, such as the cyclotransmitted 17-chain side chain cardiotonics (T. Godfraind, Récepteurs digitaliques, Pharmacologie moléculaire, Y. Cohen dir. , Masson, Paris, 1978, p. 167 et seq.] And themselves exhibit the biological activity shown by t assay for inhibition of Na K phosphatase (Repre K. Portius, J. H., Experientia 19 452). These substances allow for a fully synthetic approach to important drugs, which have so far been prepared solely by costly isolation

Even from natural material, such as foxglove (Digitalisj) or fur toad (Bufo), where they are contained only in very small quantities, this makes their preparation even more complicated.

On the other hand, in addition to the ease of preparation and the possibility of fully synthetic preparation, the independence of the natural sources of steroid substances is important for the compounds of the invention.

The present invention provides the compound 3-methoxy-17-methylene-14/3-trimethylsilyloxy-8α, 9α-1,3,5 (10) -estratriene of formula I

The compound is prepared by reacting the 14-hydroxy derivative of the Formula II

with a mixture of silylating agents trimethylsilylimidazole, bis- (trimethylsilyl) acetamide and trimethylsilyl chloride in a volume ratio of 1: 1: 1 to 5: 5: 1 in an organic solvent, preferably dimethylformamide, at 20 to 80 ° C for 2 to 24 hours and after purification of the intermediate, it is treated with a Wittig reagent prepared from triphenylmethylphosphonium iodide by treatment with a base, dimethylsulfoxide sodium salt generated in situ from sodium hydride and dimethylsulfoxide at 50 to 110 ° C for 1 to 35 hours.

The following are examples of processes for the preparation of novel compounds, including intermediates of the invention.

Example 1

To a solution of 2 g (6.6 mol) of 14/3-hydroxy-3-methoxy-8α, 9or-1,3,5 (10'-estratrien-17-one in dimethylformamide (20 ml) was added trimethylsilylimidazole (6 ml) Bis (trimethylsilyl) acetamide (6 mL) and trimethylchlorosilane (4 mL) was stirred at 65 ° C for 7 hours, then water (100 mL) was added to the reaction mixture, and the mixture was extracted with ether (3 X 50 mL). The ether extracts were dried (MgSO 4) and evaporated to give 1.96 g (83%) of 3-methoxy-14 ', 3'-trimethylsilyloxy-8a, 9o-1; 147-150 [deg.] C. and mass spectrum (m / z): 372 (M < + >), 282 (M-HOSi / CH3 / 3).

Sodium hydride (1.28 g, 50% suspension in oil) was washed with petroleum ether and treated with dimethylsulfoxide (100 mL) and heated at 65 ° C for 1 hour under argon. Then triphenylmethylphosphonium iodide (9.02 g) was added to the solution at room temperature and the mixture was stirred for 30 minutes. To the thus prepared mixture was added 3-methoxy-14/3-trimethylsilyloxy-8a, 9a-1,3,5 (10) -estratrien-17-one (1.96 g), as described above, and the mixture was further stirred at 65 ° C. ° C, for 20 hours. The reaction mixture was then treated with a solution of amine chloride in water and extracted with ether. The extracts were dried over magnesium sulfate and, after concentration, chromatographed on a silica gel column with petroleum ether. 1.34 g (68.8%) of 3-methoxy-17-methylene-14 / S-trimethylsilyloxy-8a, 9a-1,3,5 (10) -estratrlene of melting point 75-77 ° C were obtained. Mass spectrum (m / z): 370 (M < + &gt;), 280 [M-HOSi (CH3)]. @ 1 H-NMR spectrum (CDCl3): 0.94 s (3H, CH3), 3.60 s (3H, OCH3), 4.63 br (2M, .dbd.CH3), 6.47-7, 05 m (3M, aromatic protons).

For C 23 H 31 O 2 Si (370.59) calculated: 74.54% C, 9.25% M, 7.58% Si, found: 74.73% C, 9.25% M.

Example 2

To a solution of 2 g (6.6 mL) of 14/5-hydroxy-3-methoxy-8of, 9a-1,3,5 (10) -estratrien-17-one in dimethylformamide was added trimethylsilylimidazole (5 mL), bis- (trimethylsilyl) acetamide (5 mL) and trimethylchlorosilane (5 mL) and the mixture was stirred at 80 ° C for 2.5 hours. Next, the reaction mixture was worked up in the same manner as in Example 1, with the same result.

Example 3

To a solution of 2 g (6.6 mol) of 14β-hydroxy-3-methoxy-8α, 9α-1,3,5 (10) -estratrien-17-one in dimethylformamide was added trimethylsilylimidazole (5 mL), bis- (trimethylsilyl) acetamide (5 mL) and trimethylchlorosilane (1 mL) and the mixture was left at room temperature for 24 hours, and the reaction mixture was worked up as in Example 1, except that in the second part after addition of 3-methoxy-14 [3-Trimethylsilyloxy-8α, 9α-1,3,5 (10β-estratrien-17-one) (1.96 g) was heated at 100 ° C for 2.5 h. in Example 1 with the same result.

Claims (2)

come on 1. 3-Methoxy-17-methylene-14/3-trimethylsilyloxy-8, 9a-1,3,5 (10) -estratriene of formula I 2. A process for preparing 3-methoxy-17-methylene-14/3 ^L -trimethylsilyloxy-8a, 9a-l, 3,5 (10j--estratriene formula I according to claim 1, wherein reacting the 14-hydroxy derivative of formula II τ of the invention with a mixture of silylating agents trimethylsilylimidazole, bis- (trimethylsilyl) acetamide and trimethylsilyl chloride in a volume ratio of 1: 1: 1 to 5: 5: 1 in an organic solvent, preferably dimethylformamide, at a temperature of 20 to 80 ° C for 2 to 24 hours and after purification of the intermediate, it is treated with a Wittig reagent prepared from triphenylmethylphosphonium iodide by treatment with a base, dimethylsulfoxide sodium salt generated in situ from sodium hydride and dimethylsulfoxide at 50-110 ° C for 1-35 hours.