A 19-nortestosterone

A study of the lithium-ammonia reduction of 14-en-16-ones would extend our understanding of the configuration favored at C-14 in metal-ammonia reductions. Although several simple 14-en-16-ones are known, their reduction by lithium and ammonia apparently has not been described in the literature. Lithium-ammonia reduction of A-nortestosterone, a compound that structurally is somewhat analogous to a 14-en-16-one, affords roughly equal amounts of the 5a- and 5 -dihydro-A-nortestosterones. " This finding was interpreted as indicating that there is little difference in thermodynamic stability between the two stereoisomeric products. 

Dihydro-A-nortestosterone, 35 Dihydropyridylaluminum hydride, 75 3 a, 6a-Dihydroxy-5 /3-androstan-17-one, 415 3 a,6o -Dihydroxy-5j8-androstan- 17-one dinitrate, 415... 

A -Nortestosterone (N-95), 17a-methyl-A -nortestosterone (N-96) subcutaneously, and 17a-ethyl-A -nortestosterone (N-97) all exhibit greatly decreased androgenic activities while the anabolic activities are increased. I7a-Methyl-A -nortestosterone (N-96) orally shows increased androgenic and anabolic activities. The anabolic-androgenic ratio is very favorable in all cases. 

Total synthetic studies at Roussel-UCLAF produced a large number of compounds having this type of extended unsaturation. A ,A"-Nortes-tosterone 17-acetate (N-103), A, A -nortestosterone 17/3-methoxymethyl ether (N-104), A ,A -nortestosterone 17/3-decanoate (N-105), A A -nortestosterone 17-carbobenzoxy-ate (N-106), A ,A"-17a-methyl-... 

Chemical Analysis. Chemically, the various progestogens belong to one of three classes. Estranes are 19-nortestosterone derivatives (Fig. 1) gonanes are 19-nortestosterone derivatives with a C-13 ethyl group (Fig. 2) and pregnanes are 17-alpha-OH progesterone derivatives similar in stmcture to progesterone itself. 

Lithium-ammonia reduction of l7a-ethyl-19-nortestosterone (68) using Procedure 8a (section V) affords the 4,5a-dihydro compound (69) in 85% yield after a reaction time of 12 minutes after a reaction time of 80 minutes, the yield of (69) is 76%. Lfsing sodium in the same reduction, the yields of compound (69) are 79 and 77 % after reaction times of 8 and 80 minutes respectively. Both the lithium and sodium enolates appear to be reasonably stable in liquid ammonia in the presence of alkali metal. Since the enolate salts are poorly soluble in ammonia, their resistance to protonation by it may be due in part to this factor. 

Toluene is a useful co-solvent in metal-ammonia reductions as first reported by Chapman and his colleagues. The author has found that a toluene-tetrahydrofuran-ammonia mixture (1 1 2) is a particularly useful medium for various metal-ammonia reductions. Procedure 8a (section V) describes the reduction of 17-ethyl-19-nortestosterone in such a system. Ethylene dibromide is used to quench excess lithium. Trituration of the total crude reduction product with methanol affords an 85% yield of 4,5a-dihydro-17-ethyl-19-nortestosterone, mp 207-213° (after sintering at 198°), reported mp 212-213°. For the same reduction using Procedure 5 (section V), Bowers et al obtained a 60% yield of crude product, mp, 196-199°, after column chromatography of the total reduction product. A similar reduction of 17-ethynyl-19-nortestosterone is described in Procedure 8b (section V). The steroid concentration in the toluene-tetrahydrofuran-ammonia system is 0.05 M whereas in the ether-dioxane-ammonia system it is 0.029 M. 

For the reduction of conjugated enones to saturated alcohols, Procedure 5 (section V) may be modified by adding methanol in place of ammonium chloride a sufficient excess of lithium is present to effect reduction of the intermediate saturated ketone to the alcohol. Procedure 2 (section V) for effecting Birch reductions is also useful for reduction of conjugated enones to saturated alcohols. Thus, 17-ethyl-19-nortestosterone affords crude 17a-ethyl-5a-estrane-3) ,17) -diol of mp 174-181°, reported mp 181-183°, in quantitative yield. 

A solution of 17a-ethynyl-19-nortestosterone (15 g, 0.05 mole) in dioxane-ether (1 1, 250 ml) is added rapidly to a well stirred solution of lithium (2.25 g, 0.325 g-atom) in liquid ammonia (1.5 liter). Ammonium chloride... 

Although methylation of 3-keto-A -steroids generally leads to 4,4-dimethyl derivatives,Atwater has reported a practicable4-monoaikylation procedure. Thus 4-methyl- (44%), 4-vinyl- (46%), 4- -butyltestosterone (62%) and 4-methyl-19-nortestosterone (50%) are obtained when the alkyl halide is added dropwise with stirring to a refluxing basic solution of testosterone or 19-nortestosterone over a period of 2.5 hours. A" -3-Keto steroids are not methylated under these conditions. 

The Roussel group has described recently a novel method for the synthesis of 2,2-dimethyl-A" -3-keto steroids. Thus addition of potassium t-butoxide to a solution of 19-nortestosterone (25) in tetrahydrofuran containing methyl iodide and hexamethylphosphorous triamide at —70° affords the 2,2-dimethyl compound (26) in good yield.Methylation of A" -3-ketone by the classical conditions, namely addition of methyl iodide to a solution of the steroid and potassium /-butoxide, leads to the 4,4-dimethyl product. 

With 2537 k-Light. 1 g (140) in 140 ml anhydrous dioxane is irradiated for 20 hr at room temperature with a Hanau NK 6/20 low-pressure mercury lamp placed in a central water-cooled quartz finger. 0.19 g of (141) crystallize from the crude reaction mixture as described above. Chromatography of the residual material on silica gel with benzene-ethyl acetate (4 1) gives 0.29 g of B-nortestosterone acetate [(142) 28.5 %] and starting material (140). 

The A -double bond can also be introduced in saturated A-nor-2-ketones by bromination-dehydrobromination. This has been used in an alternate preparation of A-norprogesterone" and in a recent synthesis of A-nor-19-nortestosterone. ... 

N-metbylmorpboline oxide-bydrogen peroxide, 184, 221, 223 4-Metbyl-19-nortestosterone, 89 16 -Metby 1-16a, 17 a-oxidopregn-4-ene-... 

Norsteroids via 19-nitriles, 268 A-N ortestosterone, 410 B-nortestosterone, 430 D-nortestosterone, 441 19-Nortestosterone, 282, 321 B-nortestosterone acetate, 324, 329... 

A. Farjam, G. J. de Jong, R. W. Frei, U. A. Th Brinkman, W., Haasnoot, A. R. M. Hamers, R. Schilt and F. A. Huf, Immunoaffinity pre-column for selective on-line sample pre-tr eatment in liigh-perfor mance liquid cliromatogr aphy determination of 19-nortestosterone , J. Chromatogr. 452 419-433 (1988). 

Then the solution is dried on sodium sulfate, filtered, and evaporated to dryness. The residue, 1.63 grams is dissolved in hexane, this solution is filtered over 30 grams of neutral aluminum oxide, and evaporated to dryness. On paper chromatographic investigation it turned out that the obtained 19-nortestosterone 17-decanoate which at room temperature is an oil consists of a single compound, according to U.S. Patent 2,998,423. 

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