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| ECHA InfoCard | 100.024.613 |
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| Formula | C23H30O3 |
| Molar mass | 354.490 g·mol−1 |
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Melengestrol (INN,BAN) is asteroidalprogestin of the17α-hydroxyprogesterone group and anantineoplasticdrug which was never marketed.[1] Anacylated derivative,melengestrol acetate, is used as agrowth promoter in animals.[1]
Whilemelengestrol is sometimes used as a synonym formelengestrol acetate, what is usually being referred to is melengestrol acetate and not melengestrol.
6-Methyl-16-dehydropregnenolone acetate (5) is the key intermediate to the preparation of both melengesterol acetate andmedrogestone. Petrov and his collaborators have devised several interesting schemes that go back todiosgenin as the starting point. These schemes perform the necessary modifications in rings A and B with the sapogenin side chain still in place. In essence this approach employs this side chain as a protecting group for the future 16-dehydro-20-ketone function. In one of these routes, diosgenin is first converted to the 3-toluenesulfonate (1). Solvolysis of this homoallylic alcohol derivative affords the 3,5-cyclosteroid (2), via the cyclopropylcarbinyl ion (carbenium ion) (not shown). (This general reaction was probably first found in the steroids and bore the name of "i-steroid rearrangement.") Oxidation of the product by means ofPCC affords the ketone. Reaction of this withmethylmagnesium iodide affords two isomeric carbinols with the α-isomer predominating (3). Solvolysis in the presence of a nucleophile such as acetic acid reverses the cyclopropylcarbinyl transformation to afford homoallylic acetate. Removal of the sapogenin side chain leads to the desired product (5).[2]
Substitution at the 16 position was found to lead to further potentiation of progestational activity. Reaction withdiazomethane at the conjugated double bond at 16 gives first thepyrazole (6). This heterocycle affords the 16 methylenone onpyrolysis (7). Selectiveepoxidation of the conjugated double bond to the 16,17α-epoxide over that at 5,6 is achieved by oxidation with basichydrogen peroxide (8). Opening of this tetrasubstitutedoxirane ring in acid proceeds with loss of a proton from the β position (16 methyl) (9) to afford the desired 16-methylene-17α-hydroxy-20-ketone functionality in the D ring (10). The product is saponified and then the subject of anOppenauer oxidation, which is then dehydrogenated to the 4,6-diene withchloranil (11). Acetylation under forcing conditions completes the synthesis of melengesterol acetate.
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