Melengestrol (

INN Inns are generally establishments or buildings where travelers can seek lodging, and usually, food and drink. Inns are typically located in the country or along a highway; before the advent of motorized transportation they also provided accommo ...

, BAN) is a

steroid A steroid is a biologically active organic compound with four rings arranged in a specific molecular configuration. Steroids have two principal biological functions: as important components of cell membranes that alter membrane fluidity; and a ...

progestin A progestogen, also referred to as a progestagen, gestagen, or gestogen, is a type of medication which produces effects similar to those of the natural product, natural female sex hormone progesterone in the body. A progestin is a ''synthetic co ...

of the

17α-hydroxyprogesterone 17α-Hydroxyprogesterone (17α-OHP), also known as 17-OH progesterone (17-OHP), or hydroxyprogesterone (OHP), is an endogenous progestogen steroid hormone related to progesterone. It is also a chemical intermediate in the biosynthesis of many ot ...

group and an antineoplastic

drug A drug is any chemical substance that causes a change in an organism's physiology or psychology when consumed. Drugs are typically distinguished from food and substances that provide nutritional support. Consumption of drugs can be via insuffla ...

which was never marketed. An acylated derivative,

melengestrol acetate Melengestrol acetate (MLGA), sold under the brand names Heifermax and MGA among others, is a progestin medication which is used in animal reproduction. It is not approved for use in humans, and is instead used as an implantable contraceptive ...

, is used as a growth promoter in animals. While ''melengestrol'' is sometimes used as a synonym for ''melengestrol acetate'', what is usually being referred to is melengestrol acetate and not melengestrol.

Synthesis

6-Methyl-16-dehydropregnenolone acetate (5) is the key intermediate to the preparation of both melengesterol acetate and

medrogestone Medrogestone, sold under the brand name Colprone among others, is a progestin medication which has been used in menopausal hormone therapy and in the treatment of gynecological disorders. It is available both alone and in combination with an est ...

. Petrov and his collaborators have devised several interesting schemes that go back to diosgenin 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 cyclopropyl carbinyl ion (

carbenium ion A carbenium ion is a positive ion with the structure RR′R″C+, that is, a chemical species with a trivalent carbon that bears a +1 formal charge. In older literature the name carbonium ion was used for this class, but now it refers exclusivel ...

) (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 of

PCC PCC may refer to: Science and technology * Pearson correlation coefficient (''r''), in statistics * Periodic counter-current chromatography, a type of affinity chromatography * Portable C Compiler, an early compiler for the C programming language ...

affords the ketone. Reaction of this with

methylmagnesium iodide Methylmagnesium chloride is an organometallic compound with the general formula CH3MgCl. This highly flammable, colorless, and moisture sensitive material is the simplest Grignard reagent and is commercially available, usually as a solution in tet ...

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). Melengesterol synthesis

Substitution at the 16 position was found to lead to further potentiation of progestational activity. Reaction with

diazomethane Diazomethane is the chemical compound CH2N2, discovered by German chemist Hans von Pechmann in 1894. It is the simplest diazo compound. In the pure form at room temperature, it is an extremely sensitive explosive yellow gas; thus, it is almost u ...

at the conjugated double bond at 16 gives first the

pyrazole Pyrazole is an organic compound with the formula C3H3N2H. It is a heterocycle characterized by a 5-membered ring of three carbon atoms and two adjacent nitrogen atoms, which are in ortho-substitution. Pyrazole is a weak base, with p''K''b 11.5 ( ...

(6). This heterocycle affords the 16 methyl enone on

pyrolysis The pyrolysis (or devolatilization) process is the thermal decomposition of materials at elevated temperatures, often in an inert atmosphere. It involves a change of chemical composition. The word is coined from the Greek-derived elements ''py ...

(7). Selective

epoxidation In organic chemistry, an epoxide is a cyclic ether () with a three-atom ring. This ring approximates an equilateral triangle, which makes it strained, and hence highly reactive, more so than other ethers. They are produced on a large scale for ...

of the conjugated double bond to the 16,17α-epoxide over that at 5,6 is achieved by oxidation with basic

hydrogen peroxide Hydrogen peroxide is a chemical compound with the formula . In its pure form, it is a very pale blue liquid that is slightly more viscous than water. It is used as an oxidizer, bleaching agent, and antiseptic, usually as a dilute solution (3%� ...

(8). Opening of this tetrasubstituted

oxirane Ethylene oxide is an organic compound with the formula . It is a cyclic ether and the simplest epoxide: a three-membered ring consisting of one oxygen atom and two carbon atoms. Ethylene oxide is a colorless and flammable gas with a faintly swe ...

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 an

Oppenauer oxidation Oppenauer oxidation, named after , is a gentle method for selectively oxidizing secondary alcohols to ketones. The reaction is the opposite Meerwein–Ponndorf–Verley reduction. The alcohol is oxidized with aluminium isopropoxide in excess ...

, which is then dehydrogenated to the 4,6-diene with

chloranil Chloranil is a quinone with the molecular formula C6Cl4O2. Also known as tetrachloro-1,4-benzoquinone, it is a yellow solid. Like the parent benzoquinone, chloranil is a planar molecule J.-M. Lü, S. V. Rosokha, I. S. Neretin and J. K. Kochi, "Qui ...

(11). Acetylation under forcing conditions completes the synthesis of melengesterol acetate.

References

Acetate esters Antineoplastic drugs Pregnanes Progestogens Vinylidene compounds {{steroid-stub

Synthesis

See also

References