Medrogestone Chemical Properties

Melting point:

144-146°

alpha 

D23 +79° (c = 1 in chloroform)

Boiling point:

416.28°C (rough estimate)

Density 

1.0555 (rough estimate)

refractive index 

1.4480 (estimate)

Water Solubility 

1.82mg/L(25 ºC)

CAS DataBase Reference

977-79-7(CAS DataBase Reference)

Medrogestone Usage And Synthesis

Originator

Colpro,Ayerst,Italy,1970

Uses

Progestin.

Definition

ChEBI: Medrogestone is a corticosteroid hormone.

Manufacturing Process

The manufacturing process as described in US Patent 3,170,936 uses the readily available methyl 3β-hydroxy-17α-methyl-δ5-etienate (I), described by Plattner in Helv. Chim. Acta, vol. 31, p 603 (1948), as the starting material. The etienic acid ester (I) may also be called 17α-methyl-17βcarbomethoxyandrost-5-ene-3β-ol.
3β,5α,6β-Trihydroxy-17α-Methyl-17β-Carbomethoxyandrostane (II): 5 g of 17α-Methyl-17β-carbomethoxyandrost-5-ene-3β-ol (I) is dissolved in formic acid (50 ml) and heated on the steam bath for 10 minutes. The solution is cooled to room temperature and a crystalline solid precipitates. This is stirred, 30% hydrogen peroxide (5 ml) is added, and the reaction mixture is left at room temperature for 2 hours. The clear solution is poured into water 1300 ml) and the solid which precipitates is filtered.
It is dissolved in hot methanol and heated on the steam bath with 10% methanolic potassium hydroxide solution (15.8 ml) for 10 minutes. Then more potassium hydroxide solution (2 ml) is added, the solution is cooled and on dilution with water a solid (II), MP 245° to 255°C, is obtained. A second crop is obtained from the mother liquors. Several recrystallizations from acetone yield an analytical sample, MP 262° to 265°C, [α]D24 is -2.1°.
3β-Acetoxy-5α-Hydroxy-17α-Methyl-17β-Carbomethoxyandrostane-6-one (IIIb): 3β,5α,6βp-Trihydroxy-17α-methyl-17β-carbomethoxyandrostane (II, 5.2 g) is dissolved in methanol (105 ml) to which ether (105 ml) and water (84 ml) are added. Then N-bromosuccinimide (5.2 g) is added with stirring and the clear solution is left in the refrigerator for 3 hours. The ether is removed under reduced pressure at room temperature and a crystalline solid (IIIa) separates, MP 268° to 272°C.
The above substance is dissolved in pyridine (15 ml) and acetic anhydride (7.5 ml), and heated on the steam bath for ? hour. The product (IIIb) crystallizes from aqueous ethanol in leaflets, MP 237° to 239°C. An analytical sample has MP 241° to 243°C.
3β,5α,6β-Trihydroxy-6α,17α-Dimethyl-17β-Carbomethoxyandrostane (IV): 3βAcetoxy-5α-hydroxy-17α-methyl-17β-carbomethoxyandrostan-6-one (III, 1.004 g) is dissolved in dry benzene (25 ml) and methyl magnesium bromide solution in ether (3 M, 10 ml) is added. The reaction mixture is diluted with dry tetrahydrofuran (25 ml) and allowed to stand at room temperature for 20 hours, Excess Grignard reagent is quenched by adding a saturated solution of ammonium chloride. The organic layer is separated and the aqueous layer is extracted with ethyl acetate.
After washing the combined extracts with ammonium chloride solution and water and working up in the usual way a white solid (IV) is obtained which after one recrystallization from aqueous methanol has MP 242° to 243°C. The infrared spectrum of this compound indicates the presence of a carbomethoxy group (1,730 cm-1) and disappearance of the 6-keto group together with the presence of an ester group (1,727 cm-1). This substance is used without further purification for the next step.
3β,5α,6β-Trihydroxy-6α,17α-Dimethylpregnan-20-one (V): Crude 3β,5α,6βtrihydroxy-6α,17α-dimethyl-17β-carbomethoxyandrostane (IV, 773 mg) is dissolved in dry benzene (25 ml) and tetrahydrofuran (freshly distilled over lithium aluminum hydride, 25 ml). To the stirred solution under dry N2 there is added methyl magnesium bromide solution in ether (3 M, 10 ml) over a period of 10 minutes. Then the ether and tetrahydrofuran are almost all distilled and the resulting solution is refluxed for 3 hours (solid precipitates during the reaction). The reaction mixture is cooled and worked up in the same way as in the previous experiment leaving a white solid (V) with an infrared spectrum which indicates the presence of a 20-ketone group (1,690 cm-1), a sample of which is recrystallized to MP 238° to 240°C.
Analysis confirmed the empirical formula C23H38O4H2O: Required: C, 69.60%; H, 10.17%. Found: C, 69.90%; H, 10.15%.
Alternatively, 25.0 g of either 3β,5α-dihydroxy-17α-methy-17βcarbomethoxyandrostan-6-one (IIIa) or 25.0 g of its 3β-acetate (IIIb), are dissolved in dry tetrahydrofuran (1,250 ml, freshly distilled over lithium aluminum hydride) and dry benzene (2,000 ml) is added. Methyl magnesium bromide in ether solution (3 M, 750 ml) is added to the stirred solution and the resulting mixture is stirred at room temperature for 16 hours. An additional quantity of methyl magnesium bromide solution in ether (2 M, 375 ml) is added, and 1,250 ml of the solvent mixture are distilled off. The resulting mixture is refluxed for 5 hours and worked up as described above, yielding compound (V) as a colorless oil.
5α,6β-Dihydroxy-6α,17α-Dimethylpregnane-3,20-dione (VI): Crude 3β,5α,6βtrihydroxy-6α,17α-Dimethylpregnan-20-one (V, 650 mg) is dissolved in acetone (freshly distilled over potassium permanganate, 150 ml) and cooled in an ice-water bath with stirring. Then excess chromic acid solution (8 N) is added and stirring is continued at room temperature for 4 minutes. The reaction mixture is poured into water and extracted with ethyl acetate. The combined extracts are washed with dilute sodium bicarbonate solution and water and then dried over magnesium sulfate. Removal of the solvent leaves a white solid (VI). This crude product is used for the next step. Its IR spectrum shows a strong band at 1,705 cm-1. A sample is recrystallized to MP 243° to 245°C (dec.).
6,17α-Dimethyl-4,6-Pregnadiene-3,20-dione (VII): 5α,6β-Dihydroxy-6α,17αdimethylpregnane-3,20-dione (VI, 553 mg) is dissolved in absolute ethanol (60 ml) and two drops of concentrated hydrochloric acid are added. This solution is heated on a steam bath for 45 minutes, cooled, diluted with water and extracted with ether. The combined extracts are washed with dilute sodium bicarbonate solution and water and subsequently dried over magnesium sulfate. After the solvent has been removed a syrup remains and the UV spectrum of this substance indicates the presence of a δ4,6- ketone.Elution of this material over alumina (Woelm, Grade III, 25 g) with 1:1 hexane-benzene gives a crystalline substance, MP 138° to 141°C which, after one recrystallization from ether, has an infrared spectrum identical to that of an authentic sample of 6,17α-dimethyl-4,6-pregnadiene-3,20-dione (VII).

Therapeutic Function

Progestin

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