demegestone Chemical Properties

Melting point:

106°

alpha 

D -275° (c = 0.5 in ethanol)

demegestone Usage And Synthesis

Originator

Lutionex,Roussel,France,1974

Definition

ChEBI: Demegestone is a 20-oxo steroid.

Manufacturing Process

Step A: Preparation of 3-methoxy-17α-methyl-19-nor-?1,3,5(10)-pregnatriene20-one - Under agitation and an inert atmosphere, 1.150 grams of lithium were introduced into one liter of ammonia cooled to a temperature of -70°C. For 15 minutes this reaction mixture was agitated, then, while maintaining the temperature at about -75°C, one liter of ether were added thereto, followed by 20 grams of 3-methoxy-19-nor-?1,3,5(10),16-pregnatetraene20-one. The mixture was allowed to stand for 2 hours at a temperature of -75°C under continued agitation and under continued inert atmosphere. Next, 160 cc of methyl iodide were added and the reaction mixture was again agitated for 2 hours at -75°C.
Thereafter, the ammonia was evaporated, 1 liter of water was added thereto and the aqueous phase was separated and extracted with ether. The ethereal phases now combined were washed with water until the wash waters were neutral, then dried over sodium sulfate, filtered and distilled to dryness to obtain 21 grams of product, which was dissolved in 210 cc of ethanol under reflux. Next, 21 cc of acetic acid and 21 grams of Girard's reactant T were added thereto. The mixture was agitated for 1? hours under an atmosphere of nitrogen while maintaining the reflux. Thereafter, the reaction mixture was cooled to room temperature and then poured into 1,050 cc of water. Next, 155 cc of 2 N sodium hydroxide solution were added and finally the mixture was extracted with ether.
The combined ethereal phases were washed with water until the wash waters were neutral, dried over sodium sulfate, filtered and evaporated to dryness to obtain 16.80 grams of raw product which was purified by redissolving the product obtained in acetone under reflux and by recrystallization by heating and cooling.
13.185 grams of 3-methoxy-17α-methyl-19-nor-?1,3,5(10)-pregnatriene-20-one were thus obtained in the form of a colorless, solid product. The product was easily soluble in ether, soluble in alcohol, benzene and chloroform and insoluble in water. This product had a melting point of 109°C and a specific rotation of [α]D20 = +75°+/-1° (c = 0.5% in chloroform). The starting compound, 3-methoxy-19-nor-?1,3,5(10),16-pregnatetraene-20-one, was obtained according to the process described by Burn, J. Chem. SOC.1962, page 364.
13.185 grams of 3-methoxy-17α-methyl-19-nor-?1,3,5(10)-pregnatriene-20-one were thus obtained in the form of a colorless, solid product. The product was easily soluble in ether, soluble in alcohol, benzene and chloroform and insoluble in water. This product had a melting point of 109°C and a specific rotation of [α]D20 = +75°+/-1° (c = 0.5% in chloroform). The starting compound, 3-methoxy-19-nor-?1,3,5(10),16-pregnatetraene-20-one, was obtained according to the process described by Burn, J. Chem. SOC.1962, page 364.
The aqueous phase was discarded and the combined ethereal phases were washed with water, dried over sodium sulfate, filtered and distilled to dryness, to obtain 20.240 grams of 3-methoxy-17α-methyl-19-nor-?2,5(10)- pregnadiene-20-ol,which product was utilized as such for the next step. The compound occurred in the form of an amorphous product which was soluble in alcohol, ether, benzene and acetone and insoluble in water.
washed with water, dried over sodium sulfate, filtered and distilled to dryness, to obtain 20.240 grams of 3-methoxy-17α-methyl-19-nor-?2,5(10)- pregnadiene-20-ol,which product was utilized as such for the next step. The compound occurred in the form of an amorphous product which was soluble in alcohol, ether, benzene and acetone and insoluble in water.
Step D: Preparation of 17α-methyl-19-nor-?5(10)-pregnene-3,20-dione - 20.5 grams of the compound prepared in Step C were dissolved in 615 cc of acetone under an atmosphere of nitrogen and under agitation. The solution obtained was cooled to -20°C. Next 21 cc of a solution of 54 grams of chromic acid anhydride and 46 cc of dilute sulfuric acid were added thereto. The solution was allowed to stand for 1 hour under agitation at about -10°C. It was then poured into 2 liters of a mixture of ice and water and extracted with benzene. The combined organic phases were washed first with water, then with a saturated solution of sodium bicarbonate and again with water. Next these phases were dried over magnesium sulfate and distilled to dryness.
20.40 grams of crude product were thus obtained, which was purified by subjecting it to chromatography through magnesium silicate and elution with benzene containing 2.5% of acetone, and recrystallization from isopropyl ether to obtain 8.50 grams of 17α-methyl-19-nor-?5(10)-pregnene-3,20-dione in the form of a colorless crystallized product. This product was soluble in alcohol, ether, acetone, benzene and chloroform and insoluble in water. This product had a melting point of 138°C, and a specific rotation of [α]D20 = +168.5°+/-3.5° (c= 0.50% in chloroform).
Step E: Preparation of 17α-methyl-19-nor-?4,9-pregnadiene-3,20-dione - Under agitation and an atmosphere of nitrogen, 8.50 grams of the compound prepared in Step D were dissolved in 85 cc of pyridine and cooled to 0C. Next, 16.3 cc of a 29% bromine solution in methanol were added thereto. The agitation was continued for 30 minutes at the temperature of 0°C. Thereafter the temperature was raised to room temperature and the solution was allowed to stand for 16 hours under agitation. The solution was then poured into 850 cc of a mixture of ice and water and after 82 cc of hydrochloric acid were added, the mixture was extracted with methylene chloride. The combined organic phases were washed with water until the wash waters were neutral, then dried over magnesium sulfate and finally distilled to dryness to obtain 8.480 grams of a crude product which was purified by recrystallization from isopropyl ether. In this manner, 5.810 grams of 17α-methyl-19-nor-?4,9- pregnadiene-3,20-dione having a melting point of 106°C and a specific rotation [α]D20 = -270+/-4.5° (c = 0.5% in ethanol) were obtained.

Therapeutic Function

Progestin

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