cortivazol

Originator

Diaster,Diamant,France,1972

Uses

Glucocorticoid.

Definition

ChEBI: Cortivazol is a steroid. It derives from a hydride of a pregnane.

Manufacturing Process

To a suspension of 25.0 g of 11β,17α,21-trihydroxy-6,16α-dimethyl-4,6- pregnadiene-3,20-dione in 1.5 liters of alcohol-free chloroform cooled to about 5°C in an ice bath is added with constant stirring 750 ml of cold, concentrated hydrochloric acid and then 750 ml of formalin (low in methanol). The mixture is removed from the ice bath and stirred at room temperature for 7 hours.
The layers are separated and the aqueous phase is back-extracted twice with chloroform. The combined organic layers are washed twice with a 5% solution of sodium bicarbonate, and twice with a saturated salt solution. The solution is dried over magnesium sulfate and evaporated to dryness under reduced pressure.The layers are separated and the aqueous phase is back-extracted twice with chloroform. The combined organic layers are washed twice with a 5% solution of sodium bicarbonate, and twice with a saturated salt solution. The solution is dried over magnesium sulfate and evaporated to dryness under reduced pressure.
The residue is triturated with methanol to afford a crystalline solid. This material contains no detectable amount of starting material by paperstrip chromatography but shows two UV absorbing spots near the solvent front (methanol-formamide 2:1 vs benzene-n-hexane 1:1). An aliquot is recrystallized three times from a mixture of benzene and n-hexane to give 17α,20,20,21-bis(methylenedioxy)-11β-hydroxy-6,16α-dimethyl-4,6- pregnadiene-3-one which is used in the subsequent step of the synthesis without further purification. 17α,20,20,21-bis(methylenedioxy)-11β-hydroxy-6,16α-dimethyl-4,6- pregnadiene-3-one (500 mg) is dissolved in 25 cc of benzene and then about 5 cc of benzene is removed by distillation at normal pressure. The resulting solution is cooled to room temperature. Then 0.75 cc of freshly distilled ethyl formate is added. The air in the system is replaced with nitrogen and 150 mg of sodium hydride (as a 57% dispersion in mineral oil) is added. The mixture is stirred under nitrogen at room temperature for three hours. Then 15 cc of a saturated aqueous solution of sodium dihydrogen phosphate is added and the product is extracted into ether
. The ether extracts are extracted with 2 N sodium hydroxide and the sodium hydroxide extracts are acidified with sodium dihydrogen phosphate and extracted again into ether. The ether extract is evaporated to dryness to give about 500 mg of a crude product. From the ether solution there is obtained about 290 mg of yellow crystals, MP 220° to 236°C which is 17α,20,20,21- bis(methylenedioxy)-11β-formyloxy-2-hydroxy-methylene-6,16α-dimethyl-4,6- pregnadiene-3-one. The analytical sample is recrystallized from ethyl acetate and has a melting point of 249° to 255°C, [α]D27 -217°, I R 5.81 and 8.37 μm. From the mother liquor is obtained about 127 mg of 17α,20,20-21- bis(methylenedioxy)-11β-hydroxy-2-hydroxymethylene-6,16α-dimethyl-4,6- pregnadiene-3-one. The analytical sample is recrystallized from ether and has a melting point of 200° to 204°C, [α]D27 -197°, IR 6.05 to 6.2 and 6.4 μ. The 17α,20,20,21-bis(methylenedioxy)-11β-hydroxy-2-hydroxymethylene- 6,16α-dimethyl-4,6-pregnadiene-3-one (1.19 g) is dissolved in 25 cc of ethanol. 300 mg of phenyl hydrazine is added and the mixture is refluxed under nitrogen for one hour. About 25 cc of water is added. The product is then extracted into 150 cc of ether. The extracts are washed with 2N HCl, with saturated sodium bicarbonate, water and saturated sodium chloride solution, and then dried over sodium sulfate and evaporated to dryness to give about 1.2 g of crude product. On crystallization from ether there is obtained as a major component the 17α,20,20,21-bis(methylenedioxy)-11β-hydroxy-6,16α- dimethyl-2'-phenyl-4,6-pregnadieno-[3,2-c] pyrazole.
17α,20,20,21-bis(methylenedioxy)-11β-hydroxy-6,16α-dimethyl-2'-phenyl- 4,6-pregnadieno[3,2-c] pyrazole (430 mg), is heated on a steam bath under nitrogen with 40 cc of a 60% aqueous solution of formic acid for about 30 minutes. About 40 cc of water is added and the mixture is then extracted into 200 cc of chloroform. The chloroform solution is washed with water, saturated 1136 Creatinolfosfate
sodium bicarbonate solution and water, then dried over sodium sulfate and evaporated under vacuum to give 430 mg of crude product. This is dissolved in 60 cc of absolute methanol, and 0.1 equivalent of sodium methoxide in methanol is added.
The mixture is stirred under nitrogen at room temperature for 15 minutes. It is then acidified with acetic acid and the solvent is removed under vacuum at room temperature. About 20 cc of water is added and the product is extracted into 150 cc of ethyl acetate. The ethyl acetate solution is washed with saturated sodium bicarbonate and then with water. It is then dried over sodium sulfate and taken to dryness to give an amorphous solid. The crude product obtained above is dried in high vacuum and then dissolved in 4 cc of pyridine. About 3 cc of acetic anhydride is added. The mixture is then heated on the steam bath for about 15 minutes and then evaporated to dryness in vacuo. About 20 cc of water is added. The product is then extracted into 150 cc of ethyl acetate, washed with saturated sodium bicarbonate solution and water, and dried over sodium sulfate. The solvent is removed in vacuo to give a residue which is crystallized from ethyl acetatebenzene to yield about 250 mg of 11β,17α,21-trihydroxy-6,16α-dimethyl-20- oxo-2'-phenyl-4,6-p

Therapeutic Function

Glucocorticoid