9-fluoro-11beta,17-dihydroxy-16beta-methylpregna-1,4-diene-3,20-dione 21-[tricyclo[3.3.1.13,7]dec-1-ylformate]

Originator

Betamethasone,Zhejiang Xianju Pharmaceutical Co., Ltd.

Manufacturing Process

3 Methods of producing of betamethasone 21-adamantane-1'-carboxylate: 1. A suspension of betamethasone (740.0 mg) in dioxan (20 ml) was treated with adamantane carboxylic acid (1.96 g) and trifluorcacetic anhydride (0.75 ml). The mixture was stirred at room temperature for 23 h during which time the steroid completely dissolved. Addition of sodium bicarbonate (2.0 g) and water gave a waxy semi-solid which was separated from the supernatant liquid by decantation. Water and a little methanol were added to the solid and the resulting granular material was removed by filtration and washed well with water. Fractional crystallization from methanol afforded adamantane carboxylic anhydride as the less soluble component and betamethasone 21-adamantane- 1'-carboxylate as the more soluble component.
2. 9α-Fluoro-11β,17-dihydroxy-21-iodo-16β-methylpregna-1,4-diene-3,20- dione (76.65 g) was dissolved in warm acetone (400 ml) and then adamantanecarboxylic acid (54.0 g) and triethylamine (52.5 ml) was added and washed in with more acetone (100 ml). The solution was refluxed for 1 h and then poured with good stirring into cold water (2.5 L). Filtration of the precipitated material and recrystallisation from aqueous methanol with charcoaling afforded betamethasone 21-admantane-1'-carboxylate showing extensive melting 245°-250°C.
3. A solution of betamethasone (1.0 g) in dry tetrahydrofuran (40 ml) was treated with adamantane carbonyl chloride (about 2.2 equivalents) in dry tetrahydrofuran (5 ml) and then pyridine (0.8 ml) was added. The mixture was refluxed for 6 h and then most of the solvent was boiled off and the residue extracted with chloroform to afford a froth. The ether soluble portion of this froth was dissolved in chloroform and extracted repeatedly with dilute sodium bicarbonate solution. Evaporation of the chloroform layer gave a froth which was further purified by chromatography and crystallisation from chloroform-petroleum ether to yield betamethasone 21-adamantane-1'- carboxylate melting point 256°-259°C (dec.).

Therapeutic Function

Glucocorticoid