ChEBI: Betamethasone acetate is an acetate ester, a steroid ester, a fluorinated steroid, a 17alpha-hydroxy steroid, a 20-oxo steroid, an 11beta-hydroxy steroid, a 3-oxo-Delta(1),Delta(4)-steroid and a tertiary alpha-hydroxy ketone. It is functionally related to a betamethasone.
The synthesis is long and complex. For brevity, only the last steps are given
here. Refer to the patents cited below for full details.
Preparation of 9α-Bromo-11β,17α,21-Trihydroxy-16β-Methyl-4-Pregnene-3,20-
Dione 21-Acetate: To a mixture of 620 mg of 17α,21-dihydroxy-16β-methyl-
4,9(11)-pregnadiene-3,20-dione 21-acetate and 330 mg of Nbromosuccinimide in 10 ml of dioxane and 3.2 ml of water cooled to 10°C was
added 1.8 ml of cold 1 M aqueous perchloric acid. The mixture was stirred at
15°C for 3 hours. Excess N-bromosuccinimide was destroyed by addition of
aqueous sodium thiosulfate and most of the dioxane was removed in vacuo.
About 30 ml of water was added and crystalline bromohydrin, 9α-bromo-
11β,17α,21-trihydroxy-16β-methyl-4-pregnene-3,20-dione 21-acetate, was filtered, washed with water, and dried in air.
Preparation of 9β,11β-Epoxy-17α-21-Dihydroxy-16β-Methyl-4-Pregnene-3,20-
Dione 21-Acetate: To a stirred solution of 100 mg of the 9α-bromo-
11β,17α,21-trihydroxy-16β-methyl-4-pregnene-3,20-dione 21-acetate in 3 ml
of tetrahydrofuran and 1 ml of methanol under nitrogen was added 1.02 ml of
0.215N methanolic sodium methoxide. After 10 minutes at 25°C, 0.2 ml of
acetic acid was added and the methanol removed in vacuo. The residue was
acetylated with 1.00 ml of pyridine and 0.5 ml of acetic anhydride at 60°C for
70 minutes. The mixture was taken to dryness in vacuo, water added, and the
product extracted into chloroform. The residue was crystallized from etheracetone to give pure 9β,11β-epoxy-17α,21-dihydroxy-16β-methyl-4-pregnene-
3,20-dione 21-acetate.
Preparation of 9α-Fluoro-11β,17α,21-Trihydroxy-16β-Methyl-4-Pregnene-3,20-
Dione 21-Acetate: To a solution of 200 mg of 9β,11β-epoxy-17α,21-dihydroxy-
16β-methyl-4-pregnene-3,20-dione 21-acetate in 2 ml of chloroform and 2 ml
of tetrahydrofuran in a polyethylene bottle at -60°C was added 2 ml of a 2:1
(by weight) mixture of anhydrous hydrogen fluoride and tetrahydrofuran. After
4 hours at -10°C the mixture was cooled to -60°C and cautiously added to a
stirred mixture of 30 ml or 25% aqueous potassium carbonate and 25 ml of
chloroform kept at -5°C. The aqueous phase was further extracted with
chloroform and the latter phase washed with water and dried over magnesium
sulfate. The residue on crystallization from acetone-ether gave pure 9α-fluoro-
11β,17α,21-trihydroxy-16β-methyl-4-pregnene-3,20-dione 21-acetate.
Preparation of 9α-Fluoro-11β,17α,21-Trihydroxy-16β-Methyl-4-Pregnadiene-
3,20-Dione 21-Acetate 100 mg of 9α-fluoro-11β,17α,21-trihydroxy-16β-
methyl-4-pregnene-3,20-dione 21-acetate was treated with selenium dioxide
to produce the corresponding 9α-fluoro-11β,17α,21-trihydroxy-16β-methyl-4-
pregnadiene-3,20-dione 21-acetate. Alternately, Bacillus sphaericus may be
utilized.
