Description
Difluprednate is a synthetic glucocorticoid that potently activates the glucocorticoid receptor (K
i = 78 pM).
In vivo, ocular administration of difluprednate (0.05% w/v) increases intraocular pressure in sheep. Formulations containing difluprednate have been used to treat diabetic macular edema and inflammation following cataract surgery.
Originator
Epitopic,Clin Midy,France,1978
Uses
Difluprednate-d3 is the isotope labeled form of Difluprednate (D445925), a corticosteroid (derivative of prednisolone), approved for the treatment of post-operative ocular inflammation.
Manufacturing Process
Orthoesterification: A mixture of 1 g of 6α,9α-difluoroprednisolone, 10 mg of
p-toluenesulfonic acid, 5 cc of dimethylformamide and 3 cc of methyl
orthobutyrate is heated for 15 hours on an oil bath at 105°C while a slow
stream of nitrogen is passed through the mixture so that the methanol
produced as a by-product of the reaction, is distilled off. After addition of
several drops of pyridine to neutralize the acid catalyst, the reaction mixture
is evaporated under vacuum and there is obtained a solid residue which is
taken up with methanol, and filtered. The product is recrystallized from a
methylene chloride-methanol mixture to yield 682 mg of 6α,9αdifluoroprednisolone 17α,21-methylorthobutyrate, also identified as 17α,21-
(1'-methoxy)-n-butylidenedioxy-6α,9α-difluoro-δ1,4-pregnadiene-11β-ol-3,20-
dione, MP 194°C-198°C.
Upon chromatography of the mother liquor on a column of alumina another
338 mg of a crystalline mixture of the epimeric orthobutyrates are isolated.
Hydrolysis: A suspension of 1 g of the 6α,9α-difluoroprednisolone 17α,21-
methylorthobutyrate in 10 cc of methanol is treated with 2 cc of a 2 N
aqueous solution of oxalic acid and heated on a water bath at 40°-50°C for
about 5-10 minutes and, afterwards, the mixture is concentrated under
vacuum. The residue is then shaken with water, the insoluble product is
filtered off and then dried. The solid material is recrystallized from acetoneether and 6α,9α-difluoroprednisolone 17-butyrate is obtained, MP 193°-196°C
Esterification: A solution of 500 mg of 6α,9α-difluoroprednisolone-17-butyrate
in 2.5 cc of pyridine is treated with 1.25 cc of acetic anhydride and the
reaction mixture permitted to stand overnight at 0°C. The reaction mixture is
then poured into ice water and the crystalline precipitate formed is filtered off
and recrystallized from a methylene chloride-ether-petroleum ether mixture to
yield 494 mg of 6α,9α-difluoroprednisolone 17-butyrate, 21-acetate; MP 191°-
194°C.
General Description
Difluprednate, 21-(acetyloxy)-6α,9-difluoro-11β-hydroxy-17-(1-oxobutoxy)pregna-1,4-diene-3,20-dione is being developed (phase III) as a topical ophthalmicemulsion to treat inflammatory eye diseases.
