Description
Fluticasone furoate is a new corticosteroid derivative launched as a
nasal spray for the treatment of seasonal and perennial allergic rhinitis in adults
and in children aged ≥2 years. It is structurally closely related to the previously
marketed intranasal corticosteroid fluticasone propionate (FP). Both of these
steroids contain the unusual S-fluoromethyl carbothioate group, which confers
high lipophilicity and hence enhanced binding and retention of the drug by the
nasal tissue. Additionally, the carbothioate group rapidly undergoes first-pass
metabolism by CYP3A4, thus minimizing systemic exposure of the parent drug.
Fluticasone furoate is a potent ligand for the glucocorticoid receptor (GR), with
a relative receptor affinity (RRA) of 2,989 with reference to dexamethasone RRA
of 100.
Following intranasal administration, most of the dose is eventually swallowed and undergoes incomplete absorption and extensive firstpass metabolism in the liver and gut, resulting in negligible systemic exposure. Pharmacokinetic studies using oral solution dosing and intravenous dosing show that at least 30% of fluticasone furoate is absorbed and then rapidly cleared from plasma. The most common adverse reactions (W1% incidence) included headache, epistatix, sinus and throat pain, nasal ulceration, back pain, pyrexia, and cough. Fluticasone furoate is chemically derived starting from a readily available corticosteroid, 6a,9a-difluoro-11b,17a-dihydroxy-16a-methyl-3-oxoandrosta-1,4-diene-17b-carboxylic acid, by first converting the carboxylic acid group to the corresponding carbothioic acid via activation with carbonyl diimidazole followed by reaction with hydrogen sulfide gas. Subsequently, selective acylation of the 17a-hydroxyl group with 2-furoyl chloride and alkylation of the 17b-carbothioic acid group with bromofluoromethane under basic conditions provides fluticasone furoate.
Definition
ChEBI: A trifluorinated corticosteroid that consists of 6alpha,9-difluoro-11beta,17alpha-dihydroxy-17beta-{[(fluoromethyl)sulfanyl]carbonyl}-16-methyl-3-oxoandrosta-1,4-diene bearing a 2-furoyl s
bstituent at position 17. Used in combination with vilanterol trifenate for treatment of bronchospasm associated with chronic obstructive pulmonary disease.
Synthesis
The synthesis of fluticasone on large scale was
disclosed in the patent literature. The starting 6|á ,9|á-
difluoro-11|?-17|á-dihydroxy-16|á-methyl-3-oxoandrosta-1,4-
diene-17|?-carboxylic acid 35 was converted to the
analogous carbothioic acid 36 in 95% yield via activation
with carbonyl diimidazole, followed by reaction with hydrogen
sulfide gas. Conversion of the carbothioic
acid to fluticasone was completed through a three-step sequence
in a one pot process in 99% overall yield. Carbothioic
acid 36 and DMAP were dissolved in MEK. Tripropylamine
(TPA) was then added to the mixture at -8 to -5??C.
Neat furoyl chloride was then added dropwise over 2-3 minutes
and the resulting mixture was then stirred at -5 to 0??C
for 15 minutes generating a mixture of desired ester 37 and
thioanhydride 38. A solution of N-methylpiperazine in water
was then added dropwise over 2-3 minutes at -5 to 0??C to the crude reaction mixture and stirred for 10 minutes, which
enabled the conversion of thioanhydride 38 to the ester 37. A
solution of bromofluoromethane in MEK was then added
rapidly at 0??C and the resulting solution was stirred at 20??C
for 5 hours. After a simple work-up, fluticasone furoate (V)
was obtained in 99% overall yield from 36 with 97% purity.
