ChemicalBook CAS DataBase List FLUTICASONE FUROATE

FLUTICASONE FUROATE synthesis

8synthesis methods

Product Name:FLUTICASONE FUROATE
CAS Number:397864-44-7
Molecular formula:C27H29F3O6S
Molecular Weight:538.58

The synthesis of fluticasone on large scale was disclosed in the patent literature. The starting 6α ,9α- difluoro-11β-17α-dihydroxy-16α-methyl-3-oxoandrosta-1,4- diene-17β-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.

397864-40-3 Synthesis

6α,9α-difluoro-17α-(furan-2-yl)carbonyloxy-11β-hydroxy-16α-methyl-3-oxoandrosta-1,4-diene-17β-carbothioic acid

397864-40-3
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373-52-4 Synthesis

373-52-4
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397864-44-7
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Yield:397864-44-7 99.3%

Reaction Conditions:

in butanone at 0 - 22;

Steps:

1.3
Step 3: A solution of bromofluoromethane (3.28 g, 1.2 eq wrt the thioacid) in MEK (10 ml, 32.8% w/v) was then added rapidly as a single charge at 0° C. The solution was then warmed rapidly to 20-22° C. and stirred for a total of 5 hours at 20-22° C. (HPLC indicated that no thioacid furoate (compound of formula (III)) remained).The reaction mixture was then diluted with MIBK (230 ml) and washed subsequently with aqueous 2M hydrochloric acid (2×50 ml); water (1×50 ml); aqueous potassium carbonate (4% w/v, 1×30 ml) and then water (1×30 ml). The final organic phase was then concentrated under reduced pressure to give a fine off-white solid (13.01 g, 99.3% theoretical yield after correction for MIBK, 97.43% purity).

References:

GLAXO GROUP LIMITED US2009/118495, 2009, A1 Location in patent:Page/Page column 4

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