Method for the preparation of fluticasone and related 17beta-carbothioic esters using a novel carbothioic acid synthesis and novel purification methods

6α,9α-difluoro-11β,17α-dihydroxy-16α-methyl-3-oxoandrosta-1,4-diene-17β-carboxylic acid

[0114]A mixture of commercial grade Flumethasone (100 g, 243.6 mmoles), palladium(II) acetate (0.552 g, 2.46 mmol) and triphenylphosphine (1.284 g, 4.89 mmol) in DMA (500 mL) at 60° C. was stirred for 30 minutes; cooled to 15° C. and treated with water (2.0 L) over 1 hour; cooled to 0° C., stirred for 2 hours, and filtered to provide a solid. The solid was washed with cold water (2×200 mL) and dissolved in THF (500 mL). This solution was cooled to 0° C., treated with technical grade (approximately 98%) periodic acid (83.3 g, 365.4 mmol) in water (250 mL), stirred for 3 hours, and treated with water (3.75 L); warmed to room temperature, stirred for 30 minutes, and filtered to provide a solid. This solid was washed with water (500 mL) until the pH of the wash was greater than 5 and dried under vacuum at 60° C. with a nitrogen purge to provide 96.6 g (98%) of the desired product.

6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-(propionyloxy)androsta-1,4-diene-17β-carboxylic acid

[0115]A solution of Example 1 (95.2 g, 240 mmol) and triethylamine (55.9 g, 552 mmol) in acetone (1.45 L) at −15° C. was treated with pre-distilled propionyl chloride (51.1 g, 552 mmol), stirred for 1 hour, treated with diethylamine (52.7 g, 720 mmol), stirred for 1 hour, and treated with 1M HCl (1.90 L); warmed to 0° C., stirred for 1 hour, and filtered. The solid was washed with water (475 mL), dried for 12 hours at 60° C. under vacuum with a nitrogen purge, and treated sequentially with 3-pentanone (459 mL), 2-butanone (51 mL), and water (5.1 mL). This mixture was heated to reflux for one hour; cooled to room temperature over two hours, stirred for 18 hours, and filtered to provide a solid. This solid was washed with 3-pentanone (100 mL) and dried under vacuum with a nitrogen purge at 60° C. for 18 hours to provide 86.7 g (79.8%) of the desired product.

17β-(N,N-(dimethylcarbamoyl)thio)carbonyl-6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-propionyloxy-3-oxoandrosta-1,4-diene

[0116]A solution of Example 2 (86.7 g, 192 mmol) and N,N-dimethylthiocarbamoyl chloride (47.5 g, 384 mmoles) in 2-butanone (2.17 L) at room temperature was treated sequentially with triethylamine (42.7 g, 422 mmoles), anhydrous sodium iodide (28.8 g, 192 mmol), and water (8.67 mL, 10% w / w with Example 2), stirred for 2 hours, treated sequentially with DMA (694 mL) and water (4.34 L); cooled to 0° C., stirred for 2 hours, and filtered to provide a solid. The solid was washed with water (500 mL) and dried at 60° C. under vacuum with a nitrogen purge to provide 96.4 g (93%) of the desired product.