Fluticasone propionate (R—CH2CH3)/furoate (2-furyl) of formula 1, chemically known as S-fluoromethyl-6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-propionyloxy-3-oxo-androsta-1,4-diene-17β-carbothioate (1a) and S-fluoromethyl-6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-(2-furoyloxy)-3-oxo-androsta-1,4-diene-17β-carbothioate (1b), are members of the corticosteroidal androstane 17β-thioic acid fluoromethyl ester family and a synthetic steroid of the glucocorticoid family. The naturally occurring hormone, cortisol or hydrocortisone, is produced by the adrenal glands. Glucocorticoid steroids have potent anti-inflammatory actions. When used as a nasal inhaler or spray, the medication goes directly to the inside lining of the nose and very little is absorbed into the rest of the body.

U.S. Pat. No. 4,335,121 discloses the compound of formula 1a [Fluticasone propionate (R—CH2CH3)] and its preparation. It discloses the process of its preparation by treating 6α,9α-di fluoro-11β-hydroxy-16α-methyl-3-oxo-17α-(propionyloxy)androsta-1,4-dien-17β-carboxylic acid, a compound of formula 4a with dimethylthiocarbamoyl chloride to yield 17β-[(N,N-dimethylcarbamoyl)thio]carbonyl-6α,9α-difluoro-11(3-hydroxy-16α-methyl-17β-propionyloxy-3-oxoandrosta-1,4-diene, a compound of formula 5a, which is decomposed by refluxing in diethylamine to the thioic acid of formula 6a. The compound of formula 6a is then reacted with bromochloromethane in presence of sodium bicarbonate to give a chloromethyl ester of formula 7a. The compound of formula 7a, is converted to an iodomethyl ester by halogen exchange and subsequently treated with silver fluoride to yield the compound of formula 1a. This process of preparation of the compound of formula 1a is very tedious, lengthy, and involves use of expensive and sensitive chemicals, viz. silver fluoride. This prior art teaches the use of ammonia, a primary amine or more preferably a secondary amine such as diethylamine or pyrrolidine for conversion of compound of formula 5a to compound of formula 6a. However, the yield obtained with use of secondary amines such as diethylamine is poor.

WO 01/62722 discloses the method of preparing the compound of formula 1a by reacting a compound of formula 4a with dimethylthiocarbamoyl chloride and molar equivalents of sodium iodide in 2-butanaone to get compound of formula 5a. The compound of formula 5a is then reacted with a hydrolyzing agent such as sodium hydrosulfide to generate the sodium salt of formula 6a, which can be alkylated in-situ with chlorofluoromethane to yield the compound of formula 1a or alternately can be acidified to obtain the compound of formula 6a, which can be isolated and converted to compound of formula 1a by alkylation with chlorofluoromethane. This prior art publication teaches the use of an alkoxide salt, a thioalkoxide salt or a hydrated sulfide salt for hydrolyzing the compound of formula 5a to obtain the corresponding thiocarboxylic acid, the compound of formula 6a. The use of sodium hydrosulfide hydrate or sodium thiomethoxide as hydrolyzing agent for conversion of 17β-carboxylic acid to 17β-carbothioic acid, via the intermediacy of 17β-[(N,N-dimethylcarbamoyl)thio]carbonyl derivative, has been exemplified. However, sodium thiomethoxide is a corrosive and moisture sensitive reagent and use of sodium thiomethoxide would generate toxic methyl mercaptan during acidification and sodium hydrosulfide is unstable and converts to sodium thiosulfate and sodium carbonate upon storage. In the in-situ alkylation of sodium salt of compound of formula E, the excess sodium hydrosulfide would react with the chlorofluoromethane generating toxic and obnoxious organosulfur by products, which can pose health hazards. Although isolation of thioic acid of formula 6a can be performed (by treatment with an acid) to overcome the problem, the excess sodium hydrosulfide would generate toxic hydrogen sulfide. Further, the thiosulfate impurity which is invariably present in sodium hydrosulfide, would generate sulfur upon acidification, which would contaminate the thioic acid and whose removal would pose difficulties.
Gordon H. Phillipps et al, Journal of Medicinal Chemistry 37, 3717-3729 (1994), disclose the method of preparing the compound of formula 1a by treating a compound of formula 2 with carbonyldiimidazole under nitrogen, followed by a reaction with hydrogen sulfide to give the thioic acid of formula 8, which is isolated and treated with propionyl chloride to give the compound of formula 6a. This compound is then alkylated with bromofluoromethane under nitrogen to yield the compound of formula 1a in 69.3% yield.
This reference does not mention the preparation of compound of formula 1a directly from the compound of formula 5a. IL Patent No. 109656 discloses preparation of fluticasone propionate by esterification of compound of formula 6a with a halofluoromethane, optionally in the presence of a catalyst such as tetrabutylammonium bromide.
The process described in international patent application WO 2004/001369 comprising the 17β-N,N-dimethylthiocarbamoyloxycarbonyl compound 5a was treated with an alkali metal carbonate-alcohol system, for example potassium carbonate in methanol, to obtain the alkali metal salt of compound 6a (6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-propionyloxy-3-oxo-androsta-1,4-diene-17β-carbothioate sodium). Alkali metal salt was treated in situ with bromofluoromethane to obtain fluticasone propionate 1a. Alternatively, compound 6a was isolated by acid treatment and then reacted with bromofluoromethane to obtain fluticasone propionate 1a. Alternatively still, thiocarbamate 5a was reacted with a hydrosulphide reagent, such as sodium hydrosulphide, and bromofluoromethane to obtain fluticasone propionate 1a. Hence, this process also uses bromofluoromethane, which raises environmental concerns.
EP 1431305 also described a process for the preparation of fluticasone propionate 1a, a drawback associated with this process is the oxidative dimerisation of the sulphur compounds to give dimer impurities especially under pressure or with long reaction times. Such by-products are formed in significant amounts, which are difficult to control/reduce within the limits of stringent pharmacopoeial specifications even after multiple purifications.
A process disclosed by Farmabios in international patent application WO 2004/052912 used a different approach, shown in scheme 1, for the conversion of organic amine salt 6 to fluticasone propionate 1a. Amine salt 9a was hydroxymethylated using formaldehyde to give alcohol 10a (S-hydroxymethyl-6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-propionyloxy-3-oxo-androsta-1,4-diene-17β-carbothioate). This intermediate 10a was selectively fluorinated using bis(2-methoxyethyl)aminosulphur trifluoride (Deoxo-Fluor®), diethylaminosulphur trifluoride (DAST®), or hexafluoropropyldiethylamine (MEC-81®), to obtain fluticasone propionate 1a.

WO 2004/052912 also discloses a minor modification of the process described in scheme 2. In the modified process, depicted in scheme 2, 17β-N,N-dimethylthiocarbamoyloxy-carbonyl-9β,11β-epoxy-6α-fluoro-17α-propionyloxy-16α-methyl-3-oxo-androsta-1,4-diene 11a was converted to S-hydroxymethyl-9β,11β-epoxy-6α-fluoro-17α-propionyloxy-16α-memyl-3-oxo-androsta-1,4-diene-carbothioate 12a. Intermediate 12a was further converted into S-fluoromethyl-9β,11β-epoxy-6α-fluoro-17α-propionyloxy-16α-methyl-3-oxo-androsta-1,4-diene-carbothioate 13a using DAST®. Fluticasone propionate 1a was then obtained by the opening of the epoxide of compound 13a using hydrofluoric acid. The use of hazardous DAST as a fluorinating agent and the use of highly corrosive hydrofluoric acid are major disadvantages of this process described in WO 2004/052912.

WO0212265 discloses a 6α,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-11α-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioic acid S-fluoromethyl ester (Fluticasone furoate) of formula 1b and a process for preparing this compound which are common with intermediates in the synthesis of a compound of formula 1a (R—CH2CH3) are described in U.S. Pat. No. 4,335,121.
WO2002012265 discloses the compound of formula 1b (Fluticasone furoate (R-2-furyl) and its preparation. WO03013427 disclosed the process for the preparation of the compound of formula 1b (Fluticasone furoate (R-2-furyl) comprises reacting compound of formula 6b (R-2-furyl), with chlorofluoro methane and mild base.
WO2007144363 disclosed the process for the preparation of the compound of formula 1b (Fluticasone furoate (R-2-furyl) comprises reacting carbothioic acid with 2-furancarbonyl chloride using DMAP and Et3N in MeCOEt at 20-22° C. under a N2 atm. for 10 min, treatment of the resulting thioanhydride (R=2-furanylcarbonyl) with a solution of N-methylpiperazine in H2O added drop wise of t 2-3 min at −5-10° C., and finally, reacting the resulting carbothioic acid (R=2-furanylcarbonyl) with BrCH2F in methyl ethyl ketone at 20-22° C. for 5 hrs.
WO0208243 discloses processes for preparing intermediates useful in the preparation of Fluticasone propionate and Fluticasone furoate.
Like any synthetic compound, Fluticasone propionate/furoate can contain extraneous compounds or impurities that can come from many sources. They can be unreacted starting materials, by-products of the reaction, and products of side reactions or degradation products. Impurities in compound of formula 6 as in its active pharmaceutical ingredient (API), Fluticasone propionate/furoate, are undesirable and might even be harmful to a patient being treated with a dosage form containing the API.
The purity of the API produced in the commercial manufacturing process is clearly a necessary condition for commercialization. Impurities introduced during commercial manufacturing processes must be limited to very small amounts, and are preferably substantially absent. For example, the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (“ICH”) Q7A guidance (dated Nov. 10, 2000) for API manufacturers requires that process impurities be maintained below set limits by specifying the quality of raw materials, controlling process parameters, such as temperature, pressure, time, and stoichiometric ratios, and including purification steps, such as crystallization, distillation, and liquid-liquid extraction, in the manufacturing process.
The product mixture of a chemical reaction is rarely a single compound with sufficient purity to comply with pharmaceutical standards. Side products and by-products of the reaction and adjunct reagents used in the reaction will, in most cases, also be present in the product mixture. At certain stages during processing of compound of formula 6 or during the processing of an API, such as Fluticasone propionate/furoate, it must be analyzed for purity, typically, by HPLC or TLC analysis, to determine if it is suitable for continued processing and, ultimately, for use in a pharmaceutical product. The compound of formula 6 or API need not be absolutely pure, as absolute purity is a theoretical ideal that is typically unattainable. Rather, purity standards are set with the intention of ensuring that an API is as free of impurities as possible, and thus, are as safe as possible for clinical use. As discussed above, in the United States, the Food and Drug Administration guidelines recommend that the amounts of some impurities be limited to less than 0.1 percent.
Thus, providing highly pure compound of formula 6 and means for the preparation thereof is desirable.
Thus the prior art processes described above for the synthesis of fluticasone propionate/furoate (I) suffer from various limitations with respect to process parameters, yields, purity and quality, as well as serious environmental issues. In view of these drawbacks, there is a need for an improved process for the preparation of fluticasone propionate/furoate (I), which addresses the limitations associated with the prior art processes.
In view of the various drawbacks in the prior arts, a suitable reagent for the hydrolysis of N,N-dimethylthiocarbonyl group in formula 5 was required to get the compound of formula 6 in high yield and quality. In order to explore the suitable base various bases and solvent systems are tried to get compound of formula 6 in pure form and we observed that use of cyclic amines afford best quality with increased yield of the product.
The object of the present invention is to provide a facile, efficient and economic process for the preparation of better quality of Fluticasone 17α-ester derivatives. The use of various reagents and solvents were explored during the course of the exploration of the process. The present invention provides a convenient process for preparation of compound of formula 1, wherein various secondary amines are explored for the conversion of a compound of formula 5 to a compound of formula 6 in contrast to prior art. Different solvents and mixture of solvents are used for the purification of compound of formula 6, and the compound of formula 1 is treated with a various solvents or a mixture of solvents. The advantages include an improved yield, use of reagents that are easy to handle, low reaction time and use of lesser molar amounts of the reagents with the highest purity of product.