DESC:
FIELD OF THE INVENTION:
The present invention relates to the novel intermediate S-hydroxymethyl 6a,9a-difluoro-16a-methyl-3-oxo-11ß-hydroxy-17a-[(2-furoyl)oxy]-1,4-diene-17ß-carbothioate represented by the compound of Formula (II), a method for the preparation of the compound of Formula (II), and to the use of said novel intermediate in the preparation of Fluticasone furoate represented by the compound of Formula (I).

BACKGROUND OF THE INVENTION:
Fluticasone furoate chemically known as S-fluoromethyl 6a,9a-difluoro-16a-methyl-3-oxo-11ß-hydroxy-17a-[(2-furoyl)oxy]-1,4-diene-17ß-carbothioate represented by the compound of Formula (I).

Fluticasone furoate developed by Glaxo SmithKline, is a member of the corticosteroidal androstane 17ß-thioic acid fluoromethyl ester family and a synthetic steroid of the glucocorticoid family. Glucocorticoids have potent anti-inflammatory properties and are widely used for the treatment of inflammatory disorders or diseases such as asthma and rhinitis.

WO 2002/012265 A1 discloses the fluticasone furoate and process/processes for its preparation.

WO 2003/013427 A2 disclosed the process for the preparation of fluticasone furoate comprising reacting compound of formula (III), with chlorofluoro methane and mild base as shown below.

WO 2007/144363 A2 disclosed the process for the preparation of fluticasone furoate comprising reacting carbothioic acid with 2-furancarbonyl chloride using DMAP and Et3N, treatment of the resulting thioanhydride with a solution of N-methylpiperazine and finally, reacting the resulting carbothioic acid (III) with BrCH2F as shown below.

2011/151624 A1 disclosed the process for the preparation of fluticasone furoate comprising reacting carbothioic acid (III) with monfluromethylated reagents shown below

However, such monfluromethylated reagents are expensive, not commercially available and thus increases the overall cost of the process.

Thus it is seen from the above references that, fluticasone derivatives (furoate/propionate) are typically prepared by reacting a halo-fluoromethane, such as bromofluoromethane (BFM), iodofluoromethane (IFM) or chlorofluoromethane (CFM), with one or more reagents. Prior art processes utilizing halo-fluoromethane possess certain disadvantages such as highly toxic, do not decompose in the lower atmosphere, accumulates and eventually rise to the stratosphere, ozone depleting substance, and is presently not commercially available. Also reactions using halo-fluoromethane requires very high temperatures, low product yield and significant impurity content in final product.

Thus, the prior art processes described above for the synthesis of fluticasone furoate 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 furoate, which addresses the limitations associated with the prior art processes.

The object of the present invention is to provide efficient and economic process for the preparation of better quality of fluticasone furoate.

The advantages of the present invention 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.

SUMMARY OF THE INVENTION:
In one aspect, the present invention relates to the novel intermediate S-hydroxymethyl 6a,9a-difluoro-16a-methyl-3-oxo-11ß-hydroxy-17a-[(2-furoyl)oxy]-1,4-diene-17ß-carbothioate of the formula (II),

which is useful for the preparation of Fluticasone furoate of the formula (I).

In another aspect, the present invention also provides process for preparation of the novel intermediate S-hydroxymethyl 6a,9a-difluoro-16a-methyl-3-oxo-11ß-hydroxy-17a-[(2-furoyl)oxy]-1,4-diene-17ß-carbothioate of the formula (II),

which comprises reacting 6a,9a-difluoro-16a-methyl-3-oxo-11ß-hydroxy-17a-[(2-furoyl)oxy]-1,4-diene-17ß-carbothioc acid of the formula (III)

with formaldehyde optionally in the presence of base.

In yet another aspect, the present invention provides a process for preparation of fluticasone furoate of the formula (I)

comprising
S-hydroxymethyl 6a,9a-difluoro-16a-methyl-3-oxo-11ß-hydroxy-17a-[(2-furoyl)oxy]-1,4-diene-17ß-carbothioate of formula (II)

In yet another aspect, the present invention provides process for preparation of fluticasone furoate of the formula (I)

which comprises
a) reacting 6a,9a-difluoro-16a-methyl-3-oxo-11ß-hydroxy-17a-[(2-furoyl)oxy]-1,4-diene-17ß-carbothioc acid of the formula (III)

with formaldehyde optionally in the presence of base to give S-hydroxymethyl 6a,9a-difluoro-16a-methyl-3-oxo-11ß-hydroxy-17a-[(2-furoyl)oxy]-1,4-diene-17ß-carbothioate of the formula (II),

b) optionally isolating S-hydroxymethyl 6a,9a-difluoro-16a-methyl-3-oxo-11ß-hydroxy-17a-[(2-furoyl)oxy]-1,4-diene-17ß-carbothioate of the formula (II),
c) reacting S-hydroxymethyl 6a,9a-difluoro-16a-methyl-3-oxo-11ß-hydroxy-17a-[(2-furoyl)oxy]-1,4-diene-17ß-carbothioate of the formula (II) with selective nucleophilic fluorination reagent to give fluticasone furoate of the formula (I).

DETAILED DESCRIPTION OF THE INVENTION:
The present invention relates to the novel intermediate S-hydroxymethyl 6a,9a-difluoro-16a-methyl-3-oxo-11ß-hydroxy-17a-[(2-furoyl)oxy]-1,4-diene-17ß-carbothioate of the formula (II)

which is useful for the preparation of fluticasone furoate of the formula (I).

In another aspect of the present invention, there is provided a process for the preparation of novel intermediate S-hydroxymethyl 6a,9a-difluoro-16a-methyl-3-oxo-11ß-hydroxy-17a-[(2-furoyl)oxy]-1,4-diene-17ß-carbothioate of the formula (II),

which comprises
reacting 6a,9a-difluoro-16a-methyl-3-oxo-11ß-hydroxy-17a-[(2-furoyl)oxy]-1,4-diene-17ß-carbothioc acid of the formula (III)

with formaldehyde optionally in the presence of base.

In yet another aspect, the present invention provides a process for preparation of fluticasone furoate of the formula (I)

comprising
S-hydroxymethyl 6a,9a-difluoro-16a-methyl-3-oxo-11ß-hydroxy-17a-[(2-furoyl)oxy]-1,4-diene-17ß-carbothioate of formula (II)

In yet another aspect of the present invention, there is provided a process for the preparation of fluticasone furoate of the formula (I)

which comprises
a) reacting 6a,9a-difluoro-16a-methyl-3-oxo-11ß-hydroxy-17a-[(2-furoyl)oxy]-1,4-diene-17ß-carbothioc acid of the formula (III),

with formaldehyde optionally in the presence of base to give S-hydroxymethyl 6a,9a-difluoro-16a-methyl-3-oxo-11ß-hydroxy-17a-[(2-furoyl)oxy]-1,4-diene-17ß-carbothioate of the formula (II),

b) optionally isolating S-hydroxymethyl 6a,9a-difluoro-16a-methyl-3-oxo-11ß-hydroxy-17a-[(2-furoyl)oxy]-1,4-diene-17ß-carbothioate of the formula (II),
c) reacting S-hydroxymethyl 6a,9a-difluoro-16a-methyl-3-oxo-11ß-hydroxy-17a-[(2-furoyl)oxy]-1,4-diene-17ß-carbothioate of the formula (II) with selective nucleophilic fluorination reagent to give fluticasone furoate of the formula (I).

Scheme - 1 illustrates the process for preparation of fluticasone furoate of the formula (I) according to the process of the present invention.

The intermediate 6a,9a-difluoro-16a-methyl-3-oxo-11ß-hydroxy-17a-[(2-furoyl)oxy]-1,4-diene-17ß-carbothioc acid of the formula (III) used herein for the process of the present invention can be obtained by the processes known in the art, for example as described in WO 2002/012265 A1, WO 2003/035668 A2 & WO 2007/099548 A2 which are incorporated herein by reference.

In the step a) of the process of the present invention, 6a,9a-difluoro-16a-methyl-3-oxo-11ß-hydroxy-17a-[(2-furoyl)oxy]-1,4-diene-17ß-carbothioc acid of the formula (III) is treated with formaldehyde in solvent and optionally in the presence of base to obtain S-hydroxymethyl 6a,9a-difluoro-16a-methyl-3-oxo-11ß-hydroxy-17a-[(2-furoyl)oxy]-1,4-diene-17ß-carbothioate of the formula (II). The reaction temperature may range from 10 to 100 °C and preferably at a temperature in the range from 50 to 55 °C. The duration of the reaction may range from 2 to 5 hours, preferably from a period of 3 to 4 hours.

Solvent used in above step is selected from halogenated hydrocarbons selected from dichloromethane, chloroform, 1,2-dichloroethane, carbon tetrachloride; ether solvents selected from 1,4-dioxane, diethylether, tetrahydrofuran (THF) or mixtures thereof.

Base used in above step is selected from organic or inorganic base selected from triethyl amine, diethanolamine, pyridine, sodium hydroxide, sodium hydrogen carbonate, sodium carbonate, potassium hydroxide, potassium hydrogen carbonate, potassium carbonate, ammonia and ammonium carbonate, more preferably triethyl amine.

Optionally, sodium iodide in catalytic amount can be added to the reaction mixture.

In the step b) of the process of the present invention, the novel intermediate S-hydroxymethyl 6a,9a-difluoro-16a-methyl-3-oxo-11ß-hydroxy-17a-[(2-furoyl)oxy]-1,4-diene-17ß-carbothioate of the formula (II) can be optionally isolated. The isolation may be affected by removing the solvent. Suitable techniques which may be used for the removal of solvent includes one or more of filtration, filtration under vacuum, distillation using a rotational distillation device for example Buchi Rotavapor, distillation under vacuum, spray drying, agitated thin film drying (ATFD), freeze drying (lyophilization), decantation and centrifugation; or any other technique known in the art.

In a preferred embodiment of the present invention, S-hydroxymethyl 6a,9a-difluoro-16a-methyl-3-oxo-11ß-hydroxy-17a-[(2-furoyl)oxy]-1,4-diene-17ß-carbothioate of the formula (II) is isolated by filtration or filtration under vacuum and combination thereof. Optionally, the S-hydroxymethyl 6a,9a-difluoro-16a-methyl-3-oxo-11ß-hydroxy-17a-[(2-furoyl)oxy]-1,4-diene-17ß-carbothioate of the formula (II) thus obtained may be dried, preferably under vacuum at a temperature of about 40° C. to about 80° C and used further for preparation fluticasone furoate.

The S-hydroxymethyl 6a,9a-difluoro-16a-methyl-3-oxo-11ß-hydroxy-17a-[(2-furoyl)oxy]-1,4-diene-17ß-carbothioate of the formula (II) is optionally purified using solvent selected from dichloromethane, chloroform, 1,2-dichloroethane, carbon tetrachloride, 1,4-dioxane, diethylether, tetrahydrofuran (THF) or mixtures thereof. The novel intermediate is having a purity of greater than about 90%, or greater than about 95%, or greater than about 97%, or greater than about 98%, or greater than about 99%, as determined using high performance liquid chromatography (HPLC).

The S-hydroxymethyl 6a,9a-difluoro-16a-methyl-3-oxo-11ß-hydroxy-17a-[(2-furoyl)oxy]-1,4-diene-17ß-carbothioate of the formula (II) was characterized by mass, & NMR.

In the step c) of the process of the present invention, the S-hydroxymethyl 6a,9a-difluoro-16a-methyl-3-oxo-11ß-hydroxy-17a-[(2-furoyl)oxy]-1,4-diene-17ß-carbothioate of the formula (II) is treated with selective nucleophilic fluorination reagent in solvent to give fluticasone furoate of the formula (I). The reaction temperature may range from 10 to 100 °C and preferably at a temperature in the range from 50 to 55 °C. The duration of the reaction may range from 2 to 5 hours, preferably from a period of 3 to 4 hours.

Solvent used in above step is selected from dichloromethane, chloroform, 1,2-dichloroethane, carbon tetrachloride, ethyl acetate, methyl acetate, isobutyl acetate or mixtures thereof.

The selective nucleophilic fluorination reagents, preferably selected from the group consisting of diethylamino sulphur trifluoride (DAST), dimethylaminosulfur trifluoride (Methyl DAST), 2,2-difluoro-l,3-dimethylimidazolidine (DFI), bis(2-methoxyethyl) aminosulfur trifluoride (DeoXo-Fluor), difluoro(morpholino)sulfonium tetrafluoroborate (XtalFluor-M), (Diethylamino)difluorosulfonium tetrafluoroborate (XtalFluor-E) hexafluoropropyldiethylamine (MEC-81) and N,N-Diisopropylethylamine trihydrofluoride, more preferably diethylamino sulphur trifluoride (DAST).

The fluticasone furoate of the formula (I) obtained by the process of the present invention is isolated which may be affected by removing the solvent for example by one or more of filtration, filtration under vacuum, agitated thin film drying (ATFD), freeze drying (lyophilization), decantation and centrifugation; or any other technique known in the art.

In a preferred embodiment of the present invention, fluticasone furoate of the formula (I) is isolated by filtration or filtration under vacuum and combination thereof followed by drying, preferably under vacuum at a temperature of about 40° C. to about 80° C.

The fluticasone furoate of the formula (I) is optionally purified from solvent selected from acetone, methanol, ethanol, dichloromethane, chloroform, 1,2-dichloroethane, carbon tetrachloride, ethyl acetate, methyl acetate, isobutyl acetate, water or mixtures thereof.

The fluticasone furoate of the formula (I) obtained by the process of the present invention is having a purity of greater than about 95%, or greater than about 98%, or greater than about 99%, or greater than about 99.5%, or greater than about 99.9%, as determined using high performance liquid chromatography (HPLC).

The fluticasone furoate of the formula (I) obtained by the process of the present invention may be micronized to achieve the better particle size distribution in order to make suitable Formulation. Micronization may be done using one or a combination of ball milling, jet milling, jet blending, high-pressure homogenation, or any other milling method.

EXPERIMENTAL SECTION:
METHODS:
The Mass spectrum was recorded using an waters Aquity QDa mass Spectrometer system.

The NMR spectrum was recorded using a Bruker Avance III HD 500 MHz instrument.

The HPLC purity was determined using an Ascentis Express C8, (4.6 mm x 150 mm), 2.7 µm column with a flow rate 1.2 ml / minute; Column oven temperature: 35°C; Sample tray temperature: 25°C; Detector: UV at 239 nm; Injection volume: 10 µl; Run time: 50 minutes.

To understand the present invention following preparative and testing examples are set forth, which are for the purpose of illustration only and are not to be construed as limiting the scope of the invention in any way.

EXAMPLES:
Example 1: 6a,9a-difluoro-16a-methyl-3-oxo-11ß-hydroxy-17a-[(2-furoyl)oxy]-1,4-diene-17ß-carbothioc acid (III).

A suspension of 90.0 gm 17ß-[(N,N-dimethylcarbamoyl)thio]carbonyl-6a,9a-difluoro-17a-[(2-furanylcarbonyl)oxy]-11ß-hydroxy-16a-methyl-3-oxoandrosta-1,4-diene and 64.6 g potassium carbonate in 450 ml methanol was stirred at 20-30°C for 24 hrs under nitrogen atmosphere. The reaction mixture was then acidified with 10% aq. HCl at 5-15°C. The precipitated product was filtered, washed with water, and dried under vacuum to give 6a,9a-difluoro-16a-methyl-3-oxo-11ß-hydroxy-17a-[(2-furoyl)oxy]-1,4-diene-17ß-carbothioc acid (III).

Yield: 98 %
HPLC purity: 96.21 %

Example 2: S-hydroxymethyl 6a,9a-difluoro-16a-methyl-3-oxo-11ß-hydroxy-17a-[(2-furoyl)oxy]-1,4-diene-17ß-carbothioate (II)

To 10 gm 6a,9a-difluoro-16a-methyl-3-oxo-11ß-hydroxy-17a-[(2-furoyl)oxy]-1,4-diene-17ß-carbothioc acid (III) in 100 ml tetrahydrofuran was added sodium iodide 1.0 gm sodium iodide at room temperature and the mixture heated to reflux, at reflux temp added 10 gm formaldehyde. Then stir it for 12 to 18 hrs. The reaction was then cooled to 40-45°C temperature then quenched with water 100 ml and distilled to remove THF upto 1 volume under vacuum. The reaction was filtered and washed with 100 ml water. Dried the solid under vacuum to give S-hydroxymethyl 6a,9a-difluoro-16a-methyl-3-oxo-11ß-hydroxy-17a-[(2-furoyl)oxy]-1,4-diene-17ß-carbothioate (II).

Yield: 75 %
HPLC purity: 85 %

1HNMR (500 MHz, DMSO-d6), ?? (in ppm): 8.003-8.015(dd, 1H), 7.275-7.298(dd, 1H), 6.693-6.703(dd, 1H), 2.539-2.607(m, 1H), 2.217-2.280 & 1.791-1.940(m, 2H), 3.333-3.387(m, 1H), 4.249-4.254(m, 1H), 1.791-1.940(m, 1H), 2.217-2.280 & 1.271-1.318(m, 2H), 1.506-1.579 & 2.217-2.280 (m, 2H), 5.052-5.067(s, 2H, SCH2OH), 1.071(s, 3H), 0.935-0.949(d, 3H), 1.506-1.579(s, 3H), 6.255-6.285(d, 1H), 7.179-7.187(d, 1H), 6.311-6.336(d, 1H), 5.589-5.622 (m, 1H), 6.132 (d, 1H)

Mass: 537.5(+1)

Example 3: S-fluoromethyl 6a,9a-difluoro-16a-methyl-3-oxo-11ß-hydroxy-17a-[(2-furoyl)oxy]-1,4-diene-17ß-carbothioate (I)

Under nitrogen atmosphere 100 ml dichloromethane was added to 2.5 gm 6a,9a-difluoro-16a-methyl-3-oxo-11ß-hydroxy-17a-[(2-furoyl)oxy]-1,4-diene-17ß-carbothioate (II) at -20 to -10°C. 0.75 gm diethylamino sulphur trifluoride (DAST) was added slowly to above at -20 to -10°C, stirred for 4 hrs and then cooled to 20-30 °C. 100 ml of water was added to above reaction, stirred, and separated the layers. Solvent removed under vacuum to give residue which was dissolved in ethyl acetate, stirred, cooled to room temperature, filtered to give solid, washed with methanol and dried under vacuum to give Crude compound S-fluoromethyl 6a,9a-difluoro-16a-methyl-3-oxo-11ß-hydroxy-17a-[(2-furoyl)oxy]-1,4-diene-17ß-carbothioate (I).

Yield: 80 %
HPLC purity: 80 %
,CLAIMS:
1) S-hydroxymethyl 6a,9a-difluoro-16a-methyl-3-oxo-11ß-hydroxy-17a-[(2-furoyl)oxy]-1,4-diene-17ß-carbothioate of formula (II)

2) A process for the preparation of S-hydroxymethyl 6a,9a-difluoro-16a-methyl-3-oxo-11ß-hydroxy-17a-[(2-furoyl)oxy]-1,4-diene-17ß-carbothioate of formula (II)

comprising reacting 6a,9a-difluoro-16a-methyl-3-oxo-11ß-hydroxy-17a-[(2-furoyl)oxy]-1,4-diene-17ß-carbothioc acid of the formula (III)

with formaldehyde optionally in the presence of base.

3) A process for preparation of fluticasone furoate of the formula (I)

comprising
S-hydroxymethyl 6a,9a-difluoro-16a-methyl-3-oxo-11ß-hydroxy-17a-[(2-furoyl)oxy]-1,4-diene-17ß-carbothioate of formula (II)

4) A process for preparation of fluticasone furoate of the formula (I)

comprising
d) reacting 6a,9a-difluoro-16a-methyl-3-oxo-11ß-hydroxy-17a-[(2-furoyl)oxy]-1,4-diene-17ß-carbothioc acid of the formula (III)

formaldehyde optionally in the presence of base to give S-hydroxymethyl 6a,9a-difluoro-16a-methyl-3-oxo-11ß-hydroxy-17a-[(2-furoyl)oxy]-1,4-diene-17ß-carbothioate of the formula (II),

e) optionally isolating S-hydroxymethyl 6a,9a-difluoro-16a-methyl-3-oxo-11ß-hydroxy-17a-[(2-furoyl)oxy]-1,4-diene-17ß-carbothioate of the formula (II),
f) reacting S-hydroxymethyl 6a,9a-difluoro-16a-methyl-3-oxo-11ß-hydroxy-17a-[(2-furoyl)oxy]-1,4-diene-17ß-carbothioate of the formula (II) with nucleophilic fluorination reagent to give fluticasone furoate of the formula (I).

5) The process according to claim 2 and 4, wherein the base used is organic or inorganic base.

6) The process according to claim 5, wherein the organic base is selected from triethyl amine, diethanolamine, pyridine.

7) The process according to claim 5, wherein the inorganic base is selected from sodium hydroxide, sodium hydrogen carbonate, sodium carbonate, potassium hydroxide, potassium hydrogen carbonate, potassium carbonate, ammonia and ammonium carbonate.

8) The process according to claim 4, wherein selective nucleophilic fluorination reagent is selected from bis(2-methoxyethyl)aminosulfur trifluoride (DeoXo-Fluor), diethylamino sulphur trifluoride (DAST), dimethylaminosulfur trifluoride (Methyl DAST), 2,2-difluoro-l,3-dimethylimidazolidine (DFI), hexafluoropropyldiethylamine (MEC-81) and N,N-Diisopropylethylamine trihydrofluoride.