DESC:FIELD OF THE INVENTION:
The present invention provides a process for preparation and purification of thioacid (III) intermediate which is used in the preparation of fluticasone propionate (I).
BACKGROUND OF THE INVENTION:
Fluticasone propionate (I) is a synthetic corticosteroid having the chemical name S-fluromethyl-6a, 9a-difluro-11ß-hydroxy-16a-methyl-17a- propionyloxy-3-oxo-androsta-1,4-diene-17ß-carbothioate. It has been used as an anti-inflammatory and antipruritic agent.

Fluticasone propionate (I) has been prepared by reacting 6a, 9a-difluro-11ß-hydroxy-16a-methyl-17a- propionyloxy-3-oxo-androsta-1,4-diene-17ß-carbothioic acid (referred as thioacid, III) with halofluoromethane.

There are various methods described in the literature for preparation of thioacid (III).
The US patent 4335121 describes a process to prepare thioacid intermediate (III) by aminolysis of 17ß-[(N,N-dimethylcarbamoyl)thio]carbonyl-6a,9a-difluoro-11ß-hydroxy-16a-methyl-17a-propionyloxy-3-oxoandrosta-1,4-diene (referred as thioanhydride, II) with excess primary amine such as ammonia or secondary amine such as diethylamine or pyrrolidine without using organic solvent.
Another US patent 7214807 describes reaction of thioanhydride (II) with hydrolyzing agents such as alkoxide salts, thioalkoxide salts, optionally hydrated sulphide salts, and mixtures thereof followed by acid treatment to obtain thioacid (III).
The US patent 7208613 describes treatment of thioanhydride (II) with alkali metal carbonates such as sodium, potassium, cesium or lithium carbonate in alcoholic solvent followed by acid treatment to get thioacid (III).
An Indian patent 251843 discloses a process to prepare thioacid intermediate (III) by treating thioanhydride (II) with an amine consisting of aliphatic amines, aromatic amines, cyclic amines or mixtures thereof. The crude thioacid (III) intermediate is crystallised from a mixture of acetone/ethyl acetate to obtain pure thioacid (III).
The PCT publication WO 2012/029077 describes reaction of thioanhydride (II) with morpholine or piperidine in ethyl acetate or N-methyl piperdine as a solvent to provide thioacid (III) which was crystallised from mixture of methyl ethyl ketone/toluene/ethylacetate (1:1:1) to provide pure thioacid (III).
OBJECTIVE OF THE INVENTION:
An object of the present invention is to provide a process for preparation of thioacid (III) with high yield.
Another object of the present invention is to provide a process for purification of thioacid (III).
SUMMARY OF THE INVENTION:
The present invention is directed to provide a process for preparation of thioacid (III) intermediate comprising reacting thioanhydride (II) with piperidine in ester solvent.
The present invention further directed to provide a process for purification of thioacid (III) intermediate comprising treatment of thioacid (III) intermediate with base followed by washing with hydrocarbon solvent and then acid treatment.

DETAILED DESCRIPTION OF THE INVENTION:
In an embodiment of the present invention provides a process for preparation of thioacid (III) comprising;
i) reacting thioanhydride (II) with piperidine in ester solvent,
ii) acidifying the reaction mixture with acid,
iii) separating the ester layer and
iv) concentrating the solution.
The present invention is shown in the below scheme.

Scheme-I
According to the present invention, thioanhydride (II) may be prepared by any of the process known in the patents US 4,335,121, US 7,214,807 and US 7,208,613.
Thioanhydride (II) is reacted with piperidine at about 5-40°C preferably at 20-30°C.
The ratio of piperidine with respect to thioanhydride (II) is 1-10 times (weight/volume), preferably 3-5 times (weight/volume).
According to the present invention, ester solvent comprises ethyl acetate, methyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, pentyl acetate, methyl propionate, ethyl propionate and the like; preferably ethyl acetate.
The ratio of ester solvent to thioanhydride is 10-30 times (weight/volume), preferably 15-25 times (weight/volume).
After completion of reaction, the reaction mixture is acidified with acid to adjust the pH 1-2 wherein acid is selected from organic acid or inorganic acid wherein organic acid comprises formic acid, acetic acid and the like; inorganic acid comprises hydrochloric acid, sulphuric acid and the like; preferably hydrochloric acid.
The separated ester layer is subjected to partial concentration by distillation under vacuum. Alcoholic solvent is added to the partial concentrated content and co-distilled under vacuum. The alcohol solvent comprises methanol, ethanol, isopropanol or n-butanol.
In an another embodiment of the present invention provides a process for purification of thioacid (III) comprising;
i) stirring a solution of thioacid (III) in a mixture of ester/alcohol solvent with base,
ii) adding hydrocarbon solvent,
iii) separating the basic aqueous layer,
iv) adding ester solvent to basic aqueous layer,
v) acidifying the aqueous layer of bibasic solution,
vi) separating organic layer,
vii) adding hydrocarbon solvent as an anti-solvent and
viii) isolating pure thioacid (III).
The ester solvent is selected from ethyl acetate, methyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, pentyl acetate, methyl propionate, ethyl propionate and the like; preferably ethyl acetate.
The alcohol solvent is selected from methanol, ethanol, isopropanol and the like.
The hydrocarbon solvent is selected from aliphatic hydrocarbon or aromatic hydrocarbon. The aliphatic hydrocarbon is selected from hexane, heptane, cyclohexane and the like. The aromatic hydrocarbon is selected from benzene, xylene, toluene and the like; preferably toluene.
According to the present invention, base is selected from alkali or alkaline metal hydroxide, carbonate and/or bicarbonate thereof wherein hydroxide comprises lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide; carbonate comprises sodium carbonate, potassium carbonate, calcium carbonate; bicarbonate comprises sodium bicarbonate, potassium bicarbonate; preferably sodium carbonate.
Basic layer of step (i) shows HPLC purity of thioacid (III) up to 90%. After washing the basic layer with hydrocarbon solvent HPLC purity of thioacid (III) increases to = 96%.
In step (v) the aqueous layer is acidified with acid to adjust the pH to 1-2. The acid is selected from organic acid or inorganic acid wherein organic acid comprises formic acid, acetic acid and the like; inorganic acid comprises hydrochloric acid, sulphuric acid and the like; preferably hydrochloric acid.
An anti-solvent is selected from aliphatic hydrocarbon or aromatic hydrocarbon. The aliphatic hydrocarbon is selected from hexane, heptane, cyclohexane and the like; preferably cyclohexane. The aromatic hydrocarbon is selected from benzene, xylene, toluene and the like.
Pure thioacid (III) can be isolated by filtration, concentration or evaporation.
According to the present invention, the HPLC purity of pure thioacid (III) is = 97%.
According to the present invention, thioacid (III) intermediate is further converted into fluticasone propionate by any of the process known from the literature such as US 4,335,121, Phillips et al, J. Med. Chem., 1994, 37, 22, 3717-3729, US 7,214,807 and US 7,208,613.
The present invention is described in the following examples however it should be noted that the scope of the present invention is not limited by the examples.
EXPERIMENTAL SECTION:
Example-1:
a) Preparation of 6a, 9a-difluro-11ß-hydroxy-16a-methyl-17a- propionyloxy-3-oxo- androsta-1,4-diene-17ß-carbothioic acid (III)
17ß-[(N, N-dimethylcarbamoyl)thio]carbonyl-6a,9a-difluoro-11ß-hydroxy-16a-methyl-17a-propionyloxy-3-oxoandrosta-1,4-diene (II) (65 gm) was stirred with ethyl acetate (650 ml), and piperidine (227.5 ml) at 20-30°C for four hours. Reaction mixture was cooled to 5°C then the pH was adjusted to 1-2 using aqueous hydrochloride (552 ml; 227 ml of HCl: 325 ml of water) and stirred. Ethyl acetate layer was separated and distilled out up to 65-100 ml under vacuum and then methanol (130 ml) was added and co-distilled up to 65-100 ml under vacuum.
b) Purification of of 6a, 9a-difluro-11ß-hydroxy-16a-methyl-17a- propionyloxy-3-oxo- androsta-1,4-diene-17ß-carbothioic acid (III)
Sodium carbonate solution (26 gm in 325 ml of water) was added to the solution of thioacid (III) in example 1(a) (HPLC purity of thioacid (III) in aqueous layer was 90%). Toluene (520 ml) was added, stirred and layers were separated (HPLC purity of thioacid (III) in aqueous solution was 96.4%). Ethyl acetate (975 ml) was added to the separated aqueous layer and then pH was adjusted to 1-2 using aqueous HCl (1:1). Separated ethyl acetate layer was distilled out under vacuum up to 65-130 ml then cyclohexane was added (520 ml). Solid was filtered, washed with cyclohexane (130 ml) and dried under vacuum. Yield: 46.5 gm (83.31%); Purity: 97.30% (HPLC).
Example-2:
Preparation of 6a, 9a-difluro-11ß-hydroxy-16a-methyl-17a- propionyloxy-3-oxo-androsta-1,4-diene-17ß-carbothioic acid (III)
Piperidine (50 ml) was added to the suspension of 17ß-[(N,N-dimethyl carbamoyl) thio]carbonyl-6a,9a-difluoro-11ß-hydroxy-16a-methyl-17a-propionyloxy-3-oxoandrosta-1,4-diene (II) (20 gm) in acetone (100 ml) at 28°C and stirred for 3 hours 45 minutes at the same temperature. Ethyl acetate (200 ml) was added to the reaction mixture, cooled to 0°C then pH was adjusted to 1-2 using aqueous HCl (150 ml; 50 ml HCl: 100 ml water) and stirred at 20-30 °C. The separated ethyl acetate layer was distilled out under vacuum up to 20-30 ml. Cyclohexane (200 ml) was added and stirred. Solid was filtered, washed with cyclohexane and dried under vacuum. Yield: 20 gm; Purity: 89.56% (HPLC).
Example-3:
a) Preparation of 6a, 9a-difluro-11ß-hydroxy-16a-methyl-17a- propionyloxy-3-oxo-androsta-1,4-diene-17ß-carbothioic acid (III)
Piperidine (525 ml) was added to the suspension of 17ß-[(N,N-dimethylcarbamoyl)thio]carbonyl-6a,9a-difluoro-11ß-hydroxy-16a-methyl-17a-propionyloxy-3-oxoandrosta-1,4-diene (II) (150 gm) in methanol (750 ml) at 0-10°C and stirred for 21-22 hours at 20-30°C. The reaction mixture was cooled to 0-5°C, dichloromethane (1800 ml) was added then the pH was adjusted to 1.5 using aqueous HCl (1425 ml; 900 ml H2O: 525 ml Conc.HCl) and stirred at 20-30°C. The separated dichloromethane layer was distilled out under vacuum then acetone (300 ml) was added and co-distilled out under vacuum. Acetone (750 ml) followed by water (750 ml) were added. Solid was filtered, washed with mixture of acetone/water (300 ml; 1:1) and suck dried. Purity: 94% (HPLC)
b) Purification of 6a, 9a-difluro-11ß-hydroxy-16a-methyl-17a- propionyloxy-3-oxo-androsta-1,4-diene-17ß-carbothioic acid (III):
Sodium carbonate (6 g in 600 ml of water) was added to the solution of thioacid (III), obtained in example-3(a), in a mixture of methanol /dichloromethane (1200 ml; 1:1) and stirred at 20-30 °C. Dichloromethane (1200 ml) was added to the separated aqueous layer and then pH was adjusted to 1.2 using aqueous HCl (1:1) and stirred. The separated dichloromethane layer was distilled out under vacuum followed by acetone (300 ml) was added and co-distilled out. A mixture of acetone/water (1200 ml; 1:1) was added. Solid was filtered, washed with mixture of acetone/water (300 ml; 1:1) and dried under vacuum. Yield: 93 gm; Purity: 96.68% (HPLC)
,CLAIMS:1. A process for preparation of thioacid (III) comprising;
i) reacting thioanhydride (II) with piperidine in ester solvent,
ii) acidifying the reaction mixture with acid,
iii) separating the ester layer and
iv) concentrating the solution.
2. A process for purification of thioacid (III) comprising;
i) stirring a solution of thioacid (III) in a mixture of ester/alcohol solvent with base,
ii) adding hydrocarbon solvent,
iii) separating the basic aqueous layer,
iv) adding ester solvent to basic aqueous layer,
v) acidifying the aqueous layer of bibasic solution,
vi) separating organic layer,
vii) adding hydrocarbon solvent as anti-solvent and
viii) isolating pure thioacid (III).
3. The process according to claims 1 and 2, wherein the ester solvent is selected from ethyl acetate, methyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, pentyl acetate, methyl propionate, ethyl propionate; preferably ethyl acetate.
4. The process according to claim 2, wherein the alcohol solvent is selected from methanol, ethanol, isopropanol or butanol; preferably methanol.
5. The process according to claim 2, wherein the base is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, calcium carbonate, sodium bicarbonate or potassium bicarbonate; preferably sodium carbonate.
6. The process according to claim 2, wherein the hydrocarbon solvent is selected from hexane, heptane, cyclohexane, benzene, xylene, toluene; preferably toluene.
7. The process according to claims 1 and 2, wherein the acid is selected from formic acid, acetic acid, propionic acid, hydrochloric acid or sulphuric acid; preferably hydrochloric acid.
8. The process according to claim 2, wherein the anti-solvent is selected from hexane, heptane, cyclohexane, benzene, xylene, toluene; preferably cyclohexane
9. The process according to claim 2, wherein isolation of pure thioacid (III) carried out by filtration, evaporation or concentration.
10. The process for preparation of thioacid (III) according to any preceding claim, wherein thioacid (III) is further converted into fluticasone propionate (I).