Specification
Field of the Invention
The present invention relates to an improved process for preparing (4S, 6S)-4-(ethylamino)-5,6-dihydro-6-methyl-4H-thieno-[2,3-b]Aiopyran-2-sulfonamide-7,7-dioxide (Dorzolamide) and its intermediates.
Background of the Invention
Dorzolamide, chemically known as (4S, 6S)-4-(etfiylamino)-5,6-dihydro-6-metfiyl-4H-thieno-[2,3-b]thiopyran-2-sulfonamide-7,7-dioxide was first disclosed in US 4,797,413. The pharmaceutically acceptable salt of Dorzolanude is its hydrochloride salt. Dorzolamide HCl (I) is a carbonic anyhdrase inhibitor used for treating or ameliorating ocular hypertension.
US 4,797,413 discloses two schemes for making Dorzolamide as shown in Schane 1 and Scheme 2. According to Scheme 1, Dorzolamide is prepared from Thiophene 2- thiol comprising reduction of keto sulfone at RT at ovemight stirring followed by oxidation using oxone and fmal separation using column chromatogr{hy. Whereas in the other process Dorzolamide is prepared from aliphatic hydroxy 1 followed by separation of trans isomer.
The processes disclosed above are longer, multi step, involving use of oxone and column chromatogrhy, vsich is not commercially feasible, whereas in Scheme 2 water is added into reaction mass consisting of concentrated sulfuric acid, which is a highly exothermic reaction.
US 5,688,968 discloses the process for preparation of dorzolamide from 4'hydroxy sulfone in seven steps as given in Scheme 3. The reaction involves Ritter reaction followed by formation of dorzolamide hydrochloride by using chlorosulphonic acid and thionyl chloride in a series of steps.
The process uses chiral hydroxy sulfone as starting material, vsdiich is a costly reagent and involves use of chlorosulphonic acid and thionyl chloride, which are not industry friendly reagents.
US 5,157,129 discloses another alternate process for preparing dor2X)lamide as given in Scheme 4. The process involves thiophene as starting material which is converted to dorzolamide in 8 steps involving butyllithium for making &e lithium salt of thiophene and borane in presence of oxoborolidine for reduction of keto (xxiii) form to hydroxy form (xxiv).
The process involves butyllithium, vsdiich is a pyrophoric chemical and uses borane in presence of oxaborolidine catalyst, vvdiich is art expensive reagent to be used, thereby making the process unamenable for industrial scale production.
Another process of making dorzolamide is disclosed in US 7,030,250. The process as given in Scheme 5 involves protection of nitrogen by chloroacetyl chloride followed by a series of reactions to form final dorzolamide by deprotection of nitrogen.
The process uses advance intermediate (xxviii), whichris a costly intennediate to start with and uses protection and deprotection steps, which affects the impurity profile of the final molecule.
PCT application WO 2008/135770 discloses another procras for preparing dorzolamide as given in Scheme 6. The process involves oxidation of sulfide (viii) to sulfone (iv) and Ritter reaction to form dorzolamide.
The use of gaseous ammonia to quench excess sulphuric acid is not advisable on industrial scale as gaseous ammonia is irritating to eyes, nose and tiiroat The reaction also involves unnecessaiy filtration of ammonium sulphate, thus formed.
In light of the foregoing discussion there still exists a need for an improved process for large scale production of dorzolamide that overcomes the drawbacks associated with the existing processes.
Objects and Summary of the Invention
The first object of the present invention is to prepare highly pure (4S, 6S)-4-(ethylamino)-5,6-dihydro-6-methyl-4H-thieno-[2,3-b]thiopyran-2-sulfonamide-7,7-dioxide by a simple commercial process.
Another object of the present invention is to prepare (4S, 6S)-4-(ethylamino)-5,6-dihydro-6-methyl-4H-thieno-[2,3-b]thiopyran-2-sulfonamide-7,7-dio7dde by a novel process employing an intermediate 4-hydroxy-6-methyl-5,6-dihydro-4H-thieno[2,3-6]thiopyran-2-sulfonamide-7,7-dioxide of formula (iv).
Yet another object of the present invention is to disclose a novel process for preparing said intermediate 4-hydroxy-6-methyl-5,6-dihydro-4H-thieno[2,3-6]thioityran-2-sulfonamide-7,7-dioxide of formula (iv).
Still another object of the present invention is to prepare (4S, 6S)-4-(ethylamino)-5,6-dihydro-6-methyl-4H-thieno-[2,3-b]thiopyran-2-sulfonamide-7,7-dioxide hydrochloride employing the said intermediate 4-hydroxy-6-methyl-5,6-dihydro-4J¥-thifflio[2,3-6]thiopyran-2-sulfonamide-7,7-dioxide of formula (iv) by using a simple, economic and industrially scalable process
Yet another object of the invention is to separate the cis isomer of (4S, 6S)-4-(ethylamino)-5,6-dihydro-6-methyl-4H-thieno-[2,3-b]tfiiopyran-2-sulfonamide-7,7-
dioxide to maximize the yield of pure trans (4S, 6S)-4"(ethylamino)-5,6-dihydro-6-methyl-4H-thieno-[2,3-b]thiopyran-2-sulfonaniide-7,7-dioxide.
The above and other objects of fte present invention are further attained and sufrted by the following embodiments described herein. However, the scope of the invention is not restricted to the described embodiments herein after.
In accordance with one embodiment of the present invention, Aere is provided a process for preparing (4S, 6S)-4-(ethylwnino)-5,6-dihydro-6-methyl-4H-thieno-[2,3-b]thiopyran-2-sulfonamide-7,7-dioxide comprising oxidizing 6-metiiyl-4-oxo-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide (ii) to give 6-methyl-4-oxo-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide-7,7-dioxide (iii)| reducing 6-methyl-4-oxo-5,6-dihydro-4H-thieno[2,3-b]tiiiopyran-2-sulfonamide-7,7-dioxide (iii) to give 4-hydroxy-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonde-7,7-dioxide (iv), reacting 4-hydroxy-6-methyl-5,6-dihydro-4H-thieno[2,3-b]tiiiopwan-2-sulfonamide- 7,7-dioxide (iv) with acetonitrile in presence of acid to form N-(6-inethyl-7,7-dioxido-2-sulfamoyl-5,6-dihydro-4H-thieno[2,3-b]tiiiopyran-4-yl)acetamide (y), followed lyy reducing tiie N-(6-methyl-7,7-dioxido-2-sulfamoyl-5,6-dihydro-4H-thieno[2,3-b]tiiiopyran-4-yl)acetamide (v) to give racemic mixture of 4-(ethylamino)6-methyl-5,6-dihydroxy dihydro-4H-thieno[2,3,b]thiopyran -2-sulfonamide-7,7-dioxide (vi) (Racemic dorzolamide), subsequently separating trans (4S, 6S)-4-(ethylamino)-5,6-diltydro-6-methyl-4H-thieno-[2,3-b]thiopyran-2-sulfonamide-7,7-dioxide from racemic (4S, 6S)-4-(ethylamino)-5,6-dihydro-6-methyl-4H-thieno-[2,3-b]1hiopyran-2-sulfonamide-7,7-dioxide (dorzolamide) by making acid addition salt with carboxylic acid and r«iolving with a suitable resolving ag«it to obtain pure trans (4S, 6S)-4-(ethylamino)-5,6-dihydro-6-methyl-4H-thieno-[2,3 -b]1hiopyran-2-sulfonamide-7,7-dioxide (vii).
In accordance with another embodiment of the present invention, there is provided a novel process for synthesis of intermediate 4-hydroJO'-6-methyl-5,6-dihydro-4i/-thieno[2,3-fe]thiopyran-2-sdfonamide-7,7-dioxide (hydroxy sulfone (iv)) from 6-methyl-4-oxo-5,6-dihydro-4i/-thieno[2,3-6]thiopyran-2-sulfonamide (keto sulfide (ii)). The
reaction proceeds by oxidation of 6-methyl-4-oxo-5,6-dihydro-4//-thieno[2,3-i]thiopyran-2-sulfonanude (keto sulfide (ii)) to form 6-methyl-4-oxo-5,6-dihydro-4H-thieno[2,3-6]thiopyran-2-sulfonamide-7,7-dioxide (keto sulfone (iii)) followed by reduction to form 4-hydroxy-6-methyl-5,6-dihydro-4H-thieno[2,3-6]thiopyran-2-sulfonamide-7,7-dioxide (iv) (hydroxy sulfone). The reaction may be done with or without isolating the intermediate 6-methyl-4-oxo-5,6-dihydro-4if-thieno[2,3-6]thiopyran-2-sulfonamide-7,7-dioxide (keto sulfone (iii)).
In accordance with still another embodiment of Ihe present invention there is provided a process for preparing the intermediate 4-hydroxy-6-methyl-5,6-dihydro-4//-thieno[2,3-Z>]thiopyran-2-sulfonamide-7,7-dioxide (iv) from 6-methyl-4-oxo-5,6-dihydro-4H-thieno[2,3-6]thiopyran-2-sulfonamide (ii) comprising tl steps of oxidizing 6-methyl-4-oxo-5,6-dihydro-4i/-thieno[2,3-6]thiopyran-2-sulfonwnide (ii) to give 6-methyl-4-oxo-5,6-dihydro-4H-thieno[2,3-6]thiopyran-2-sulfonamide-7|7-dioxide (iii) and rediwing 6-methyl-4-oxo-5,6-dihydro-4iy-thieno[2,3-6]thiopyran-2-suIfonamide-7,7-dioxide (iii) to give 4-hydroxy-6-methyl-5,6-dihydro-4H-thienol2,3-6]thiopyran-2-sulfonamide-7,7-dioxide (iv).
In accordance with still anoer embodiment of the present invention, there is provided trans (-) Dorzolamide hydrochloride having a purity of at least 95%, preferably at least 97%, more preferably at least 99.5%.
Detailed Description of the Invention
While tills specification concludes with claims particularly pointing out and distinctly claiming that, which is regarded as the invention, it is anticipated tiiat the invention can be more readily understood tiirough reading the following detailed descripticm of die invention and study of the included examples.
The present invention discloses an improved process for preparing (4S, 6S)-4-(ethylamino)-5,6-dihydro-6-methyl-4H-thieno-[2,3-b]thiopyran-2-sulfonamide-7,7-dioxide (dorzolamide) by a novel process employing an intermediate 4-hydioxy-6-
methyl-5,6-dihydro-4H-thieno[2,3-6]thiopyran-2-sulfonamide-7,7-dioxide Oydroxy sulfone) (formula (iv)).
The improved process for preparing dorzolamide comprise &e steps of:
a) oxidizing 6-methyl-4-oxo-5,6-dihydro-4//-thieno[2,3-6]thiopyran-2-siilfonaniide (ii) to
give 6-methyl-4-oxo-5,6-dihydro-4H-Aieno[2,3-6]tiiiopyran-2-sxilfonamide-7,7-dioxide
(iii),
b) reducing 6-me%l-4-oxo-5,6-dihydro-4H-thieno[2,3-6]tfiiopyran-2-sulfonanude-7,7-dioxide (iii) to give 4-hydroxy-6-methyl-5,6-dihydro-4H-thieno[2,3-6]thiopyran-2-sulfonamide-7,7-dioxide (iv),
c) reacting 4-hydroxy-6-methyl-5,6-dihydro-4//-thienQ[2,3-6]thiopyran-2-sulfonamide-7,7-dioxide (iv) with acetonitrile in presence of acid to form iV-(6-methyI-7,7-dioxido-2-sulfamoyl-5,6-dihydro-4i/-thieno[2,3-6]tfiiopyran-4-yl)fipetamide(v),
d) reducing JV-(6-methyl-7,7-dioxido-2-sulfamoyI-5,6-dihydro-4H-thieno[2,3-
6]thiopyran-4-yl)acetamide (v) to give racemic mixture of 4-(etiiylamino)6-meAyl-5,6-
dihydroxy dihydro-4H-thieno[2,3,b]thiopyran -2-sulfonamide-7,7-dioxide (vi) (racemic
dorzolnide),
e) separating trans dorzolamide from racemic Dorzolamide l making acid addition salt with carboxylic acid, and
f) obtaining pure trans dorzolamide (vii) by resolving with a suitable resolving agoit.
Further, the present invention provides a novel process for synAesis of the intwmediate 4-hydroxy-6-methyl-5,6-dihydro-4i/-thieno[2,3-6]thiopyran-2-sulfonamide-7,7-dioxide (hydroxy sulfone (iv)) from 6-methyl-4-oxo-5,6-dihydro-4H-thi«io[2,3-&]tiiiqtyran-2-sulfonamide (keto sulfide (ii)). The reaction proceeds by oxidation of 6-methyl-4-oxo-5,6-dihydro-4jiy-thieno[2,3-61thiopyran-2-sulfonamide (keto sulfide (ii)) to form 6-methyl-4-oxo-5,6-dihydro-4H-thieno[2,3 -6]thiopyran-2-sulfonamide-7,7-dioxide (keto sulfone (iii)) followed by reduction to form 4-hydroxy-6-methyl-5,6-dihydro-4H-thieno[2,3-6]thiopyran-2-sulfonamide-7,7-dioxide (hydroxy svdfone (iv)).
The oxidizing agent used for oxidation of (ii) to (iii) is selected from per acicb such as peroxy benzoic acid, m-chloro per benzoic acid, peralthiopvran-4-vnacetamide
To 4-hydroxy-6-methyl-5,6-dihydro-4if-thieno[2,3-6]1hiopyran-2-sulfonamide-7,7-
dioxide (200 gms) in acetonitrile (2000 ml) was added sulphuric acid 98% (300 ml) drop wise at 0-5''C over a period of 45-60 minutes. The reaction mass was allowed to warm to room temperature (25-3 0°C) and stirred for 4 -5 hours. The progress of the reaction was monitored by TLC. Once the reaction was completed, the reaction mass was quenched in ice cold water (1400ml) below lOC. The reaction mass pH was adjusted to 7.0-8.0 using aqueous ammonia and stirred for 10 -15 minutes. The organic layer was separated from the reaction mixture, and distilled out the solvent completely under vacuum. Water was added to the resultant residue and stirred for 10 minutes. The title compound was isolated from the water by filtration (175 gms)
Exaniple-4
Preparation of 4-retfavl amino')-6-methvl-5.6-dihvdro-4/r-thienor2.3-61thiopvran-2-sulfonamide-7.7-dioxide maleate salt
a) A suspension of iV-(6-methyl-7,7-dioxido-2-sulfamoyl-5,6-dihydro-4H-thieno[2,3-6]thiopyran-4-yl)acetamide (200 gms) in tetrahydrofuran 1000 ml was cooled to -SC and sodium borohydride (70 gms) was added portion wise over a period of 20-30
minutes by maintaining temperature less than 5°C. Reaction mass was stirred for 15-20 minutes. Boron trifluoride diethyletherate (300ml) was added dropwise by maintaining the temperature below 5°C over a period of 80-90 minutes. The reaction mass was stirred for 3-4 hours at room temperature. Reaction progress was monitored by HPLC. The reaction mass was cooled to 0°C and 300 ml of methanol was added followed by IM sulphuric acid (2000 ml). The reaction mass was stirred at 40-45°C for 50-60 minutes. The organic solvent was distilled under reduced pressure. The reaction mass was cooled to 5-10°C and pH adjusted to 7.0-8.0 using sodium hydrpxide solution. The material was extracted twice with ethyl acetate (Chiral HPLC Purity 80:20). To this ethyl acetate solution 100 gms of maleic acid was added and the reacon mass was stirred for 2 hrs at reflux temperature. Cooled the reaction mass and filtered. The resultant crude maleate salt was purified with water to get rid of the cis isomer to obtain pure compound (Chiral HPLC: 99.9 :< 0.1:: Trans: Cis.).
b) The above obtained maleate salt was treated with sodium hydroxide solution pH 7.5-8.0) at room temperature for 25-30 minutes and filtered the reaction mass to get the racemic Dorzolamide. (115 gms) (Chiral HPLC purity 99.8 %:0.2% ::trans:cis).
Example-5
Preparation of Dorzolamide hydrochloride
a) A mixture of 4-(ethyl amino)-6-methyl-5,6-dihydro-4H-thieno[2,3-6]thiopyran-2-
sulfonamide-7,7-dioxide (75 gms), isopropanol (600 ml) and acetonitrile (325 ml) was
heated to 70''C. Di-para toluoyl (L) tartaric acid (35.8 gms) was added at 70°C. The
reaction mass was refluxed for 1 hour and cooled to room temperature and stirred for 60-
90 minutes. The taratrate salt of Dorzolamide was isolated by filtration and reciystallized
in isopropanol andacetonitrile(34 gms).
trans(-) Dorzolamide di-p-toluoyl-L-taratrate >99.5%
trans (+) Dorzolamide di-p-toluoyl-L-taratrate <0.5% by HPLC
b) Dorzolamide di-p-toluyl L-tartate salt (28 gms) was taken into ethyl acetate (200
ml) and basified with sodium bicarbonate solution. Reaction mass was stirred for 15-20
minutes at room temperature and the layers were separated. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were distilled out completely under reduced pressure .The resultant residue was dissolved in methanol and treated with isopropanol/ hydrochloride and stirred for 40 minutes and filtered to get the title compound (18 gms).
Example-6
One Dot synthesis of 4-hvdroxv-6-mevl-5.6-dihvdro-4i?-thienof2.3-61thiopvran-2-sulfonamide-7.7-dioxi4e
A suspension of 6-methyl-4-oxo-5,6-dihydro-4//-tiiieno[2,3-6]thiopyran-2-sulfonamide (100 gms), 5 gms of sodium tungstate dihydrate in ethy| acetate (400 ml) and water (SO ml) was cooled to 20°C. To the above cooled reaction mass hydrogen peroxide was added over a period of 45 minutes by maintaining the temperte less than 20°C. The reaction mass was stirred for 45-60 minutes. The reaction progress was monitored by TLC. ITie excess hydrogen peroxide was destroyed by adding the aqueous sodium sulphite and stirred for 30 minutes. Methanol (100 ml) was added to the above reaction mass and cooled to lOC. Sodium borohydride (7.5 gms) was added in lots by maintaining the temperature less than 20''C. The reaction mass was stirred for 30-45 minutes, and the reaction progress was monitored by TLC. The reaction mass was kept at room temperature and separated the layers and extracted the aqueous layer twice with ethyl acetate. Combined organic layers and solvent was distilled out completely under vacuum. Water was added to the resultant residue and stirred for 20-30 minutes and filtered the reaction mass to get the title compound (95 gms).
Certain modification and improvements of the disclosed invention will occur to those skilled in the art without darting from the scope of invaition, wiiich is limited only by the appended claims.
We Claim:
1 A process for preparing (4S, 6S)-4-(ethylamino)-5,6-dihydro-6-methyl-
4H-thieno-[2,3-b]thiopyran-2-sulfonamide-7,7-dioxide (Donsolamide) comprising:
a) oxidizing 6-methyl-4-oxo-5,6-dihydro-4H-thieno[2,3-6]1hiopyran-2-sulfonamide (ii) to give 6-methyl-4-oxo-5,6-dihydro-4H-thieno[2,3-6]thiopyran-2-sulfonamide-7,7-dioxide (iii);
b) reducing 6-methyl-4-oxo-5,6-dihydro-4if-tfiieno[2,3-6]thiopyran-2-sulfonamide-7,7-dioxide (iii) to give 4-hydroxy-6-meftyl-5,6-diltydro-4H-thieno[2,3-i]thiopyran-2-sulfonamide-7,7-dioxid9(iv);
c) reacting 4-hydroxy-6-methyl-5,6-dihydro-4Jy'-thieno[2,3-6]thiopyran-2-
sulfonamide- 7,7-dioxide (iv) with acetonitrile in presence of acid to form iV-(6-
methyl-7,7-dioxido-2-sulfamoyl-5,6-dihydro-4//-thi«io[2,3-&]thiopyran-4-
yl)acetamide (v); I
d) reducing A-(6-methyl-7,7-dioxido-2-sulfamoyl-5,6-dihydro-4H-
thieno[2,3-6]thiopyran-4-yl)acetamide (v) to »ve racemic mixture of 4-
(ethylamino)6-methyl-5,6-dihydroxy dihydroH-thieno[2,3,b]thiopyran -2-
sulfonamide-7,7-dioxide (vi) (Racemic Dorzolamide);
e) separating trans Dorzolamide from racemic Dorzolamide by making acid addition salt with carboxylic acid; and
f) obtaining pure trans Dorzolamide (vii) by resolving with a suitable resolving agent.
2. The process according to claim 1, wherein the oxidation is carried out using oxidizing agent selected from per acids consisting of peroTQ benzoic acid, m-chloro per benzoic acid, peracetic acid, peroxytrifluoro acetic acid, perboric acid, performic acid, peroxy maleic acid, peroxy dichloro maleic acid and hydrogen peroxide.
3. The process according to claim 2, wherein the oxidizing agent is hydrogen peroxide.
4. The process according to claim 1, wherein the oxidation is optionally catalyzed by tungstic acid or a salt of tungstic acid.
5. The process according to claim 4, wherdn the salt of tungstic acid is sodium tungstate.
6. The process according to claim 1, wherein tiiie oxidation is carried out in presence of a solvent selected from the group consisting of esters such as ethyl acetate, isopropyl acetate; alcohols like methanol, ethanol, nropanol, isopropanol, butanol; ethers like diethylether. diisopropylether, tetrahydrofuran, 1,4-dioxan; chlorinated solvents like dichloromethane, chloroform, monochlorp benzene; acids such as acetic acid, sulphuric acid, trifluoroacetic acid; hydrocarbons such as toluene, benzene, xylene and a mixture thereof
7. The process according to claim 6, wdierein the solvent is ethyl acetate.
8. The process according to claim lb, wherein Ae reduction is carried out using a reducing agent selected from metal borohydride such as sodium borohydride, lithium borohydride, potassium borohydride.
9. The process according to claim 8, wiierein the reducing agent is sodium boro hydride.
10. The process according to claim lb, wiierein the reduction is carried out in presence of a solvent selected from the group of protic solvents such as water, ethanol,
methanol, isopropanol, n-propanol, butanol; and mixture of alcohol with hydrocarbons and chlorinating solvaits such as benzene, toluene, dichloromethane, mono chlorobenzene and mixture thereof
11. The process according to claim 10, wdierein the solvent is methanol.
12. The process according to claim lb, wherein the reduction of 6-methyI-4-oxo-5,6-dihydro-4H-thieno[2,3-6]thiopyran-2-sulfonamide 7,7-dioxide (iii) proceeds with or without isolating the same.
13. The process according to claim 3, wherein the process further comprises of optionally decomposing excess peroxide present in the reaction mass after the oxidation, by quenching the reaction mass in a solution of sodium sulphite, manganese dioxide, sodium bisulphate, sodium thiosulphite, preferly sodiiun sulphite.
14. The process according to claim 1, vsierein the acid is sulphuric acid.
15. The process according to claim 14, .wdierein the sulphuric acid is neutralized by using organic bases such as methylami|ie, etfaylamine, triethytamine or inorganic bases such as aqueous ammonia, sodium hydroxide, potassium ldroxide, potassium carbonate, sodium carbonate, preferably aqueous ammonia.
16. The process according to claim Id, wherein the reduction is carried out using the reducing agent selected from sodium borohydride or lithium aluminium hydride with borontrifluoride diethyl ether or borane methyl sulfide, preferably sodium borohydride with borontrifluoride diethyl ether.
17. The process according to claim 1, wherein the carboxylic acid is selected from maleic acid, benzoic acid, fumaric acid, salicylic acid and p-hydroxy benzoic acid.
18. The process according to claim 17, wherein the carbox/lic acid is maleic acid.
19. The process according to claim 1, wherein the acid addition salt is further purified in water.
20. The process according to claim 1, where in the resolving agent used is di-para toluoyl-L(-)- tartaric acid, D(+)-tartaric acid, D(+)- mandelic acid, preferably di-para-toluoyl-L(-) -tartaric acid.
21. The process according claim 1, wiierein the resolution is carried out in a solvent selected from a polar protic or aprotic solvent or a nonpolar solvent or mixtures thereof
22. The process according to claim 21, wherein Ae solvent used is a mixture of isopropanol and acetonitrile.
23. The process according to claim 1, vserein the Dorzolamide is further converted into hydrochloride salt using hydrochloric acid gas in alcoholic solvent.
*
24. The process according to claim 23, vserein the alcoholic solvent is isopropanol.
25. A process for preparing 4-hydroxy-6-methyl-5,6-dihydro-4H-thieno[2,3-*]thiopyran-2-sulfonamide-7,7-dioxide of formula (iv) comprising:
a) oxidizing 6-methyl-4-oxo-5,6-dihydro-4-1hieno[2,3-6]thiopyran-2-sulfonamide (ii) to give 6-methyl-4-oxo-5,6-dihydro-4H-thieno[2,3-6]thiopyran-2-sulfonamide-7,7-dioxide (iii); and
b) reducing 6-methyl-4-oxo-5,6-dihydro-4/ir-thieno[2,3-i!»]thiopyran-2-sulfonamide-7,7-dioxide (iii) to give 4-hydroxy-6-methyl-5,6-dihydro-4H-thieno[2,3 -6]thiopyran-2-sulfonamide-7,7-dioxide (iv).
26. The process according to claim 25, verein the oxidation is carried out using oxidizing agent selected from group consisting of peroxy boizoic acid, m-chloro per benzoic acid, peracetic acid, peroxytrifluoro acetic acid, perboric acid, performic acid, peroxy maleic acid, peroxy dichloro maleic acid and hydrogm peroxide.
27. The process according to claim 26, wherein the oxidizing agent is hydrogen peroxide.
28. The process according to claims 25, verein tiie oxidation is catalyzed by tungstic acid or a salt of tungstic acid.
29. The process according to claim 28, verein the salt of tungstic acid is sodium tungstate.
30. The process according to claim 26, wdiern the oxidation is carried out in presence of a solvent selected from the group of estersuch as ethyl acetate, isopropyl acetate, alcohols like methanol, ethanol, n-propanol, ifopropanol, butanol, ethers like diethylether, di-isopropylelher, tetrahydrofuron, 1,4-dioxan, chlorinated solvoits like dichloromethane, chloroform, monochloro benzene, acids such as acetic acid, sulphuric acid, trifluoroacetic acid, hydrocarbons such as toluene, hmzme, xylene and the mixtures thereof.
31. The process according to claim 30, wdierein the solvent is ethyl acetate.
32. The process according to claim 25, wiierein the reduction is carried out using reducing agent selected from a group consisting of metal borohydride such as sodium borohydride, lithium borohydride, potassium borolqrdride, preferably sodium borohydride
33. The process according to claim 25, vvdierein the reduction is carried out in presence of a solvent selected from the group consisting of protic solvents such as water.
ethanol, methanol, isopropanol, n-propanol, butanol, hydrocarbons and chlorinating solvents with alcohol such as benzene toluene, dichloromethane, mono chlorobenzene and mixture thereof.
34. The process according to claim 33, wherein the solvent is methaiwl.
35. The process according to claim 25, wherein the reaction proceeds with or
without isolating 6-methyl-4-oxo-5,6-dihydro-4H-thieno[2,3-6]thiopyran-2-suifonamide-
7,7-dioxide (iii).