FORM 2
THE PATENT ACT, 1970
(39 OF 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
PROCESS FOR THE PREPARATION OF DORAOLZMIDE HYDROCHLORIDE
2. APPLICANT:
a. NAME: INDOCO REMEDIES LIMITED
b. NATIONALITY: INDIAN
c. ADDRESS: Indoco House,166 C.S.T. Road, Santacruz East,
Mumbai - 400 098, Maharashtra, India
3. PREAMBLE TO THE DESCRIPTION:
The following specification particularly describes the invention and the manner in which it is to be performed.

TITLE: Process for the preparation of dorzolamide hydrochloride.
FIELD OF INVENTION:
The present invention relates to an improved process for the preparation of dorzolamide hydrochloride.
BACKGROUND OF THE INVENTION:
Dorzolamide hydrochloride is a carbonic anhydrase (CA) inhibitor. It is chemically represented by (4S,6S)-4-(ethylamino)-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide hydrochloride; and is structurally represented by Formula I.
It acts as an anti-glaucoma agent, in open-angle glaucoma and ocular hypertension. It is used in ophthalmic solutions to lower intraocular pressure (IOP).
The compound dorzolamide hydrochloride has been in the market for very long time. It is administered as a topical ophthalmic in the form of a solution and marketed under the brand name Trusopt.
Dorzolamide hydrochloride and process for its preparation are first described in the patent, US 4,797,413 (US'413 Patent) and its corresponding European patent, EP 0296879. The process described in US'413 patent involves reacting

thiophene-2-thiol with but-2-enoic acid and proceeds along with formation of
racemic 4-(emylamino)-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-
sulfonamide 7,7-dioxide (dorzolamide base).
A number of further processes for the preparation of dorzolamide hydrochloride have been devised and in many of these, as well as in the above US'413 Patent, the last step of the process involves the removal of diastereomeric impurity from the racemic mixture of dorzolamide base. To obtain pure dorzolamide hydrochloride devoid of the diastereomeric impurity of cis-isomer from the racemic compound as per the patent US'413 is subjected to column chromatography and then resolution is carried out using resolving agent di-p-toluoyl-L-tartaric acid monohydrate in n-propanol. The salt formed is treated with base to get dorzolamide base, which is reacted with ethanolic hydrochloric acid to get dorzolamide hydrochloride. The compound is further recrystallised from mixture of solvent methanol and isopropanol to get pure dorzolamide hydrochloride.
The patent US 5,688,968 describes a process for preparation of dorzolamide hydrochloride, wherein chiral hydroxyl sulfone compound having fixed chirality, proceeds via Ritter reaction to obtain dorzolamide base having mixture of cis-and trans-isomer. The compound dorzolamide base is reacted with maleic acid to isolate maleate salt of dorzolamide. The salt is again converted to base and then reacted with hydrochloric acid in ethyl acetate to get required pure trans-isomer of dorzolamide hydrochloride.
The PCT patent application WO2006038222 discloses the preparation of dorzolamide hydrochloride, wherein the cis- and trans-isomer of racemic dorzolamide base is separated using resolution via chiral salt formation with dibenzoyl-L-tartaric acid monohydrate or di-p-toluoyl-L-tartaric acid monohydrate in methanol which on neutralization results in dorzolamide base. The base is then reacted with hydrochloric acid in isopropanol to give
i

dorzolamide hydrochloride which is recrystalised in isopropanol to obtain pure dorzolamide hydrochloride.
Another US patent US 7,109,353 discloses the process for preparation of dorzolamide hydrochloride, wherein racemic 4-(ethylamino)-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide is treated with mineral acid to form the corresponding salt, which is then converted to racemic trans-4-(ethylammo)-6-memyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide and resolved with di-p-toluoyl-D-tartaric acid followed by neutralization of the chiral salt to isolate trans-(4S,6S)-4-(ethylamino)-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide. The compound trans-(4S,6S)-4-(ethylamino)-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide on reaction with hydrochloric acid in ethanol results in required trans-dorzolamide hydrochloride.
PCT patent application WO2007122130 discloses the process for preparation of (4S,6S)-4-(ethylamino)-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide, wherein racemic 4-(ethylamino)-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide having transxis diastereomeric mixture of 80:20 is treated with maleic acid in acetone to isolate racemic trans-4-(ethylamino)-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide maleate salt having transxis diastereomeric mixture of 95:5. The isolated maleate salt is then treated with base and reacted with (1S)-(+)-10-camphorsulfonic acid to get corresponding (4S,6S)-4-(ethylamino)-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide (1S)-(+)-10-camphorsulfonate salt, which is neutralized to give pure (4S,6S)-4-(ethylamino)-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide.
PCT patent application WO2008135770 discloses the process for the preparation of dorzolamide hydrochloride, wherein the racemic 4-(ethylamino)-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide is treated with

carboxylic acid selected from the group consisting of fumaric acid, benzoic acid,
acetic acid, salicylic acid and p-hydroxybenzoic acid, which selectively forms an
acid addition salt with the trans-isomer and removes the undesirable cis-isomer
from the mixture of cis and trans-isomers. The trans-4-(ethylamino)-6-methyl-
5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide acid addition
salt is converted to trans-(±)-4-(ethylamino)-6-methyl-5,6-dihydro-4H-
thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide by conventional methods. The
compound trans-(±)-4-(ethylamino)-6-methyl-5,6-dihydro-4H-thieno[2,3-
b]thiopyran-2-sulfonamide 7,7-dioxide is resolved with di-p-toluoyl-L-tartaric acid followed by neutralization of the chiral salt yields the compound (4S,6S)4-(ethylamino)-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide, which on reaction with hydrochloric acid in isopropanol results in the required (4S,6S)4-(ethylamino)-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide hydrochloride.
PCT patent application WO2010061398 discloses the process for the preparation of dorzolamide hydrochloride, wherein the racemic 4-(ethylamino)-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide is treated with maleic acid in water to get trans-dorzolamide maleate salt. The maleate salt is further neutralized and then resolution with di-p-toluoyl-L-tartaric acid followed by neutralization of the chiral salt yields (4S,6S)-4-(ethylamino)-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide. The compound (4S,6S)-4-(ethylamino)-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide on reaction with hydrochloric acid in isopropanol results in the required pure trans-dorzolamide hydrochloride.
PCT patent application WO2011101704 and corresponding Indian Patent application 426/CHE/2010 describes the process for the preparation of trans-dorzolamide hydrochloride by forming the maleate salt of racemic 4-(ethylamino)-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide. The maleate salt is further neutralized and then resolution with di-p-toluoyl-L-tartaric acid followed by neutralization of the chiral salt yields trans-

(4S,6S)-4-(ethylamino)-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide. The compound trans-(4S,6S)-4-(ethylamino)-6-methyl-5,6-dmydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide on reaction with hydrochloric acid in isopropanol results in the required trans-(S,S)-dorzolamide hydrochloride.
Indian Patent application 3431/MUM/2012 discloses the process wherein racemic 4-(ethylamino)-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide is resolved using dibenzoyl-L-tartaric acid monohydrate or di-p-toluoyl-L-tartaric acid monohydrate in methanol followed by neutralization of the chiral salt, and then the (4S,6S)-4-(ethylamino)-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide obtained is treated with hydrochloric acid in isopropanol results in the required trans-(S,S)-dorzolamide hydrochloride. The compound is further recrystallised in solvent isopropanol to isolate pure dorzolamide hydrochloride.
The prior art processes disclosed have several drawbacks in the preparation of pure trans-dorzolamide hydrochloride viz.
1. involves column chromatography for separation of diastereomer;
2. involves preparation of corresponding diastereomeric salts and converting again to base before preparation and isolation of pure trans-dorzolamide hydrochloride;
3. reacting the racemic dorzolamide base with mineral acid to isolate corresponding dorzolamide salt which is again converted to dorzolamide base and resolved using resolving agent to form the corresponding salt, isolating the chiral dorzolamide base before reacting with hydrochloric acid to obtain dorzolamide hydrochloride; and
4. reacting the racemic dorzolamide base with carboxylic acid to isolate corresponding dorzolamide salt which is again converted to dorzolamide base and resolved using resolving agent to form the corresponding salt,

isolating the chiral dorzolamide base before reacting with hydrochloric acid to obtain dorzolamide hydrochloride.
It is evident from the prior art drawbacks that to prepare pure dorzolamide hydrochloride the inventors have either used column chromatography for isolation of trans-isomer and used resolving agent to prepare pure dorzolamide hydrochloride or applied repeated chiral or diastereomeric salt preparation, use of resolving agent and converting into base and then isolating pure dorzolamide hydrochloride devoid of the diastereomeric impurity of cis-isomer.
Therefore, there remains a need in the art to develop a simple and cost effective process for the preparation of dorzolamide hydrochloride which ameliorates the above drawbacks in the prior art and makes the process industrially viable and advantageous. The present invention therefore seeks to address these issues.
The present inventors have developed an alternative process of isolating pure dorzolamide hydrochloride substantially free from the cis-isomer without using the time consuming column chromatography technique, repeated preparation of chiral salts, diastereomeric salt and converting into base before hydrochloride salt formation to isolate pure trans-(S,S)-dorzolamide hydrochloride.
OBJECTIVE OF THE INVENTION:
The object of the present invention is to provide a process for the preparation of pure dorzolamide hydrochloride substantially free from impurity of cis-isomer.
Yet another objective of the present invention is to provide a process for the preparation of dorzolamide hydrochloride without using the chiral resolving agent to remove the cis-isomer.
Yet another objective of the present invention is to provide a process for the preparation of pure dorzolamide hydrochloride by using industrially safe, environment friendly and cost effective process avoiding the repeated acid base

treatment of 4-(ethylamino)-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide.
SUMMARY OF THE INVENTION:
Accordingly, the present invention provides a process for preparing dorzolamide hydrochloride the compound of Formula I using industrially safe and cost effective process avoiding the repeated acid base treatment of 4-(ethylamino)-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide.
According to primary object of the present invention, there is provided a process for the preparation of dorzolamide hydrochloride the compound of Formula I, which comprises the steps of:
a. reacting (6S)-4-(ethylamino)-6-methyl-5,6-dihydro-4H-thieno[2,3-
b]thiopyran-2-sulfonamide 7,7-dioxide with hydrochloric acid in the
presence of solvent to isolate mixture of cis- and trans-isomer of crude
(6S)-4-(ethylamino)-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-
sulfonamide 7,7-dioxide hydrochloride;
b. treating mixture of cis- and trans-isomer of crude (6S)-4-(ethylamino)-6-
methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-
dioxide hydrochloride with an organic solvent to isolate trans-(4S,6S)-4-
(ethylamino)-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-
sulfonamide 7,7-dioxide hydrochloride substantially free from cis-
diastereomer impurity; and
c. treating the trans-(4S,6S)-4-(ethylamino)-6-methyl-5,6-dihydro-4H-
thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide hydrochloride with a
solvent to get pure (4S,6S)-4-(ethylamino)-6-methyl-5,6-dihydro-4H-
thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide hydrochloride.
These and the other objects of the present invention will be apparent from the following detailed description.

DETAILED DESCRITION OF THE INVENTION:
All the terms used in the present application, unless otherwise indicated, must be interpreted in their ordinary meaning as known in the field. Other more specific definitions for some terms used in the present application are given below and are intended to be applied uniformaly to the entire description and claims, unless otherwise indicated.
The term substantially used in the application means the compound dorzolamide hydrochloride having the impurity of the cis-isomer less than 1.0%
The term substantially used in the application means the compound dorzolamide hydrochloride having the impurity of the cis-isomer less than 0.5%.
The term substantially used in the application means the compound dorzolamide hydrochloride having the impurity of the cis-isomer less than 0.2%.
The term racemic used in the present application means the compound having mixture of cis-isomer and trans-isomer in any ratio.
The present invention provides an improved process for the preparation of (4S,6S)-4-(ethylamino)-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide hydrochloride of the Formula I, which comprises the steps of:
a. reacting (6S)-4-(ethylamino)-6-memyl-5,6-dihydro-4H-thieno[2,3-
b]thiopyran-2-sulfonamide 7,7-dioxide with hydrochloric acid in the

presence of solvent to isolate mixture of cis- and trans-isomer of crude (6S)-4-(ethylamino)-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide hydrochloride;
b. treating the mixture of cis- and trans-isomer of crude (6S)-4-(ethylamino)-
6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-
dioxide hydrochloride with an organic solvent to isolate trans-(4S,6S)-4-
(ethylamino)-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-
sulfonamide 7,7-dioxide hydrochloride substantially free from cis-
diastereomer impurity; and
c. treating the trans-(4S,6S)-4-(ethylamino)-6-methyl-5,6-dihydro-4H-
thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide hydrochloride with a
solvent to get pure (4S,6S)-4-(ethylamino)-6-methyl-5,6-dihydro-4H-
thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide hydrochloride.
In an embodiment of the present invention the compound (6S)-4-(ethylamino)-6-
methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide
containing mixture of cis- and trans-diastereomer is converted to its corresponding pharmaceutically acceptable salt by reacting with hydrochloric acid at temperature range of 0°C to 5°C to isolate crude mixture of cis- and trans-(6S)-4-(ethylamino)-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide hydrochloride.
In an embodiment of the present invention, the hydrochloric acid used for the preparation of pharmaceutically acceptable salt of the (6S)-4-(ethylamino)-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide is gaseous hydrochloric acid and the pharmaceutically acceptable salt is dorzolamide hydrochloride salt.
In an embodiment of the present invention, the reaction in step (a) is carried out in presence of solvent selected from the group consisting of methanol, isopropanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl acetate,

isopropyl acetate or a mixture thereof. In a preferred embodiment the solvent used for the preparation of hydrochloride salt is acetone.
In an embodiment of the present invention, in the reaction of step (b), the compound crude (6S)-4-(ethylamino)-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide hydrochloride is treated with an organic solvent to isolate trans-(4S,6S)-4-(ethylamino)-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide hydrochloride substantially free from cis-diastereomer impurity.
In an embodiment of the present invention, the organic solvent used for the removal of cis-diastereomer impurity is selected from the group consisting of linear or branched Ci to C4 alcohol comprising of methanol, ethanol, propanol, isopropanol, n-butanol, sec-butanol, tert-butanol and water or a mixture thereof. In a preferred embodiment the solvent used for the removal of cis-diastereomer impurity is methanol and water or mixture thereof.
In an embodiment of the present invention, the organic solvent used for the removal of cis-diastereomer impurity is methanol.
In an embodiment of the present invention, the reaction of step (b) is carried out at a suitable temperature, preferably at a temperature ranging from 30°C to the reflux temperature of the solvent used for the reaction. In a preferred embodiment, the reaction is carried out at 50°C to 70°C.
In an embodiment of the present invention, the reaction of step (b) is carried out
at a temperature in the range of 55°C to 65°C. i
In an embodiment of the present invention, the compound trans-(6S)-4-(ethylamino)-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide hydrochloride substantially free from cis-diastereomer impurity obtained from step (b) is further purified using single or mixture of solvent selected from the group of methanol, isopropanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, and water or a mixture thereof. In a preferred

embodiment the solvent used for the purification is mixture of solvent acetone and water.
In an embodiment of the present invention, the purification in the step (c) is carried out by making the slurry of the trans-(4S,6S)-4-(ethylamino)-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide hydrochloride in the preferred solvent at the temperature in the range of 50°C to 60°C.
The process of the present invention has advantage over the prior art because it
avoids using the time consuming column chromatography technique, repeated
preparation of chiral salts, diastereomeric salt and converting into base before
hydrochloride salt formation. Further the process has advantage as to isolate pure
the trans-(4S,6S)-4-(ethylamino)-6-methyl-5,6-dihydro-4H-thieno[2,3-
b]thiopyran-2-sulfonamide 7,7-dioxide hydrochloride substantially free from the cis-diastereomer impurity the inventors employed the solvent treatment technique thereby rendering the process very economic and simple to implement on the industrial scale.
The following examples, which fully illustrate the practice of the preferred embodiments of the present invention, are intended to be for illustrative purpose only, and should not be considered to be limiting to the scope of the present invention.
Examples:
Example 1: Preparation of (6S)-4-(ethyIamino)-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide hydrochloride:
Taken (6S)-4-(ethylamino)-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide (50.0 gm) in acetone (700 ml) under stirring and cooled to 0°C. Maintaining the temperature at 0°C to 5°C purged hydrochloric acid gas to adjust the pH acidic between the range of 1-2. After attaining pH, maintained

the reaction mass for two hours at 0°C to 5°C under stirring. Filtered the precipitated compound (6S)-4-(ethylamino)-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide hydrochloride and washed the solid mass with chilled acetone (50 ml). Dried the compound at 60-65°C till constant weight. Dry weight: 50 g HPLC purity: 77.62% [cis-isomer: 22.11%]
Example 2: Preparation of trans-(4S,6S)-4-(ethylamino)-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-suifonamide 7,7-dioxide hydrochloride [Crude dorzolamide hydrochloride]:
In a dry flask charged (6S)-4-(ethylamino)-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide hydrochloride (19.0 g) and methanol (190 ml) at temperature of 25°C to 30°C. Under stirring raised the temperature of the reaction mass to reflux and maintained at reflux temperature for a period of two hour. After maintaining cooled the reaction mass gradually to 10°C to 15°C. Filtered the compound trans-(4S,6S)-4-(ethylamino)-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide hydrochloride and washed the solid mass with chilled methanol. Dried the compound at 60-65°C till constant weight.
Dry weight: 12.8 g HPLC purity: 99.33% [cis-isomer: 0.5%]
Example 3: Purification of trans-(4S,6S)-4-(ethylamino)-6-methyl-5,6-
dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide
hydrochloride:
In a dry 250 ml R.B. flask charged trans-(4S,6S)-4-(ethylamino)-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide hydrochloride (11.0 g), acetone (11 ml) and purified water (5.5 ml) at the temperature 25°C to 30°C. Raised the temperature of the reaction slurry to reflux and maintained at

reflux for one hour. Diluted the reaction mass with fresh acetone (44 ml)
maintaining the temperature at reflux and continued maintaining at reflux
temperature further for one hour. Cooled the reaction mass gradually to 10°C to
15°C and maintained. Filtered the compound pure (4S,6S)-4-(ethylamino)-6-
methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide
hydrochloride solid mass and washed the pure compound with chilled acetone (11 ml). Dry at 55°C to 60°C till constant weight. Dry weight: 8.8 g
HPLC purity: 99.89% [cis-isomer: not detected] [Total impurities: 0.11%]
Example 4: Preparation of trans-(4S,6S)-4-(ethylamino)-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide hydrochloride [Crude dorzolamide hydrochloride]:
Charged (6S)-4-(ethylamino)-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-
sulfonamide 7,7-dioxide hydrochloride (5.0 g), methanol (22.5 ml) and 2.5 ml
purified water at temperature of 25°C to 30°C. Under stirring raised the
temperature of the reaction mass to reflux and maintained at reflux temperature
for a period of two hours. After maintaining cooled the reaction mass gradually to
30°C to 35°C. Filtered the solid compound trans-(4S,6S)-4-(ethylamino)-6-
methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide
hydrochloride and washed with methanol (10 ml). Dried the compound at 60°C to 65°C till constant weight. Dry weight: 3.2 g HPLC purity: 99.47% [cis-isomer: 0.43%]

We claim;
1. A process for preparation of (4S,6S)-4-(ethylamino)-6-methyl-5,6-
dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide
hydrochloride the compound of Formula I
which comprises the steps of; '
a. reacting (6S)-4-(ethylamino)-6-methyl-5,6-dihydro-4H-thieno[2,3-
b]thiopyran-2-sulfonamide 7,7-dioxide with hydrochloric acid in
the presence of solvent to isolate mixture of cis- and trans-isomer
of (6S)-4-(ethylamino)-6-methyl-5,6-dihydro-4H-thieno[2,3-
b]thiopyran-2-sulfonamide 7,7-dioxide hydrochloride;
b. treating the mixture of cis- and trans-isomer of (6S)-4-
(ethylamino)-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-
sulfonamide 7,7-dioxide hydrochloride with an organic solvent to
isolate (4S,6S)-4-(ethylamino)-6-rnethyl-5,6-dihydro-4H-
thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide hydrochloride
substantially free from cis-diastereomer impurity; and
c. treating the (4S,6S)-4-(ethylamino)-6-methyl-5,6-dihydro-4H-
thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide hydrochloride
with a solvent to get pure (4S,6S)-4-(ethylamino)-6-methyI-5,6-
dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide
hydrochloride the compound of Formula I.

2. The process according to claim 1, wherein, the reaction of step (a) is carried out in the presence of solvent selected from the group consisting of methanol, isopropanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl acetate, isopropyl acetate or a mixture thereof.
3. The process according to claim 1, wherein, the reaction of step (a) the hydrochloric acid used is gaseous hydrochloric acid.
4. The process according to claim 1, wherein, the reaction of step (b) is carried out in the presence of solvent selected from the group consisting of linear or branched d to C4 alcohol comprising of methanol, ethanol, propanol, isopropanol, n-butanol, sec-butanol, tert-butanol and water or a mixture thereof.
i
5. The process according to claim 1, wherein, the reaction of step (b) is carried out in the presence of solvent methanol and water or a mixture thereof.
6. The process according to claim 1, wherein, the reaction of step (b) is carried out at a temperature in the range of 50°C to 70°C.
7. The process according to claim 1, wherein, the reaction of step (c) the solvent used is selected from the group of methanol, isopropanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, and water or a mixture thereof.
8. The process according to claim 1, wherein, the reaction of step (c) the
solvent used is mixture of solvent acetone and water. '
9. The process according to claim 1, wherein, the reaction of step (c) is
carried out at a temperature in the range of 50°C to 60°C.