FORM 2
THE PATENT ACT 1970 (39 of 1970) & The Patents Rules,2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
An improved process for the preparation of Dorzolamide hydrochloride
2. APPLICANT (S)
(a) NAME: Enaltec Labs Pvt. Ltd.
(b) NATIONALITY:
An Indian Company incorporated under the Indian Companies ACT 1956
(c) ADDRESS:
Enaltec Labs Pvt. Ltd., 17th Floor, Kesar Solitaire, Plot No. 5, Sector 19, Sanpada, Navi Mumbai- 400705, Maharashtra, India.

Technical field of the invention
Present invention relates to an improved process for the preparation of Dorzolamide hydrochloride compound represented by structural formula I.

Background of the invention
Dorzolamide hydrochloride is chemically known as (4S-trans)-4-(ethylamino)-5, 6-dihydro-6-methyl-4H-thieno [2, 3-b] thiopyran-2-sulfonamide 7, 7-dioxide mono-hydrochloride and was first disclosed in U.S. patent number 4,797,413 and is represented by structural formula I.

Dorzolamide hydrochloride is well tolerated and effective drug indicated as carbonic anhydrase inhibitor, ophthalmic for treatment of elevated intraocular pressure in patients with ocular hypertension or open-angle glaucoma.

U.S. patent number 4,797,413 discloses a process for the preparation of Dorzolamide hydrochloride compound represented by structural formula I as depicted below in Scheme I, wherein racemic hydroxysulfonamide compound represented by structural formula II gives compound represented by structural formula III via Ritter reaction by using acetonitrile and a strong acid such as sulfuric acid followed by reduction of amido group using boranedimethylsulfide complex, column chromatography to give compound represented by structural formula TV, which on resolution gives desired isomer of Dorzolamide compound represented by structural formula V, which on treatment with HC1 gives Dorzolamide hydrochloride compound represented by structural formula I.

U.S. patent number 5,688,968 discloses a process for the preparation of Dorzolamide hydrochloride compound represented by structural formula I as depicted below in Scheme II, wherein chiral N-acyl compound represented by structural formula VI is

reduced to compound represented by structural formula V using sodium borohydride/boron trifluoride etherate followed by preparation of maleate salt represented by structural formula VII, which on treating with HC1 gives Dorzolamide hydrochloride compound represented by structural formula I.
Scheme II

The preparation method disclosed in U.S. patent number 4,797,413 is disadvantageous in the following aspects. Use of racemic hydroxysulfonamide compound represented by structural formula II as starting compound results in formation of racemic Dorzolamide compound represented by structural formula IV. The desired isomer is obtained by resolution which results in low yield. Further, amido compound represented by structural formula III is reduced using boranedimethylsulfide complex as reducing agent, which is flammable and reacts readily with water to produce a flammable gas.

The preparation method disclosed in U.S. patent number 5,688,968 is disadvantageous in the following aspects. Amido compound represented by structural formula VI is reduced using sodium borohydride/boron trifluoride etherate as reducing agent, which is adduct of boron trifluoride with diethyl ether and reacts violently with water.
The aforementioned prior art processes for preparation of Dorzolamide compound represented by structural formula I involve use of hazardous reducing agents which are very unsafe to handle at commercial scale.
Accordingly there is a need in the art to develop a process of preparing Dorzolamide hydrochloride compound represented by structural formula I using a reducing agent which is safe to handle at commercial scale, has robust shelf life, less sensitive against oxygen & having good solubility in organic solvents.

Object of the invention
i) The main object of the invention is to provide an improved process for
preparation of Dorzolamide hydrochloride compound represented by structural formula I, in good yield and purity.

ii) Another object of present invention is to provide a process for reduction of N-((4S,6S)-6-methyl-7,7-dioxido-2-sulfamoyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-4-yl)acetamide compound represented by structural formula VI using a reducing agent which is safe to handle at commercial scale to get the compound represented by structural formula V.

iii) Yet another object of present invention is to provide simple, economic, safe and industrially viable process for the preparation of Dorzolamide hydrochloride compound represented by structural formula I.

Summary of the invention
A first aspect of the present invention is to provide an improved process for preparation of Dorzolamide hydrochloride compound represented by structural formula I

comprising the steps of:
a) reduction of N-((4S,6S)-6-methyl-7,7-dioxido-2-sulfamoyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-4-yl)acetamide compound represented by structural formula VI using a reducing agent which is safe to handle at commercial scale in an organic solvent to give compound represented by structural formula V; with a proviso that reducing agent includes but not limited to Sodium bis(2-methoxyethoxy) aluminumhydride (Red-Al).

b) treating the compound represented by structural formula V with solution of hydrochloric acid in an organic solvent to obtain Dorzolamide hydrochloride compound represented by structural formula I


Another aspect of present invention is to provide a process for reduction of N-((4S,6S)-6-methyl-7,7-dioxido-2-sulfamoyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-4-yl)acetamide compound represented by structural formula VI using Sodium bis(2-methoxyethoxy) aluminiumhydride (Red-Al) in an organic solvent to give compound represented by structural formula V

Yet another aspect of the present invention is to provide a process of preparing Dorzolamide hydrochloride compound represented by structural formula I as shown below in scheme III:


Detailed description of the invention:
N-((4S,6S)-6-methyl-7,7-dioxido-2-sulfamoyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-4-yl)acetamide compound represented by structural formula VI can be prepared using process known in the prior art.
In an embodiment of present invention; N-((4S,6S)-6-methyl-7,7-dioxido-2-
sulfamoyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-4-yl)acetamide compound
represented by structural formula VI is reduced using a reducing agent which is safe to handle at commercial scale in an organic solvent to get compound represented by structural formula V
In accordance with an embodiment of the present invention; the reducing agent for reduction of N-((4S,6S)-6-methyl-7,7-dioxido-2-sulfamoyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-4-yl)acetarnide compound represented by structural formula

VI is selected but not limited to Sodium bis(2-methoxyethoxy) aluminiumhydride (Red-Al).
In accordance with an embodiment of the present invention; the organic solvent for reduction of N-((4S,6S)-6-methyl-7,7-dioxido-2-sulfamoyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-4-yl)acetamide compound represented by structural formula VI can be selected from the group consisting of aromatic hydrocarbon and ether.
In accordance with an embodiment of the present invention the aromatic hydrocarbon solvent can be selected but not limited to the group consisting of toluene and xylene; ether solvent can be selected but not limited to the group consisting of diethyl ether, methyl tertiary butyl ether, dioxane, tetrahydrofuran, 2-methyl tetrahydrofuran, diisopropyl ether or mixture(s) thereof.
In accordance with an embodiment of the present invention; reducing agent is added to a solution of N-((4S,6S)-6-methyl-7,7-dioxido-2-sulfamoyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-4-yl)acetamide compound represented by structural formula VI in an organic solvent at a temperature in the range of-5°C to 15°C.
In accordance with an embodiment of the present invention; N-((4S,6S)-6-methyl-7,7-dioxido-2-sulfamoyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-4-yl)acetamide compound represented by structural formula VI is treated with a reducing agent at a temperature in the range of 50°C to 80°C for a period of 2 hours to 6 hours to get compound represented by structural formula V
In accordance with an embodiment of the present invention; the compound represented by structural formula V can be isolated by steps of distillation, filtration, centrifugation, drying or combination thereof.
In accordance with an embodiment of the present invention; the compound represented by structural formula V having purity above 99%.

In another embodiment of the present invention; the compound represented by structural formula V is treated with solution of hydrochloric acid in an organic solvent to obtain Dorzolamide hydrochloride compound represented by structural formula I.
In accordance with another embodiment of the present invention; solution of hydrochloric acid can be selected but not limited to the group consisting of methanol-HC1, ethanol-HCl & IPA-HC1.
In accordance with another embodiment of the present invention; the organic solvent can be selected but not limited to the group consisting of alkyl acetate such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate, isobutyl acetate; alcohol such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, or mixture(s) thereof.
In accordance with another embodiment of the present invention; the compound represented by structural formula V is treated with solution of hydrochloric acid in an organic solvent at a temperature in the range of 15°C to 35°C for a period of 1 hour to 4 hours to obtain Dorzolamide hydrochloride compound represented by structural formula I.
In accordance with another embodiment of the present invention; Dorzolamide hydrochloride compound represented by structural formula I can be isolated by steps of filtration, centrifugation, drying or combination thereof.
In accordance with another embodiment of the present invention; Dorzolamide hydrochloride compound represented by structural formula I having purity greater than 99.5%.
In the following example, the preferred aspects of the present invention are described only by way of illustrating the process of the invention. However, these are not intended to limit the scope of the present invention in any way.

Example:
Example 1: Preparation of Dorzolamide hydrochloride
Step A: Preparation of Dorzolamide compound represented by structural formula V:
Solution of N-((4S,6S)-6-methyl-7,7-dioxido-2-sulfamoyl-5,6-dihydro-4H-
thieno[2,3-b]thiopyran-4-yl)acetamide (100 gm) in THF (500 ml) was added Vitride solution (128 gm) at 0°C-10°C slowly and then stirred the reaction mass at 60°C-70°C. Added ethyl acetate (1000 ml) and water (500 ml) to reaction mass. Stirred the reaction mass for 30 min and separated the organic layer. Organic layer was washed with saturated brine solution (200 ml). The organic layer was concentrated under vacuum, cooled to 0°C-10°C and filtered to get Dorzolamide compound represented by structural formula V.
Yield - 77 g (80%) Purity by HPLC - 99.5%
Step B: Preparation of Dorzolamide hydrochloride compound represented by structural formula I:
A solution of Dorzolamide compound represented by structural formula V (77 g) was in Ethyl acetate (1155 ml) was added IPA-HC1 (60 ml) and stirred at 25°C to 30°C for 90 minutes. The reaction mass was filtered and obtained solid was washed with ethyl acetate (50 ml) and dried the cake under reduced pressure at 40°C to 55°C.
Yield - 75 g (87.56%)
Purity by HPLC-99.81%

We claim:
1. Process for preparation of Dorzolamide hydrochloride compound represented by structural formula I

comprising the steps of:
a) reduction of N-((4S,6S)-6-methyl-7,7-dioxido-2-sulfamoyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-4-yl)acetamide compound represented by structural formula VI using sodium bis(2-methoxyethoxy) aluminumhydride (Red-Al) as a reducing agent in an organic solvent to give compound represented by structural formula V

b) treating the compound represented by structural formula V with solution of hydrochloric acid in an organic solvent to obtain Dorzolamide hydrochloride compound represented by structural formula I


2. The process as claimed in claim 1, step a) wherein organic solvent is selected from the group consisting of aromatic hydrocarbon such as toluene, xylene or mixture(s) thereof; ether solvents such as diethyl ether, methyl tertiary butyl ether, dioxane, tetrahydrofuran, 2-methyl tetrahydrofuran, diisopropyl ether or mixture(s) thereof.
3. The process as claimed in claim 1, step a) wherein reducing agent is added to a solution of N-((4S,6S)-6-methyl-7,7-dioxido-2-sulfamoyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-4-yl)acetamide compound represented by structural formula VI in an organic solvent at a temperature in the range of-5°C to 15°C.
4. The process as claimed in claim 1, step a) wherein N-((4S,6S)-6-methyl-7,7-dioxido-2-sulfamoyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-4-yl)acetamide compound represented by structural formula VI is treated with a reducing agent at a temperature in the range of 50°C to 80°C to get compound represented by structural formula V.
5. The process as claimed in claim 1, step b) wherein solution of hydrochloric acid is selected from the group consisting of methanol-HCl, ethanol-HCl, IPA-HC1 or mixture(s) thereof.
6. The process as claimed in claim 1, step b) wherein the organic solvent is selected from the group consisting of alkyl acetate such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate, isobutyl acetate; alcohol such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, or mixture(s) thereof.

7. The process as claimed in claim 1, step b) wherein the compound represented by structural formula V is treated with solution of hydrochloric acid in an organic solvent at a temperature in the range of 15°C to 35°C to obtain Dorzolamide hydrochloride compound represented by structural formula I.
8. The process as claimed in claim 1, step b) wherein Dorzolamide hydrochloride compound represented by structural formula I is isolated by steps of filtration, centrifugation, drying or combination thereof.
9. Process for preparation of Dorzolamide compound represented by structural formula V

comprising:
reduction of N-((4S,6S)-6-methyl-7,7-dioxido-2-sulfamoyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-4-yl)acetamide compound represented by structural formula VI using sodium bis(2-methoxyethoxy) aluminumhydride (Red-Al) as a reducing agent in an organic solvent at a temperature in the range of 50°C to 80°C to give compound represented by structural formula V


10. The process as claimed in claim 9 wherein organic solvent is selected from the group consisting of aromatic hydrocarbon such as toluene, xylene or mixture(s) thereof; ether solvents such as diethyl ether, methyl tertiary butyl ether, dioxane, tetrahydrofuran, 2-methyl tetrahydrofuran, diisopropyl ether or mixture(s) thereof.