FORM 2
THE PATENTS ACT 1970
(39 of 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
"A PROCESS FOR PREPARATION OF DORZOL AMIDE"
2. APPLICANT (S):
(a) NAME: FDC Limited
(b)NATIONALITY. Indian company incorporated under the Companies Act 1956
(c) ADDRESS: 142-48, S.V. Road, Jogeshwari (West), Mumbai - 400 102, Maharashtra, India.
3. PREAMBLE TO THE DESCRIPTION:
The following specification particularly describes the invention and the manner in which it is to be performed

FIELD OF INVENTION:
The present invention relates to a process for preparation of Dorzolamide and its hydrochloride salt.
BACKGROUND OF INVENTION:
Dorzolamide is a carbonic anhydrase inhibitor useful in treatment of glaucoma and ocular hypertension. It is chemically represented by (4S, 6S)-4-(ethylamino)-6-methyl-5,6-dmydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7 dioxide; and is structurally represented as follows:

As seen from the above structure, Dorzolamide is an optically active enantiomer having 2 chiral centers, one at C-4 position and another at C-6 position, with trans-configuration. Such configuration gives rise to several enantiomers and impurities during the preparation process, which makes preparation of Dorzolamide and its pharmaceutically acceptable hydrochloride salt, a tedious, complex, time-consuming and cost-involving process.
US 4797413 discloses two processes for preparation of Dorzolamide and its hydrochloride salt as depicted in Schemes 1 & 2 respectively.


In the first process as depicted in Scheme 1, the reaction starts with thiophene 2-thiol and proceeds along with formation of racemic compounds that further leads to formation of several diastereomers which are carried forward in subsequent steps of the process, and the desired trans-isomer of Dorzolamide is obtained after column chromatography and resolution. In the second process as depicted in Scheme 2, the reaction starts with

racemic hydroxysulfonamide compound and proceeds via Ritter reaction by treatment with acetonitrile and a strong acid such as sulfuric acid to form a corresponding acetoamidosulfone with retention of configuration, followed by reduction of amido group, column chromatography and resolution, to obtain the desired trans-isomer of Dorzolamide. Both the processes mentioned in US patent 4797413, proceeds through formation of several diastereomers, and require column chromatography followed by resolution to obtain the desired trans-isomer of Dorzolamide, making these processes tedious, complex and time-consuming.
US 5688968 describes a process for preparation of Dorzolamide as depicted in Scheme 3, wherein the reaction process starts with a chiral hydroxyl sulfone compound having desired chirality at C-4 and C-6 positions, and proceeds via Ritter reaction to obtain desired trans-isomer of Dorzolamide after recrystallization of Dorzolamide as its maleate salt followed by conversion to its hydrochloride salt. The said process produces Dorzolamide in good yields and purity, however the process does not appear economical due to the use of expensive chiral starting material and mentions a long procedure for obtaining Dorzolamide hydrochloride salt from Dorzolamide base.


US 20100113804 discloses a process for preparation of dorzolamide, as depicted in Scheme 4, wherein the reaction starts with a hydroxysuifonamide compound not having defined chiralities at C-4 and C-6 positions, which proceeds via Ritter reaction; and the resulting racemic Dorzolamide is resolved using an acid [H+A"] to form an acid addition salt to obtain the desired trans-isomer of Dorzolamide, while avoiding cumbersome column chromatography. However, said process leads to formations of three other undesired isomers in significant amounts, which results in tedious purifications and poor yields.


WO 2011101704 discloses a process for preparation of Dorzolamide, as depicted in Scheme 5, wherein the reaction starts with a racemic compound and proceeds with formation of undesired diastereomers which are carried forward throughout the reaction until resolution, leading to production of Dorzolamide in low yield. Further, the purification of Dorzolamide is carried out using an organic solvent which is not environment-friendly.


From the aforementioned prior art processes for preparation of Dorzolamide, it is evident that use of racemic compound as starting materia!, produces racemic Dorzolamide. Since the molecule is racemic, in order to achieve the desired trans conformation, several purifications have to be performed, which results in low yield of the product thus increasing not only the cost of production but also the reaction time. Although, the use of chiral starting material along with chiral reducing agents increases the yield of the product, but it makes the process significantly more expensive,
Therefore, the present inventors have developed a process for preparing Dorzolamide and its pharmaceutically acceptable hydrochloride salt, by using relatively cheaper starting material having only one chiral center to provide Dorzolamide with good yields and purity in a cost effective mariner with reduced reaction times.
Summary of Invention
In accordance with the above, the present invention discloses a process for preparation of Dorzolamide and its hydrochloride salt with high yield and high purity, wherein the reaction starts with 6-methyl thieno[2,3-b]thiopyran 4-one compound having desired

chirality at C-6 position and non-chirality at C-4 position. The process of present invention yields dorzolamide HC1 in reduced reaction times with good yields and purity, as compared to prior art processes which use racemic compound as the starting material. The process of present invention is depicted in Scheme 6.

The advantage of the process of present invention lies in avoidance of costly stereoselective reducing agents & yet achieving selectivity of the desired trans isomer of

Dorzolamide and its hydrochloride salt, with significantly higher yield and in a cost effective manner.
Detailed Description of Invention
The present invention describes a process for preparation of Dorzolamide of formula (I) and its hydrochloride salt

which comprises the steps of:
a) oxidizing a compound of formula (II)


b) reducing the keto sulfone of formula (III) to a hydroxy sulfone of formula (IV)

in presence of a reducing agent;
c) subjecting the hydroxy sulfone of formula (IV) to a Ritter reaction using acetonitrile and concentrated sulfuric acid, to obtain an acetamido sulfone of formula (V)

d) subjecting the acetamido sulfone of formula (V) to sulfoamidation to obtain a sulfonamide of Formula (VI)


e) reducing the sulfonamide of formula (VI) to obtain a compound of formula (VII)

f) reacting the compound of formula (VII) with dibenzoyl-(L)-tartaric acid (DBTA) to obtain its corresponding dibenzoyl-(L)-tartaric acid (DBTA) salt, followed by resolution to give a compound of formula (VIII)

g) converting the compound of formula (VIII) into Dorzolamide of formula (I) or its hydrochloride salt.
In the present invention, the oxidizing agent used in step a) is hydrogen peroxide. The reducing agent used in step b) is sodium borohydride.
According to the present invention, the sulfoamidation of step d) involves sulfonylation of the acetamido sulfone of formula (V) using chlorosulfonic acid, and reacting the resulting sulfonated compound with thionyl chloride to obtain a sulfonyl chloride

compound, which is then treated with liquor ammonia to yield sulfonamide compound of Formula (VI).
In the present invention, the reduction of sulfonamide in step e) is carried out in presence of sodium borohydride and boron trifluoride etherate solution; and the conversion to dibenzoyl -(L)- tartaric acid (DBTA) salt in step f) is carried out in presence of methanol.
According to the present invention, the conversion of compound of formula (VIII) into Dorzolamide of formula (I) or its hydrochloride salt in step g), involves treatment of the compound of formula (VIII) with a weak base to obtain Dorzolamide free base, which is optionally isolated, followed by treatment with hydrochloric acid in presence of an alcohol, to yield crude hydrochloride salt of Dorzolamide, which is then purified by dissolution in water. In step (g), the weak base used is sodium carbonate, and the alcohol is isopropyl alcohol.
As compared to prior-art preparation processes for Dorzolamide and its hydrochloride salt using expensive starting compounds with chirality at C-4 and C-6 positions and expensive chiral reducing agents, the reaction process of present invention starts with a relatively cheaper 6-methyl thieno[2,3-b]thiopyran 4-one compound having defined S-configuration at C-6 position.
The process of present invention produces desired trans-isomer of Dorzolamide and its pharmaceutically acceptable hydrochloride salt in a cost-effective manner with good yield and high purity, in reduced reaction times and in less tedious manner.
Examples:

Step a) Preparation of (6S)-6-methvl-5. 6-dihvdro-4H-thieno [2. 3-bl thiopvran-4-one 7, 7-dioxide (111)

A mixture containing (6S)-6-methyl-5, 6-dihydro-4H-thieno [2, 3-b] thiopyran-4-one (200 g), ethyl acetate (1750 ml), toluene (350 ml) and sodium tungstate (53 g) was cooled to 5-10°C. To this mixture 30 % hydrogen peroxide (530 ml) was added slowly. After addition, the reaction mixture was stirred for 1 hour at 5-10°C. Progress of reaction was checked by TLC. After completion of reaction, 10 % solution of sodium bicarbonate was added slowly to reaction mass. Organic layer separated, aqueous layer extracted using ethyl acetate. All organic layers were combined and the solvent was removed by distillation to obtain white to off-white colored (6S)-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-4-one 7,7-dioxide as a solid.
Step b) Preparation of (6S)-6-methyl-5. 6-dihvdro-4H-thieno \2, 3-bl thiopvran-4-ol 7. 7-dioxide (IV)

To the compound (HI) obtained from step a) , ethyl acetate (1750 ml), toluene (300 ml), and ethanol (600 ml) was charged and stirred at 30°C for 15 minutes. Sodium borohydride (52 g) was added slowly over I hour (exothermic reaction). Reaction mass was stirred at 30-50°C for 1-2 hours. The progress of reaction was checked by TLC. After completion of reaction, 1200 ml of 10 % HC1 was added to reaction mass and stirred for 1 hour at 30°C. Two layers were separated by solvent extraction. Organic layer

washed with 800 ml 10 % HC1. Aqueous layer extracted using ethyl acetate. All organic layers were combined and solvent removed by distillation. Brown coloured (6S)-6-methyl-5,6-dihydro-4H-thieno [2,3-b] thiopyran-4-ol 7,7-dioxide obtained as a solid,
Step c) Preparation of N-[(6S)-6-methyl-7. 7-dioxido-5. 6-dihvdro-4H-thieno [2, 3-b] thiopyran-4-vll acetamide (V).

A mixture containing (6S)-6-methyl-5, 6-dihydro-4H-thieno [2, 3-b] thiopyran-4-ol 7, 7-dioxide (IV) obtained from step b) and acetonitrile (1250 ml) was stirred at -5 to +5°C for 30 minutes. To this solution conc, sulfuric acid (264 ml) was added slowly maintaining temperature -5 to +5°C. Temperature of reaction mass was allowed to come at 5 to 20°C. 30 % sulfuric acid (44 ml) was added to reaction mass and maintained at 5 to 20°C for 2 hours. Further the mixture was stirred at 30oC for 12-15 hours. The progress of reaction was monitored on TLC. After completion of reaction, mixture was slowly added to 2.5 kg ice and stirred for 30 minutes. pH of reaction mass adjusted to 4.5-5.5 using 48 % NaOH solution. Resulting mixture was extracted using ethyl acetate (2000 ml x 2). Both organic layers were combined and washed with brine (1000 ml). Resulting organic layer was distilled to remove solvent till dryness. To the semisolid obtained after distillation, fresh ethyl acetate (400 ml) was added and stirred for 15 minutes at 30°C. To the mixture water (2400 ml) was added slowly and stirred at 30°C for 1 hour. The solid was collected by filtration and washed witb.200 ml water, and dried at 60-65°C to constant weight of 260 g. Yield: 92.36 %. Chiral Purity by HPLC: Trans isomer 74.29 %, Cis isomer 23.57 %.

Step d) Preparation of N-[(6S)-6-methyl-7, 7-dioxido-2-sulfamoyl-5.6-dihvdro-4H-thieno [2,3 -b] thiopyran-4 - yl] acetamide (V I)

N-[(6S)-6-methyl-7, 7-dioxido-5, 6-dihydro-4H-thieno [2, 3-b] thiopyran-4-yl] acetamide (240 g) (V) obtained from step c), was added slowly to chlorosulphonic acid (570 ml) at 0-10°C. The mixture was slowly heated to 50-55°C and stirred at 50-55°C for 6 hours. After completion of reaction, cooled to 10-15°C and thionyl chloride was added slowly. The resulting reaction mixture was heated to 50-55°C and stirred for 6 hours. After completion of reaction, the mixture was slowly added to crushed ice (3.85 kg) and stirred for 30 minutes. The solid obtained was separated by filtration and washed with cold water. The wet solid obtained was mixed with THF (1290 ml) and cooled to 0-10°C. To this reaction mixture liquor ammonia was added slowly maintaining temperature 0-10°C and stirred at 0-10°C for 3 hours. The progress of reaction was monitored by TLC. After completion of reaction pH of reaction mixture was adjusted to 3-5 using slow addition of cone, sulfuric acid. The mixture was stirred for 30 minutes and two layers separated, Aqueous layer was extracted using THF (480 ml). Both organic layers combined and mixed with water (960 ml). THF removed using distillation. To the resulting mixture water (1440 ml) was added and stirred for 8 hours at 30°C. The product was separated by using filtration, washed with water and dried at 80-85°C to the constant weight of 200 g. Yield: 63.86 %. Chiral Purity by HPLC: Trans isomer 73.50 %, Cis isomer 25.13 %.

Step e) Preparation of (4S,6S)4-(ethylaminoV6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide.

To a mixture containing N-[(6S)-6-methyl-7, 7-dioxido-2-sulfamoyl-5,6-dihydro-4H-
thieno[2,3-b]thiopyran-4-yl]acetamide (200 g) (VI) obtained from step d) and THF (2000
ml), sodium borohydride (115 g ) was added slowly and stirred at 25-30°C for 30
minutes. Inert atmosphere created using nitrogen. The resulting reaction mass was cooled
to 0-10°C and BF3-Etherate solution was added dropwise over 2- 3 hours. The mixture
was stirred at 0-10°C for 2 hours and at 25-35°C for 12 hours. The progress of reaction
was monitored by TLC. In the meantime dilute sulfuric acid was prepared by mixing
140 ml of cone, sulfuric acid with 2.4 lit water. After completion of reaction, cooled to 0-
10°C and to the mixture dil.sulfuric acid (2.54 lit) was added slowly and stirred at 0-10°C
for 2 hours. THF removed using distillation and pH of reaction mass adjusted to 4-60
using 48 % NaOH solution. To this mixture ethyl acetate (3.0 lit) was added and p H
adjusted to 7-8 using 48 % NaOH solution. Inorganic salts removed using filtration. Clear
solution was separated and aqueous layer was extracted using ethyl acetate. All organic
layers combined and washed with brine solution. Resulting organic layer was dried over
sodium sulfate to get clear solution. Solvent removed using distillation to get (6S)-4-
(etiiylamino)-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonarnide 7,7-
dioxide as an oily mass.
Step f) Preparation of r4S,6S)-4-(ethylamino)-6-methvl-5,6-dihydro-4H-thieno[2.3-b]thiopvran-2-sulfonamide 7,7-dioxide Dibenzoyl-L-Tartaric Acid salt (WW)


To the oily mass obtained from Part 1 of step e), methanol (500 ml) and ethyl acetate (600 ml) was added and stirred at 25-35°C for 30 minutes. Meanwhile, di benzoyl-(L)-tartaric acid (225 g) dissolved in methanol (400 ml) and added slowly to reaction mixture. The resulting mixture was stirred at 25-35X for 12 hours and at 5-10°C for 1 hour. The solid collected by filtration, washed with ethyl acetate (400 ml) and dried at 60-65°C to constant weight of 185 g.Yield: 45.85 %. Purity by HPLC : 99.14 %.Chiral Purity by HPLC: Trans isomer 98.84 %, Cis isomer 0.97 %.
Step g) Preparation of (4S,6S)-4-femvlaminoV6-methvl-5.6-dihvdro-4H-thienor2,3-blthiopyran-2-sulfonamide 7.7-dioxide hydrochloride salt

A mixture containing (4S,6S)-4-(ethylamino)-6-methyI-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide dibenzoyl-L-tartaric acid salt (185 g) (VI)

obtained from part II of step e), ethyl acetate (1300 ml) and 2 % sodium carbonate solution (1400 ml) was stirred at 25-35°C for 30 minutes to get clear solution. Two layers separated and aqueous layer was extracted using ethyl acetate. All organic layers combined and pH adjusted to 1-2 using 10 % IPA-HC1 solution at 5-10°C and stirred for 1 hour. The solid collected by filtration, washed using ethyl acetate and dried at 65-70°C to a constant weight of 90 g. This crude Dorzolamide hydrochloride was mixed with water (220 ml) and heated to 85-90°C to get clear solution. The solution was stirred at 89-90°C for 30 minutes and then slowly cooled to 25-35°C to get precipitate. The resulting mixture was then cooled to 5-10°C and stirred for 1 hour. The solid was collected by filtration, washed with chilled water and dried at 65-70°C to a constant weight of 80g. Yield : 81.80 %. ;Purity by HPLC : 99.9 % (On dried basis); Chiral Purity by HPLC : Trans isomer 99.88 %, Cis isomer 0.06 %. .

We claim:
1. A process for preparation of Dorzolamide of formula (I) and its hydrochloride salt

which comprises the steps of:
a) oxidizing a compound of formula (II)

in presence of an oxidizing agent; b) reducing the ketosulfone of formula (III) to a hydroxy sulfone of formula (IV)


in presence of a reducing agent;
c) subjecting the hydroxy sulfone of formula (IV) to a Ritter reaction using acetonitriie and concentrated sulfuric acid, to obtain an acetamido sulfone of formula (V)

d) subjecting the acetamido sulfone of formula (V) to sulfoamidation to obtain a sulfonamide of Formula (VI)

e) reducing the sulfonamide of formula (VI) to obtain a compound of formula (VII)


f) reacting the compound of formula (VII) with dibenzoyl-(L)-tartaric acid (DBTA) to obtain its corresponding dibenzoyl-(L)-tartaric acid (DBTA) salt, followed by resolution to give a compound of formula (VIII) and

g) converting the compound of formula (VIII) into Dorzolamide of formula (I) or its hydrochloride salt.
2. The process of preparation as claimed in claim 1, wherein the oxidizing agent used in step a) is hydrogen peroxide.
3. The process of preparation as claimed in claim 1, wherein the reducing agent used in step b) is sodium borohydride.
4. The process of preparation as claimed in claim 1, wherein the sulfoamidation of step d) comprises a) sulfonylation of the acetamido sulfone of formula (V) using chlorosulfonic acid b) reacting the resulting sulfonated compound with thionyl chloride to obtain a sulfonyl chloride compound and c) treating sulfonyl chloride compound with liquor ammonia to yield sulfonamide compound of Formula (VI).
5. The process of preparation as claimed in claim 1, wherein the reduction of sulfonamide in step e) is carried out in presence of sodium borohydride and boron trifluoride etherate solution.
6. The process of preparation as claimed in claim 1, wherein dibenzoyl -(L)- tartaric acid (DBTA) salt in step f) is obtained in presence of methanol.

7. The process of preparation as claimed in claim 1, wherein step (g) involves treating the compound of formula (VIII) with a weak base to obtain Dorzolamide of formula (1), followed by treatment with hydrochloric acid in presence of an alcohol, to yield crude hydrochloride salt of Dorzolamide, which is then purified by dissolution in water.
8. The process of preparation as claimed in claim 7, wherein the Dorzolamide of formula (1) is optionally isolated prior to conversion into its hydrochloride salt
9. The process of preparation as claimed in claim 7, wherein the weak base is sodium carbonate.
10. The process of preparation as claimed in claim 7, wherein the alcohol is isopropyl alcohol.