(WO2018066004) PROCESS FOR THE PREPARATION OF DORAOLZMIDE HYDROCHLORIDE

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SHETH, Nilima

Aditi Kare Panandikar, Managing Director, Indoco Remedies

Process for preparing dorzolamide hydrochloride is claimed. It is disclosed that dorzolamide hydrochloride is a carbonic anhydrase inhibitor. 

Trusopt is an ophthalmic solution containing the carbonic anhydrase inhibitor dorzolamide hydrochloride for treating intraocular pressure in patients with ocular hypertension or open-angle glaucoma, which was developed and launched by Merck & Co , and is also now marketed by Santen Pharmaceuticals and Mundipharma International . 

In April 2018, Newport Premium™ reported that Indoco Remedies was capable of producing commercial quantities of dorzolamide hydrochloride and holds an active US DMF since 2010

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

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 T rusopt.

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, E P 0296879. The process described in US ^“413 patent involves reacting thiophene-2-thiol with but-2-enoic acid and further proceeds with formation of racemic 4- ( ethyl ami no) – 6- methyl -5, 6- di hydro-4H -thi eno[2, 3- b] thi opy ran-2-sul f onami de 7, 7-di oxide (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, racemic mixture of dorzolamide base is subjected to column chromatography and then resolution is carried out using resolving agent di-p-tol uoyl-L -tartaric acid monohydrate in n-propanol. The salt formed is treated with base to get dorzolamide free base, which is reacted with ethanolic hydrochloric acid to get dorzolamide hydrochloride. The compound is further recrystallised from mixture of solvents viz., methanol and isopropanol to get pure dorzolamide hydrochloride.

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 free base and then reacted with hydrochloric acid in ethyl acetate to get required pure trans-isomer of dorzolamide hydrochloride.

The PCT patent publication W 02006038222 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 di benzoyl -L -tartaric acid monohydrate or di-p-tol uoyl-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

dorzol amide hydrochloride which is recrystalised in isopropanol to obtain pure dorzol amide 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-(ethylamino)-6-methyl-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 publication 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 trans:cis 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 trans:cis diastereomeric mixture of 95:5. The isolated maleate salt is then treated with base and reacted with (1 S)-(+)-10-camphorsulfonic acid to get corresponding (4S,6S)-4-(ethylamino)-6-methyl-5, 6-di hydro-4H -thi eno[2, 3- b] thi opy ran-2-sul f onami de 7, 7-di ox i de ( 1 S ) -( + )- 10-camphorsulfonate salt, which is neutralized to give pure (4S,6S)-4-(ethylamino)-6- methyl -5, 6-di hydro-4H -thi eno[2,3- b] thi opyran-2-sulf onami de 7, 7-di oxi de.

PCT patent publication W 02008135770 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 c is- 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-(e)-4-(ethylamino)-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide by conventional methods. The compound trans-(e)-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-( ethyl ami no) – 6- methyl -5, 6- di hydro-4H -thi eno[2, 3- b] thi opy ran-2-sul f onami de 7, 7-di oxide hydrochloride.

PCT patent publication 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 publication WO2011101704 and corresponding Indian Patent application 426/C H E/2010 describes the process for the preparation of trans-dorzolamide hydrochloride by forming the maleate salt of racemic 4-( ethyl ami no) – 6- methyl -5, 6- di hydro-4H -thi eno[2, 3- b] thi opy ran-2-sul f onami de 7, 7-di oxide. 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- dihydro-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)-dorzol amide hydrochloride.

Indian Patent application 3431 /M U M/2012 discloses the process wherein racemic 4-( ethyl ami no) -6- methyl – 5, 6- di hydro-4H -thi eno[2, 3- b] thi opy ran-2-sul f onami de

7.7- dioxide is resolved using di benzoyl- 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 thus obtained is treated with hydrochloric acid in isopropanol to result in the required trans-(S,S)-dorzolamide hydrochloride. The compound is further recrystallised in isopropanol to isolate pure dorzol amide hydrochloride.

The prior art processes disclosed as above have several drawbacks in the preparation of pure trans-dorzolamide hydrochloride viz.,

1. involves column chromatography for separation of the desired diastereomer;

2. involves preparation of corresponding diastereomeric salts and converting again to base before preparation and isolation of pure trans-dorzolamide hydrochloride;

3. involves additional step of reacting the racemic dorzolamide base with mineral acid to isolate corresponding dorzolamide salt which is again converted to dorzolamide base and further resolved using resolving agent to form the corresponding salt, neutralization and isolation of the chiral dorzolamide base before reacting with hydrochloric acid to obtain dorzolamide hydrochloride; and

4. involves an additional step of 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, neutralization and isolation of the chiral dorzolamide base before reacting with hydrochloric acid to obtain dorzolamide hydrochloride.

As is evident from the cursory review of the prior arts that the preparation of pure dorzolamide hydrochloride involves either column chromatography for isolation of trans- isomer followed by use of resolving agent or involves repeated preparations of chiral or diastereomeric salts, use of resolving agent followed by converting into dorzolamide 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 of the prior arts and makes the process industrially viable and economically advantageous. The present invention therefore seeks to address these issues by providing an improved and cost-effective process that can easily be scaled for industrial production of dorzolamide hydrochloride.

The present inventors have developed an alternative process for isolating pure dorzolamide hydrochloride substantially free from the cis-isomer without using the time consuming column chromatography technique, repeated preparation of chiral salts, diastereomeric salts and converting into base before hydrochloride salt formation to isolate pure trans-(S,S)-dorzolamide hydrochloride.

E xamples:

E xample 1 : Preparation of (6S)-4-(ethylamino)-6-methyl-5,6-dihydro-4H -thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide 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 (50.0 gm) in acetone (700 ml) under stirring and cooled to OeC. Maintaining the temperature at OeC to 5eC purged hydrochloric acid gas to adjust the pH to acidic between the range of 1-2. After attaining desired pH, maintained the reaction mass for two hours at OeC to 5eC under stirring. Filtered the precipitated compound (6S)-4-(ethylamino)-6-methyl-5, 6-di hydro-4H -thi eno[2,3- b] thi opyran-2-sulf onami de 7,7-di oxi de hydrochl ori de and washed the solid mass with chilled acetone (50 ml). Dried the compound at 60-65eC till constant weight.

Dry weight: 50 g

H PL C purity: 77.62% [cis-isomer: 22.11 % ]

E xample 2: Preparation of trans-(4S,6S)-4-(ethylamino)-6-methyl-5,6-dihydro-4H -thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide hydrochloride [C rude 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 25eC to 30eC. 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 10eC to 15eC. 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 60-65eC till constant weight.

Dry weight: 12.8 g

H PL C purity: 99.33% [cis-isomer: 0.5% ]

E xample 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 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 of 25eC to 30eC. 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 10eC to 15eC 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). Dried at 55eC to 60eC till constant weight.

Dry weight: 8.8 g

H PL C purity: 99.89% [cis-isomer: not detected]

[T otal impurities: 0.11 % ]

E xample 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 [C rude 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 25eC to 30eC. 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 30eC to 35eC. 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 60eC to 65eC till constant weight.

Dry weight: 3.2 g

H PL C purity: 99.47% [cis-isomer: 0.43% ]

////////WO 2018066004, NEW PATENT, INDOCO REMEDIES LIMITED, DORZOLAMIDE