Title of Invention	IMPROVED PROCESS FOR THE PREPARATION OF DORZOLAMIDE HYDROCHLORIDE AND PREPARATION OF ITS NOVEL INTERMEDIATE
Abstract	The present invention relates to an improved process for the preparation of (4S,6S)-4-(ethylamino)-5,6-dihydro-6-methyl-4H-thieno[2,3-b]thiopyran-2-sulfonamide-7,7-dioxide hydrochloride having formula 1. The compound of formula l_ has adopted name "Dorzolamide hydrochloride". Dorzolamide hydrochloride is prepared by the process of the present invention with high chemical and diastereomeric purity. The present invention also relates to novel intermediate of the formula 20 and a process for its preparation. The novel intermediate of formula 20 is used in preparation of Dorzolamide hydrochloride having formula 1. Dorzolamide hydrochloride is useful in the treatment of ocular hypertension by inhibiting carbonic anhydrase enzyme.

Title of Invention

IMPROVED PROCESS FOR THE PREPARATION OF DORZOLAMIDE HYDROCHLORIDE AND PREPARATION OF ITS NOVEL INTERMEDIATE

Abstract

The present invention relates to an improved process for the preparation of (4S,6S)-4-(ethylamino)-5,6-dihydro-6-methyl-4H-thieno[2,3-b]thiopyran-2-sulfonamide-7,7-dioxide hydrochloride having formula 1. The compound of formula l_ has adopted name "Dorzolamide hydrochloride". Dorzolamide hydrochloride is prepared by the process of the present invention with high chemical and diastereomeric purity. The present invention also relates to novel intermediate of the formula 20 and a process for its preparation. The novel intermediate of formula 20 is used in preparation of Dorzolamide hydrochloride having formula 1. Dorzolamide hydrochloride is useful in the treatment of ocular hypertension by inhibiting carbonic anhydrase enzyme.

Full Text	Field of the Invention The present invention relates to an improved process for the preparation of (4S,6S)-4-(ethy]amino)-5,6-dihydro-6-methyl-4H-tliieno[2,3-b]thiopyran-2-sulfonamide-7,7-dio\ide hydrochloride having formula \_. The compound of formula 1 has adopted name "Dorzolamide hydrochloride". Dorzolamide hydrochloride is prepared by the process of the present invention with high chemical and diastereomeric purity. The present invention also relates to novel intermediate of the formula 20 and a process for its preparation. The novel intermediate of formula 20 is used in preparation of Dorzolamide hydrochloride having formula .1. Dorzolamide hydrochloride is useful in the treatment of ocular hypertension by inhibiting carbonic anhydrase enzyme. Background of the Invention The process for preparation of Dorzolamide hydrochloride was first reported in EP 296879 (Equivalent to US 4797413). This patent discloses the preparation of Dorzolamide hydrochloride of the formula 1 starting from 2-mercaptothiophene of the formula 2, by reacting with crotonic acid to form 3-(2-mercaptothiophene)butanoic acid of the formula 3. The compound of the formula 3 is reacted with oxalyl chloride and followed by cyclisation with stannic chloride to obtain 5,6-dihydro-4H-6-methyIthieno[2,3-b]thiopyran-4-one of the formula 4. The compound of the formula 4 is reacted with acetic anhydride and sulfuric acid to obtain 5,6-dihydro-4H-6-methylthieno[2,3-bJlhiupyran-4-one-2-sulfonic acid of the formula 5. The compound of the formula 5 is reacted with phosphorous pentachloride to obtain the 5,6-dihydro-4H-6-methylthieno[2,3-b] thiopyran-4-one-2-sulfonyIchloride of the formula 6 and then followed by treating with ammonia gives 5,6-dihydro-4H-6-methylthieno[2,3-b]thiopyran-4-one-2-sulfonamide the formula 7. Reduction of compound of the formula 7 using sodium borohydride gives 5,6-dihydro-4H-4-hydroxy-6-methylthieno[2,3-b]thiopyran-2-sulfonamide of the formula 8. Oxidation of the compound of die formula 8 using oxone provides 5,6-dihydro-4H-4-hydroxy-6-methyIthieno[2,3-b]thiopyran-2-sulfonamide'7,7-dioxide of the formula 9. The compound of the formula 9 is reacted with acetonitrile and sulfuric acid by Ritter reaction to results in 5,6-dihydro-4H-4-acetylamino-6-methylthieno[2,3-b]thiopyran-2-sulfonamide-7,7-dioxide of the formula 10. Reduction of the compound of the formula 10 using borane-dimethyl sulfide gives 5,6-dihydro-4H-4-ethylaim'no-6-metriylmieno[2,3-b]t]iiopyi'aii-2-su!fonamide-7,7-dioxide of the formula 1_1. The racemic cis/trans isomer of the formula 11, on separation by column chromatography gives the pure (±)trans 5,6-dihydro-4H-4-ethylamino-6-methyIthieno[2,3-b]thiopyran-2-sulfonamide-7,7-dioxjde of the formula 12- This trans isomer of the formula 12 on resolution using di-p-toluoyl-D-tartaric acid and di-p-toluoyl-L-tartaric acid, followed by treating with hydrochloric acid provides Dorzolamide hydrochloride of the formula 1 as described in the Scheme-1. The above prior art process has the following disadvantages when the process is to be scaled-up for industrial use: (a) The starting material 2-mercaptothiphene of the formula 2 is highly expensive and it also tends to oxidize to form disulfide during storage and transportation. It also has the disadvantage of handling as it gives pungent smell in the pure form and it is very difficult to handle in the large scale. (b) The separation of Cis/trans isomer of the formula 11 was done by column chromatography which is very cumbersome and inconvenient for industries and also purity of trans isomer after column chromatography has not been reported. (c) The resolution of racemic trans isomeric Dorzolamide of the formula _12 to Dorzolamide hydrochloride of the formula 1 had been done using both di-p-toluoyl-L-tartaric acid and di-p-toluoyl- D-tartaric acid and isolating required isomer which is very long process and not suitable for plant operation and large scale production. (d) The overall yield is reported to be around 5% from 2-mercaptothiphene of the formula 2. Another process for the preparation of Dorzolamide Hydrochloride are described in US 5688968 starting from chiral hydroxysulfone ie., 5,6-dihydro-4-(S)-hydroxy-6(S)-methyl-4H-thiopyran-7,7,-dioxide of the formula J3. The 5,6-dihydro-4(S)-hydroxy-6(S)-methylthieno[2,3-b]thiopyran-7,7,-dioxide of the formula 13 is reacted with acetonitrile and sulfuric acid by Ritter reaction to obtain 5,6-dihydro-4(S)-acetylamino-6(S)-methyIthieno[2,3-b]thiopyran-7,7,-dioxide of the formula _14. The compound of the formula M is reacted with chlorosulfontc acid and thionyl chloride to give 5,6-dihydro-4(S)-acelylamino-6(S)-methylthieno[2,3-b]thiopyran-2-suffonylchloride-7,7,-dioxide of the formula 15 and followed by treating with ammonia to obtain 5,6-dihydro-4(S)-acetylamino-6(S)-meUiyHhieno[2,3-b]tliiopyran-2-sulfonamide-7,7,-dioxide of the formula Ij6. Reduction of the compound of formula .16 using borontrifluoride-etherate in sodium borohydride to obtain 5,6-dihydro-4(S)-ethylamino-6(S)-methylthieno[2,3-b]thiopyran-2-su!fon amide-7,7,-dioxide of the formula \1_. The compound of formula 11_ is treated with maleic acid to obtain trans 5,6-dihydro-4(S)-ethylamino-6(S)-methylthieno[2,3-b]thiopyran-2-sulfon amide-7,7^-Hioxide maleate of the formula ljt. The compound of formula 18 is treated with sodium bicarbonate and hydrochloric acid to obtain Dorzolamide hydrochloride of the formula I as described in the Scheme-2. The process for making the chiral hydroxysulfone of the formula .13 is described in EP 0590549, EP 658211, US 5391772, US 5474919 and US 5760249. The above described process is not suitable for industrial product production as the process of making is cumbersome and involves enzymatic process. Further US 7109353 described the process for the preparation of Dorzolamide hydrochloride from 2-bromothiophene of the formula 19. The compound of the formula 19 is reacted with magnesium, sulphur and crotonic acid to obtain 3-(2-mercaptothiophene)butanoic acid of the formula 3. The compound of the formula £ is reacted with thionyl chloride and followed by cyclisation with stannic chloride to obtain 5,6-dihydro-4H-6-methylthieno[2,3-b]thiopyran-4-one of the formula 4. The compound of the formula 4 is reacted with chlorosulfonic acid and thionyl chloride to obtain 5,6-dihydro-4H-6-methylthieno[2,3-b]thiopyran-4-one-2-sulfonyIchloride of the formula 6 and followed by treating with ammonia gives 5,6-dihydro-4H-6-methylthieno[2,3-b]thiopyran-4-one-2-sulfonamide the formula 7. Reduction of the compound of the formula 2 using sodium borohydride to obtain 5,6-dihydro-4H-4-hydroxy-6-methyltl?ieno[2,3-b]thiopyran-2-sulfonamide of the formula 8. Oxidation of the compound of the formula 8 using sodium perborate provides 5,6-dihydro-4H-4-hydroxy-6-metliyilhieiio[2,3-b]thiopyran-2-su\|fonamide-7,7-dioxide of the formula 9. The compound of the formula 9 is reacted with acetonitrile and sulfuric acid by Ritter reaction to obtain 5,6-dihydro-4H-4-acety!amino-6-methylthieno[2,3-b]thiopyran-2 -sulfonamide -7,7-dioxide of the formula HI-Reduction of the compound of the formula .10 using borane-dimethy (sulfide yields 5,6-dihydro-4H-4-ethylamino-6-methylthieno[2,3-b]thiopyran-2-sulfonaniide-7,7-dioxide of the formula JT. The racemic cis/trans isomer of the formula 1_1, is treated with ethanolic-hydrochloride and followed by sodium bicarbonate to get the (±)tfans 5,6-dihydro-4H~4-ethy}antino--6-methyithieno[2,3-b]thiopyran-2-sulfonamide-7,7-dioxide of the formula 12. This trans isomer of the formula 12 on resolution using di-p-toluoyl-D-tartaric acid and di-p-toluoyl-L-tartaric acid and followed by treating with hydrochloric acid to obtain Dorzolamide hydrochloride of the formula! as described in the Scheme-3. The above processes have the following disadvantages; (a) The preparation of 3-(2-mercaptothiophene)butanoic acid of the formula 3 from 2- bromothiophene of the formula ,19 uses sulphur, and handling of sulphur is inconvenient in industrial scale with pungent smell. (b) The lower yield (50 %) was reported for the preparation of 5,6-dihydro-4H-6-methyltliieno[2,3- b]thiopyran-4-one-2-sulfonamide the formula 7 from S,6-dihydro-4H-6-metbylthieno[2,3- bJtliiopyratt-4-one of the formula 4. (c) The lower yield (37.98 %) was reported for the preparation of trans 5,6-dihydro-4H-4- emylamino-6-methyltiireno[2,3-b]thiopyran-2-sulfbnarnide -7,7-dioxide of the formula 12 from the Cis-Trans isomer of the formula U.- (d) The resolution of racemic trans isomeric Dorzolamide of the formula 12 to trans-(S)-Dorzolamide of the formula 1 been done using both di-p-toluoyl-D-tartaric acid and di-p-toluoyl-L-tartaric acid and isolating required isomer which is very long process and not suitable for plant operation and large scale production (e) The poor yield of 22.5 % of Dorzolamide hydrochloride of the formula I. from (±)trans 5,6- Dihydro-4H-4-ethyJamino-6>methyIthieno[2,3-b] thiopyran-2-suIfonamide-7,7-dioxide of the formula 12 via resolution was reported. (f) The over all yield reported was only 1.78 % from 2-bromothiophene of the formula \9_. Yet another patent WO 2006/038222 also has disclosed a process for the preparation of (4S,6S)-4-(ethylamino)-5,6-dihydro-6-methyl-4H-thieno[2,3-b]thiopyran-2-suifonamide7,7-dioxide hydrochloride (Dorzolamide hydrochloride) of the formula 1_ by doing resolution of (±)trans 5,6-Dihydro-4H-4-ethylamino-6-methylthieno[2,3-b]thiopyran-2-sulfonamide-7,7-dioxide of the formula t2 using dibenzoyl-L-tartaric acid or di-p-toluoyl-L-tartaric acid in methanol solvent. The poor yield (15.4%) is reported for resolution step. Yet another patent WO 2007/122130 has also disclosed a process for the isolation of trans 5,6-dihydro-4H-4-ethylamino-6-methylthieno[2,3-b]thiopyran-2-sulfonamide-7,7-dioxide maleate of the formula 25 from cis/trans isomer of 5,6-dihydro-4H-4-ethylamiHo-6-methylthierto[2,3-b]thiopyran-2-sulfonamide-7,7-dioxide of the formula jl using maleic acid in acetone solvent, the yield 48.3 % and purity trans/cis ratio > 95/5 is reported. Also disclosed resolution of (±)trans 5,6-dihydro-4H-4-ethylamino-6-methylthieno[2,3-b]thiopyran-2-sulfon amide-7,7-dioxide of the formula \|2 using (ISH^-'O-camphorsulfonic acid. The lower yield (31.0 %) is reported for this resolution step. All the above mentioned reported processes for the preparation of Dorzolamide hydrochloride are not readily amenable for industrial preparation, and contained some intermediate with a stability/odor concern with respect to large scale manufacturing. Considering the importance of Dorzolamide hydrochloride and considering the difficulties in the manufacture of Dorzolamide hydrochloride on an industrial scale prompted us to develop an improved process for the large scale manufacture of Dorzolamide hydrochloride with high purity and simple process using less expensive and easily available raw materials. Objects of the present invention The main objective of the present invention is to provide an improved process for preparation of Dorzolamide hydrochloride of the formula 1. by overcoming the drawbacks of the hitherto known process. Another objective of the present invention is to provide a novel intermediate 3-{thiophen-2-yIsuIfanylpropionic acid 2-ethylhexyl ester of the formula 20 useful for the preparation of Dorzolamide hydrochloride of the formula L Stilt another objective of the present invention is to provide a process to isolate the trans 5,6-dihydro-4H-4-ethylamino-6-methylthienot2,3-b]thiopyran-2-sulfonamide-7,7-dioxide maleate of the formula 25 from cis/trans isomer of 5,6-dihydro-4H-4-ethylamino-6-methyIthieno[2,3-b]thiopyran-2-sulfbnamide-7,7-dioxide of the formula _U using maleic acid and water as a solvent which is very economical and environmentally friendly solvent. Yet another objective of the present invention is to provide a process for the resolution of racemic trans isomeric Dorzolamide of the formula \2_ using only one di-p-toluoyl-L-tartaric acid to get the 5,6-dihydro-4H-4(S)-ethylamino-6(S)-methylthicno[2,3-b]thiopyrari-2-sulfonamide-7,7- dioxide hemidi-p-toluoyl-D-tartarate of the formula 26 with diastereomeric excess of 99.9 % pure and Yet another objective of the present invention is to provide a process to isolate pure Dorzolamide hydrochloride of the formula 1 from 5,6-dihydro-4H-4(S)-ethylamino-6(S)-methylthieno[2,3-b]thiopyran-2-sulfc'narnide-7,7-dioxide hemidi-p-toluoyl-D-tartarate of the formula 26 in simple and recovering di-p-toluoyl-L-tartaric acid for reuse. Summary of the Invention The present invention provides an improved process for the preparation of Dorzolamide Step-Ill: Reacting the compound of the formula 2 with crotonic acid in presence of aprotic polar or non-polar solvent and suitable hase at a temperature in the range of 100-120 °C to obtain 3-(2-mercaptothiophene)butanoic acid of the formula 3. Step-VIII: Reacting the compound of the formula 15 with chlorosulfonic acid and chlorinating agent at a temperature in the range of 40-60 °C to give 5,6-dihydro-4H-4-acetylamino-6-methylthieno[2,3-b]thiopyran-2-sulfonylchloride-7,7,-dioxide of the formula 24. followed by treating with ammonia at a temperature in the range of 0-20 °C in the presence of aprotic polar solvent to obtain 5,6-dihydro-4H-4-acetylammo-6-methylthieno[2,3-b] thiopyran-2-sulfonamide-7,7,-dioxide of the formula JJJ. Stcp-IX: Reducing the compound of formula 10 using reducing agent in suitable solvent at a temperature in the range of 30-50 °C to obtain 5,6-dihydro-4H-4-ethylamino-6~methylthieno[2,3-b]thiopyran-2-sulfonamide-7,7,-dioxide of the formula 11. Step-X: Isolating the Trans isomer of the formula 25 from the trans/cis isomer of the formula 11 at a temperature in the range of 30-100 °C by making mineral or organic acid salt in suitable solvent. Stcp-XI: Treating the compound of the formula 25 with suitable base in a water solvent at a temperature in the range of 20-40 °C to obtain Trans 5,6-dihydro-4H-4-ethylamino-6-methylthieno[2,3-b]thiopyran-2-sulfonamide-7,7,-dioxide of the formula .12. Step XII: Treating the racemic trans isomeric compound of formula 12 in suitable solvent with optically active resolving agent by resolution to obtain trans (-) isomer of the formula 26. Step-XIII: Treating the compound of the formula 26 with suitable strong acid to recover the di-p-toluyl-L-tartaric acid and followed by adjusting the pH: 8-9 using a suitable base and extracted by using suitable solvent. The extracted solvent is treated with hydrochloric acid to obtain the Dorzolamide hydrochloride of the formula X- The present invention also provides a process for the preparation of the novel intermediate 3-(thiophen-2-ylsulfanyl(propionic acid 2-ethylhexyl ester of the formula 20 useful for the preparation of Dor/olamide hydrochloride of formula _!_• which comprises: Step-I: Reacting 2-bromothiophene of the formula 19, with 2-Ethylhexyl 3-mercaptopropionate in the presence of tris(dibenzylideneacetone)dipalladium(0) and xantphos in suitable base and solvent at a temperature in the range of 90-110 °C to obtain the novel intermediate 3-(thiophen-2-ylsulfanyl)propionic acid 2-ethylhexyl ester of the formula 20. Detailed Description of Invention The improved process for preparation of Dorzolamide hydrochloride of formula X of the present invention is illustrated by Scheme-4 given below: Step-I: Reacting 2-bromothiophene of the formula .19 with 2-Ethylhexyi 3-mercaptopropionate in the presence of tris(di benzyl ideneacetone)dipalladium(O) and xantphos in suitable base and solvent at suitable temperature to obtain the novel intermediate 3-(thiophen-2-ylsuIfanyI)propionic acid 2-ethylhexyl ester of the formula 20. The base used in reaction can be selected from pyridine, triethylamine, N-methylmorpholine, 2,6-dimethylpyridine, 2,4,6-trimethylpyridine or diisopropylethyl amine and preferably using diisopropylethyl amine. The solvent used in reaction can be selected from tetrahydrofuran, toluene, acetonitrile, dioxane or xylene and preferably using toluene. The reaction temperature may range from 90-110 °C and preferably at a temperature in the range of 90-95 °C. Step-H: Reacting the novel intermediate of the formula 20 with strong base in suitable solvent at suitable temperature to give 2-mercaptothiopriene of the formula 2. The base used in reaction can be selected from sodium methoxide, sodium hydroxide, potassium hydroxide, potassium methoxide, sodium hydride or lithium hydroxide and preferably using sodium methoxide. The solvent used in reaction is selected from C\|-C4 alcohol and preferably using methanol. The reaction temperature may range from 50-90 °C and preferably at a temperature in the range of 80-85 °C. Stcp-III: Reacting the compound of the formula 2 with crotonic acid in presence of aprotie polar or non-pofar solvent and suitable base at suitable temperature to obtain 3-(2-mercaptothiophene)butanoic acid of the formula 3. The base used in reaction can be selected from pyridine, 2,6-dimethylpyridine, 2,4,6-trimethylpyridine, triethylamine, N-methylmorpholine or diisopropylethyl amine and preferably using triethylamine. The solvent used in reaction can be selected from tetrahydrofuran, dioxane, ethyl acetate, acetonitrile or toluene and preferably using toluene. The reaction temperature may range from 100-120 °C and preferably at a temperature in the range of 105-110 °C. Step-IV: Reacting the compound of the formula 3 with chlorinating agent, and followed by treating with Lewis acid in non-pofar solvent at suitable temperature to obtain 576-dihydro-4H-6-methylthieno[2,3-b]thiopyran-4-one of the formula 4. The chlorinating agent used in reaction can be selected from thionyl chloride, oxalyl chloride, phosphorous pentachloride, phosphorous oxychloride, phosphorous trichloride or sulfuryl chloride and preferably usiiiK oxalyl chloride. The Lewis acids used in renction can be selected from aluminium chloride, atannic chloride, borontrifiuoride-elhereale, zinc chloride or ferric chloride and preferably using stannic chloride. The non polar solvent used in reaction can be selected from dichloromethane, chloroform or toluene and preferably using dichloromelhane. The reaction temperature may range from 0-30 °C and preferably at a temperature in the range of 0-5 °C. Step-V: Oxidation of the compound of the formula 4 by using oxidizing agent in suitable solvent at suitable temperature to obtain 5,6-dihydro-4H-6-methylthieno[2,3-b]thiopyran-4-one-7,7-dioxide of the formula 21,. The oxidizing agent used in reaction can be selected from oxone, 3-chloroperbenzoic acid, hydrogen peroxide in sodium tungstate or sodium perborate and preferably using hydrogen peroxide in sodium tungstate. The solvent used in reaction can be selected from dichloromethane, chloroform, ethyl acetate, isopropyl acetate, methanol, ethanol or acetic acid and preferably using ethyl acetate. The reaction temperature may range from 50-80 °C and preferably at a temperature in the range of 65-70 °C. Step-VI: Reducing the compound of the formula 21. by using reducing agent in suitable solvent at suitable temperature to obtain 5,6-dihydro-4H-4-hydroxy-6-methylthieno[2,3-b]thiopyran-7,7-dioxide of the formula 22.The reducing agent used in reaction can be selected from sodium borohydride, lithium aluminium hydride, palladium on carbon in hydrogen or Raney nickel in hydrogen and preferably using sodium borohydride. The solvent used in reaction can be selected from C1-C4 alcohol and preferably using methanol. The reaction temperature may range from 0-30 °C and preferably at a temperature in the range of 25-30 °C. Step-VII: Reacting of the compound of the formula 22 by using acetonitrile and strong acid by Ritter reaction at suitable temperature to obtain 5,6-dihydro-4H-4-acetyl amino-6-mcthylthieno\|2,3-b]thiopyran-7,7-dioxide of the formula 23. The strong acid used in reaction can be selected from sulfuric acid, methane sulfonic acid, phosphoric acid, trifluoroacetic acid or trifluoromethanesulfonic acid and preferably using sulfuric acid. The reaction temperature may range from 0-30 °C and preferably at a temperature in the range of 25-30 °C. Step-VIII: Reacting the compound of the formula 23 with chlorosulfonic acid and chlorinating agent at suitable temperature to give 5,6-dihydro-4H-4-acetylamino-6-methylthieno[2,3-b]thiopyran-2-sulfonylchloride-7,7,-dioxide of the formula 24. The chlorinating agent used in reaction can be selected from thionyl chloride, oxalyl chloride, phosphorous pentachloride, phosphorous oxychtoride, phosphorous trichloride or sulfuryl chloride and preferably using thionyl chloride. The reaction temperature may range from 40-60 °C and preferably at a temperature in the range of 50-55 °C. The conversion of the compound °f tn^ compound formula 24 to 5,6-dihydro-4H-4-acetylamino-6-methylthieno[2,3-b]thiopyran-2-sulfonamidc-7,7,-dioxide of the formula H) may be done with aqueous ammonia at a suitable temperature in the presence of aprotic polar solvent. The aprotic solvent used in reaction can be selected from tetrahydrofuran, acetone, dioxane or methylethylketone and preferably using acetone. The reaction temperature may range from 0-20 °C and preferably at a temperature in the range of 0-5 °C. Step-IX: Reducing the compound of formula 10 using reducing agent in suitable solvent at suitable temperature to obtain 5,6-dihydro-4H-4-ethylamino-6-methylthieno[2,3-b]thiopyran-2-sulfonamide-7,7,-dioxide of the formula II. The reducing agent used in reaction can be selected from borane-dimethylsulfide complex, borontrifluoride-etherate in sodium borohydride or lithium aluminium hydride and preferably borontrifluoride-etherate in sodium borohydride. The solvent used in reaction can be selected from ethers or cyclic ethers and preferably using tetrahydrofuran. The reaction temperature may range from 30-50 °C and preferably at a temperature in the range of 40-45 °C. Step-X: Isolating the Trans isomer of the formula 25 from the trans/cis isomer of the formula H at suitable temperature in the range of 30-100 °C by making mineral or organic acids salt in suitable solvent. The mineral acid used in reaction can be selected from hydrochloric acid, hydrobromic acid, sulfuric acid or nitric acid. The organic acid used in reaction is selected from maleic acid, fumaric acid, malonic acid, oxalic acid, benzoic acid, succinic acid, p-toluic acid, citric acid, salicylic acid or p-nitrobenzoic acid and preferably using maleic acid. The solvent used in reaction can be selected from ketone, ester, alcohol, polar-aprotic solvents or water and preferably using water. The reaction temperature may range from 30-100 °C and preferably at a temperature in the range of 95-100 °C. The purity of compound formula 25 has improved to 99.5 % with maximum yield 67 % beside environment friendly solvent water as a solvent for separation of trans isomer from cis/trans mixture that has not been reported henceforth. Step-XI: Treating the compound of the formula 25 with suitable base in a water solvent al suitable temperature in the range of 20-40 °C to obtain Trans 5,6-dihydro-4H-4-ethylamino-6-methylthieno[2,3-b]thiopyran-2-sulfonamide-7,7,-dioxide of the formula ,12. The base used in reaction can be selected from ammonia, sodium bicarbonate, sodium carbonate, sodium hydroxide, potassium hydroxide or potassium bicarbonate and preferably using sodium bicarbonate. The reaction temperature may range from 20-40 °C and preferably at a temperature in the range of 25-30 °C. Step-XII: Treating the racemic trans isomeric compound of formula ^2_ in suitable solvent with optically active resolving agent by resolution to obtain trans (-) isomer of the formula 26. The optically active resolving agent used in reaction can be selected from tartaric acids, di-p-tolujI-L-tartaric acid, malic acids, mendelic acids or camphour-10-sulfonic acids and preferably using di-p-toluyl-L-tartaric acid (L-DPTTA). The solvent used for recrystallisation may be selected from alcohols, water or polar-aprotic solvents and preferably using n-propanol. Step-XIII: Treating the compound of the formula 26 with suitable strong acid to recover the di-p-toluyl-L-tartaric acid and followed by adjusting the pH: 8-9 using suitable base and extracted by using suitable solvent. The extracted solvent is treated with hydrochloric acid to obtain the Dorzolamide hydrochloride of the formula L The acid used for neutralization of the tartarate salt may be selected from sulfuric acid, hydrochloric acid, hydrobromic acid or methanesulfonic and preferably using sulfuric acid. The base used in reaction can be selected from sodium bicarbonate, sodium carbonate, sodium hydroxide or potassium hydroxide and preferably using sodium hydroxide. The solvent used for extraction is selected from ethyl acetate, dichloromethane or chloroform and preferably using ethyl acetate. It is to be noted that the process can be carried out continuously without the isolation of the compounds of the formulae 20, 2 & 3. The details of the invention are given in examples provided below, which are given to illustrate the invention only and therefore should not be construed to limit the scope of the present invention. Example 1: Preparation of Dorzolamide hydrochloride Step-I: Preparation of novel intermediate 3-(thiophen-2-ylsulfanyl)propionic acid 2-ethylhexyl ester (formula 20) To the solution of 2-bromothiophene (100 grams, 0.613 mmol) in toluene (3 L) was added 2-Ethylhexyl 3-mercaptopropionate (218.36 grams, 0.613 mmol) and N,N-diisopropyiamine (158.5 grams, 1.226 mmol) at ambient temperature. After nitrogen evacuation, tris(dibenzylideneacetone) dipalladium(O) (1.4 grams, 1.533 mmol), xantphos (0.88 grams, 1.533 mmol) was added. The mixture was heated to 90-95 °C and stirred for 2 hours. After reaction was over, the reaction mixture was cooled to ambient temperature and stirred with 50 grams of silica gel. The mixture was filtered and the organic layer was concentrated to obtain the product of the formula 20 as light yellow liquid. Output: 180 grams; Purity: 98.0 %; Yield: 97.6 %; 'H-NMR(CDCI3): 5 0.89(m, 6H), !.33(m, 8H), l.55(m,lH), 2.62(t, 2H), 3.01(t, 2H), 4.00(dd, 2H), 6.98(dd, IH), 7.15(dd, 1H), 7.37(dd, 1H); nC-NMR(CDCl3): 5 10.96, 14.02, 22.94, 23.75, 28.89, 30.37, 33.72, 34.57, 38.70, 67.14, 127.61, 129.88, 133.18, 134.57, 171.74; LC-MS: (m/z) = 300.00 (M). Step-U: Preparation of 2-mercaptofhiophene (formula 2) The product obtained from the above Step-I (90 grams, 0.2995 mmol) was dissolved in methanol (540 mL). Sodium methoxide solution (25 %) (270 mL) was added to the reaction mass at ambient temperature. The reaction mixture was heated to reflux and maintained for I hour. After completion of reaction, the solvent was distilled out completely and cooled to ambient temperature. Water (450 mL) was added to the residue and washed with MDC. The product containing water layer was acidified to pH: 1-2 using concentrated hydrochloric acid. The product was extracted in to MDC (3 x 270 mL). The organic extracts was combined and washed with water. The organic layer was concentrated to obtain the product of the formula 2 as yellow oil. Output: 30.4 grams; Purity: 92.0 %; Yield: 87.3%; 'H-NMR(CDCI3): 6 3.5t(s, IH), 6.92(q, IH), 7.08 (m, IH), 7.26(dt, IH); nC-NMR(CDCI3): 5 124.54, 127.59, 128.98, 134.01; MS: (m/z)- 114.8(M-1). Step-Ill: Preparation of 3-(2-mercaptothiophene)butanoic (formula 3) The product obtained from the above Step-II (25 grams, 0.2151 mmol) was dissolved in toluene (250 mL) and added crotonic acid (18.52 grams 0.2151 mmol) at 15-20 °C. Triethyl amine (65.31 grams, 0.6455 mmol) was added slowly at below 25 °C. After the addition was over, the reaction mixture was heated to reflux and stirred for 10 hours. The reaction mixture was cooled to ambient temperature, added water (500 mL) and stirred. The layer was separated and acidified the product containing water layer to pH: 1-2 using concentrated hydrochloric acid. The product was extracted in to toluene (3 x 125 mL). The organic layer was combined, washed with water and concentrated to obtain the product of formula 3 as yellow oil. Output: 37 grams; Purity: 98.0 %; Yield: 85.0 %; 'H-NMR(CDCI3): 5 1.33(d, 3H), 2.47(dd. 1H), 2.70(dd, 1H), 4.00(dd, J2H), 6.98(dd. IH), 7.15(dd. IH),7.37(dd, IH); ,3C-NMR(CDC13): 6 10.96, 14.02, 22.94, 23.75, 28.89, 30.37, 33.72, 34.57, 38.70, 67.14, 127.61, 129.88, 133.18, 134.57, 171.74; MS:(m/z) = 203.0(M+l). Step-IV: Preparation of 5,6-dihydro-4H-6-methylthieno[2,3-b]thiopyran-4-one (formula 4) The product obtained from the above Step-Ill (30 grams, 0.1483 mmol) was dissolved in MDC (240 mL) and dimethylformamide (0.8 mL) at ambient temperature Oxalyl chloride (20.7 grams, 0.1631 mmol) was added dropwise and maintained at ambient temperature for 2 hours. The reaction mixture was cooled to 0-5 "C, and added dropwise a solution of stannic chloride (19.3 grams, 0.0741 mmol) in MDC by maintaining the temperature below 5 °C. The reaction was stirred for 2 hours at 0-5 °C. After completion of reaction, water (120 L) was added and stirred. The layer was separated and the product containing MDC layer was washed with 5%hydrochloride solution and water. The product containing organic layer was concentrated completely to obtain the product of the formula 4 as yellow liquid. Output1 27 grams; Yield: 98.9 %; Purity: 97 %; 'H-NMR(CDC1,): S 1.48(d, 3H),2.69(dd, IH), 2.88(dd, IH), 3.79 (m, IH), 7.0l(d, IH). 7.45(d, IH); l3C-NMR(CDCI3):5 19.93,40.83,46.69, 121.95, 125.86, 134.62, 150.74, 189.30; MS:(m/z)= 185.1(M+1). Step-V: Preparation of 5,6-dihydro-4H-6-methylthieno[2^-b]thiopyran-4-one-7,7-dioxide (formula 21} The product obtained from the above Step-IV (174 grams, 0.9442 mmol) was dissolved in ethyl acetate (1.74 L) at ambient temperature. Sodium tungstate dihydrate (31.1 grams, 0.0944 mmol) and sulfuric acid (0.5 mL) was added at ambient temperature. The mixture was cooled to 0-5 °C, and 30% hydrogen peroxide (375.3 grams, 3.309 mmol) was added dropwise at below 10 °C. The reaction mixture was heated to reflux and maintained for 2 hours. The reaction was cooled to ambient temperature and separated the layers. The product containing organic layer was washed with 5% sodium sulfite solution (522 mL) and followed by water (522 mL). The organic layer is concentrated completely, hexane (522 mL) is added and stirred. The product was filtered and washed with hexane and dried to obtain the product of the formula 21 as off-white solid. Output: I 81.5 grams; Yield: 88.8%; Purity: 99 %; Melting Range: 103-109 °C; 'H-NMR(CDC13):S 1.57(d, 3H), 3.22(m, 2H), 3.87 (m, lH),7.49(d, IH), 7.61(d, IH); i3C-NMR(CDCl3):5 15.81,49.26,61.86, 130.76, 137.69, 145.22, 151.44, 192.16; MS:(m/z) = 217.1(M+l). Step-VI: Preparation of 6-dihydro-4H-4-hydroxy-6-methylthieoo[2^-b\|thiopyran-7,7-dioxkle (formula 22) The product obtained from the above Step-V (180 grams, 0.8325 mmol) was suspended in methanol (540 mL) and cooled to 10 °C. Sodium borohydride (19.23 grams, 0.5076 mmol) was added to the reaction mass at below 10 °C. The reaction mixture was warmed to ambient temperature and stirred for 1 hour. The reaction mixture out concentrated under vacuum, water (720 mL) was added, stirred and extracted in to ethyl acetate (1.8 & 0.54 L). The product containing organic layer was combined and washed with brine solution. The organic layer was concentrated completely. Hexane (540 mL) was added to the residue and utiired. The product was filtered, washed with hexane and dried to obtain the product of the formula 22 as solid. Output: 169.14 grams; Yield: 93.1 %; Melting Range: 110-120 °C; 'H-NMR(DMSO-d6) : S 1.32(d, 3H), 2.13(m, 1H), 2.32(m, IH), 3.70(m, 1H), 4.79 (m, 1H), 5.88(d, IH). 7.l6(d7 lH);7.92(d, 1H); ,3C-NMR(DMSO-d6)-. 5 10.92,39.14,55.72,64.87,127.53,131.62, 134.00, 149.34. Step-VII: Preparation of 5,6-dihydro-4H-4-acetyl amino-6-methylthieno\|2^-b\|thiopyran-7,7-dioxide (formula 23) The product obtained from the above Step-VI (165 grams, 0.7558 mmol) was suspended in acetonitrile (247.5 mL) and cooled to 10 °C. Sulfuric acid (247.5 mL) was added dropwise to a reaction mass at below 10 °C over 2-3 hours. The reaction mixture was warmed to ambient temperature and stirred for 2 hours. This reaction mixture was quenched in to ice (1.981 kg) at below 10 °C. The pH was adjusted to 6-7 using sodium hydroxide solution, and the mixture was stirred, filtered and washed with water. The filtered wet product again leached with water, filtered and dried to obtain the product of the formula 23 Output: 177.5 grams; Yield: 90.5 %; Purity: Trans-79.2%, Cis-20.3%; Melting Range: 194-198 °C; 'H-NMR(DMSO-d6) Trans : 5 1.33(d, 3H), 1.83(s, 3H), 2.23(m, IH), 2.39(m, IH), 3.60(m, IH), 5.17 (m, IH), 7.02(d, III), 7.95(d, III), 8.55(d, IH); Cis: 6 1.31(d, 3H), l.83(s, 3H), 2.23(m, IH), 2.39(m, IH), 3.88(m, IH), 5.23(m, III), 6.94(d, IH), 7.93(d, IH), 8.50(d, IH); l3C-NMR(DMSO-tl6) Trans : 5 10.82,22.90,35.58,53.05, 128.20, 131.92, 135.62,144.88,169.08. Cis : 8 10.57, 27.90, 36.47, 45.17, 55.88, 127.48, 13 1.70, 135.10, 146.60, 169.50; MS:(m/z) = 260.2(M+1). Step-VIII: Preparation of 5,6-dihydro-4H-4-acetylamino-6-melhylthieno\|2r3-b\|thiopyran-2-sulfonamide-7,7,-dioxide (formula ,10) The product obtained from the above Step-VH (125 grams, 0.4819 mmol) was added lo chlorosulfonic acid (250 mL) at below 10 °C over 1 hour. The reaction mixture was heated gradually to 50-55 °C and stirred for 10 hours. The reaction mixture was cooled to ambient temperature and added thionyl chloride (250 mL). The reaction mixture was heated to 50-55 °C and stirred for 10 hours. The obtain reaction mixture was cooled and quenched in to ice+water (2.5 kg) at below 10 °C, and stirred. The product was filtered at 0-5 °C, and washed with chilled water, and suck dried to obtain the product of the formula 24. Wet Product: 170 grams. The above wet product was added in lot wise to a solution of acetone (998 mL) and aqueous ammonia (258 mL) at below 5 °C, and stirred for 1 hour. The reaction mixture was concentrated under vacuum, water (517 mL) was added and stirred. The pH was adjusted to 6.0-7.0 using concentrated hydrochloric acid and stirred for 2 hours. The product was filtered, washed with water, and dried to obtain the product of the formula M). Output: 121 grams; Yield: 74.1 %; Purity: Trans-76.5%, Cis-19.8 %; 'H-NMR(DMSO-d6)Trans:5 1.35(d, 3H), 1.85(s, 3H), 2.28(m, 1H), 2.47(m, 1H), 3.86(m, 1H), 5.17 (m, 1H), 7.40(s, 1H), 8.05(s, 2H), 8.62(d, 1H); Cis: 5 1.32 (d, 3H), 1.89(s, 3H), 2.28(m, 1H), 2.47(m, 1H), 3.94(m, 1H), 5.25 (m, 1H), 7.31 (s,lH), 8.05(s, 2H), 8.59(d, fH); l3C-NMR (DMSO-d6) Trans: 5 10.50, 22.63, 34.70, 41.71, 53.14, 129.58, 138.11, 144.63, 149.82, 168.90; Cis: 6 10.12,21.00,35.65,44.75,55.78, 120.80, 137.80, 146.39, 149.60, 169.90; MS:(m/z) = 337.2(M+l). Step-IX; Preparation of5,6-dihydro-4H-4-ethylamino-6-niethyltbieno\|2t3-b\|tbiopyran-2-sulfonamide-7,7,-dioxide (formula 11) The product obtained from the above Step-VIII (120 grams, 0.3545 mmol) was suspended in tetrahydrofuran (960 mL) and cooled to 5-10 °C. Sodium borohydride (26.8 grams, 0.7091 mmol) was added to the reaction mass at below 10 °C, and stirred. Borontrifluoride-etherate (100.6 grams, 0.7091 mmol) was added at below 10 ^C. The reaction mixture was heated to 40-45 °C, and stined for 8 hours. The reaction mixture was cooled and acidified with concentrated hydrochloric acid (270 mL), and stirred for 10 hours at ambient temperature. The reaction mixture was concentrated under vacuum, added of water (480 mL). The pH was adjusted to 7-7.5 using sodium hydroxide solution and stirred for 5 hours. The product was filtered and washed with water, and dried to obtain the product of the formula l_l-Output: 107 grams; Yield: 93.0%; Purity: Trans-77.1 %, Cis-19.2 %; MS: (m/z) = 325.4 (M+l). Step-X: Preparation of formula 25 The product obtained from the above Step-IX (105 grams, 0.3236 mmol) was suspended in water (1.47 L) at ambient temperature. Maleic acid (37.5 grams, 0.3236 mmol) was added to reaction mass and heated to reflux to get clear solution. The clear mass was cooled to 5-10 °C, and stirred for 1 hour. The product was filtered and washed with water. The wet product was recrystallized again with water, and dried to obtain the product of the formula 25 as white solid. Output: 88.2 grams; Yield: 61.8%; Purity: Trans-99.0 %, Cis-0.6 %; Melting Range: 207-214 °C; ]H-NMR(DMSO-d6) : 6 l.20(t, 3H), 1.38(d, 3H), 2.60(s, 2H), 3.01(m, 1H), 3.2l(m, IH), 4.03 (m, JH),4.65(t, JH), 6.07(s, IH, Maleic acid), 7.82(s, JH), 8.I6(br-s,IH); nC-NMR(DMSO-d6) : 8 10.40, 11.89, 31.30,41.31,49.85, 51.90, 130.72, 138.26, 141.85, 150.06, 135.93, 167.75 (Maleic acid); MS:(m/z) = 325.3(M+l). Slep-XI: Preparation of Trans 5,6-dihydro-4H-4-ethylamino-6-methylthieno\|2^-b]thiopyran-2- suIfonamide-7,7,-dioxide (formula 12) The product obtained from the Step-X (88 grams, 0.1997 mmol) was added in lot wise to a solution of sodium bicarbonate (88 grams) in water (1.76 L) at ambient temperature, and stirred for 1 hour. The product was filtered and washed with water. The wet product was again leached with water, and dried to obtain the product of the formula _12-Output: 62 grams; Yietd: 95.6 %; Purity: Trans-99.0 %, Cis-0.6 %; Melting Range: 182-188 °C; (H-NMR(DMSO-d6): 5 1.00(t, 3H), 1.33(d, 3H), 2.32(s, 2H), 2.57(m, 2H), 3.90(m, 2H), 7.55(s, IH), 8.02(br-s, IH); nC-NMR(DMSO-d6 : 8 10.53, 15.25,33.61,40.92,50.22,52.21, 130.52, 137.64, 146.92, 148.82; MS:(m/z) = 325.3(M+l). Step-XII: Preparation of formula 26 The product obtained from the above Step-XI (60 grams, 0.1849 mmol) was suspended in n-propanol (2.1 L) at ambient temperature. Di-p-toluyl-L-tartaric acid monohydrate (18.7 grams, 0.0462 moles) was added to the reaction mixture and heated to reflux to get clear solution. The clear mass was cooled to 25-30°C, and stirred for 2 hours. The product was filtered and washed with n-propanol. The wet product was recrystallized again with n-propanol (950 mL), and dried to obtain the product of the formula 26. Output: 34.5 grams: Yield: 36.0%; Purity: Trans-99.2 %, Cis-0.3 %, S(-> 99.97%, R(+)- 0.03%; Melting Range: 158-165 QC; 'H-NMR(DMSO-d6) : 5 l.00(t, 3H), 1.33 8.02(br-s, IH); L,C-NMR(DMSO-d6):5 10.53,15.25,33.61,40.92,50.22,52.21, 130.52, 137.64,146.92, 148.82;. MS:(m/z) = 325.3(M+l). Step-XIIJ: Preparation of Dorzolamide hydrochloride (formula I) The product obtained from the above Step-XII {15 grams, 0.0289 mmol) was suspended in water (105 mL) at ambient temperature. Sulfuric acid (7.9 grams, 0.0806 mmol) was added slowly to the reaction mixture and stirred for 6 hours. The solid product was filtered and washed with water (30 mL), dried to obtain 5.2 grams of di-p-toluyLL-tartaric acid monohydrate (88.7 %) as white solid. The pH of the filtrate was adjusted to 8 using sodium hydroxide solution and extracted the product in to ethyl acetate (2 x 150 mL). The combined organic layers were washed with brine solution (75.0 mL). Approximately 150 mL of ethyl acetate was distilled out atmospherically, and eharcolised the organic layer. IPA-HCI (15%) (13.5 mL) was added to the filtered organic layer at ambient temperature and stirred for 2 hours. The product was filtered, washed with ethyl acetate and dried to obtain the product of the formula I. as white crystalline solid. Output: 8.8 grams; Purity: 99.8 %; Yield: 84.2%; 'H-NMR(DMSO-d6) Trans : 5 1.26(t, 3H), 1.37(d, 3H), 2.53(m, IH), 2.53(m, IH), 2.74(m, IH), 3.02(m, IH), 3.18(m, IH), 4.27(m,lH), 4.67(br, s, IH), 7.96(s, IH), 8.18(s, 2H), 9.45(br, s, IH), 9.69(br,s, IH); l3C-NMR(DMSO-d6) Trans : 8 10.26, 11.43, 30.99, 41.07, 49.51, 51.86, 131.00, 137.64, 142.21, 149.96; MS:(m/z)-325.3(M+l). Example 2: Preparation of Dorzolamide hydrochloride (without isolation of the compounds 20, 2 and 3) Step-A: Preparation of 5,6niihydro-4H-6-methylthieno[2,3-b]tliiopyrau-4-one (formula 4) To the solution of 2-bromothiophene (50 grams, 0.3066 mmol) in toluene (300 mL) was added 2-Ethylhexyl 3-mercaptopropionate (66.96 grams, 0.3066 mmol) and N,N-Diisopropylamine (49.52 grams, 0.3833 mmol) at ambient temperature. After nitrogen evacuation, tris(di benzyl ideiieacetone) dipalladium(O) (0.70 grams, 0.76 mmol), and xantphos (0.44 grams, 0.76 mmol) was added. The mixture was heated to 90-95 °C and stirred for 2 hours. After reaction was over, the reaction mass was cooled to ambient temperature and filtered through hyflo and washed with toluene. Sodium methoxide solution (25%) (180.0 mL) was added to the above filtrate and heated lo 80-85 °C. The reaction mass was stirred for 1 hour at 80-85 °C and cooled to ambient temperature. The product was extracted in to water (250 mL) and acidified the water layer to pH: 1-2 using concentrated hydrochloric acid. The product was extracted three times in to toluene and washed with water. Crotonic acid (25 grams 0.2904 mmol) was added to the above toluene layer and cooled to 15-20 °C. Triethylamine was added (77.5 grams, 0.7661 mmol) at below 25 °C. After the addition was over, the mixture is heated to reflux and stirred for 10 hours. The reaction was cooled to ambient temperature and extracted the product by using water. The product containing water layer was acidified to pH: 1-2 using concentrated hydrochloric acid and extracted in to MDC. The MDC layer was washed with water and brine solution. Di methyl formamide (1.6 mL) and oxaly! chloride (37.9 grams, 0.2986 mmol) was added dropwise to the above MDC layer at ambient temperature and the mixture stirred for 2 hours. The mixture was cooled to 0-5 °C, and a solution of stannic chloride (35.4 grams, 0.1359 mmol) in MDC (50 mL) is added dropwise by maintaining the temperature below 5 °C. The reaction is stirred for 2 hours at 0-5 °C. After reaction is over, water (220 mL) is added and stirred. The layer is separated and the product MDC layer is washed with hydrochloric acid solution and water. The product containing organic layer was concentrated completely to obtain the product of the formula 4 as yellow liquid. Output: 43 grams; Purity: 97.0%; Yield: 76.1 % (from 2-bromothiophene) 'H-NMR(CDC1,): 5 I.48(d, 3H), 2.69(dd, 1H), 2.88(dd, IH), 3.79 (m, 1H), 7.01(d, 1H), 7.45(d, 1H); !?C-NMR(CDC!,):8 19.93,40.83,46.69, 121.95, 125.86, 134.62, 150.74, 189.30; MS:(m/z)= 185.1(M+1). Step-B: Preparation of 5,6-dihydro-4H-6-methylthieno\|2^-b\|thiopyran-4-one-7,7-dioxide (formula 21) The product obtained from the Step-A (450 grams, 2.4419 mmol) was dissolved in ethyl acetate (4.5 L). Sodium tungstate dihydrate (80.5 grams, 0.2442 mmol) and sulfuric acid (0.9 mL) was added at ambient temperature. The mixture was cooled to 0-5 °C, and 30% hydrogen peroxide (969.2 grams, 8.5467 mmol) was added dropwise at below 10 °C. The reaction mixture was heated to reflux and maintained for 2 hours. The reaction was cooled to ambient temperature and separated the layers. The organic layer was washed with 5% sodium sulfite solution and followed by water. The organic layer was concentrated completely, added hexane (1.35 L) and stirred. The product was filtered, washed with hexane and dried to obtain the product of the formula 21 as off white solid. Output: 476 grams; Yield: 90.1 %; Purity: 99.5 %; Melting Range: 104-107 °C; 'H-NMR(CDC]3):5 1.57(d, 3H), 3.22(m, 2H), 3.87 (m, lH),7.49(d, !H),7.6l(d, IH); nC-NMR(CDCI3): 5 15.81,49.26,61.86, 130.76, 137.69, 145.22, 151.44, 192.16; MS:(m/z) = 217.l(M+t). Step-C: Preparation of 6-dihydro-4H-4-hydroxy-6-methylthieno[2rJ-b)thiopyran-7,7-dioxidc (formula 22) The product obtained from the above Step-B (460 grams, 2.1268 mmol) was suspended methanol (1.38 L) and cooled to 10 °C. Sodium borohydride (48.34 grains, 1.2761 mmol) was added to the reaction mass at below 10°C. The reaction mixture was warmed to ambient temperature and stirred for 1 hour. The reaction mixture out concentrated under vacuum. Water (1.84 L) was added. stirred and extracted in to ethyl acetate (4.6 & 1.38 L). The organic layer was combined and washed with brine solution. The organic layer was concentrated completely; added hexane (1.38 L) was added to the residue and stirred. The product was filtered, washed with hexane and dried to obtain the product of the formula 22, as solid. Output; 442 grams; Yield: 95.2%; Purity: 97.4 %; Melting Range: 119-120DC; 'H-NMR(DMSO-d6) : 5 1.32(d, 3H), 2.13(m, IH), 2.32(m, IH), 3.70(m, IH), 4.79 (m, IH), 5.88(d, IH),7.16(d, lH),7.92(d, IH); nC-NMR(DMSO-d6) : S 10.92,39.14,55.72,64.87, 127.53, 131.62, 134.00, 149.34. Step-D: Preparation of 5,6-dihydro-4H-4-acctyl amino-6-methylthieno[2,3-blthiopyran-7,7- dioxrde (formula 23) The product obtained from the above Step-C (425 grams, 1.9468 mmol) was suspended in acelonitrile (637.5 mL) and cooled to 10 °C. Sulfuric acid (637.5 mL) was added dropwise to a reaction mass at below 10 °C over 2-3 hours. The reaction mixture was warmed to ambient temperature and stirred for 2 hours. The reaction mixture was quenched in to ice (5.1 kg) at below 10 °C. The pH was adjusted to 6-7 using sodium hydroxide solution, and the mixture was stirred, filtered and washed with water. The filtered wet product again [eached with water, filtered and dried to obtain the product of the formula 23. Output: 451 grams; Yield: 89.3 %; Purity: Trans-75.6 %, Cis-23.6 %; Melting Range: 192-196 °C; 'H-NMR(DMSO-d6) Trans : 5 1.33(d, 3H), 1.83(s, 3H), 2.23(m, IH), 2.39(m, IH), 3.60(m, IH), 5.17(m, lH),7.02(d, IH), 7.95(d, IH), 8.55(d, IH); Cis: 5 1.31(d, 3H), 1.83(s, 3H), 2.23{m, IH), 2.39(m, IH), 3.88(m, IH), 5.23 (m, IH), 6.94(d, IH), 7.93(d, IH), 8.50(d, IH); l3C-NMR(DMSO-d6) Trans :S 10.82,22.90,35.58,53.05, 128.20, 131.92, 135.62, 144.88, 169.08; Cis:S 10.57,22.90,36.47,45.17,55.88, 127.48, 131.70, 135.10, 146.60, 169.50; MS :(m/z)= 260.2(M+1). Step-E: Preparation of 5,6-dihydro-4H-4-acerylamino-6-methylthieno[2,3-b]thiopyran-2- sulfonamide-7,7,-dioxide (formula .10) The product obtained from the above Step-D (420 grams, 1.6194 mmol) was added to chtorosulfonic acid (840 mL) at below 10 °C over 1 hour. The reaction mixture was heated gradually to 50-55 °C and stirred for 10 hours. The reaction mixture was cooled to ambient temperature and added thionyl chloride (840 mL). The reaction mixture was heated to 50-55 °C and stirred for 10 hours. The reaction mixture was cooled and quenched in to ice+water (8.4 kg) at below 10 °C, and stirred. The product was filtered at 0-5 °C, washed with chilled water, and suck dried to obtain the product of the formula 24. Wet Product: 700 grams. The above wet product added in lot wise to a solution of acetone (3.474 V) and aqueous ammonia (868.5 mL) at below 5 °C, and stirred for 1 hour. The reaction mixture was concentrated under vacuum, water (1.737 L) was added and stirred. The pH was adjusted to 6.0-7.0 using concentrated hydrochloric acid and stirred for 2 hours. The product was filtered, washed with water, and dried to obtain the product of the formula 10. Output: 413 grams; Yield: 75.3 %; Purity: Trans-75.9 %, Cis-19.9 %. 'H-NMR(DMSO-d6)Trans:o 1.35(d, 3H), 1.85(s, 3H), 2.28(m, lH),2.47(m, IH),3.86(m, 1H), 5.17 (m, 1H), 7.40(s, 1H), 8.05(s, 2H), 8.62(d, 1 H); Cis: 5 1.32 (d, 3H), 1.89(s, 3H), 2.28(m, IH), 2.47(m, 1H), 3.94(m, 1H), 5.25 (m, 1H), 7-31 (s,lH), 8.05(s, 2H), 8.59(d, IH); ,3C-NMR (DMSO-d6) Trans: S 10.50, 22.63, 34.70, 41.71, 53.14, 129.58, 138.11, 144.63, 149.82. 168.90; Cis: 8 10.12,21.00,35.65,44.75,55.78, 120.80, 137.80, 146.39,149.60, 169.90; MS:(m/z) = 337.2(M+l). Stcp-F: Preparation of 5,6-dihydro-411-4-ethylamino-6-methyIthieno[2^-b)thiopyran-2-sulfonamide-7,7,-dio\ide (formula 1_1_) The product obtained from the above Step-E (390 grams, 1.1523 mmol) was suspended in tetrahydrofuran(3.l2 L) and cooled to 5-10 °C. Sodium borohydride (87.3 grams, 2.3Q46 mmol) was added to the reaction mass at below 10 °C, and stirred. Borontrifluoride-etherate (327.1 grams, 2.3046 mmol) was added at below 10 °C. The reaction mixture was heated to 40-45 °C, and stirred for 8 hours. The reaction mixture was cooled and acidified with concentrated hydrochloric acid (881 mL), and stirred for 10 hours, at ambient temperature. The reaction mixture was concentrated under vacuum, added of water (1.56 L). The pH was adjusted to 7-7.5 using sodium hydroxide solution and stirred for 5 hours. The product was filtered, washed with water, and dried to obtain the product of the formula 11 as off white solid. Output: 338 grams; Yield: 90.4 %; Purity: Trans-78.4 %, Cis-17.4 %; MS: (m/z) = 325.4 (M+l). Step-G: Preparation of formula 25 The product obtained from the above Step-F (325 grams, 1.0017 mmoi) was suspended in water (4.55 L) at ambient temperature. Maleic acid (116.3 grams, 1.0017 mmol) was added to reaction mass and heated to reflux to get clear solution. The clear mass was cooled to 5-10 °C, and stirred for 1 hour. The product was filtered and washed with water. The wet product was recrystallized again with water, and dried to obtain the product of the formula 25 as white solid. Output: 298 grams; Yield: 67.5 %; Purity: Trans-99.3 %, Cis-0.2 %; Melting Range: 207-214 °C; 'H-NMR(DMSO-d6) : 5 l.20(t, 3H), 1.38(d, 3H), 2.60(s, 2H), 3.01(m, 1H), 3.2l(m, 1H), 4.03 (m, 1H), 4.65 (t, III), 6.07(s, 111, Maleic acid), 7.82(s, 1H), 8.16(br-s,lH); l3C-NMR(DMSO-d6):5 10.40, 11.89, 31.30, 41.31, 49.85, 51.90, 130.72, 138.26, 141.85, 150.06, 135.93, 167.75 (Maleic acid); MS:(m/z) = 325.3(M+l). Step-H: Preparation of Trans 5,6-dihydro-4H-4-ethyiamino-6-methylthieno\|2,3-b\|thiopyran-2-sulfonamide-7,7,-dioxide (formula \2) The product obtained from the above Step-G (360 grams, 0.8172 mmol) was added in lot wise to a solution of sodium bicarbonate (360 grams) in water (7.2 L) at ambient temperature, and stirred for 1 hour. The product was filtered and washed with water. The wet product was again leached with water, and dried to obtain the product of the formula 12. Output: 254 grams; Yield: 95.8%; Purity: Trans-99.3 %, Cis-0.3 %; Melting Range: 180-183 °C; 'H-NMR(DMSO-d6): 5 1,00(t, 3H), 1.33(d, 3H), 2.32(s, 2H), 2.57(m, 2H), 3.90(m, 2H), 7.55(s, 1H), 8.02(br-s,lH); l3C-NMR(DMSO-d6): 5 10.53, 15.25,33.61,40.92,50.22,52.21, 130.52, 137.64, 146.92, 148.82; MS:(m/z) = 325.3(M+l). Step-T: Preparation of formula 26 The product obtained from the above Step-H (240 grams, 0.7397 mmol) was suspended in n-propanol (8.4 L) at ambient temperature. Di-p-toluyl-L-tartaric acid monohydrate (74.78 grams, 0.1849 mmol) was added to the reaction mixture and heated to reflux to get clear solution. The clear mass was cooled to 25-30 °C, and stirred for 2 hours. The product was filtered and washed with n- propanol. The wet product was recrystallized again with n-propanol (5.28 L), and dried to obtain the product of the formula 26. Output: 144 grams; Yield: 37.6%; Purity: S(-)-99.94 %, R(+)-0.06 %; Melting Range: 158-163 °C; 'H-NMR(DMSO-d6) : 5 1.00(t, 3H), 1.33(d, 3H), 2.32(s,2H), 2.57(m, 2H), 3.90(m, 2H), 7.55(s, 1H), 8.02(br-s, IH); l3C-NMR(DMSO-d6):5 10.53, 15.25,33.61,40.92,50.22,52.21, 130.52, 137.64, 146.92, 148.82;. MS:(m/z) = 325.3(M+l). Step-J: Preparation of Dorzolamidc hydrochloride (formula X) The product obtained from the above Step-I (30 grams, 0.0579 mmol) was suspended in water (210 mL) at ambient temperature. Sulfuric acid (15.9 grams, 0.1622 mmol) was added slowly to the reaction mixture and stirred for 6 hours. The solid product was filtered and washed with water (60 mL), dried to obtain the di-p-toluyl-L-tartaric acid as white solid. Wieght: 10 grams The pH of the filtrate was adjusted to 8 using sodium hydroxide solution and extracted the product in to ethyl acetate (2 x 300 mL). The combined organic layers were washed with brine solution (150 mL). Approximately 300 mL of ethyl acetate was distilled out atmospherically, and charcolised the organic layer. IPA-HCI (15%) (27.0 mL) was added to the filtered organic layer at ambient temperature and stirred for 2 hours. The product was filtered, washed with ethyl acetate and dried to obtain the product of the formula I as white crystalline solid. Output: 18.2 grams; Purity: 99.8 %; Yield: 87.0%; SOR: - 8.2 (C=l in Methanol); 'H-NMR(DMSO-d6) Trans : S 1.26(t, 3H), 1.37(d, 3H), 2.53(m,lH), 2.53(m,lH), 2.74(m, IH), 3.02(m, IH), 3.18(m, IH), 4.27(m,lH), 4.67(br, s, IH), 7.96(s, IH), 8.18(s, 2H), 9.45(br, s, IH), 9.69(br, s, IH); nC-NMR(DMSO-d6) Trans : 5 10.26, 11.43, 30.99, 41.07, 49.51, 51.86, 131.00, 137.64, 142.21, 149.96; MS:(m/z) = 325.3(M+l). Advantages of the invention: 1. The process is very simple and starts from the readily available starting material which makes the piucess economical and industrially viable. 2. The separation uf cis/lrans isomer to pure trans isomer has been done using water as the solvent which is environmentally friendly with 67.5 % yield in slead of 37 % yield as reported by the prior art processes. 3. The separation of chiral dorzoiamide form Trans recemic mixture using only one di-p-toluoyl-L-tartaric acid instead of both the D & L acids used in the reported process with improved yield. 4. The di-p-toluoyl-L-tartaric acid can be easily recovered while isolating the pure dorzoiamide and can be reused makes the process more cost competitive and environment friendly. We Claim: I. An improved process for the preparation of Dorzotamide hydrochloride of the formula i which comprises: Step-I: Reacting 2-bromothiophene of the formula 19, with 2-Ethylhexyl 3-mercaptopropionate in the presence of tris(dibenzylideneacetone)dipalladium(0) and xantphos in suitable base and solvent at a temperature in the range of 90-110 °C to obtain the novel intermediate 3-(thiophen-2-ylsulfanyl)propionic acid 2-ethylhexyl ester of the formula 20. Step-II; Reacting the novel intermediate of the formula 20 with strong base in suitable solvent at a temperature in the range of 50-90 °C to give 2-mercaptothiophene of the formula 2. Step-III: Reacting the compound of the formula 2 with crotonic acid in presence of aprotic polar or non-polar solvent and suitable base at a temperature in the range of 100-120 °C to obtain 3-(2-mercaptothiophene)butanoic acid of the formula 3. Step-IV: Reacting the compound of the formula 3 with chlorinating agent, and followed by treating with Lewis acid in non-polar solvent at a temperature in the range of 0-30 °C to obtain 5,6-dihydro- 4H-6-methylthieno[2,3-n]thiopyran-4-one of the formula 4. 4 Step-V: Oxidation of the compound of the formula 4 by using oxidizing agent in suitable solvent at a temperature in the range of 50-80 °C to obtain 5,6-dihydro-4H-6~methylthieno[2,3-b]thiopyran-4-one-7,7-dioxide of the formula 21. Step-VI: Reducing the compound of the formula 21 by using reducing agent in suitable solvent at a temperature in the range of 0-30 °C to obtain 5,6-dihydro-4H-4-hydroxy-6-methylthieno[2,3-b]thiopyran-7,7-dioxide of the formula 22. Step-VJI: Reacting of the compound of the formula 22 by using acetoriitrile and suitable strong acid by Ritter reaction at a temperature in the range of 0-30 °C to obtain 5,6-dihydro-4H-4-aceryl amino-6-methylthieno[2,3-b]thiopyran-7,7-dioxide of the formula 23. Step-VIII: Reacting the compound of the formula 23 with chlorosulfonic acid and chlorinating agent at a temperature in the range of 40-60 °C to give 5,6-dihydro-4H-4-acetylamino-6-methylthieno[2,3-b]thiopyran-2-sulfonylchloride-7,7,-dioxide of the formula 24. followed by treating with ammonia at a temperature in the range of 0-20 "C in the presence of aprotic polar solvent to obtain 5,6-dihydro-4H-4-acetylamino-6-methytthieno[2,3-b] thiopyran-2-sulfonamide-7,7,-dioxide of the formula 10. Step-IX: Reducing the compound of formula M) using reducing agent in suitable solvent at a temperature in the range of 30-50 °C to obtain 5,6-dihydro-4H-4-etfty/amino-6-rnethy/thieno[2,3-b]thiopyran-2-sulfonamide-7,7,-dioxide of the formula 1_1. Step-X: Isolating the Trans isomer of the formula 25 from the trans/cis isomer of the formula 11 at a temperature in the range of 30-100 °C by making mineral or organic acid salt in suitable solvent. Step-XI: Treating the compound of the formula 25 with suitable base in a water solvent at a temperature in the range of 20-40 °C to obtain Trans 5,6-dihydro-4H-4-ethylamino-6-methyithieno[2,3-b]thiopyran-2-sulfonamide-7,7,-diox.ideof the formula 17. Step-XII: Treating the racemic trans isomeric compound of formula \2 in suitable solvent with optically active resolving agent by resolution to obtain trans (-) isomer of the formula 26. Step-XIII: Treating the compound of the formula 26 with suitable strong acid to recover the di-p-toluyl-L-tartaric acid and followed by adjusting the pH: 8-9 using a suitable base and extracted by using suitable solvent. The extracted solvent is treated with hydrochloric acid to obtain the Dorzolamide hydrochloride of the formula 1. 2. Novel intermediate compound 3-(thiophen-2-ylsulfanyl)propionic acid 2-ethylhexyl ester of the formula 20. 3. The novel intermediate compound as claimed formula 20 as claimed in claim 2 is useful in preparation of Dorzolamide hydrochloride of the formula X. 4. The process for preparation of novel intermediate compound of formula 20 as claimed in claim 2, which comprises: Step-I: Reacting 2-bromothiophene of the formula 19, with 2-Ethylhexyl 3-mercaptopropionate in the presence of tris(dibenzylideneacetone)dipalladium(0) and xantphos in suitable base and solvent at a temperature in the range of 90-110 °C to obtain the novel intermediate 3-(thiophen-2-ylsulfanyl)propionic acid 2-ethylhexyl ester of the formula 20. 5. The process as claimed in claims 1 and 4, wherein said base in Step-I is selected from pyridine, triethylamine, N-methylmorphoIine, 2,6-dimethylpyridine, 2,4,6-trimethylpyridine or diisopropylethyl amine. 6. The process as claimed in claims 1 and 4, wherein said solvent in Step-I is selected from tetrabydrofuran, toluene, acetonitrile, dioxane or xylene. 7. The process as claimed in claim 1, wherein said base in Step-Il is selected from sodium methoxide, sodium hydroxide, potassium methoxide, potassium hydroxide, sodium hydride or lithium hydroxide. 8. The process as claimed in claim I, wherein said solvent in Step-11 is selected from C1-C4 alcohol. 9. The process as claimed in claim 1, wherein said base in Step-Ill is selected form pyridine, 2,6-dimethy) pyridine, 2,4,6-trimethyJpjridine, Iriejrtylami/ie, N-methylmorphoiine or diisopropyiethyl amine. 10. The process as claimed in claim 1, wherein said solvent in Step-III is selected form tetranydrofuran, dioxane, ethyl acetate, acetonitrile or toluene. 11. The process as claimed in claim 1, wherein said chlorinating agent in Step-IV is selected from thionyl chloride, oxalyl chloride, phosphorous pentachloride, phosphorous oxychloride, phosphorous trichloride or sulfuryl chloride. 12. The process as claimed in claim 1, wherein said Lewis acid in Step-IV is selected from aluminium chloride, stannic chloride, borontrifluoride-ethereate, zinc chloride or ferric chloride. 13. The process as claimed in claim 1, wherein said solvent in Step-IV is selected from dichloromethane, chloroform or toluene. 14. The process as claimed in claim 1, wherein said oxidizing agent in Step-V is selected from oxonc, 3-chloroperbenzoic acid, hydrogen peroxide in sodium tungstate or sodium perborate. 15. The process as claimed in claim 1, wherein said solvent in Step-V is selected from dichloromethane, chloroform, ethyl acetate, isopropyl acetate, methanol, ethanol or acetic acid. 16. The process as claimed in claim 1, wherein said reducing agent used in Step-VI is selected from sodium borohydride, lithium aluminium hydride, palladium on carbon in hydrogen or Raney nickel in hydrogen. 17. The process as claimed in claim ls wherein said solvent in Step-VI is selected from C,-Ci alcohol. 18. The process as claimed in claim 1, wherein said strong acid in Step-VII is selected from sulfuric acid, methane sulfonic acid, phosphoric acid, trifluoroacetic acid or trifluoromethanesulfonic acid. 19. The process as claimed in claim 1, wherein said chlorinating agent in Step-VIH is selected from thionyl chloride, oxalyl chloride, phosphorous pentachloride, phosphorous oxychloride, phosphorous trichloride or sulfuryl chloride. 20. The process as claimed in claim 1, wherein said aprotic polar solvent in Step-VIII is selected from tetrahydrofuran, acetone, dioxane or methylethylketone. 21. The process as claimed in claim I. wherein said reducing agent in Step-IX is selected from borane-dimethylsulfide complex, borontrifluoride-etherate in sodium borohydride or lithium aluminium hydride. 22. The process as claimed in claim 1, wherein said solvent in Step-IX is selected from ethers or cyclic ethers. 23. The process as claimed in claim 1, wherein said mineral acid in Step-X is selected from hydrochloric acid, hydrobromic acid, sulfuric acid or nitric acid. 24. The process as claimed in claim 1, wherein said organic acid in Step-X is selected from maleic acid, fumaric acid, malonic acid, oxalic acid, benzoic acid, citric acid, succinic acid, p-toluic acid, salicylic acid or p-nitrobenzoic acid. 25. The process as claimed in claim 1, wherein said solvent in Step-X is selected from ketone, ester, alcohol, polar-aprotic solvent or water. 26. The process as c/aimed in claim I, wherein said base is Step-XI is selected from ammonia, sodium bicarbonate, sodium carbonate, potassium bicarbonate, sodium hydroxide or potassium hydroxide. 27. The process as claimed in claim 1, wherein said optically active resolving agent in Step-XM is selected from tartaric acids, di-p-toluyl-L-tartaric acids, malic acids, mendelic acids or camphour-lG- sulfonic acids. 28. The process as claimed in claim 1, wherein said solvent in Step-XII is selected from alcohols, water or polar-aprotic solvent. 29. The process as claimed in claim I, wherein said strong acid in Step-XHI is selected from sulfuric acid, hydrochloric acid, hydrobromic acid or methanesulfonic. 30. The process as claimed in claim 1, wherein said base in Step-XIIl is selected from sodium bicarbonate, sodium carbonate, sodium hydroxide or potassium hydroxide. 31. The process as claimed in claim I, wherein said solvent in Step-XIH is selected from ethyl acetate, dichloromethane or chloroform. 32. The process for the preparation of the novel intermediate 3-(thiophen-2-ylsulfanyl)propionic acid 2-ethylhexyI ester of (lie formula 20 claimed in claim 4 is substantially as herein described with reference to the Step - I of Example 1. 33. The process for the preparation of Dorzolamide hydrochloride of the formula J. as claimed in claim I is substantially as herein described with reference to the Examples 1 & 2.

Full Text

Field of the Invention
The present invention relates to an improved process for the preparation of (4S,6S)-4-(ethy]amino)-5,6-dihydro-6-methyl-4H-tliieno[2,3-b]thiopyran-2-sulfonamide-7,7-dio\ide hydrochloride having formula \_.

The compound of formula 1 has adopted name "Dorzolamide hydrochloride". Dorzolamide hydrochloride is prepared by the process of the present invention with high chemical and diastereomeric purity. The present invention also relates to novel intermediate of the formula 20 and a process for its preparation.

The novel intermediate of formula 20 is used in preparation of Dorzolamide hydrochloride having formula .1. Dorzolamide hydrochloride is useful in the treatment of ocular hypertension by inhibiting carbonic anhydrase enzyme. Background of the Invention
The process for preparation of Dorzolamide hydrochloride was first reported in EP 296879 (Equivalent to US 4797413). This patent discloses the preparation of Dorzolamide hydrochloride of the formula 1 starting from 2-mercaptothiophene of the formula 2, by reacting with crotonic acid to form 3-(2-mercaptothiophene)butanoic acid of the formula 3. The compound of the formula 3 is reacted with oxalyl chloride and followed by cyclisation with stannic chloride to obtain 5,6-dihydro-4H-6-methyIthieno[2,3-b]thiopyran-4-one of the formula 4. The compound of the formula 4 is reacted with acetic anhydride and sulfuric acid to obtain 5,6-dihydro-4H-6-methylthieno[2,3-bJlhiupyran-4-one-2-sulfonic acid of the formula 5. The compound of the formula 5 is reacted with phosphorous pentachloride to obtain the 5,6-dihydro-4H-6-methylthieno[2,3-b] thiopyran-4-one-2-sulfonyIchloride of the formula 6 and then followed by treating with ammonia gives 5,6-dihydro-4H-6-methylthieno[2,3-b]thiopyran-4-one-2-sulfonamide the formula 7. Reduction of compound of the formula 7 using sodium borohydride gives 5,6-dihydro-4H-4-hydroxy-6-methylthieno[2,3-b]thiopyran-2-sulfonamide of the formula 8. Oxidation of the compound of die formula 8 using oxone provides 5,6-dihydro-4H-4-hydroxy-6-methyIthieno[2,3-b]thiopyran-2-sulfonamide'7,7-dioxide of the formula 9. The compound of the formula 9 is reacted with acetonitrile and sulfuric acid by Ritter reaction to results in 5,6-dihydro-4H-4-acetylamino-6-methylthieno[2,3-b]thiopyran-2-sulfonamide-7,7-dioxide of the formula 10. Reduction of the compound of the formula 10 using

borane-dimethyl sulfide gives 5,6-dihydro-4H-4-ethylaim'no-6-metriylmieno[2,3-b]t]iiopyi'aii-2-su!fonamide-7,7-dioxide of the formula 1_1.
The racemic cis/trans isomer of the formula 11, on separation by column chromatography gives the pure (±)trans 5,6-dihydro-4H-4-ethylamino-6-methyIthieno[2,3-b]thiopyran-2-sulfonamide-7,7-dioxjde of the formula 12- This trans isomer of the formula 12 on resolution using di-p-toluoyl-D-tartaric acid and di-p-toluoyl-L-tartaric acid, followed by treating with hydrochloric acid provides Dorzolamide hydrochloride of the formula 1 as described in the Scheme-1.

The above prior art process has the following disadvantages when the process is to be scaled-up for industrial use:
(a) The starting material 2-mercaptothiphene of the formula 2 is highly expensive and it also tends to
oxidize to form disulfide during storage and transportation. It also has the disadvantage of handling as
it gives pungent smell in the pure form and it is very difficult to handle in the large scale.
(b) The separation of Cis/trans isomer of the formula 11 was done by column chromatography which is very cumbersome and inconvenient for industries and also purity of trans isomer after column chromatography has not been reported.
(c) The resolution of racemic trans isomeric Dorzolamide of the formula _12 to Dorzolamide hydrochloride of the formula 1 had been done using both di-p-toluoyl-L-tartaric acid and di-p-toluoyl-

D-tartaric acid and isolating required isomer which is very long process and not suitable for plant
operation and large scale production.
(d) The overall yield is reported to be around 5% from 2-mercaptothiphene of the formula 2.
Another process for the preparation of Dorzolamide Hydrochloride are described in US 5688968 starting from chiral hydroxysulfone ie., 5,6-dihydro-4-(S)-hydroxy-6(S)-methyl-4H-thiopyran-7,7,-dioxide of the formula J3. The 5,6-dihydro-4(S)-hydroxy-6(S)-methylthieno[2,3-b]thiopyran-7,7,-dioxide of the formula 13 is reacted with acetonitrile and sulfuric acid by Ritter reaction to obtain 5,6-dihydro-4(S)-acetylamino-6(S)-methyIthieno[2,3-b]thiopyran-7,7,-dioxide of the formula _14. The compound of the formula M is reacted with chlorosulfontc acid and thionyl chloride to give 5,6-dihydro-4(S)-acelylamino-6(S)-methylthieno[2,3-b]thiopyran-2-suffonylchloride-7,7,-dioxide of the formula 15 and followed by treating with ammonia to obtain 5,6-dihydro-4(S)-acetylamino-6(S)-meUiyHhieno[2,3-b]tliiopyran-2-sulfonamide-7,7,-dioxide of the formula Ij6. Reduction of the compound of formula .16 using borontrifluoride-etherate in sodium borohydride to obtain 5,6-dihydro-4(S)-ethylamino-6(S)-methylthieno[2,3-b]thiopyran-2-su!fon amide-7,7,-dioxide of the formula \1_. The compound of formula 11_ is treated with maleic acid to obtain trans 5,6-dihydro-4(S)-ethylamino-6(S)-methylthieno[2,3-b]thiopyran-2-sulfon amide-7,7^-Hioxide maleate of the formula ljt. The compound of formula 18 is treated with sodium bicarbonate and hydrochloric acid to obtain Dorzolamide hydrochloride of the formula I as described in the Scheme-2.

The process for making the chiral hydroxysulfone of the formula .13 is described in EP 0590549, EP 658211, US 5391772, US 5474919 and US 5760249. The above described process is not suitable for industrial product production as the process of making is cumbersome and involves enzymatic process.
Further US 7109353 described the process for the preparation of Dorzolamide hydrochloride from 2-bromothiophene of the formula 19. The compound of the formula 19 is reacted with

magnesium, sulphur and crotonic acid to obtain 3-(2-mercaptothiophene)butanoic acid of the formula 3. The compound of the formula £ is reacted with thionyl chloride and followed by cyclisation with stannic chloride to obtain 5,6-dihydro-4H-6-methylthieno[2,3-b]thiopyran-4-one of the formula 4. The compound of the formula 4 is reacted with chlorosulfonic acid and thionyl chloride to obtain 5,6-dihydro-4H-6-methylthieno[2,3-b]thiopyran-4-one-2-sulfonyIchloride of the formula 6 and followed by treating with ammonia gives 5,6-dihydro-4H-6-methylthieno[2,3-b]thiopyran-4-one-2-sulfonamide the formula 7. Reduction of the compound of the formula 2 using sodium borohydride to obtain 5,6-dihydro-4H-4-hydroxy-6-methyltl?ieno[2,3-b]thiopyran-2-sulfonamide of the formula 8. Oxidation of the compound of the formula 8 using sodium perborate provides 5,6-dihydro-4H-4-hydroxy-6-metliyilhieiio[2,3-b]thiopyran-2-su|fonamide-7,7-dioxide of the formula 9. The compound of the formula 9 is reacted with acetonitrile and sulfuric acid by Ritter reaction to obtain 5,6-dihydro-4H-4-acety!amino-6-methylthieno[2,3-b]thiopyran-2 -sulfonamide -7,7-dioxide of the formula HI-Reduction of the compound of the formula .10 using borane-dimethy (sulfide yields 5,6-dihydro-4H-4-ethylamino-6-methylthieno[2,3-b]thiopyran-2-sulfonaniide-7,7-dioxide of the formula JT. The racemic cis/trans isomer of the formula 1_1, is treated with ethanolic-hydrochloride and followed by sodium bicarbonate to get the (±)tfans 5,6-dihydro-4H~4-ethy}antino--6-methyithieno[2,3-b]thiopyran-2-sulfonamide-7,7-dioxide of the formula 12. This trans isomer of the formula 12 on resolution using di-p-toluoyl-D-tartaric acid and di-p-toluoyl-L-tartaric acid and followed by treating with hydrochloric acid to obtain Dorzolamide hydrochloride of the formula! as described in the Scheme-3.

The above processes have the following disadvantages;
(a) The preparation of 3-(2-mercaptothiophene)butanoic acid of the formula 3 from 2-
bromothiophene of the formula ,19 uses sulphur, and handling of sulphur is inconvenient in industrial
scale with pungent smell.
(b) The lower yield (50 %) was reported for the preparation of 5,6-dihydro-4H-6-methyltliieno[2,3-
b]thiopyran-4-one-2-sulfonamide the formula 7 from S,6-dihydro-4H-6-metbylthieno[2,3-
bJtliiopyratt-4-one of the formula 4.
(c) The lower yield (37.98 %) was reported for the preparation of trans 5,6-dihydro-4H-4-
emylamino-6-methyltiireno[2,3-b]thiopyran-2-sulfbnarnide -7,7-dioxide of the formula 12 from the
Cis-Trans isomer of the formula U.-
(d) The resolution of racemic trans isomeric Dorzolamide of the formula 12 to trans-(S)-Dorzolamide
of the formula 1 been done using both di-p-toluoyl-D-tartaric acid and di-p-toluoyl-L-tartaric acid and
isolating required isomer which is very long process and not suitable for plant operation and large
scale production
(e) The poor yield of 22.5 % of Dorzolamide hydrochloride of the formula I. from (±)trans 5,6-
Dihydro-4H-4-ethyJamino-6>methyIthieno[2,3-b] thiopyran-2-suIfonamide-7,7-dioxide of the formula
12 via resolution was reported.

(f) The over all yield reported was only 1.78 % from 2-bromothiophene of the formula \9_.
Yet another patent WO 2006/038222 also has disclosed a process for the preparation of (4S,6S)-4-(ethylamino)-5,6-dihydro-6-methyl-4H-thieno[2,3-b]thiopyran-2-suifonamide7,7-dioxide hydrochloride (Dorzolamide hydrochloride) of the formula 1_ by doing resolution of (±)trans 5,6-Dihydro-4H-4-ethylamino-6-methylthieno[2,3-b]thiopyran-2-sulfonamide-7,7-dioxide of the formula t2 using dibenzoyl-L-tartaric acid or di-p-toluoyl-L-tartaric acid in methanol solvent. The poor yield (15.4%) is reported for resolution step.
Yet another patent WO 2007/122130 has also disclosed a process for the isolation of trans 5,6-dihydro-4H-4-ethylamino-6-methylthieno[2,3-b]thiopyran-2-sulfonamide-7,7-dioxide maleate of the formula 25 from cis/trans isomer of 5,6-dihydro-4H-4-ethylamiHo-6-methylthierto[2,3-b]thiopyran-2-sulfonamide-7,7-dioxide of the formula jl using maleic acid in acetone solvent, the yield 48.3 % and purity trans/cis ratio > 95/5 is reported. Also disclosed resolution of (±)trans 5,6-dihydro-4H-4-ethylamino-6-methylthieno[2,3-b]thiopyran-2-sulfon amide-7,7-dioxide of the formula |2 using (ISH^-'O-camphorsulfonic acid. The lower yield (31.0 %) is reported for this resolution step.
All the above mentioned reported processes for the preparation of Dorzolamide hydrochloride are not readily amenable for industrial preparation, and contained some intermediate with a stability/odor concern with respect to large scale manufacturing.
Considering the importance of Dorzolamide hydrochloride and considering the difficulties in the manufacture of Dorzolamide hydrochloride on an industrial scale prompted us to develop an improved process for the large scale manufacture of Dorzolamide hydrochloride with high purity and simple process using less expensive and easily available raw materials. Objects of the present invention
The main objective of the present invention is to provide an improved process for preparation of Dorzolamide hydrochloride of the formula 1. by overcoming the drawbacks of the hitherto known process.
Another objective of the present invention is to provide a novel intermediate 3-{thiophen-2-yIsuIfanylpropionic acid 2-ethylhexyl ester of the formula 20 useful for the preparation of Dorzolamide hydrochloride of the formula L
Stilt another objective of the present invention is to provide a process to isolate the trans 5,6-dihydro-4H-4-ethylamino-6-methylthienot2,3-b]thiopyran-2-sulfonamide-7,7-dioxide maleate of the formula 25 from cis/trans isomer of 5,6-dihydro-4H-4-ethylamino-6-methyIthieno[2,3-b]thiopyran-2-sulfbnamide-7,7-dioxide of the formula _U using maleic acid and water as a solvent which is very economical and environmentally friendly solvent.
Yet another objective of the present invention is to provide a process for the resolution of racemic trans isomeric Dorzolamide of the formula \2_ using only one di-p-toluoyl-L-tartaric acid to get the 5,6-dihydro-4H-4(S)-ethylamino-6(S)-methylthicno[2,3-b]thiopyrari-2-sulfonamide-7,7-

dioxide hemidi-p-toluoyl-D-tartarate of the formula 26 with diastereomeric excess of 99.9 % pure and Yet another objective of the present invention is to provide a process to isolate pure Dorzolamide hydrochloride of the formula 1 from 5,6-dihydro-4H-4(S)-ethylamino-6(S)-methylthieno[2,3-b]thiopyran-2-sulfc'narnide-7,7-dioxide hemidi-p-toluoyl-D-tartarate of the formula 26 in simple and recovering di-p-toluoyl-L-tartaric acid for reuse. Summary of the Invention
The present invention provides an improved process for the preparation of Dorzolamide

Step-Ill: Reacting the compound of the formula 2 with crotonic acid in presence of aprotic polar or non-polar solvent and suitable hase at a temperature in the range of 100-120 °C to obtain 3-(2-mercaptothiophene)butanoic acid of the formula 3.

Step-VIII: Reacting the compound of the formula 15 with chlorosulfonic acid and chlorinating agent at a temperature in the range of 40-60 °C to give 5,6-dihydro-4H-4-acetylamino-6-methylthieno[2,3-b]thiopyran-2-sulfonylchloride-7,7,-dioxide of the formula 24.

followed by treating with ammonia at a temperature in the range of 0-20 °C in the presence of aprotic polar solvent to obtain 5,6-dihydro-4H-4-acetylammo-6-methylthieno[2,3-b] thiopyran-2-sulfonamide-7,7,-dioxide of the formula JJJ.

Stcp-IX: Reducing the compound of formula 10 using reducing agent in suitable solvent at a temperature in the range of 30-50 °C to obtain 5,6-dihydro-4H-4-ethylamino-6~methylthieno[2,3-b]thiopyran-2-sulfonamide-7,7,-dioxide of the formula 11.

Step-X: Isolating the Trans isomer of the formula 25 from the trans/cis isomer of the formula 11 at a temperature in the range of 30-100 °C by making mineral or organic acid salt in suitable solvent.

Stcp-XI: Treating the compound of the formula 25 with suitable base in a water solvent at a temperature in the range of 20-40 °C to obtain Trans 5,6-dihydro-4H-4-ethylamino-6-methylthieno[2,3-b]thiopyran-2-sulfonamide-7,7,-dioxide of the formula .12.

Step XII: Treating the racemic trans isomeric compound of formula 12 in suitable solvent with optically active resolving agent by resolution to obtain trans (-) isomer of the formula 26.

Step-XIII: Treating the compound of the formula 26 with suitable strong acid to recover the di-p-toluyl-L-tartaric acid and followed by adjusting the pH: 8-9 using a suitable base and extracted by using suitable solvent. The extracted solvent is treated with hydrochloric acid to obtain the Dorzolamide hydrochloride of the formula X-
The present invention also provides a process for the preparation of the novel intermediate 3-(thiophen-2-ylsulfanyl(propionic acid 2-ethylhexyl ester of the formula 20 useful for the preparation of Dor/olamide hydrochloride of formula _!_•
which comprises:
Step-I: Reacting 2-bromothiophene of the formula 19,

with 2-Ethylhexyl 3-mercaptopropionate in the presence of tris(dibenzylideneacetone)dipalladium(0) and xantphos in suitable base and solvent at a temperature in the range of 90-110 °C to obtain the novel intermediate 3-(thiophen-2-ylsulfanyl)propionic acid 2-ethylhexyl ester of the formula 20.

Detailed Description of Invention
The improved process for preparation of Dorzolamide hydrochloride of formula X of the present invention is illustrated by Scheme-4 given below:

Step-I: Reacting 2-bromothiophene of the formula .19 with 2-Ethylhexyi 3-mercaptopropionate in the presence of tris(di benzyl ideneacetone)dipalladium(O) and xantphos in suitable base and solvent at suitable temperature to obtain the novel intermediate 3-(thiophen-2-ylsuIfanyI)propionic acid 2-ethylhexyl ester of the formula 20. The base used in reaction can be selected from pyridine, triethylamine, N-methylmorpholine, 2,6-dimethylpyridine, 2,4,6-trimethylpyridine or diisopropylethyl amine and preferably using diisopropylethyl amine. The solvent used in reaction can be selected from

tetrahydrofuran, toluene, acetonitrile, dioxane or xylene and preferably using toluene. The reaction temperature may range from 90-110 °C and preferably at a temperature in the range of 90-95 °C.

Step-H: Reacting the novel intermediate of the formula 20 with strong base in suitable solvent at suitable temperature to give 2-mercaptothiopriene of the formula 2. The base used in reaction can be selected from sodium methoxide, sodium hydroxide, potassium hydroxide, potassium methoxide, sodium hydride or lithium hydroxide and preferably using sodium methoxide. The solvent used in reaction is selected from C|-C4 alcohol and preferably using methanol. The reaction temperature may range from 50-90 °C and preferably at a temperature in the range of 80-85 °C.

Stcp-III: Reacting the compound of the formula 2 with crotonic acid in presence of aprotie polar or non-pofar solvent and suitable base at suitable temperature to obtain 3-(2-mercaptothiophene)butanoic acid of the formula 3. The base used in reaction can be selected from pyridine, 2,6-dimethylpyridine, 2,4,6-trimethylpyridine, triethylamine, N-methylmorpholine or diisopropylethyl amine and preferably using triethylamine. The solvent used in reaction can be selected from tetrahydrofuran, dioxane, ethyl acetate, acetonitrile or toluene and preferably using toluene. The reaction temperature may range from 100-120 °C and preferably at a temperature in the range of 105-110 °C.

Step-IV: Reacting the compound of the formula 3 with chlorinating agent, and followed by treating with Lewis acid in non-pofar solvent at suitable temperature to obtain 576-dihydro-4H-6-methylthieno[2,3-b]thiopyran-4-one of the formula 4. The chlorinating agent used in reaction can be selected from thionyl chloride, oxalyl chloride, phosphorous pentachloride, phosphorous oxychloride, phosphorous trichloride or sulfuryl chloride and preferably usiiiK oxalyl chloride. The Lewis acids used in renction can be selected from aluminium chloride, atannic chloride, borontrifiuoride-elhereale, zinc chloride or ferric chloride and preferably using stannic chloride. The non polar solvent used in reaction can be selected from dichloromethane, chloroform or toluene and preferably using

dichloromelhane. The reaction temperature may range from 0-30 °C and preferably at a temperature in the range of 0-5 °C.

Step-V: Oxidation of the compound of the formula 4 by using oxidizing agent in suitable solvent at suitable temperature to obtain 5,6-dihydro-4H-6-methylthieno[2,3-b]thiopyran-4-one-7,7-dioxide of the formula 21,. The oxidizing agent used in reaction can be selected from oxone, 3-chloroperbenzoic acid, hydrogen peroxide in sodium tungstate or sodium perborate and preferably using hydrogen peroxide in sodium tungstate. The solvent used in reaction can be selected from dichloromethane, chloroform, ethyl acetate, isopropyl acetate, methanol, ethanol or acetic acid and preferably using ethyl acetate. The reaction temperature may range from 50-80 °C and preferably at a temperature in the range of 65-70 °C.

Step-VI: Reducing the compound of the formula 21. by using reducing agent in suitable solvent at suitable temperature to obtain 5,6-dihydro-4H-4-hydroxy-6-methylthieno[2,3-b]thiopyran-7,7-dioxide of the formula 22.The reducing agent used in reaction can be selected from sodium borohydride, lithium aluminium hydride, palladium on carbon in hydrogen or Raney nickel in hydrogen and preferably using sodium borohydride. The solvent used in reaction can be selected from C1-C4 alcohol and preferably using methanol. The reaction temperature may range from 0-30 °C and preferably at a temperature in the range of 25-30 °C.

Step-VII: Reacting of the compound of the formula 22 by using acetonitrile and strong acid by Ritter reaction at suitable temperature to obtain 5,6-dihydro-4H-4-acetyl amino-6-mcthylthieno|2,3-b]thiopyran-7,7-dioxide of the formula 23. The strong acid used in reaction can be selected from sulfuric acid, methane sulfonic acid, phosphoric acid, trifluoroacetic acid or trifluoromethanesulfonic

acid and preferably using sulfuric acid. The reaction temperature may range from 0-30 °C and preferably at a temperature in the range of 25-30 °C.

Step-VIII: Reacting the compound of the formula 23 with chlorosulfonic acid and chlorinating agent at suitable temperature to give 5,6-dihydro-4H-4-acetylamino-6-methylthieno[2,3-b]thiopyran-2-sulfonylchloride-7,7,-dioxide of the formula 24. The chlorinating agent used in reaction can be selected from thionyl chloride, oxalyl chloride, phosphorous pentachloride, phosphorous oxychtoride, phosphorous trichloride or sulfuryl chloride and preferably using thionyl chloride. The reaction temperature may range from 40-60 °C and preferably at a temperature in the range of 50-55 °C.
The conversion of the compound °f tn^ compound formula 24 to 5,6-dihydro-4H-4-acetylamino-6-methylthieno[2,3-b]thiopyran-2-sulfonamidc-7,7,-dioxide of the formula H) may be done with aqueous ammonia at a suitable temperature in the presence of aprotic polar solvent. The aprotic solvent used in reaction can be selected from tetrahydrofuran, acetone, dioxane or methylethylketone and preferably using acetone. The reaction temperature may range from 0-20 °C and preferably at a temperature in the range of 0-5 °C.

Step-IX: Reducing the compound of formula 10 using reducing agent in suitable solvent at suitable temperature to obtain 5,6-dihydro-4H-4-ethylamino-6-methylthieno[2,3-b]thiopyran-2-sulfonamide-7,7,-dioxide of the formula II. The reducing agent used in reaction can be selected from borane-dimethylsulfide complex, borontrifluoride-etherate in sodium borohydride or lithium aluminium hydride and preferably borontrifluoride-etherate in sodium borohydride. The solvent used in reaction can be selected from ethers or cyclic ethers and preferably using tetrahydrofuran. The reaction temperature may range from 30-50 °C and preferably at a temperature in the range of 40-45 °C.

Step-X: Isolating the Trans isomer of the formula 25 from the trans/cis isomer of the formula H at suitable temperature in the range of 30-100 °C by making mineral or organic acids salt in suitable solvent. The mineral acid used in reaction can be selected from hydrochloric acid, hydrobromic acid, sulfuric acid or nitric acid. The organic acid used in reaction is selected from maleic acid, fumaric acid, malonic acid, oxalic acid, benzoic acid, succinic acid, p-toluic acid, citric acid, salicylic acid or p-nitrobenzoic acid and preferably using maleic acid. The solvent used in reaction can be selected from ketone, ester, alcohol, polar-aprotic solvents or water and preferably using water. The reaction temperature may range from 30-100 °C and preferably at a temperature in the range of 95-100 °C.
The purity of compound formula 25 has improved to 99.5 % with maximum yield 67 % beside environment friendly solvent water as a solvent for separation of trans isomer from cis/trans mixture that has not been reported henceforth.

Step-XI: Treating the compound of the formula 25 with suitable base in a water solvent al suitable temperature in the range of 20-40 °C to obtain Trans 5,6-dihydro-4H-4-ethylamino-6-methylthieno[2,3-b]thiopyran-2-sulfonamide-7,7,-dioxide of the formula ,12. The base used in reaction can be selected from ammonia, sodium bicarbonate, sodium carbonate, sodium hydroxide, potassium hydroxide or potassium bicarbonate and preferably using sodium bicarbonate. The reaction temperature may range from 20-40 °C and preferably at a temperature in the range of 25-30 °C.

Step-XII: Treating the racemic trans isomeric compound of formula ^2_ in suitable solvent with optically active resolving agent by resolution to obtain trans (-) isomer of the formula 26. The

optically active resolving agent used in reaction can be selected from tartaric acids, di-p-tolujI-L-tartaric acid, malic acids, mendelic acids or camphour-10-sulfonic acids and preferably using di-p-toluyl-L-tartaric acid (L-DPTTA). The solvent used for recrystallisation may be selected from alcohols, water or polar-aprotic solvents and preferably using n-propanol.

Step-XIII: Treating the compound of the formula 26 with suitable strong acid to recover the di-p-toluyl-L-tartaric acid and followed by adjusting the pH: 8-9 using suitable base and extracted by using suitable solvent. The extracted solvent is treated with hydrochloric acid to obtain the Dorzolamide hydrochloride of the formula L
The acid used for neutralization of the tartarate salt may be selected from sulfuric acid, hydrochloric acid, hydrobromic acid or methanesulfonic and preferably using sulfuric acid. The base used in reaction can be selected from sodium bicarbonate, sodium carbonate, sodium hydroxide or potassium hydroxide and preferably using sodium hydroxide. The solvent used for extraction is selected from ethyl acetate, dichloromethane or chloroform and preferably using ethyl acetate.

It is to be noted that the process can be carried out continuously without the isolation of the compounds of the formulae 20, 2 & 3.
The details of the invention are given in examples provided below, which are given to illustrate the invention only and therefore should not be construed to limit the scope of the present invention.
Example 1: Preparation of Dorzolamide hydrochloride
Step-I: Preparation of novel intermediate 3-(thiophen-2-ylsulfanyl)propionic acid 2-ethylhexyl ester (formula 20)
To the solution of 2-bromothiophene (100 grams, 0.613 mmol) in toluene (3 L) was added 2-Ethylhexyl 3-mercaptopropionate (218.36 grams, 0.613 mmol) and N,N-diisopropyiamine (158.5 grams, 1.226 mmol) at ambient temperature. After nitrogen evacuation, tris(dibenzylideneacetone) dipalladium(O) (1.4 grams, 1.533 mmol), xantphos (0.88 grams, 1.533 mmol) was added. The mixture was heated to 90-95 °C and stirred for 2 hours. After reaction was over, the reaction mixture was

cooled to ambient temperature and stirred with 50 grams of silica gel. The mixture was filtered and
the organic layer was concentrated to obtain the product of the formula 20 as light yellow liquid.
Output: 180 grams;
Purity: 98.0 %;
Yield: 97.6 %;
'H-NMR(CDCI3): 5 0.89(m, 6H), !.33(m, 8H), l.55(m,lH), 2.62(t, 2H), 3.01(t, 2H), 4.00(dd, 2H),
6.98(dd, IH), 7.15(dd, 1H), 7.37(dd, 1H);
nC-NMR(CDCl3): 5 10.96, 14.02, 22.94, 23.75, 28.89, 30.37, 33.72, 34.57, 38.70, 67.14, 127.61,
129.88, 133.18, 134.57, 171.74;
LC-MS: (m/z) = 300.00 (M).
Step-U: Preparation of 2-mercaptofhiophene (formula 2)
The product obtained from the above Step-I (90 grams, 0.2995 mmol) was dissolved in methanol (540 mL). Sodium methoxide solution (25 %) (270 mL) was added to the reaction mass at ambient temperature. The reaction mixture was heated to reflux and maintained for I hour. After completion of reaction, the solvent was distilled out completely and cooled to ambient temperature. Water (450 mL) was added to the residue and washed with MDC. The product containing water layer was acidified to pH: 1-2 using concentrated hydrochloric acid. The product was extracted in to MDC (3 x 270 mL). The organic extracts was combined and washed with water. The organic layer was concentrated to obtain the product of the formula 2 as yellow oil. Output: 30.4 grams; Purity: 92.0 %; Yield: 87.3%;
'H-NMR(CDCI3): 6 3.5t(s, IH), 6.92(q, IH), 7.08 (m, IH), 7.26(dt, IH); nC-NMR(CDCI3): 5 124.54, 127.59, 128.98, 134.01; MS: (m/z)- 114.8(M-1). Step-Ill: Preparation of 3-(2-mercaptothiophene)butanoic (formula 3)
The product obtained from the above Step-II (25 grams, 0.2151 mmol) was dissolved in toluene (250 mL) and added crotonic acid (18.52 grams 0.2151 mmol) at 15-20 °C. Triethyl amine (65.31 grams, 0.6455 mmol) was added slowly at below 25 °C. After the addition was over, the reaction mixture was heated to reflux and stirred for 10 hours. The reaction mixture was cooled to ambient temperature, added water (500 mL) and stirred. The layer was separated and acidified the product containing water layer to pH: 1-2 using concentrated hydrochloric acid. The product was extracted in to toluene (3 x 125 mL). The organic layer was combined, washed with water and concentrated to obtain the product of formula 3 as yellow oil. Output: 37 grams; Purity: 98.0 %; Yield: 85.0 %;

'H-NMR(CDCI3): 5 1.33(d, 3H), 2.47(dd. 1H), 2.70(dd, 1H), 4.00(dd, J2H), 6.98(dd. IH), 7.15(dd.
IH),7.37(dd, IH);
,3C-NMR(CDC13): 6 10.96, 14.02, 22.94, 23.75, 28.89, 30.37, 33.72, 34.57, 38.70, 67.14, 127.61,
129.88, 133.18, 134.57, 171.74;
MS:(m/z) = 203.0(M+l).
Step-IV: Preparation of 5,6-dihydro-4H-6-methylthieno[2,3-b]thiopyran-4-one (formula 4)
The product obtained from the above Step-Ill (30 grams, 0.1483 mmol) was dissolved in MDC (240 mL) and dimethylformamide (0.8 mL) at ambient temperature Oxalyl chloride (20.7 grams, 0.1631 mmol) was added dropwise and maintained at ambient temperature for 2 hours. The reaction mixture was cooled to 0-5 "C, and added dropwise a solution of stannic chloride (19.3 grams, 0.0741 mmol) in MDC by maintaining the temperature below 5 °C. The reaction was stirred for 2 hours at 0-5 °C. After completion of reaction, water (120 L) was added and stirred. The layer was separated and the product containing MDC layer was washed with 5%hydrochloride solution and water. The product containing organic layer was concentrated completely to obtain the product of the formula 4 as yellow liquid. Output1 27 grams; Yield: 98.9 %; Purity: 97 %;
'H-NMR(CDC1,): S 1.48(d, 3H),2.69(dd, IH), 2.88(dd, IH), 3.79 (m, IH), 7.0l(d, IH). 7.45(d, IH); l3C-NMR(CDCI3):5 19.93,40.83,46.69, 121.95, 125.86, 134.62, 150.74, 189.30; MS:(m/z)= 185.1(M+1).
Step-V: Preparation of 5,6-dihydro-4H-6-methylthieno[2^-b]thiopyran-4-one-7,7-dioxide (formula 21}
The product obtained from the above Step-IV (174 grams, 0.9442 mmol) was dissolved in ethyl acetate (1.74 L) at ambient temperature. Sodium tungstate dihydrate (31.1 grams, 0.0944 mmol) and sulfuric acid (0.5 mL) was added at ambient temperature. The mixture was cooled to 0-5 °C, and 30% hydrogen peroxide (375.3 grams, 3.309 mmol) was added dropwise at below 10 °C. The reaction mixture was heated to reflux and maintained for 2 hours. The reaction was cooled to ambient temperature and separated the layers. The product containing organic layer was washed with 5% sodium sulfite solution (522 mL) and followed by water (522 mL). The organic layer is concentrated completely, hexane (522 mL) is added and stirred. The product was filtered and washed with hexane and dried to obtain the product of the formula 21 as off-white solid. Output: I 81.5 grams; Yield: 88.8%; Purity: 99 %;
Melting Range: 103-109 °C;
'H-NMR(CDC13):S 1.57(d, 3H), 3.22(m, 2H), 3.87 (m, lH),7.49(d, IH), 7.61(d, IH); i3C-NMR(CDCl3):5 15.81,49.26,61.86, 130.76, 137.69, 145.22, 151.44, 192.16;

MS:(m/z) = 217.1(M+l).
Step-VI: Preparation of 6-dihydro-4H-4-hydroxy-6-methylthieoo[2^-b|thiopyran-7,7-dioxkle
(formula 22)
The product obtained from the above Step-V (180 grams, 0.8325 mmol) was suspended in methanol (540 mL) and cooled to 10 °C. Sodium borohydride (19.23 grams, 0.5076 mmol) was added to the reaction mass at below 10 °C. The reaction mixture was warmed to ambient temperature and stirred for 1 hour. The reaction mixture out concentrated under vacuum, water (720 mL) was added, stirred and extracted in to ethyl acetate (1.8 & 0.54 L). The product containing organic layer was combined and washed with brine solution. The organic layer was concentrated completely. Hexane (540 mL) was added to the residue and utiired. The product was filtered, washed with hexane and dried to obtain the product of the formula 22 as solid. Output: 169.14 grams; Yield: 93.1 %; Melting Range: 110-120 °C;
'H-NMR(DMSO-d6) : S 1.32(d, 3H), 2.13(m, 1H), 2.32(m, IH), 3.70(m, 1H), 4.79 (m, 1H), 5.88(d, IH). 7.l6(d7 lH);7.92(d, 1H);
,3C-NMR(DMSO-d6)-. 5 10.92,39.14,55.72,64.87,127.53,131.62, 134.00, 149.34. Step-VII: Preparation of 5,6-dihydro-4H-4-acetyl amino-6-methylthieno|2^-b|thiopyran-7,7-dioxide (formula 23)
The product obtained from the above Step-VI (165 grams, 0.7558 mmol) was suspended in acetonitrile (247.5 mL) and cooled to 10 °C. Sulfuric acid (247.5 mL) was added dropwise to a reaction mass at below 10 °C over 2-3 hours. The reaction mixture was warmed to ambient
temperature and stirred for 2 hours. This reaction mixture was quenched in to ice (1.981 kg) at below 10 °C. The pH was adjusted to 6-7 using sodium hydroxide solution, and the mixture was stirred,
filtered and washed with water. The filtered wet product again leached with water, filtered and dried
to obtain the product of the formula 23
Output: 177.5 grams;
Yield: 90.5 %;
Purity: Trans-79.2%, Cis-20.3%;
Melting Range: 194-198 °C;
'H-NMR(DMSO-d6) Trans : 5 1.33(d, 3H), 1.83(s, 3H), 2.23(m, IH), 2.39(m, IH), 3.60(m, IH), 5.17
(m, IH), 7.02(d, III), 7.95(d, III), 8.55(d, IH);
Cis: 6 1.31(d, 3H), l.83(s, 3H), 2.23(m, IH), 2.39(m, IH), 3.88(m, IH), 5.23(m, III), 6.94(d, IH),
7.93(d, IH), 8.50(d, IH);
l3C-NMR(DMSO-tl6) Trans : 5 10.82,22.90,35.58,53.05, 128.20, 131.92, 135.62,144.88,169.08.
Cis : 8 10.57, 27.90, 36.47, 45.17, 55.88, 127.48, 13 1.70, 135.10, 146.60, 169.50;
MS:(m/z) = 260.2(M+1).

Step-VIII: Preparation of 5,6-dihydro-4H-4-acetylamino-6-melhylthieno|2r3-b|thiopyran-2-sulfonamide-7,7,-dioxide (formula ,10)
The product obtained from the above Step-VH (125 grams, 0.4819 mmol) was added lo chlorosulfonic acid (250 mL) at below 10 °C over 1 hour. The reaction mixture was heated gradually to 50-55 °C and stirred for 10 hours. The reaction mixture was cooled to ambient temperature and added thionyl chloride (250 mL). The reaction mixture was heated to 50-55 °C and stirred for 10 hours. The obtain reaction mixture was cooled and quenched in to ice+water (2.5 kg) at below 10 °C, and stirred. The product was filtered at 0-5 °C, and washed with chilled water, and suck dried to obtain the product of the formula 24. Wet Product: 170 grams.
The above wet product was added in lot wise to a solution of acetone (998 mL) and aqueous ammonia (258 mL) at below 5 °C, and stirred for 1 hour. The reaction mixture was concentrated under vacuum, water (517 mL) was added and stirred. The pH was adjusted to 6.0-7.0 using concentrated hydrochloric acid and stirred for 2 hours. The product was filtered, washed with water, and dried to obtain the product of the formula M). Output: 121 grams; Yield: 74.1 %;
Purity: Trans-76.5%, Cis-19.8 %;
'H-NMR(DMSO-d6)Trans:5 1.35(d, 3H), 1.85(s, 3H), 2.28(m, 1H), 2.47(m, 1H), 3.86(m, 1H), 5.17 (m, 1H), 7.40(s, 1H), 8.05(s, 2H), 8.62(d, 1H);
Cis: 5 1.32 (d, 3H), 1.89(s, 3H), 2.28(m, 1H), 2.47(m, 1H), 3.94(m, 1H), 5.25 (m, 1H), 7.31 (s,lH), 8.05(s, 2H), 8.59(d, fH);
l3C-NMR (DMSO-d6) Trans: 5 10.50, 22.63, 34.70, 41.71, 53.14, 129.58, 138.11, 144.63, 149.82, 168.90;
Cis: 6 10.12,21.00,35.65,44.75,55.78, 120.80, 137.80, 146.39, 149.60, 169.90; MS:(m/z) = 337.2(M+l).
Step-IX; Preparation of5,6-dihydro-4H-4-ethylamino-6-niethyltbieno|2t3-b|tbiopyran-2-sulfonamide-7,7,-dioxide (formula 11)
The product obtained from the above Step-VIII (120 grams, 0.3545 mmol) was suspended in tetrahydrofuran (960 mL) and cooled to 5-10 °C. Sodium borohydride (26.8 grams, 0.7091 mmol) was added to the reaction mass at below 10 °C, and stirred. Borontrifluoride-etherate (100.6 grams, 0.7091 mmol) was added at below 10 ^C. The reaction mixture was heated to 40-45 °C, and stined for 8 hours. The reaction mixture was cooled and acidified with concentrated hydrochloric acid (270 mL), and stirred for 10 hours at ambient temperature. The reaction mixture was concentrated under vacuum, added of water (480 mL). The pH was adjusted to 7-7.5 using sodium hydroxide solution and stirred for 5 hours. The product was filtered and washed with water, and dried to obtain the product of the formula l_l-Output: 107 grams; Yield: 93.0%;

Purity: Trans-77.1 %, Cis-19.2 %;
MS: (m/z) = 325.4 (M+l).
Step-X: Preparation of formula 25
The product obtained from the above Step-IX (105 grams, 0.3236 mmol) was suspended in
water (1.47 L) at ambient temperature. Maleic acid (37.5 grams, 0.3236 mmol) was added to reaction
mass and heated to reflux to get clear solution. The clear mass was cooled to 5-10 °C, and stirred for 1
hour. The product was filtered and washed with water. The wet product was recrystallized again with
water, and dried to obtain the product of the formula 25 as white solid.
Output: 88.2 grams;
Yield: 61.8%;
Purity: Trans-99.0 %, Cis-0.6 %;
Melting Range: 207-214 °C;
]H-NMR(DMSO-d6) : 6 l.20(t, 3H), 1.38(d, 3H), 2.60(s, 2H), 3.01(m, 1H), 3.2l(m, IH), 4.03 (m,
JH),4.65(t, JH), 6.07(s, IH, Maleic acid), 7.82(s, JH), 8.I6(br-s,IH);
nC-NMR(DMSO-d6) : 8 10.40, 11.89, 31.30,41.31,49.85, 51.90, 130.72, 138.26, 141.85, 150.06,
135.93, 167.75 (Maleic acid);
MS:(m/z) = 325.3(M+l).
Slep-XI: Preparation of Trans 5,6-dihydro-4H-4-ethylamino-6-methylthieno|2^-b]thiopyran-2-
suIfonamide-7,7,-dioxide (formula 12)
The product obtained from the Step-X (88 grams, 0.1997 mmol) was added in lot wise to a solution of sodium bicarbonate (88 grams) in water (1.76 L) at ambient temperature, and stirred for 1 hour. The product was filtered and washed with water. The wet product was again leached with water, and dried to obtain the product of the formula _12-Output: 62 grams; Yietd: 95.6 %;
Purity: Trans-99.0 %, Cis-0.6 %; Melting Range: 182-188 °C;
(H-NMR(DMSO-d6): 5 1.00(t, 3H), 1.33(d, 3H), 2.32(s, 2H), 2.57(m, 2H), 3.90(m, 2H), 7.55(s, IH), 8.02(br-s, IH);
nC-NMR(DMSO-d6 : 8 10.53, 15.25,33.61,40.92,50.22,52.21, 130.52, 137.64, 146.92, 148.82; MS:(m/z) = 325.3(M+l). Step-XII: Preparation of formula 26
The product obtained from the above Step-XI (60 grams, 0.1849 mmol) was suspended in n-propanol (2.1 L) at ambient temperature. Di-p-toluyl-L-tartaric acid monohydrate (18.7 grams, 0.0462 moles) was added to the reaction mixture and heated to reflux to get clear solution. The clear mass was cooled to 25-30°C, and stirred for 2 hours. The product was filtered and washed with n-propanol. The wet product was recrystallized again with n-propanol (950 mL), and dried to obtain the product of the formula 26.

Output: 34.5 grams:
Yield: 36.0%;
Purity: Trans-99.2 %, Cis-0.3 %, S(-> 99.97%, R(+)- 0.03%;
Melting Range: 158-165 QC;
'H-NMR(DMSO-d6) : 5 l.00(t, 3H), 1.33 8.02(br-s, IH);
L,C-NMR(DMSO-d6):5 10.53,15.25,33.61,40.92,50.22,52.21, 130.52, 137.64,146.92, 148.82;.
MS:(m/z) = 325.3(M+l).
Step-XIIJ: Preparation of Dorzolamide hydrochloride (formula I)
The product obtained from the above Step-XII {15 grams, 0.0289 mmol) was suspended in water (105 mL) at ambient temperature. Sulfuric acid (7.9 grams, 0.0806 mmol) was added slowly to the reaction mixture and stirred for 6 hours. The solid product was filtered and washed with water (30 mL), dried to obtain 5.2 grams of di-p-toluyLL-tartaric acid monohydrate (88.7 %) as white solid.
The pH of the filtrate was adjusted to 8 using sodium hydroxide solution and extracted the product in to ethyl acetate (2 x 150 mL). The combined organic layers were washed with brine solution (75.0 mL). Approximately 150 mL of ethyl acetate was distilled out atmospherically, and eharcolised the organic layer. IPA-HCI (15%) (13.5 mL) was added to the filtered organic layer at ambient temperature and stirred for 2 hours. The product was filtered, washed with ethyl acetate and dried to obtain the product of the formula I. as white crystalline solid. Output: 8.8 grams; Purity: 99.8 %; Yield: 84.2%;
'H-NMR(DMSO-d6) Trans : 5 1.26(t, 3H), 1.37(d, 3H), 2.53(m, IH), 2.53(m, IH), 2.74(m, IH), 3.02(m, IH), 3.18(m, IH), 4.27(m,lH), 4.67(br, s, IH), 7.96(s, IH), 8.18(s, 2H), 9.45(br, s, IH), 9.69(br,s, IH);
l3C-NMR(DMSO-d6) Trans : 8 10.26, 11.43, 30.99, 41.07, 49.51, 51.86, 131.00, 137.64, 142.21, 149.96;
MS:(m/z)-325.3(M+l).
Example 2: Preparation of Dorzolamide hydrochloride (without isolation of the compounds 20, 2 and 3) Step-A: Preparation of 5,6niihydro-4H-6-methylthieno[2,3-b]tliiopyrau-4-one (formula 4)
To the solution of 2-bromothiophene (50 grams, 0.3066 mmol) in toluene (300 mL) was added 2-Ethylhexyl 3-mercaptopropionate (66.96 grams, 0.3066 mmol) and N,N-Diisopropylamine (49.52 grams, 0.3833 mmol) at ambient temperature. After nitrogen evacuation, tris(di benzyl ideiieacetone) dipalladium(O) (0.70 grams, 0.76 mmol), and xantphos (0.44 grams, 0.76 mmol) was added. The mixture was heated to 90-95 °C and stirred for 2 hours. After reaction was over, the reaction mass was cooled to ambient temperature and filtered through hyflo and washed with toluene.

Sodium methoxide solution (25%) (180.0 mL) was added to the above filtrate and heated lo 80-85 °C. The reaction mass was stirred for 1 hour at 80-85 °C and cooled to ambient temperature. The product was extracted in to water (250 mL) and acidified the water layer to pH: 1-2 using concentrated hydrochloric acid. The product was extracted three times in to toluene and washed with water.
Crotonic acid (25 grams 0.2904 mmol) was added to the above toluene layer and cooled to 15-20 °C. Triethylamine was added (77.5 grams, 0.7661 mmol) at below 25 °C. After the addition was over, the mixture is heated to reflux and stirred for 10 hours. The reaction was cooled to ambient temperature and extracted the product by using water. The product containing water layer was acidified to pH: 1-2 using concentrated hydrochloric acid and extracted in to MDC. The MDC layer was washed with water and brine solution.
Di methyl formamide (1.6 mL) and oxaly! chloride (37.9 grams, 0.2986 mmol) was added dropwise to the above MDC layer at ambient temperature and the mixture stirred for 2 hours. The mixture was cooled to 0-5 °C, and a solution of stannic chloride (35.4 grams, 0.1359 mmol) in MDC (50 mL) is added dropwise by maintaining the temperature below 5 °C. The reaction is stirred for 2 hours at 0-5 °C. After reaction is over, water (220 mL) is added and stirred. The layer is separated and the product MDC layer is washed with hydrochloric acid solution and water. The product containing organic layer was concentrated completely to obtain the product of the formula 4 as yellow liquid. Output: 43 grams; Purity: 97.0%;
Yield: 76.1 % (from 2-bromothiophene)
'H-NMR(CDC1,): 5 I.48(d, 3H), 2.69(dd, 1H), 2.88(dd, IH), 3.79 (m, 1H), 7.01(d, 1H), 7.45(d, 1H); !?C-NMR(CDC!,):8 19.93,40.83,46.69, 121.95, 125.86, 134.62, 150.74, 189.30; MS:(m/z)= 185.1(M+1).
Step-B: Preparation of 5,6-dihydro-4H-6-methylthieno|2^-b|thiopyran-4-one-7,7-dioxide (formula 21)
The product obtained from the Step-A (450 grams, 2.4419 mmol) was dissolved in ethyl acetate (4.5 L). Sodium tungstate dihydrate (80.5 grams, 0.2442 mmol) and sulfuric acid (0.9 mL) was added at ambient temperature. The mixture was cooled to 0-5 °C, and 30% hydrogen peroxide (969.2 grams, 8.5467 mmol) was added dropwise at below 10 °C. The reaction mixture was heated to reflux and maintained for 2 hours. The reaction was cooled to ambient temperature and separated the layers. The organic layer was washed with 5% sodium sulfite solution and followed by water. The organic layer was concentrated completely, added hexane (1.35 L) and stirred. The product was filtered, washed with hexane and dried to obtain the product of the formula 21 as off white solid. Output: 476 grams; Yield: 90.1 %; Purity: 99.5 %; Melting Range: 104-107 °C;

'H-NMR(CDC]3):5 1.57(d, 3H), 3.22(m, 2H), 3.87 (m, lH),7.49(d, !H),7.6l(d, IH); nC-NMR(CDCI3): 5 15.81,49.26,61.86, 130.76, 137.69, 145.22, 151.44, 192.16;
MS:(m/z) = 217.l(M+t).
Step-C: Preparation of 6-dihydro-4H-4-hydroxy-6-methylthieno[2rJ-b)thiopyran-7,7-dioxidc
(formula 22)
The product obtained from the above Step-B (460 grams, 2.1268 mmol) was suspended
methanol (1.38 L) and cooled to 10 °C. Sodium borohydride (48.34 grains, 1.2761 mmol) was added
to the reaction mass at below 10°C. The reaction mixture was warmed to ambient temperature and
stirred for 1 hour. The reaction mixture out concentrated under vacuum. Water (1.84 L) was added.
stirred and extracted in to ethyl acetate (4.6 & 1.38 L). The organic layer was combined and washed
with brine solution. The organic layer was concentrated completely; added hexane (1.38 L) was added
to the residue and stirred. The product was filtered, washed with hexane and dried to obtain the
product of the formula 22, as solid.
Output; 442 grams;
Yield: 95.2%;
Purity: 97.4 %;
Melting Range: 119-120DC;
'H-NMR(DMSO-d6) : 5 1.32(d, 3H), 2.13(m, IH), 2.32(m, IH), 3.70(m, IH), 4.79 (m, IH), 5.88(d,
IH),7.16(d, lH),7.92(d, IH);
nC-NMR(DMSO-d6) : S 10.92,39.14,55.72,64.87, 127.53, 131.62, 134.00, 149.34.
Step-D: Preparation of 5,6-dihydro-4H-4-acctyl amino-6-methylthieno[2,3-blthiopyran-7,7-
dioxrde (formula 23)
The product obtained from the above Step-C (425 grams, 1.9468 mmol) was suspended in
acelonitrile (637.5 mL) and cooled to 10 °C. Sulfuric acid (637.5 mL) was added dropwise to a
reaction mass at below 10 °C over 2-3 hours. The reaction mixture was warmed to ambient
temperature and stirred for 2 hours. The reaction mixture was quenched in to ice (5.1 kg) at below 10
°C. The pH was adjusted to 6-7 using sodium hydroxide solution, and the mixture was stirred, filtered
and washed with water. The filtered wet product again [eached with water, filtered and dried to obtain
the product of the formula 23.
Output: 451 grams;
Yield: 89.3 %;
Purity: Trans-75.6 %, Cis-23.6 %;
Melting Range: 192-196 °C;
'H-NMR(DMSO-d6) Trans : 5 1.33(d, 3H), 1.83(s, 3H), 2.23(m, IH), 2.39(m, IH), 3.60(m, IH),
5.17(m, lH),7.02(d, IH), 7.95(d, IH), 8.55(d, IH);
Cis: 5 1.31(d, 3H), 1.83(s, 3H), 2.23{m, IH), 2.39(m, IH), 3.88(m, IH), 5.23 (m, IH), 6.94(d, IH),
7.93(d, IH), 8.50(d, IH);
l3C-NMR(DMSO-d6) Trans :S 10.82,22.90,35.58,53.05, 128.20, 131.92, 135.62, 144.88, 169.08;

Cis:S 10.57,22.90,36.47,45.17,55.88, 127.48, 131.70, 135.10, 146.60, 169.50;
MS :(m/z)= 260.2(M+1).
Step-E: Preparation of 5,6-dihydro-4H-4-acerylamino-6-methylthieno[2,3-b]thiopyran-2-
sulfonamide-7,7,-dioxide (formula .10)
The product obtained from the above Step-D (420 grams, 1.6194 mmol) was added to chtorosulfonic acid (840 mL) at below 10 °C over 1 hour. The reaction mixture was heated gradually to 50-55 °C and stirred for 10 hours. The reaction mixture was cooled to ambient temperature and added thionyl chloride (840 mL). The reaction mixture was heated to 50-55 °C and stirred for 10 hours. The reaction mixture was cooled and quenched in to ice+water (8.4 kg) at below 10 °C, and stirred. The product was filtered at 0-5 °C, washed with chilled water, and suck dried to obtain the product of the formula 24. Wet Product: 700 grams.
The above wet product added in lot wise to a solution of acetone (3.474 V) and aqueous ammonia (868.5 mL) at below 5 °C, and stirred for 1 hour. The reaction mixture was concentrated under vacuum, water (1.737 L) was added and stirred. The pH was adjusted to 6.0-7.0 using concentrated hydrochloric acid and stirred for 2 hours. The product was filtered, washed with water, and dried to obtain the product of the formula 10. Output: 413 grams; Yield: 75.3 %;
Purity: Trans-75.9 %, Cis-19.9 %.
'H-NMR(DMSO-d6)Trans:o 1.35(d, 3H), 1.85(s, 3H), 2.28(m, lH),2.47(m, IH),3.86(m, 1H), 5.17 (m, 1H), 7.40(s, 1H), 8.05(s, 2H), 8.62(d, 1 H);
Cis: 5 1.32 (d, 3H), 1.89(s, 3H), 2.28(m, IH), 2.47(m, 1H), 3.94(m, 1H), 5.25 (m, 1H), 7-31 (s,lH), 8.05(s, 2H), 8.59(d, IH);
,3C-NMR (DMSO-d6) Trans: S 10.50, 22.63, 34.70, 41.71, 53.14, 129.58, 138.11, 144.63, 149.82. 168.90;
Cis: 8 10.12,21.00,35.65,44.75,55.78, 120.80, 137.80, 146.39,149.60, 169.90; MS:(m/z) = 337.2(M+l).
Stcp-F: Preparation of 5,6-dihydro-411-4-ethylamino-6-methyIthieno[2^-b)thiopyran-2-sulfonamide-7,7,-dio\ide (formula 1_1_)
The product obtained from the above Step-E (390 grams, 1.1523 mmol) was suspended in tetrahydrofuran(3.l2 L) and cooled to 5-10 °C. Sodium borohydride (87.3 grams, 2.3Q46 mmol) was added to the reaction mass at below 10 °C, and stirred. Borontrifluoride-etherate (327.1 grams, 2.3046 mmol) was added at below 10 °C. The reaction mixture was heated to 40-45 °C, and stirred for 8 hours. The reaction mixture was cooled and acidified with concentrated hydrochloric acid (881 mL), and stirred for 10 hours, at ambient temperature. The reaction mixture was concentrated under vacuum, added of water (1.56 L). The pH was adjusted to 7-7.5 using sodium hydroxide solution and stirred for 5 hours. The product was filtered, washed with water, and dried to obtain the product of the formula 11 as off white solid.

Output: 338 grams;
Yield: 90.4 %;
Purity: Trans-78.4 %, Cis-17.4 %;
MS: (m/z) = 325.4 (M+l).
Step-G: Preparation of formula 25
The product obtained from the above Step-F (325 grams, 1.0017 mmoi) was suspended in
water (4.55 L) at ambient temperature. Maleic acid (116.3 grams, 1.0017 mmol) was added to
reaction mass and heated to reflux to get clear solution. The clear mass was cooled to 5-10 °C, and
stirred for 1 hour. The product was filtered and washed with water. The wet product was
recrystallized again with water, and dried to obtain the product of the formula 25 as white solid.
Output: 298 grams;
Yield: 67.5 %;
Purity: Trans-99.3 %, Cis-0.2 %;
Melting Range: 207-214 °C;
'H-NMR(DMSO-d6) : 5 l.20(t, 3H), 1.38(d, 3H), 2.60(s, 2H), 3.01(m, 1H), 3.2l(m, 1H), 4.03 (m,
1H), 4.65 (t, III), 6.07(s, 111, Maleic acid), 7.82(s, 1H), 8.16(br-s,lH);
l3C-NMR(DMSO-d6):5 10.40, 11.89, 31.30, 41.31, 49.85, 51.90, 130.72, 138.26, 141.85, 150.06,
135.93, 167.75 (Maleic acid);
MS:(m/z) = 325.3(M+l).
Step-H: Preparation of Trans 5,6-dihydro-4H-4-ethyiamino-6-methylthieno|2,3-b|thiopyran-2-sulfonamide-7,7,-dioxide (formula \2)
The product obtained from the above Step-G (360 grams, 0.8172 mmol) was added in lot wise to a solution of sodium bicarbonate (360 grams) in water (7.2 L) at ambient temperature, and stirred for 1 hour. The product was filtered and washed with water. The wet product was again leached with water, and dried to obtain the product of the formula 12. Output: 254 grams; Yield: 95.8%;
Purity: Trans-99.3 %, Cis-0.3 %; Melting Range: 180-183 °C;
'H-NMR(DMSO-d6): 5 1,00(t, 3H), 1.33(d, 3H), 2.32(s, 2H), 2.57(m, 2H), 3.90(m, 2H), 7.55(s, 1H), 8.02(br-s,lH);
l3C-NMR(DMSO-d6): 5 10.53, 15.25,33.61,40.92,50.22,52.21, 130.52, 137.64, 146.92, 148.82; MS:(m/z) = 325.3(M+l). Step-T: Preparation of formula 26
The product obtained from the above Step-H (240 grams, 0.7397 mmol) was suspended in n-propanol (8.4 L) at ambient temperature. Di-p-toluyl-L-tartaric acid monohydrate (74.78 grams, 0.1849 mmol) was added to the reaction mixture and heated to reflux to get clear solution. The clear mass was cooled to 25-30 °C, and stirred for 2 hours. The product was filtered and washed with n-

propanol. The wet product was recrystallized again with n-propanol (5.28 L), and dried to obtain the
product of the formula 26.
Output: 144 grams;
Yield: 37.6%;
Purity: S(-)-99.94 %, R(+)-0.06 %;
Melting Range: 158-163 °C;
'H-NMR(DMSO-d6) : 5 1.00(t, 3H), 1.33(d, 3H), 2.32(s,2H), 2.57(m, 2H), 3.90(m, 2H), 7.55(s, 1H),
8.02(br-s, IH);
l3C-NMR(DMSO-d6):5 10.53, 15.25,33.61,40.92,50.22,52.21, 130.52, 137.64, 146.92, 148.82;.
MS:(m/z) = 325.3(M+l).
Step-J: Preparation of Dorzolamidc hydrochloride (formula X)
The product obtained from the above Step-I (30 grams, 0.0579 mmol) was suspended in water (210 mL) at ambient temperature. Sulfuric acid (15.9 grams, 0.1622 mmol) was added slowly to the reaction mixture and stirred for 6 hours. The solid product was filtered and washed with water (60 mL), dried to obtain the di-p-toluyl-L-tartaric acid as white solid. Wieght: 10 grams
The pH of the filtrate was adjusted to 8 using sodium hydroxide solution and extracted the product in to ethyl acetate (2 x 300 mL). The combined organic layers were washed with brine solution (150 mL). Approximately 300 mL of ethyl acetate was distilled out atmospherically, and charcolised the organic layer. IPA-HCI (15%) (27.0 mL) was added to the filtered organic layer at ambient temperature and stirred for 2 hours. The product was filtered, washed with ethyl acetate and dried to obtain the product of the formula I as white crystalline solid. Output: 18.2 grams; Purity: 99.8 %; Yield: 87.0%;
SOR: - 8.2 (C=l in Methanol);
'H-NMR(DMSO-d6) Trans : S 1.26(t, 3H), 1.37(d, 3H), 2.53(m,lH), 2.53(m,lH), 2.74(m, IH), 3.02(m, IH), 3.18(m, IH), 4.27(m,lH), 4.67(br, s, IH), 7.96(s, IH), 8.18(s, 2H), 9.45(br, s, IH), 9.69(br, s, IH);
nC-NMR(DMSO-d6) Trans : 5 10.26, 11.43, 30.99, 41.07, 49.51, 51.86, 131.00, 137.64, 142.21, 149.96;
MS:(m/z) = 325.3(M+l). Advantages of the invention:
1. The process is very simple and starts from the readily available starting material which makes the piucess economical and industrially viable.
2. The separation uf cis/lrans isomer to pure trans isomer has been done using water as the solvent which is environmentally friendly with 67.5 % yield in slead of 37 % yield as reported by the prior art processes.

3. The separation of chiral dorzoiamide form Trans recemic mixture using only one di-p-toluoyl-L-tartaric acid instead of both the D & L acids used in the reported process with improved yield.
4. The di-p-toluoyl-L-tartaric acid can be easily recovered while isolating the pure dorzoiamide and can be reused makes the process more cost competitive and environment friendly.

We Claim:
I. An improved process for the preparation of Dorzotamide hydrochloride of the formula i

which comprises:
Step-I: Reacting 2-bromothiophene of the formula 19,

with 2-Ethylhexyl 3-mercaptopropionate in the presence of tris(dibenzylideneacetone)dipalladium(0) and xantphos in suitable base and solvent at a temperature in the range of 90-110 °C to obtain the novel intermediate 3-(thiophen-2-ylsulfanyl)propionic acid 2-ethylhexyl ester of the formula 20.

Step-II; Reacting the novel intermediate of the formula 20 with strong base in suitable solvent at a temperature in the range of 50-90 °C to give 2-mercaptothiophene of the formula 2.

Step-III: Reacting the compound of the formula 2 with crotonic acid in presence of aprotic polar or non-polar solvent and suitable base at a temperature in the range of 100-120 °C to obtain 3-(2-mercaptothiophene)butanoic acid of the formula 3.

Step-IV: Reacting the compound of the formula 3 with chlorinating agent, and followed by treating with Lewis acid in non-polar solvent at a temperature in the range of 0-30 °C to obtain 5,6-dihydro-
4H-6-methylthieno[2,3-n]thiopyran-4-one of the formula 4.

4
Step-V: Oxidation of the compound of the formula 4 by using oxidizing agent in suitable solvent at a
temperature in the range of 50-80 °C to obtain 5,6-dihydro-4H-6~methylthieno[2,3-b]thiopyran-4-one-7,7-dioxide of the formula 21.

Step-VI: Reducing the compound of the formula 21 by using reducing agent in suitable solvent at a temperature in the range of 0-30 °C to obtain 5,6-dihydro-4H-4-hydroxy-6-methylthieno[2,3-b]thiopyran-7,7-dioxide of the formula 22.

Step-VJI: Reacting of the compound of the formula 22 by using acetoriitrile and suitable strong acid by Ritter reaction at a temperature in the range of 0-30 °C to obtain 5,6-dihydro-4H-4-aceryl amino-6-methylthieno[2,3-b]thiopyran-7,7-dioxide of the formula 23.

Step-VIII: Reacting the compound of the formula 23 with chlorosulfonic acid and chlorinating agent at a temperature in the range of 40-60 °C to give 5,6-dihydro-4H-4-acetylamino-6-methylthieno[2,3-b]thiopyran-2-sulfonylchloride-7,7,-dioxide of the formula 24.

followed by treating with ammonia at a temperature in the range of 0-20 "C in the presence of aprotic polar solvent to obtain 5,6-dihydro-4H-4-acetylamino-6-methytthieno[2,3-b] thiopyran-2-sulfonamide-7,7,-dioxide of the formula 10.

Step-IX: Reducing the compound of formula M) using reducing agent in suitable solvent at a temperature in the range of 30-50 °C to obtain 5,6-dihydro-4H-4-etfty/amino-6-rnethy/thieno[2,3-b]thiopyran-2-sulfonamide-7,7,-dioxide of the formula 1_1.

Step-X: Isolating the Trans isomer of the formula 25 from the trans/cis isomer of the formula 11 at a temperature in the range of 30-100 °C by making mineral or organic acid salt in suitable solvent.

Step-XI: Treating the compound of the formula 25 with suitable base in a water solvent at a temperature in the range of 20-40 °C to obtain Trans 5,6-dihydro-4H-4-ethylamino-6-methyithieno[2,3-b]thiopyran-2-sulfonamide-7,7,-diox.ideof the formula 17.

Step-XII: Treating the racemic trans isomeric compound of formula \2 in suitable solvent with optically active resolving agent by resolution to obtain trans (-) isomer of the formula 26.

Step-XIII: Treating the compound of the formula 26 with suitable strong acid to recover the di-p-toluyl-L-tartaric acid and followed by adjusting the pH: 8-9 using a suitable base and extracted by using suitable solvent. The extracted solvent is treated with hydrochloric acid to obtain the Dorzolamide hydrochloride of the formula 1.
2. Novel intermediate compound 3-(thiophen-2-ylsulfanyl)propionic acid 2-ethylhexyl ester of the
formula 20.

3. The novel intermediate compound as claimed formula 20 as claimed in claim 2 is useful in
preparation of Dorzolamide hydrochloride of the formula X.
4. The process for preparation of novel intermediate compound of formula 20 as claimed in claim 2,
which comprises:
Step-I: Reacting 2-bromothiophene of the formula 19,

with 2-Ethylhexyl 3-mercaptopropionate in the presence of tris(dibenzylideneacetone)dipalladium(0) and xantphos in suitable base and solvent at a temperature in the range of 90-110 °C to obtain the novel intermediate 3-(thiophen-2-ylsulfanyl)propionic acid 2-ethylhexyl ester of the formula 20.
5. The process as claimed in claims 1 and 4, wherein said base in Step-I is selected from pyridine, triethylamine, N-methylmorphoIine, 2,6-dimethylpyridine, 2,4,6-trimethylpyridine or diisopropylethyl amine.
6. The process as claimed in claims 1 and 4, wherein said solvent in Step-I is selected from tetrabydrofuran, toluene, acetonitrile, dioxane or xylene.
7. The process as claimed in claim 1, wherein said base in Step-Il is selected from sodium methoxide, sodium hydroxide, potassium methoxide, potassium hydroxide, sodium hydride or lithium hydroxide.
8. The process as claimed in claim I, wherein said solvent in Step-11 is selected from C1-C4 alcohol.
9. The process as claimed in claim 1, wherein said base in Step-Ill is selected form pyridine, 2,6-dimethy) pyridine, 2,4,6-trimethyJpjridine, Iriejrtylami/ie, N-methylmorphoiine or diisopropyiethyl amine.
10. The process as claimed in claim 1, wherein said solvent in Step-III is selected form
tetranydrofuran, dioxane, ethyl acetate, acetonitrile or toluene.
11. The process as claimed in claim 1, wherein said chlorinating agent in Step-IV is selected from thionyl chloride, oxalyl chloride, phosphorous pentachloride, phosphorous oxychloride, phosphorous trichloride or sulfuryl chloride.
12. The process as claimed in claim 1, wherein said Lewis acid in Step-IV is selected from aluminium chloride, stannic chloride, borontrifluoride-ethereate, zinc chloride or ferric chloride.
13. The process as claimed in claim 1, wherein said solvent in Step-IV is selected from dichloromethane, chloroform or toluene.
14. The process as claimed in claim 1, wherein said oxidizing agent in Step-V is selected from oxonc, 3-chloroperbenzoic acid, hydrogen peroxide in sodium tungstate or sodium perborate.

15. The process as claimed in claim 1, wherein said solvent in Step-V is selected from
dichloromethane, chloroform, ethyl acetate, isopropyl acetate, methanol, ethanol or acetic acid.
16. The process as claimed in claim 1, wherein said reducing agent used in Step-VI is selected from
sodium borohydride, lithium aluminium hydride, palladium on carbon in hydrogen or Raney nickel in
hydrogen.
17. The process as claimed in claim ls wherein said solvent in Step-VI is selected from C,-Ci alcohol.
18. The process as claimed in claim 1, wherein said strong acid in Step-VII is selected from sulfuric
acid, methane sulfonic acid, phosphoric acid, trifluoroacetic acid or trifluoromethanesulfonic acid.
19. The process as claimed in claim 1, wherein said chlorinating agent in Step-VIH is selected from thionyl chloride, oxalyl chloride, phosphorous pentachloride, phosphorous oxychloride, phosphorous trichloride or sulfuryl chloride.
20. The process as claimed in claim 1, wherein said aprotic polar solvent in Step-VIII is selected from tetrahydrofuran, acetone, dioxane or methylethylketone.
21. The process as claimed in claim I. wherein said reducing agent in Step-IX is selected from borane-dimethylsulfide complex, borontrifluoride-etherate in sodium borohydride or lithium aluminium hydride.
22. The process as claimed in claim 1, wherein said solvent in Step-IX is selected from ethers or cyclic ethers.
23. The process as claimed in claim 1, wherein said mineral acid in Step-X is selected from hydrochloric acid, hydrobromic acid, sulfuric acid or nitric acid.
24. The process as claimed in claim 1, wherein said organic acid in Step-X is selected from maleic acid, fumaric acid, malonic acid, oxalic acid, benzoic acid, citric acid, succinic acid, p-toluic acid, salicylic acid or p-nitrobenzoic acid.
25. The process as claimed in claim 1, wherein said solvent in Step-X is selected from ketone, ester, alcohol, polar-aprotic solvent or water.
26. The process as c/aimed in claim I, wherein said base is Step-XI is selected from ammonia, sodium bicarbonate, sodium carbonate, potassium bicarbonate, sodium hydroxide or potassium hydroxide.

27. The process as claimed in claim 1, wherein said optically active resolving agent in Step-XM is
selected from tartaric acids, di-p-toluyl-L-tartaric acids, malic acids, mendelic acids or camphour-lG-
sulfonic acids.
28. The process as claimed in claim 1, wherein said solvent in Step-XII is selected from alcohols,
water or polar-aprotic solvent.
29. The process as claimed in claim I, wherein said strong acid in Step-XHI is selected from sulfuric
acid, hydrochloric acid, hydrobromic acid or methanesulfonic.
30. The process as claimed in claim 1, wherein said base in Step-XIIl is selected from sodium
bicarbonate, sodium carbonate, sodium hydroxide or potassium hydroxide.
31. The process as claimed in claim I, wherein said solvent in Step-XIH is selected from ethyl acetate,
dichloromethane or chloroform.
32. The process for the preparation of the novel intermediate 3-(thiophen-2-ylsulfanyl)propionic acid 2-ethylhexyI ester of (lie formula 20 claimed in claim 4 is substantially as herein described with reference to the Step - I of Example 1.
33. The process for the preparation of Dorzolamide hydrochloride of the formula J. as claimed in claim I is substantially as herein described with reference to the Examples 1 & 2.

Documents:

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Patent Number

268270

Indian Patent Application Number

2969/CHE/2008

PG Journal Number

35/2015

Publication Date

28-Aug-2015

Grant Date

24-Aug-2015

Date of Filing

27-Nov-2008

Name of Patentee

SUVEN LIFE SCIENCES LIMITED

Applicant Address

SERENCE CHAMBERS, ROAD-5, AVENUE - 7, BANJARA HILLS, HYDERABAD-500 034

Inventors:

#	Inventor's Name	Inventor's Address
1	CHINNAPILLAI, RAJENDIRAN	SUVEN LIFE SCIENCES LIMITED, SERENCE CHAMBERS, ROAD-5, AVENUE - 7, BANJARA HILLS, HYDERABAD 500 034
2	PERIYANDI, NAGARAJAN	SUVEN LIFE SCIENCES LIMITED, SERENCE CHAMBERS, ROAD-5, AVENUE - 7, BANJARA HILLS, HYDERABAD 500 034
3	JASTI, VENKATESWARALU	SUVEN LIFE SCIENCES LIMITED, SERENCE CHAMBERS, ROAD-5, AVENUE - 7, BANJARA HILLS, HYDERABAD 500 034

PCT International Classification Number

C07D495/00

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA