3 June 2010 ( ) WO 2010/ Al

Transcription

1 (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (43) International Publication Date (10) International Publication Number 3 June 2010 ( ) WO 2010/ Al (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every C07D 333/34 ( ) C07D 495/04 ( ) kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, (21) International Application Number: PCT/IN2009/ CA, CH, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, (22) International Filing Date: HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, 6 April 2009 ( ) KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, (25) Filing Language: English MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL, PT, RO, RS, RU, SC, SD, SE, SG, (26) Publication Language: English SK, SL, SM, ST, SV, SY, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (30) Priority Data: 2969/CH/ November 2008 ( ) IN (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (71) Applicant (for all designated States except US): SUVEN GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, LIFE SCIENCES LIMITED [IN/IN]; Serene Cham ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, bers, Road No. 5, Avenue -7, Banjara Hills, Hyderabad - TM), European (AT, BE, BG, CH, CY, CZ, DE, DK, EE, , Andhra Pradesh (IN). ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, SE, SI, SK, TR), (72) Inventors; and OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, ML, (75) Inventors/Applicants (for US only): CHINNAPILLAI, MR, NE, SN, TD, TG). Rajendiran [IN/IN]; Suven Life Sciences Limited, Serene Chambers, Road No. 5, Avenue -7, Banjara Hills, Declarations under Rule 4.17: Hyderabad , Andhra Pradesh (IN). PERIYAN- DI, Nagarajan [US/IN]; Suven Life Sciences Limited, Serene Chambers, Road No. 5, Avenue -7, Banjara Hills, Hyderabad , Andhra Pradesh (IN). JASTI, Published: Venkateswarlu [US/IN]; Suven Life Sciences Limited, Serene Chambers, Road No. 5, Avenue -7, Banjara Hills, Hyderabad , Andhra Pradesh (IN). (74) Agents: SUBRAMANIAM, Hariharan et al; Subramaniam, Nataraj & Associates, E-556, Greater Kailash-11, New Delhi , INDIA (IN). as to applicant's entitlement to apply for and be granted a patent (Rule 4.1 7(H)) with international search report (Art. 21(3)) (54) Title: PROCESS FOR PREPARING DORZOLAMIDE HYDROCHLORIDE AND ITS INTERMEDIATE (57) 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 ("Dorzolamide hydrochloride") having formula 1. 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. Dorzolamide hydrochloride is useful in the treatment of ocular hypertension by inhibiting carbonic anhydrase enzyme.

2 PROCESS FOR PREPARING DORZOLAMIDE HYDROCHLORIDE AND ITS INTERMEDIATE Field of the Invention 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. IO I 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 15 hypertension by inhibiting carbonic anhydrase enzyme. Background of the Invention The process for preparation of Dorzolamide hydrochloride was first reported in EP (Equivalent to US ). This patent discloses the preparation of Dorzolamide hydrochloride of the formula 1 starting from 2-mercaptothiophene of the formula 2, by reacting 0 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-methylthieno[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-dihydiO-4H-6-methylthieno[2.3-b]thiopyran-4-one-2-sulfonic acid of the formula 5. The 5 compound of the formula 5 is reacted with phosphorous pentachloride to obtain the 5.6- dihydio-4h-6-methylthieno[2,3-b] thiopyran-4-one-2-sulfonylchloride 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-s ιιlfonamide the formula 7. Reduction of compound of the formula 7 using sodium boroh\dride gives 5,6-dihydro-4H-4-hydroxy-6-methylthieno[2,3-b]thiopyran-2-s ιilfonamide

3 of the formula 8. Oxidation of the compound of the formula 8 using oxone provides 5,6- dihydro-4h-4-hydroxy-6-methylthieno[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-acetyiamino-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-dimethylsulfide gives 5,6-dihydro-4H-4-ethylamino-6-methylthieno[2,3- b]thiopyran-2-sulfonamide-7,7-dioxide of the formula 11. 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-methylthieno[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-toluoyj-l-tartaric acid, followed by treating with hydrochloric acid provides Dorzolamide hydrochloride of the formula 1 as described in the Scheme-1. Scheme-1: 10 II 12 The above prior art process has the following disadvantages when the process is to be scaled-up for industrial use:

4 (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-ptoluoyl-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 starting from chiral hydroxysulfone ie., 5,6-dihydro-4-(S)-hydroxy-6(S)-methyl-4Hthiopyran-7,7,-dioxide of the formula 13. 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-dihydiO-4(S)-acerylamino-6(S)-metliylthieno[2,3- b]thiopyran-7,7,-dioxide of the formula 14. The compound of the formula 14 is reacted with clilorosulfonic acid and thionyl chloride to give 5,6-dihydro-4(S)-acetylamino-6(S)- ιnethylthieno[2,3-b]thiopyran-2-sulfonyichloride-7,7,-dioxide of the formula -15 and followed by treating with ammonia to obtain 5,6-dihydro-4(S)-acetylamino-6(S)-methylthieno[2,3- b]thiopyran-2-sulfonamide-7,7 -dioxide of the formula 16. 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-sulfon amide-7,7,-dioxide of the formula 17. The compound of formula 17 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,-dioxide maleate of the formula 18. The compound of formula 18 is treated with sodium bicarbonate and hydrochloric acid to obtain Dorzolamide hydrochloride of the formula 1 as described in the Scheme-2.

5 Scheme-2: The process for making the chiral hydroxysulfone of the foπnula 13 is described in EP , EP , US , US and US The above described process is not suitable for industrial product production as the process of making is cumbersome and involves enzymatic process. Further US 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 3 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-sulfonylchloride 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 7 using sodium borohydride to obtain 5,6-dihydro- 4H-4-hydiOxy-6-methylthieno[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- methylthieno[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 obtain 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-dimethylsulf ϊ de yields 5,6-dihydro-4H-4-ethylamino-6-methylthieno[2,3-b]thiopyran-2-sulfonamide-7,7-dioxide of the formula 11. The racemic cis/trans isomer of the formula 11, is treated with ethanolichydrochloride and followed by sodium bicarbonate to get the (±)trans 5,6-dihydro-4H-4-

6 ethylamino-6-methyltliieno[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 1 as described in the Scheme-3. Scheme-3: 10 U 12 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- methylthieno[2,3-b]thiopyran-4-one-2-sulfonamide the formula 7 from 5,6-dihydro-4H-6- methylthieno[2,3-b]thiopyran-4-one of the formula 4. (c) The lower yield (37.98 %) was reported for the preparation of trans 5,6-dihydro-4H-4- ethylamino-6-methylthieno[2,3-b]thiopyran-2 -sulfonamide -7,7-dioxide of the formula 12 from the Cis-Trans isomer of the formula 11. (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-

7 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 1 from (±)trans 5,6- DihydtO-4H-4-ethylamino-6-methylthieno[2,3-b] thiopyran-2-sulfonamide-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 19. Yet another patent WO 2006/ also has disclosed a process for the preparation of (4S,6S)-4-(ethylamino)-5,6-dihydro-6-methyl-4H-thieno[2,3-b]thiopyra π-2-sulfonamide7,7- dioxide hydrochloride (Dorzolamide hydrochloride) of the formula 1 by doing resolution of (±)trans 5,6-Diliydro-4H-4-ethylamino-6-methyIthieno[2,3-b]thiopyran-2-sulfonamide-7,7- dioxide of the formula 12 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/ lias 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-ethylamino-6- methylthieno[2,3-b]thiopyran-2-sulfonamide-7,7-dioxide of the formula 11 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-diliydro-4H-4-ethylamino-6-methylthieno[2,3-b]thiopyra i-2-sulfon amide-7,7-dioxide of the formula 12 using (ls)-(+)-io-camphorsulfonic acid. The lower yield (3 1.0 %) 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-ylsulfanyl)propionic acid 2-ethylhexyl ester of the formula 20 useful for the preparation of Dorzolamide hydrochloride of the formula 1.

8 Still another objective of the present invention is to provide a process to isolate the trans 5,6-dihydro-4H-4-ethylamino-6- ιnethylthieno[2,3-r ]thiopyran-2-sulfonamide-7,7-dioxide maleate of the formula 25 from cis/trans isomer of 5,6-dihydro-4H-4-ethylamino-6- methylthieno[2,3-b]thiopyran-2-sulfonamide-7,7-dioxide of the formula 11 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 12 using only one di-p-toluoyl-l-tartaric acid to get the 5,6-dihydro-4H-4(S)-ethylamino-6(S)-methylthieno[2,3-b]thiopyran-2-_ sulfonamide-7,7-dioxide hemidi-p-toluoyl-d-tartarate of the formula 26 with diastereomeric excess of 99.9 % pure and < 0.02 % of cis-dorzolamide. 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-sulfonamide-7,7-dioxide hemidi-p-toluoyl-d-tartarate of the formula 26 in simple and recovering di-p-toluoyl-l-tartaric acid forreuse. Summary of the Invention The present invention provides an improved process for the preparation of Dorzolamide hydrochloride of the formula 1. which comprises: Step-I: Reacting 2-bromothiophene of the formula 19, i 12 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 C to obtain the novel intermediate 3-(thiophen-2- ylsulfanyl)propionic acid 2-ethylhexyl ester of the formula 20.

9 Step-II: Reacting the novel intermediate of the formula 20 with strong base in suitable solvent at a temperature in the range of C to give 2-mercaptothiophene of the formula 2. Step-Ill: 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 C to obtain 3-(2-mercaptothiophene)butanoic acid of the formula 3. 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 C to obtain 5,6-dihydro-4H-6-methylthieno[2,3-b]thiopyran-4-one of the formula 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 C to obtain 5,6-dihydro-4H-6-methylthieno[2,3- b]thiopyran-4-one-7,7-dioxide of the formula Step-VI: Reducing the compound of the formula 21 by using reducing agent in suitable solvent at a temperature in the range of C to obtain 5,6-dihydro-4H-4-hydroxy-6- niethylthieno[2,3-b]thiopyran-7,7-dioxide of the formula 22.

10 22 Step- VH: Reacting of the compound of the formula 22 by using acetonitrile and suitable strong acid by Ritter reaction at a temperature in the range of C to obtain 5,6-dihydro-4H-4- acetyl 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 C to give 5,6-dihydro-4H-4-acetylamino-6- methylthieno[2,3-b]thiopyran-2-sulfonylchloride-7,7,-dioxide of the formula followed by treating with ammonia at a temperature in the range of C in the presence of aprotic polar solvent to obtain 5,6-dihydro-4H-4-acetylamino-6-methylthieno[2,3-b] thiopyran- 2-sulfonamide-7,7,-dioxide of the formula Step-IX: Reducing the compound of formula 10 using reducing agent in suitable solvent at a temperature in the range of C to obtain 5,6-dihydro-4H-4-ethylamino-6- methylthieno[2,3-b]thiopyran-2-sulfonamide-7,7,-dioxide of the formula 11.

11 H 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 C by making mineral or organic acid salt in suitable solvent. 25 Step-XI: Treating the compound of the formula 25 with suitable base in a water solvent at a temperature in the range of 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. H N 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. H N. Hetni di-p-toluyl-l-tartarate o o H 26 Step-XIII: Treating the compound of the formula 26 with suitable strong acid to recover the dip-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.

12 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 Dorzolamide hydrochloride of formula 1. HN which comprises: Step-I: Reacting 2-bromothiophene of the formula 19, 12 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 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 1 of the present invention is illustrated by Schenie-4 given below:

13 U HCI Scheme-4 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 suitable temperature to obtain the novel intermediate 3-(thiophen-2- ylsulfanyl)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 C and preferably at a temperature in the range of C.

14 X = Cl, Br, I Step-H: Reacting the novel intermediate of the formula 20 with strong base in suitable solvent at suitable temperature to give 2-mercaptothiophe πe 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 Ci-C 4 alcohol and preferably using methanol. The ieaction temperature may range from C and preferably at a temperature in the range of C. 20 Step-Ill: Reacting the compound of the formula 2 with crotonic acid in presence of aprotic polar or non-polar 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 C and preferably at a temperature in the range of C. 2 Step-IV: Reacting the compound of the formula 3 with chlorinating agent, and followed by treating with Lewis acid in non-polar solvent at suitable temperature to obtain 5,6-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 using oxalyl chloride. The Lewis acids used in reaction can be selected from aluminium chloride, stannic chloride, borontrifluoride-ethereate, zinc chloride or ferric chloride and preferably using stannic chloride.

15 The non-polar solvent used in reaction can be selected from dichloromethane, chloroform or toluene and preferably using dichloromethane. The reaction temperature may range from C and preferably at a temperature in the range of 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 C and preferably at a temperature in the range of C. 2 1 Step- VI: Reducing the compound of the formula 2 1 by using reducing agent in suitable solvent at suitable temperature to obtain 5,6-dilϊ ydro-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 C r C alcohol and preferably using methanol. The reaction temperature may range from C and preferably at a temperature in the range of 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-

16 methyltliieno[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 C and preferably at a temperature in the range of 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 oxychloride, phosphorous trichloride or sulfuryl chloride and preferably using thionyl chloride. The reaction temperature may range from G and preferably at a temperature in the range of C. The conversion of the compound of the compound formula 24 to 5,6-dihydro-4H-4- acetylamino-6-methylthieno[2,3-b]thiopyran-2-sulfonamide-7,7,-dioxide of the formula 10 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 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-ethyIamino-6-methylthieno[2,3-b]thiopyran-2- sulfonamide-7,7,-dioxide of the formula 11. The reducing agent used in reaction can be selected from borane-dimethylsulfide complex, borontrifluoride-etherate in sodium

17 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 C and preferably at a temperature in the range of C. 10 u Step-X: Isolating the Trans isomer of the formula 25 from the trans/cis isomer of the formula 11 at suitable temperature in the range of 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 C and preferably at a temperature in the range of 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 at suitable temperature in the range of 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 C and preferably at a temperature in the range of C.

18 25 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. The optically active resolving agent used in reaction can be selected from tartaric acids, di-p-toluyl- 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. HN HN II 26 Step-XIlI: Treating the compound of the formula 26 with suitable strong acid to.recover the dip-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 1. The acid used for neutralization of the tartarate salt may be selected from sulfuric acid, hydrochloric acid, hydrobromic acid or inethanesulfonic 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.

19 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 grains, mmol) in toluene (3 L) was added 2-Etliylhexyl 3-mercaptopropionate ( grams, mmol) and N,Ndiisopropylamine (158.5 grams, mmol) at ambient temperature. After nitrogen evacuation, tris(dibenzylideneacetone) dipalladium(o) (1.4 grams, mmol), xantplios (0.88 grams, mmol) was added. The mixture was heated to 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 %; 1 H-NMR(CDCh): δ 0.89(m, 6H), 1.33(m, 8H), 1.55(m,lH), 2.62(t, 2H), 3.01(t, 2H), 4.00(dd, 2H), 6.98(dd, 1H), 7. 15(dd, 1H), 7.37(dd, 1H); ' 'C-NMR(CDCh): δ 10.96, 14.02, 22.94, 23.75, 28.89, 30.37, 33.72, 34.57, 38.70, 67.14, , , , , ; LC-MS: (m/z) = (M). Step-II: Preparation of 2-mercaptothiophene (formula 2) The product obtained from the above Step-1 (90 grams, 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 1 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 %; 1 H-NMR(CDCI 3 ): δ 3.5 l(s, IH), 6.92(q, IH), 7.08 (m, IH), 7.26(dt, IH);

20 "C-NMR(CDCI 3 ): δ , , ; MS: (m/z) = (M-I). Step-III: Preparation of 3-(2-mercaptothiophene)butanoic (formula 3) The product obtained from the above Step-II (25 grams, mmol) was dissolved in toluene (250 ml) and added crotonic acid ( grams mmol) at C. Triethyl amine ( grams, mmol) was added slowly at below 25 0 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(CDCI 3 ): δ 1.33(d, 3H), 2.47(dd, IH), 2.70(dd, IH), 4.00(dd, J2H), 6.98(dd, IH), 7.1 5(dd, IH), 7.37(dd, IH); "C-NMR(CDCI ): δ 10.96, 14.02, 22.94, 23.75, 28.89, 30.37, 33.72, 34.57, 38.70, 67.14, , , , , ; MS: (m/z) = 203.0(M+l). Step- ϊ V: Preparation of 5,6-dihydro-4H-6-methylthieno[2 3-b]thiopyran-4-one (formula 4) The product obtained from the above Step-III (30 grams, mmol) was dissolved in MDC (240 ml) and dimethylformamide (0.8 ml) at ambient temperature Oxalyl chloride (20.7 grams, mmol) was added dropwise and maintained at ambient temperature for 2 hours. The reaction mixture was cooled to C, and added dropwise a solution of stannic chloride (19.3 grains, mmol) in MDC by maintaining the temperature below 5 0 C. The reaction was stirred for 2 hours at 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. Output: 27 grams; Yield: 98.9 %; Purity: 97 %; 1 H-NMR(CDCI 3 ): δ 1.48(d, 3H), 2.69(dd, IH), 2.88(dd, IH), 3.79 (m, IH), 7.01(d, IH), 7.45(d, IH); 13 C-NMR(CDCI 3 ): δ 19.93, 40.83, 46.69, , , , , ;

21 MS: (m/z) = 185.1(M+1). Step-V: Preparation of 5,6-dihydro-4H-6-methylthieno[2,3-b]thiopyran-4-one-7,7-dioxide (formula 21) The product obtained from the above Step-IV (174 grams, mmol) was dissolved in ethyl acetate ( 1.74 L) at ambient temperature. Sodium tungstate dihydrate ( grams, mmol) and sulfuric acid (0.5 nil) was added at ambient temperature. The mixture was cooled to C, and 30% hydrogen peroxide (375.3 grams, mmol) was added dropwise at below 10 0 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: grams; Yield: 88.8 %; Purity: 99 %; Melting Range: C; 1 H-NIvIR(CDCI 3 ) : δ 1.57(d, 3H), 3.22(m, 2H), 3.87 (m, IH), 7.49(d, IH), 7.6 l(d, IH); 1 C-NM R(CDCI,): δ 15.81, 49.26, , , , , , ; MS: (m/z) = 217.1(M+1). Step- VI: Preparation of 6-dihydro-4H-4-hydroxy-6-methylthieno[2,3-b]thiopyran-7,7- dioxide (formula 22) The product obtained from the above Step-V (180 grams, mmol-) -was suspended in methanol (540 ml) and cooled to 10 0 C. Sodium borohydride (19.23 grams, mmol) was added to the reaction mass at below 10 0 C. The reaction mixture was warmed to ambient temperature and stirred for I 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 stirred. The product was filtered, washed with hexane and dried to obtain the product of the formula 22 as solid. Output: grams; Yield: 93.1 %; Melting Range: C; Η -NMR(DMSO-d6) : δ L32(d, 3H), 2.13(m, IH), 2.32(m, IH), 3.70(m, IH), 4.79 (m, IH), 5.88(d, I H), 7.16(d, IH), 7.92(d, IH); C-NMR(DMSO-d6) : δ 10.92, 39.14, 55.72, 64.87, , , ,

22 Step-VII: Preparation of 5,6-dihydro-4H-4-acetyl amino-6-methylthieno[2,3-b]thiopyran- 7,7-dioxide (formula 23) The product obtained from the above Step-VI (165 grams, mmol) was suspended in acetonitrile (247.5 ml) and cooled to 10 0 C. Sulfuric acid (247.5 nil) was added dropwise to a reaction mass at below 10 0 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 0 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: grams; Yield: 90.5 %; Purity: Trans-79.2%, Cis-20.3%; Melting Range: C; 'H-NMR(DMSO-do) Trans : δ 1.33(d, 3H), 1.83(s, 3H), 2.23(m, IH), 2.39(m, IH), 3.60(m, 1H), (m, 1H), 7.02(d, 1H), 7.95(d, 1H), 8.55(d, 1H); Cis: δ 1.31(d, 3H), 1.83(s, 3H), 2.23(m, IH), 2.39(m, IH), 3.88(m, IH), 5.23(m, I H), 6.94(d, I H), 7.93(d, IH), 8.50(d, IH); π C-NMR(DMSO-d6) Trans : δ 10.82, 22.90, 35.58, 53.05, , , , , Cis : δ 10.57, 22.90, 36.47, 45.17, 55.88, , , , , ; MS : (m/z) = 260.2(M+l). Step- VIII: Preparation of 5,6-dihydro-4H-4-acetylamino-6-methylthieno[2,3- b)thiopyran-2-sulfonamide-7,7,-dioxide (formula 10) The product obtained from the above Step-VII (125 grams, mmol) was added to chlorosulfonic acid (250 ml) at below 10 0 C over 1 hour. The reaction mixture was heated gradually to 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 C and stirred for 10 hours. The obtain reaction mixture was cooled and quenched in to ice+water (2.5 kg) at below 10 0 C, and stirred. The product was filtered at 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 0 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 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.

23 Output: 121 grams; Yield: 74.1 % ; Purity: Trans-76.5%, Cis-19.8 %; Η -NMR(DMS0-d6) Trans : δ 1.35(d, 3H), 1.85(s, 3H), 2.28(m, IH), 2.47(m, IH), 3.86(m, 1H), (m, 1H), 7.40(s, 1H), 8.05(s, 2H), 8.62(d,.1 H); Cis: δ 1.32 (d, 3H), 1.89(s, 3H), 2.28(m, IH), 2.47(m, IH), 3.94(m, IH), 5.25 (m, IH), 7.31 (s,l H), 8.05(s, 2H), 8.59(d, I H); 13 C-NMR (DMSO-d6) Trans: δ 10.50, 22.63, 34.70, 41.71, 53.14, , , , , ; Cis: δ 10.12, 21.00, 35.65, 44.75, 55.78, , , , , ; MS: (m/z) = 337.2(M+l). Step-IX: Preparation of 5,6-dihydro-4H-4-ethylamino-6-methylthieno(2,3-b]thiopyran-2- sulfonamide-7,7,-dioxide (formula 11) The product obtained from the above Step-VIII (120 grams, mmol) was suspended in tetrahydrofuran (960 ml) and cooled to C. Sodium borohydride (26.8 grams, mmol) was added to the reaction mass at below 10 0 C, and stirred. Borontrifluoride-etherate (100.6 grams, mmol) was added at below 10 0 C. The reaction mixture was heated to C, and stirred 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 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 11. Output: 107 grams; Yield: 93.0 %; Purity: Trans-77.1 %, Cis-19.2 %; MS: (m/z) = (M+l). Step-X: Preparation of formula 25 The product obtained from the above Step-IX (105 grams, mmol) was suspended in water (1.47 L) at ambient temperature. Maleic acid (37.5 grams, mmol) was added to reaction mass and heated to reflux to get clear solution. The clear mass was cooled to 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: %; Purity: Trans-99.0 %, Cis-0.6 %;

24 Melting Range: C; Η -NMR(DMSO-d6) : δ 1.20(t, 3H), 1.38(d, 3H), 2.60(s, 2H), 3.01(m, IH), 3.21(m, IH), 4.03 (m, I H), 4.65 (t, I H), 6.07(s, I H, Maleic acid), 7.82(s, IH), 8.16(br-s,lH); π C-NMR(DMSO-d6) : δ 10.40, 11.89, 31.30, , 49.85, , , , , , , (Maleic acid); MS: (m/z) = 325.3(M+l). Step-XI: Preparation of Trans 5,6-dihydro-4H-4-ethylamino-6-methylthieno[2,3- b]thiopyran-2-sulfonamide-7,7,-dioxide (formula 12) The product obtained from the Step-X (88 grams, 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; Yield: 95.6 %; Purity: Trans-99.0 %, Cis-0.6 %; Melting Range: C; Η -NMR(DMSO-d6): δ 1.00(t, 3H), 1.33(d, 3H), 2.32(s, 2H), 2.57(m, 2H), 3.90(m, 2H), 7.55(s, I H), 8.02(br-s, IH); C-NMR(DMSO-d6 : δ 10.53, 15.25, 33.61, 40.92, 50.22, 52.21, , , , ; MS: (m/z) = 325.3(M+l). Step-XII: Preparation of formula 26 The product obtained from the above Step-XI (60 grams, mmol) was suspended in n-propanol (2.1 L) at ambient temperature. Di-p-toluyl-L-tartaric acid monohydrate (18.7 grams, moles) was added to the reaction mixture and heated to reflux to get clear solution. The clear mass was cooled to 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 ITiL), 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(-) %, R(+)- 0.03%; Melting Range: C; Η -NMR(DMSO-d6) : δ 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); ''C-NM R(DM SO-d6) : δ 10.53, 15.25, 33.61, 40.92, 50.22, 52.21, , , , ;.

25 MS. (m/z) = 325.3(M+l). Step-XIH: Preparation of Dorzolamide hydrochloride (formula 1) The product obtained from the above Step-XII (15 grams, mmol) was suspended in water (105 ml) at ambient temperature. Sulfuric acid (7.9 grams, 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-toluyl-l-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 charcolised 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 1 as white crystalline solid. Output: 8.8 grams; Purity: 99.8 %; Yield: 84.2 %; Η -NMR(DMSO-d ό) Trans : δ 1.26(t, 3H), 1.37(d, 3H), 2.53(m, IH), 2.53(m, IH), 2.74(m, I H), 3.02(m, IH), 3.1 8(m, IH), 4.27(m,lH), 4.67(br, s, IH), 7.96(s, I H), 8.18(s, 2H), 9.45(br, s, l H), 9.69(br, s, IH); π C-NMR(DMSO-d6) Trans : δ 10.26, 11.43, 30.99, 41.07, 49.51, 51,86, , , , ; 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 5,6-dihydro-4H-6-methylthieno[2,3-b]thiopyran-4-one (formula 4) To the solution of 2-bromothiophene (50 grams, mmol) in toluene (300 ml) was added 2-Ethylhexyl 3-mercaptopropionate (66.96 grams, mmol) and N,N- Diisopropylamine (49.52 grams, mmol) at ambient temperature. After nitrogen evacuation, tris(dibenzylideneacetone) dipalladium(o) (0.70 grams, 0.76 mmol), and xantphos (0.44 grams, 0.76 mmol) was added. The mixture was heated to 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 to C. The reaction mass was stirred for 1 hour at C and cooled to ambient temperature. The product was extracted in to water (250 ml) and acidified the water layer to

26 ph: 1-2 using concentrated hydrochloric acid. The product was extracted three times in to toluene and washed with water. Crotonic acid (25 grams mmol) was added to the above toluene layer and cooled to C. Triethylamine was added (77.5 grams, mmol) at below 25 0 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. Dimethylformamide ( 1.6 ml) and oxalyl chloride (37.9 grams, mmol) was added dropwise to the above MDC layer at ambient temperature and the mixture stirred for 2 hours. The mixture was cooled to C, and a solution of stannic chloride (35.4 grams, mmol) in MDC (50 ml) is added dropwise by maintaining the temperature below 5 0 C. The reaction is stirred for 2 hours at 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) 1 H-NMR(CDCl 3 ): δ 1.48(d, 3H), 2.69(dd, IH), 2.88(dd, IH), 3.79 (m, IH), 7.01 (d, IH), 7.45(d, 1H); 1 C-NMR(CDCI 3 ): δ 19.93, 40.83, 46.69, , , , , ; MS: (m/z) = 185.1(M+1). Step-B: Preparation of 5,6-dihydro-4H-6-methylthieno[2,3-b]thiopyran-4-one-7,7-dioxide (formula 21) The product obtained from the Step-A (450 grams, mmol) was dissolved in ethyl acetate (4.5 L). Sodium tungstate dihydrate (80.5 grams, mmol) and sulfuric acid (0.9 ml) was added at ambient temperature. The mixture was cooled to C, and 30% hydrogen peroxide (969.2 grams, mmol) was added dropwise at below 10 0 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 %;

27 Melting Range: C; 1 H-NMR(CDCI 3 ) : δ 1.57(d, 3H), 3.22(m, 2H), 3.87 (m, IH), 7.49(d, IH), 7.61(d, IH); ''C-NMR(CDCh): δ 15.81, 49.26, , , , , , ; MS: (m/z) = 217.1(M+1). Step-C: Preparation of 6-dihydro-4H-4-hydroxy-6-methylthieno[2,3-bJthiopyran-7,7- dioxide (formula 22) The product obtained from the above Step-B (460 grams, mmol) was suspended methanol (1.38 L) and cooled to 10 0 C. Sodium borohydride (48.34 grams, mmol) was added to the reaction mass at below 10 0 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: C; Η -NMR(DMSO-d6) : δ 1.32(d, 3H), 2.13(m, I H), 2.32(m, I H), 3.70(m, I H), 4.79 (m, IH), 5.88(d, 1H), 7. 16(d, 1H), 7.92(d, 1H); π C-NMR(DMSO-d6) : δ 10.92, 39.14, 55.72, 64.87, , , , Step-D: Preparation of 5,6-dihydro-4H-4-acetyl amino-6-methylthieno[2,3-b]thiopyran- 7,7-dioxide (formula 23) The product obtained from the above Step-C (425 grams, mmol) was suspended in acetonitrile (637.5 iiil) and cooled to 10 0 C. Sulfuric acid ( ml) was added dropwise to a reaction mass at below 10 0 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 0 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: 45 1 grams; Yield: 89.3 %; Purity: Trans-75.6 %, Cis-23.6 %; Melting Range: C; Η -NMR(DMSO-d6) Trans : δ l.33(d, 3H), 1.83(s, 3H), 2.23(m, IH), 2.39(m, I H), 3.60(m, I H), 5.17(m, IH), 7.02(d, IH), 7.95(d, IH), 8.55(d, IH);