FORM 2
THE PATENT ACT 1970
(39 of 1970)
AND
The Patents Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10 and rulel3)
1. TITLE OF THE INVENTION:
"PROCESS FOR THE PREPARATION OF INTERMEDIATES"
2. APPLICANT:
(a) NAME: INDOCO REMEDIES LIMITED

(b)NATIONALITY: Indian Company incorporated under the Indian Companies ACT, 1956
(c) ADDRESS: Indoco House, 166 C S. T. Road, Santacruz (East), Mumbai - 400 098, Maharashtra, India.
3. PREAMBLE TO THE DESCRIPTION:
The following specification describes the invention.

FIELD OF INVENTION:
The present invention relates to an improved process for the preparation of 0S>3,4-dihydro-6- chloro-4-hydroxy-2-(3-methoxypropyl)-4//-thieno[3,2-£]-],2-thiazine 1,1-
dioxide of Formula-I

BACKGROUND OF THE INVENTION;
The compound (5)-3,4-dihydro-6-chloro-4-hydroxy-2-(3-methoxypropyl)-4//-thieno[3,2-e]-],2-thiazine 1,1-dioxide of Formula-I is a key intermediate for the synthesis of Brinzolamide used as a carbonic anhydrase inhibitor for controlling intraocular pressure associated with glaucoma.
The carbonic anhydrase inhibitor described above is disclosed in US patent No. 5,378,703, which discloses a process for preparing the racemic modification of the compound which after resolution yields the compound Brinzolamide, US patent "No. 5,344,929 describes the synthesis of (5)-3,4-dihydro-6-chloro-4-hydroxy-2-(3-methoxypropyl)-4//-thieno[3.2-e]-l,2-thiazine 1,1-dioxide of Formula-I starting from 3-acetyl-2,5-dichlorothiophene (Formula-Il). The process involves preparation of thioether 3-acetyl-5-chloro-2-(benzylthio)thiophene (Formula-Ill) by reacting 3-acetyl-2,5-dichlorothiophene (Formula-II) with thiourea and benzyl chloride in presence of ethanol and sodium hydroxide solution as base. The benzylthio group of the compound of Formula-Ill is converted into sulfonamide group by either carrying out oxidative chlorination using chlorine gas in dilute aqueous acetic acid/hydrochloric acid followed by treatment with ammonium hydroxide or by bubbling chlorine gas into solution of thioether in ethyl acetate, treating the intermediate sulfenyl chloride with ammonia gas to get the intermediate sulfenamide (Formula-IV), which on oxidation with hydrogen peroxide in the presence of sodium tungstate dihydrate yields 3-acetyl-5-chIoro-2-thiophenesulfonamide (Formula-V). Bromination of the compound of Formula-V in ethyl acetate using pyridinium bromide perbromide in presence of sulfuric acid forms 3-
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3
bromoacetyl-5-chloro-2-thiophenesulfonamide (Formuta-VI) which is triturated with solvent to limit the dibromo impurity less than 10%. Asymmetric reduction of the compound of Formula-VI in methyl ter(-buty\ ether using (+)-fi-chlorodiisopinocamphenylborane results in chiral intermediate (S)-3-(2-bromb 1-hydroxyethyl)-2-thiophenesulfonamide (Formula-VII), \vhich on cyclisation with aqueous sodium hydroxide yields (6}-3,4-dihydro-6-chloro-4-hydroxy-4^-thieno[3,2-^]-l,2-thiazine Ll-dioxide (Formula-VIII). Alkylation of the compound of Formula-VIII with l-bromo-3-methoxypropane in the presence of potassium carbonate and dimethylsuifoxide results in the required (5)-3,4-dihydro-6-chloro-4-hydroxy-2-(3-methoxypropyl)-4//-thieno[3,2-e]-l ,2-thiazine 1,1 -dioxide of Formula-I.


The drawbacks of the invention are;
■ requires excess ammonium hydroxide for neutralizing acetic acid or hydrochloric acid after oxidative chlorination increasing load of ammonium salts in effluent treatment plant:
■ use of explosive reagent hydrogen peroxide for oxidation;
■ use of costly sodium tungstate as catalyst for oxidation results in sludge formation which is difficult to dispose off makes the process environmentally unsafe;
■ use of expensive, unstable, hygroscopic pyridinium bromide perbromide for bromination results in the formation of undesired dibromo impurity;
■ requires trituration to limit the dibromo impurity less than 10%;
■ requires resolution of the racemic modification of the compound of Formula-I to get the desired isomer.
US patent No. 5,470,973 describes another process for the preparation of racemic modification of the intermediate compound (S)-3,4-dihydro-6-chloro-4-hydroxy-2-(3-methoxypropyl)-4#-thieno[3, 2-e]-l,2-thiazine 1,1-dioxide of Formula-I, starting from 3-bromoacety]-5-chloro-2-thiophenesu]fonamide (Formula-VI) as per the reaction sequence shown in Scheme-2 below;
Scheme-2
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The process involves reduction of 3-bromoacetyl-5-chioro-2-thiophenesulfonamide
(Formula-VI) with sodium borohydride resulting in formation of bromohydrin
intermediate (Formula-VII), which on cyclisation with sodium hydroxide yields 3,4-
dihydro-6-chloro-4-hydroxy-4H-thieno[3,2-e]-1.2-thiazine 1,1-dioxide (Formula-VIII).
Alkylation of the compound of Formula-VIII with l-bromo-3-methoxypropane in
the presence of potassium carbonate and dimethylsulfoxide results in racemic
modification of the compound of Formula-I. The 4-hydroxy group of racemic compound
is further oxidized with sodium dichromate and sulfuric acid which results in the
intermediate 6-chloro-2-(3-methoxypropyl)-2v3-dihydro-4H-thieno[3,2-e][l,2]thiazin-4-
one 1,1-dioxide (Formula-IX). The compound of Formula-IX on asymmetric reduction
using borane- tetrahydrofuran complex and catalytic amount of oxazaborol results in the
required intermediate compound (S)-3,4-dihydro-6-chloro-4-hydroxy-2-(3-
methoxypropyI)-4H-thieno[3,2-e]-I,2-thiazine 1,1-dioxide of Formula-I.
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The drawbacks of the invention are; . ■ involves reduction of the keto group once to form racemic alcohol and then oxidation of the hydroxyl group to get keto group reintroduced in the cyclic compound, which on asymmetric reduction yields the required isomer resulting in the increased number of steps; and ■ use of costly reagent borane-tetrahydrofuran complex with oxazaborol catalyst that renders the process industrially uneconomical.
Therefore, there remains a need for an improved process for preparing the intermediate (•S7-3,4-dihydro-6-chloro-4-hydroxy-2-(3-me(hoxypropyl)-4//-thieno[3J2-^]-],2-thiazine 1,1-dioxide of Formula-I that eliminates or substantially reduces the impurities, decreases the number of steps, and employs a more robust process which is industrial friendly and economical.
Thus the present inventors have come out with a process which ameliorates the problems in the prior art with the use of stable and less costlier reagents which are industrially safe to handle and does not generate the sludge which makes the process rigid and environmentally unsafe.
OBJECTIVES OF THE INVENTION:
The main objective of the present invention is to provide an improved process to prepare the intermediate compound (5)-3,4-dihydro-6-chloro-4-hydroxy-2-(3-methoxypropyl)-4#-thieno[3,2-e]-l;2-thiazine 1,1-dioxide of Formula-I;
Another objective of the present invention is to prepare the intermediate compound of Fonnula-1 with the use of easily available, stable and cost effective reagents.
SUMMARY OF THE INVENTION:
The present invention provides a process for preparation of the compound (5)-3,4-dihydro-6- chloro-4-hydroxy-2-(3-methoxypropyl)-4H-thieno[3, 2-e]-l,2-thiazine 1,1-dioxide of Formula-I;
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Comprising of;
i)
carrying out oxidative chlorination of compound 3-acetyl-5-chloro-2-(benzylthio) thiophene of Formula-Ill to get intermediate sulfonyl chloride (Formula-X), followed by in situ reaction with ammonium hydroxide solution to get sulfonamide compound of Formula-V.


bromination of the compound of Formula-V with brominating reagent in solvent to get the compound 3-bromoacetyl-5-chloro-2-thiophenesulfonamide of Formula-VI;

iii) reducing the compound of Formuia-VI using chirai reducing agent to form the compound 3-(2-bromo l-hydroxyethyl)-2-thiophenesulfonamide of Formula-VII; followed by cyclisation of compound of Formula-VII in presence of base to isolate compound (5)-3,4-dihydro-6-chIoro-4-hydroxy-47/-thieno[3.2-e]-1,2-thiazine 1.1-dioxide (Formula-VIII);
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Formula- VII Formula - VIII
iv) reacting the compound of Formula-VIJI with l-bromo-3-methoxypropane to
isolate (5)-3,4-dihydro-6-chloro-4-hydroxy-2-(3-methoxypropyI)-4//-
thieno[3,2-e]-l,2-thiazine 1,1-dioxide of Formula-I.
DESCRIPTION OF THE INVENTION:
The present invention provides an improved process to prepare the compound (5)-3,4-dihydro-6- chloro-4-hydroxy-2-(3-methoxypropyl)-4//-thieno[3,2-e]-l,2-thiazine 1,1-dioxide of Formula -1. Further, the present invention overcomes the inherent difficulties that exist in prior art when it is desirable to produce the intermediate on commercial scale.
Specifically the problems in the prior art, such as, the use of hydrogen peroxide in presence of sodium tungstate for oxidation, use of unstable, hygroscopic pyridinium bromide perbromide in presence of sulphuric acid and ethyl acetate for bromination that results in the formation of undesired dibromo derivative and use of dimethyl sulfoxide an expensive solvent for alkylation are completely avoided in the present invention. The present invention utilizes oxochlorination reaction carrying out insitu oxidation in organic solvent avoiding the extra oxidation step and uses a brominating agent for bromination followed by isolating the brominated product from water whereby reducing the dibromo impurity to less than 3% thus making the process robust, rigid and commercially viable. The reaction sequence is represented by the scheme-3 below;


Accordingly, in one of the embodiment of the present invention the compound 3-acetyl-5-chloro-2-(benzylthio) thiophene of Formula-Ill is subjected to oxochlorination by bubbling chlorine gas in presence of solvent mixture ethyl acetate and water. The ratio of ethyl acetate and water used is 90:10 to 98:2. The compound 3-acetyI-5-chloro-2-(benzylthio) thiophene was dissolved in ethyl acetate: water mixture and stirred, maintaining the temperature in the range of-5°C to I0°C and passing chlorine gas till complete consumption of the starting material. The reaction mass is then cooled to 0°C. Aqueous ammonia solution is added maintaining the temperature in the range of 0-20°C until pH of the reaction mass is in the range of 9-10. The mixture is stirred and the solvent distilled out under reduced pressure below 60°C. To the residual mass 1:1 mixture of cyclohexane and water is charged, and stirred at 25 - 30°C for about 1.0 hour. The
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solid mass is filtered and dried to get 3-acetyl-5-chloro-2-thiophenesulfonamide (Formula-V).
In another embodiment of the present invention the compound of Formula-V is subjected to bromination using brominating agent in presence of solvent selected from Ci - C4 linear or branched chain alcohols and aliphatic esters either single or mixture thereof. The brominating agent used is selected from dibromo dimethylhydantoin, N-bromosuccinimide, sodium bromide with oxone, liquid bromine with trimethylborate and liquid bromine. The preferred brominating agent used for bromination is dibromo dimethylhydantoin, liquid bromine with trimethylborate and liquid bromine. The C| - C4 linear or branched chain alcoholic solvent is selected from methanol, ethanol, propanol, butanok isopropanol and sec-butanol; wherein the aliphatic esters which are used as solvents include ethyl acetate, methyl acetate, isopropyl acetate, butyl acetate and isobutyl acetate. The compound of Formula-V is taken in selected solvent, to this trimethylborate is added with constant stirring and cooled the reaction mixture to 0 - 5°C. Liquid bromine is then added slowly to the reaction mass maintaining temperature at 0 - 10°C. After complete addition, the reaction mixture was stirred further for 1.0 hour and raised the temperature slowly to 25 - 35°C. Saturated solution of sodium hydrogen sulfite is added to the reaction mass to destroy any excess of free bromine. The solvent is distilled out completely under vacuum below 40°C. Water is then added to the residual mass and further acidified to pH = 1 with dilute sulphuric acid. The temperature of the reaction mass is raised to 50°C and maintained at 50 - 60°C for 2.0 hours. The mixture is cooled to 20 - 30°C, and filtered to get the solid mass of 3-bromoacetyl-5-chloro-2-thiophenesulfonamide of Formula-VI.
By carrying out bromination using the present invention, inventors are able to control the contamination of dibromo impurity in the isolated product to less than 3.0% as compared to 10% or more reported in the prior art.
The compound of Formula-VI is subjected to asymmetric reduction using (+)-/?-chlorodiisopinocamphenylborane at temperature of -30 to 0°C in presence of solvent methyl tert- butyl ether using the known prior art process to isolate (5)-3-(2-bromo 1-hydroxyethyl)-2- thiophenesulfonamide of Formula-VII. After completion of the
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reduction reaction, aqueous solution of sodium hydroxide is added and the mixture is stirred for 2-3 hours at a temperature in the range of 20-30°C to accomplish complete cyclisation. The product is isolated by phase separation and the aqueous phase is acidified to pH=l-2 with dilute hydrochloric acid followed by extraction with ethyl acetate and distillation of the solvent to get the residual mass which is crystallized using toluene to isolate (5)-3.4-dihydro-6-chloro-4-hydroxy-4i/-thieno[3,2-e]-1,2-thiazine 1,1 -dioxide (Formula-VIII).
In another embodiment of the present invention the compound of Formula-VIII is subjected to N- alkylation with l-bromo-3-methoxypropane in presence of base and catalyst. The reaction is carried out in presence of solvent acetone. The preferred base used in the alkylation reaction is anhydrous potassium carbonate. The catalyst used in the reaction is selected from N, N- dimethylformamide, dimethyl sulfoxide and potassium iodide. The reaction is carried out by taking the compound of Formula-VIII in acetone to which a catalyst and the base are added with constant stirring. Alkylating reagent 1-bromo-3- methoxypropane is added and heated to reflux and maintained there for 12-15 hours monitoring the completion of the reaction on TLC. After completion of the reaction, reaction mass is cooled to 25-30°C and filtered. The solvent is distilled out completely and, after this, water is added to the residual mass and extracted with ethyl acetate. The organic layer is washed with dilute sodium hydroxide solution and dried over anhydrous sodium sulfate. Residual solvent is distilled out completely under reduced pressure below 40°C to get the light yellow mass of compound (5)-3,4-dihydro-6-chloro-4-hydroxy-2-(3-methoxypropyl)-4H-thieno[3,2-e]-1,2-thiazine 1,1 -dioxide of Formula-I.
The present invention is further illustrated in detail with reference to the following examples. It is desired that the examples be considered in all respect as illustrative and non restrictive to the invention.
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Examples:
Example 1: Preparation of 3-Acetyl-5-chloro-2-(benzylthio) thiophene:
Thiourea (107.50 gm) and benzyl chloride (161.50 gm) charged in a premixed solution of isopropyl alcohol (1125 ml) and water (375 ml). Raised the temperature to reflux under stirring and maintained for 2.0 hours. Cooled the reaction mixture to 60°C and further charged with 3-acetyl- 2,5-dichlorothiophene (250 gm) followed by addition of 4M sodium hydroxide solution (770 ml) maintaining at 60-65°C. The mixture was again brought to reflux and maintained for 3.0 hours. Cooled the reaction mixture to 25-30°C, charged water (425 ml) and stirred for 30 minutes. Charged 2.25% sodium hypochlorite solution (250 ml) and stirred for 30 minutes. The solid mass obtained was filtered and washed with water followed by isopropyl alcohol, and dried at 50°C to get the product 3-acetyl-5-chloro-2- (benzylthio) thiophene till constant weight.
Yield = 354.00 gm % yield = 98.0%
Example 2: Preparation of 3-AcetyI -5-chloro-2-thiophenesulfonamide:
Charged 3-acetyl-5-chloro-2-(benzylthio) thiophene (200 gm) in mixture of ethyl acetate: water (4.40 ltr) and cooled under stirring to 0-5°C. The chlorine gas was bubbled under stirring maintaining the temperature range and monitoring the reaction on TLC for completion. After completion of the reaction, charged slowly ammonium hydroxide solution (500 ml). Reaction mixture was then stirred for 30 min. at 0-5°C and monitored for completion on TLC. Solvent was distilled out under reduced pressure below 60°C till complete removal of ethyl acetate. 1:1 Mixture of water and cyclohexane (800 ml) was then added to the reaction mixture and stirred at 25-30°C for 1 hour. The solid obtained after filtration was washed with water followed by cyclohexane and then dried at 50°C to get 3-acetyl-5-chloro-2-thiophenesulfonamide till constant weight.
Yield = 116.38 gm % yield = 68.5%
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Example 3: Preparation of 3-Bromoacetyl-5-chloro-2-thiophenesulfonamide:
Charged trimethylborate (125 ml) in premixed solution of 3-acetyl-5-chloro-2-thiophenesulfonamide (100 gm) and methanol (800 ml) at 25-30°C and stirred for 10 minutes. Cooled the reaction mixture to 0-5°C followed by slow addition of bromine (32.3 ml) maintaining the temperature at 0-\0°C. Reaction mixture was stirred at 0-10°C for 1.0 hour. Further raised the temperature of the reaction slowly to 25-30°C under constant stirring for 17-20 hours. Charged aqueous 20% sodium hydrogen sulfite solution (100 ml) to the reaction mixture and stirred at 25-30°C for 30 minutes. Then distilled out methanol completely under vacuum below 40°C. Charged water (700 ml) followed by 4M sulfuric acid solution (50 ml) to the reaction mixture and raised the temperature of the reaction mixture to 50-55°C for 1.5 hours. Cooled the reaction mixture to 25-30°C. Filtered the product 3-bromoacetyl-5-chloro-2-thiophenesulfonamide, washed with water till neutral pH. Dried the product at 50°C till constant weight. Yield- 127.00 gm % yield = 95.5% HPLC Purity = 95.44%, Dibromo = 2.3%
Example 4: 3-Bromoacetyl-5-chloro-2-thiophenesulfonamide:
Charged 3-acetyI-5-chIoro-2-thiophenesuIfonamide (100 gm) to the premixed reaction solution of dibromo dimethylhydantoin (70.44 gm) in ethyl acetate (5.00 ltr.) at 20-30°C and maintained under stirring for 1.0 hour. Cooled the reaction mixture to 0-5°C followed by addition of cone, sulfuric acid (100 ml) maintaining temperature at 0-5°C under stirring for 1.0 hour, the temperature is gradually raised to 20-25°C and maintained at.20-25°C for 15-18 hours, while monitoring the reaction for completion on HPLC. After completion of the reaction charged water (2.5 lit.) and stirred, separated the organic layer, washed with brine solution (4x1.0 lit.). Organic layer separated and dried over anhydrous sodium sulfate. Filtered and concentrated the solvent under reduced pressure below 50°C to get pale yellow colored solid residue. Charged methylene chloride (300 ml) at 25-30°C and stirred for 1.0 hour and cooled to 15-20°C. Maintained for 1.0 hour and filtered, washed with cold methylene chloride (2*75 ml). Dried the compound 3-bromoacetyl-5-chloro-2-thiophenesulfonamide at 30-35°C till constant weight.
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Yield = 125.00 gm
% yield = 94.0%
HPLC Purity = 95.60%, Dibromo - 2.7%
Example 5: (S)-3,4-Dihydro-6-chloro-4-hydroxy-4//-thieno[3,2-e]-l,2-thiazine 1,1-dioxide:
Charged under stirring 3-bromoaceryl-5-chloro-2-thiophenesulfbnamide (40 gm) in methyl /er/-butyl ether (720 ml). Cooled the reaction mixture to -30°C and charged solution of (+)-/?-chlorodiisopinocamphenylborane in hexane (140 ml) under nitrogen atmosphere. Maintained the reaction mixture at -25 to -20°C for 1.5 hour. The reaction mixture was then warmed to -20 to -15°C and charged cooled solution of 1 M aqueous sodium hydroxide (520 ml). The temperature of the reaction mixture was raised to 25-30°C and stirred vigorously for 2.0 hours. The separated aqueous layer was then acidified to pH=l using 12 M hydrochloric acid solution. The aqueous layer was further extracted twice with ethyl acetate (2*225 ml). The combined ethyl acetate extracts was washed with brine and dried over anhydrous sodium sulfate. Filtered the inorganic salt and concentrated the filtrate. Charged toluene (80 ml) and stirred at 25-30°C for 1.0 hour. Filtered the product and washed with toluene (50 ml) and methylene chloride (30 ml). Dried the compound (5)-3,4-dihydro-6-chloro-4-hydroxy-4//-thieno[3,2-e]-l,2-thiazine 1,1-dioxide in air at 25-35°C till constant weight.
Yield-25.10 gm % yield-80.0%
Example 6: (5)-3,4-Dihydro-6-chloro-4-hydroxy-2-(3-methoxypropyl)-4H-thieno [3,2-e]-l,2 -thiazine 1,1-dioxide:
Charged l-bromo-3-methoxypropane (3.83 gm) in the suspension of (S)-3,4-dihydro-6-chloro-4-hydroxy-4H-thieno [3,2-e]-l,2-thiazine 1.1-dioxide (5.0 gm), potassium carbonate (5.77 gm) and potassium iodide (0.69 gm) in acetone (35 ml). Raised the reaction temperature to 53-56°C and maintained for 12-15 hours at reflux. Reaction was monitored by TLC. After completion of the reaction, cooled the reaction mixture to 25-30°C and filtered. The residue was washed with acetone (25 ml). Filtrate was
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concentrated under vacuum, charged water (50 ml) to the residue and extracted with ethyl acetate (2*50 ml). Combined the ethyl acetate extracts and washed with 1 M aqueous sodium hydroxide (25 ml), followed by sodium hypochlorite solution (20 ml). Dried over anhydrous sodium sulfate, filtered, and concentrated the solvent to provide light-yellow (5)-3,4-dihydro-6-chloro-4-hydroxy-2-(3-methoxypropyl)-4//-thieno [3,2-e]-l,2-thiazine 1.1-dioxide.
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Yield = 5.50 gm %vield = 85.0%