MX2007007923A - PROCESS FOR PREPARING 5,6-DIHYDRO-4-(S)-(ETHYLAMINO)-6-(S) METHYL-4H-THIENO[2,3b]THIOPYRAN-2-SULPHONAMIDE-7,7-DIOXIDE HCI. - Google Patents

Abstract

The present invention relates to an improved process for the preparation of 5,6-dihydro-4-(S)-(ethylamino)-6-(S)methyl-4H-thieno[2,3b]thiop yran-2-sulphonamide-7,7-dioxide hydrochloride of formula (I) commonly known as Dorzolamide Hydrochloride useful as an agent to reduce intraoccular pressure by inhibiting carbonic anhydrase enzyme.

Description

PROCEDURE FOR PREPARING CHLORHYDRATE OF 5.6-DIHYDRO-4- (S, -. ETHYLAMINO) -6- (S) METlL-4H-TIENO.2,3bl TIOPIRAN-2- SULFONAMIDE-7-DIOXIDE FIELD OF THE INVENTION The present invention relates to an improved process for the preparation of 5,6-dihydro-4- (S) - (ethylamino) -6- (S) methyl-4H-thieno [2,3b] thiopyran-2-hydrochloride. sulfonamide-7,7-dioxide, commonly known as dorzolamide hydrochloride. This compound is described in U.S. Patent 4,797,413 as an agent for reducing intraocular pressure by inhibiting the carbonic anhydrase enzyme.

NH " HCl SO? N ?? 0 O (0 BACKGROUND OF THE INVENTION A process for the preparation of dorzolamide hydrochloride and its derivatives is known. U.S. Patent 5,688,968 describes the preparation of dorzolamide hydrochloride from 5,6-dihydro-4- (S) -hydroxy-6- (S) -methyl-4H-thiopyran-7,7-chiral dioxide as illustrated in scheme 1.

SCHEME 1 The process described in EP 0 296 879 (equivalent of US 4,797,413) is of particular relevance. EP 0 296 879 describes the synthesis of dorzolamide hydrochloride starting from thiophene-2-thiol as illustrated in scheme 2 and 3 SCHEME 2 WILDEBEEST < 1) SCHEME 3 (I) The process described in EP 0,296,879 (Scheme 2) has the following disadvantages: (a) the thiophen-2-thiol starting material is unstable and undergoes oxidation to form disulfide, leading to a lower yield of xiii; (b) the yield of sulfonamide (xii) from sulfonic acid (c) is very poor (35%) and requires the use of 18-crown-6 ether, which is expensive; (c) the oxidation of alcohol (xiii) to sulfone is carried out using oxone which is expensive and dangerous; and the separation of the cis / trans isomer is carried out by column chromatography which is industrially inconvenient.

OBJECT OF THE INVENTION The object of the present invention is to provide an improved process for the commercial manufacture of 5,6-dihydro-4- (S) - (ethylamino) -6- (S) methyl-4H-thieno hydrochloride [2 , 3b] thiopyran-2-sulfonamide-7,7-dioxide commonly known as dorzolamide hydrochloride from stable 2-bromo thiophene. Another object of the present invention is to provide an improved process for the preparation of dorzolamide hydrochloride, which consumes less time and involves fewer steps and increases the efficiency of the product. Another object of the invention is to provide a process for the manufacture of dorzolamide hydrochloride, which avoids the use of an expensive catalyst.

Another object of the invention is to provide a method for the manufacture of dorzolamide hydrochloride, which avoids the use of expensive reagents.

Another object of the present invention is to provide a procedure for the manufacture of dorzolamide hydrochloride, which is industrially feasible.

BRIEF DESCRIPTION OF THE INVENTION | Accordingly, the present invention provides a process for preparing 5,6-dihydro-4- (S) - (ethylamino) -6- (S) methyl-4H-thieno [2,3b] thiopyran-2-sulfonamide hydrochloride. 7,7-dioxide of formula (I), NH KCl ( the process comprising (a) reacting the compound of formula II wherein X is halo with metal of magnesium and treat the Grignard reagent generated in an on-site solvent with sulfur, triethylamine hydrochloride, protonic acid and a suitable base to obtain the compound of formula III, p ni (b) reacting the compound of formula III with a chlorinating agent to obtain an acid chloride, followed by subjecting the acid chloride to cyclization in the presence of a Lewis acid to obtain a compound of formula IV; (c) reacting the compound of formula IV with a mixture of chlorosulfonic acid and a chlorinating agent to form a sulfonyl chloride of formula XX, extracting the sulfonyl chloride in a chlorinated solvent, washing with water, drying and evaporating the solvent chlorinated to obtain the compound of formula V, XX V (d) reducing the compound of formula V to obtain the compound of formula VI; VI (e) oxidizing the compound of formula VI to obtain the compound of formula Vile; vp (f) subjecting the compound of formula VII to a Ritter reaction to obtain the compound of formula VIII vrp (g) reducing the compound of formula VIII to obtain the compound of formula IX IX (h) converting the compound of formula IX to an acid addition salt thereof of formula XXI and recrystallizing the salt enriched from the solvent and then converting the salt of formula XXI to the compound of formula X X (i) reducing the compound of formula X in the compound of formula (I). In one embodiment of the invention, in step (a), the organic solvent is selected from the group consisting of ethers, cyclic ethers and aromatic hydrocarbon. In another embodiment of the invention, the organic solvent used in step (a) is tetrahydrofuran. In still another embodiment of the invention, step (a) is carried out in the presence of a base selected from the group consisting of organic alkylamine and pyridine.

In a further embodiment of the invention, the base is trialkylamine. In a preferred embodiment, the base is triethylamine. In another embodiment of the invention, in the compound of formula II, X is a halo selected from the group consisting of Cl, Br, and I. In another embodiment of the invention, step (a) is carried out at a temperature on the scale from 0o to 70 ° C. In another embodiment of the invention, in step (b), the organic solvent is a non-polar aprotic solvent. In another embodiment of the invention, the non-polar aprotic solvent used is a chlorinated solvent such as MDC. In another embodiment of the invention, the Lewis acid is selected from the group consisting of AICI3, ZnCl2 and SnCl4 and more preferably SnCl4. In another embodiment of the invention, the sulfonyl chloride of formula XX is dissolved in an organic solvent selected from the group consisting of ether and ketone. In a further embodiment of the invention, the organic solvent is tetrahydrofuran. In another embodiment of the invention, the sulfonyl chloride of formula XX is dissolved in an organic solvent and then treated with ammonia followed by chlorination with a chlorinating agent selected from the group consisting of POCI3, PCI5, PCI3, SOCI2 and more preferably SOCI2 and in presence of a chlorinating solvent selected from the group consisting of CHCl3, MDC, and EDC, preferably MDC. In another embodiment of the invention, in step (d) the reduction is carried out using sodium borohydride in the presence of a solvent and at a temperature in the range of 0 ° C to 40 ° C. In still another embodiment of the invention, the solvent is an inferred aliphatic alcohol and more preferably methanol. In another embodiment of the invention, in step (e) the compound of formula VI is oxidized with sodium perborate in the presence of acetic acid at 20 ° C to 70 ° C. In another embodiment of the invention in step (f) the Ritter reaction of the compound of formula VII is carried out in a strong acid with acetonitrile at 10 ° C to 40 ° C. In a further embodiment of the invention, the strong acid is selected from the group consisting of sulfuric acid and a mixture of concentrated sulfuric acid and fuming sulfuric acid. In another embodiment of the invention, in the vessel (g), the reduction is effected using borane dimethisulfide complex in an organic solvent selected from ether and cyclic ether. In a further embodiment of the invention, the organic solvent used in step (g) is tetrahydrofuran. In another embodiment of the invention, in step (h), the organic solvent is selected from the group consisting of an acetone, an ester, a bipolar aprotic solvent, lower aliphatic alcohol, aliphatic hydrocarbon and aromatic hydrocarbon. In a further embodiment of the invention, the ester is ethyl acetate. In a further embodiment of the invention, the salt used for the formation of salt in step (h) is a mineral acid selected from the group consisting of HCl, H2SO4l HNO3, and HBr more preferably HCl dissolved in a lower aliphatic alcohol. In a further embodiment of the invention, the acid used for the formation desired in step (h) is ethanolic HCl. In one embodiment of the invention, the organic solvent used for recrystallization is selected from the group consisting of an acetone, an ester, a bipolar aprotic solvent, lower aliphatic alcohol, aliphatic hydrocarbon or aromatic hydrocarbon, preferably an ester, lower aliphatic alcohol or mixtures of these, more preferably ethyl acetate, ethanol or mixtures thereof. In a further embodiment of the invention, the compound of formula X is reduced using di-p-toluyl-L-tartarate and di-p-toluyl-D-tartarate.

DETAILED DESCRIPTION OF THE INVENTION The invention provides a process for preparing 5,6-dihydro-4- (S) - (ethylamine) -6- (S) methyl-4H-thieno [2,3b] thiopyran-2-sulfonamide hydrochloride-7,7- dioxide of formula (I), comprising nine steps, as illustrated in scheme 4 below: SCHEME 4 Step 1: Preparation of the compound of formula III when reacting the compound of formula II with magnesium metal followed by the treatment of the Grignard reagent thus generated in a solvent in place with sulfur, hydrochloride of triethylamine, protonic acid and a suitable base at 0 ° C to 70 ° C as shown in Scheme 5.

SCHEME 5 ? v Base M XV I I I Li! X of formula II is a -Cl, -Br, -I preferably -Br. The organic solvents are ethers, cyclic ethers and aromatic hydrocarbon but preferably cyclic ethers and more preferably THF. The base is an organic alkylamine or pyridine, preferably trialkylamine and more preferably triethylamine.

Step II Preparation of compound IV by reacting the compound of formula III with chlorinating agent followed by the cyclisation of acid chloride of formula XIX generated on site in the presence of Lewis acid in a solvent at 0 ° C to 40 ° C as shown in scheme 6.

SCHEME 6 The organic solvents are non-polar aprotic solvents, preferably chlorinated solvents and more preferably MDC. The Lewis acids are AICI3, ZnCl2, SnCl and more preferably SnCl.

Step III: Preparation of the compound of formula V by reacting the compound of formula IV with the mixture of chlorosulfonic acid and chlorinating agent at -10 ° C to 10 ° C, extracting the thus formed sulfonyl chloride of formula XX in a solvent chlorinated, wash with water, dry and evaporate the chlorinated solvent. Dissolve the sulfonyl chloride of formula XX in suitable organic solvents followed by treatment with ammonia as shown in scheme 7.

SCHEME 7 IV XX V The chlorinating agent is selected from POCI3, PCI5, PCI3, SCOI2 and more preferably SOCI2. The chlorinating solvents are preferably selected from CHCl3, MDC, and EDC, more preferably MDC. The organic solvent for dissolving sulfonyl chloride is an ether or an acetone, preferably ether and more preferably THF.

Step IV Preparation of the compound of formula VI by reducing the compound of formula V with sodium borohydride in the presence of solvent at 0 ° C to 40 ° C as found in scheme 8.

SCHEME 8 V VI The organic solvent is lower aliphatic alcohol and more preferably methanol.

Step V: Preparation of the compound of formula VII by oxidizing the compound of formula VI with sodium perborate in the presence of acetic acid at 20 ° C to 70 ° C as shown in scheme 9.

SCHEME 9 vi vp Step VI: Preparation of the compound of formula VIII by Ritter reaction of the compound of formula VII in strong acid with acetonitrile at 10 ° C to 40 ° C as found in scheme 10.

SCHEME 10 Strong acids are concentrated sulfuric acid or a mixture of concentrated sulfuric acid or a mixture of concentrated sulfuric acid and fuming sulfuric acid.

Step VII: Preparation of the compound of formula IX by reducing the compound of formula VIII with borane dimethisulfide complex in organic solvents as shown in scheme 11.

SCHEME 11 VIII LX The organic solvents are ethers, cyclic ethers, preferably cyclic ethers and more preferably THF.

Step VIII Preparation of the compound of formula X by converting the compound of formula IX to its acid addition salt in a solvent followed by recrystallization of the salt enriched from an organic solvent or a mixture of solvents as shown in scheme 12. The organic solvent is a ketone, an ester, a dipolar aprotic solvent, lower aliphatic alcohol, aliphatic hydrocarbon or aromatic hydrocarbon, preferably an ester and more preferably ethyl acetate. The acid used for the formation of the salt is a mineral acid like HCl, H2SO, HNO3, HBr more preferably HCl dissolved in lower aliphatic alcohol preferably ethanol. The acid used for salt formation is more preferably ethanolic HCl. The organic solvent for recrystallization is a ketone, an ester, a dipolar aprotic solvent, lower aliphatic alcohol, aliphatic hydrocarbon or aromatic hydrocarbon, preferably an ester, lower aliphatic alcohol or mixtures thereof, more preferably ethyl acetate, ethanol or mixtures thereof. these.

SCHEME 12 X xxi Step IX Preparation of a compound of formula I by reduction of the compound of formula X using di-p-toluyl-L-tartarate and di-p-toluyl-D-tartarate. The process of making Dorzolamide hydrochloride by the present invention comprises the use of 2-bromo thiophene as a starting material, avoiding the use of unstable thiophen-2-thiol. The process of the said invention requires a smaller number of steps since the sulfonamide of formula IV is prepared directly from the compound of formula III avoiding the isolation of sulfonic acid X. This eliminates the use of an expensive catalyst. The process of the invention utilizes cheap sodium perborate and commercially available as an oxidizing agent, thus making the process more economical. The process of said invention makes use of the formation of hydrochloride salt as a means to separate the cis: trans isomer thus avoiding the industrially inconvenient column chromatography.

Experiments EXAMPLE 1 Preparation of (RS) - (2-mercaptothiophene) butanic acid (III) To a mechanically stirred mixture of magnesium swarf (20 gm, 0.833 mole) in THF (700 ml), iodine crystal and 2-bromo thiophene (II) (5.0 gm 0.0305 mole) were added to initiate the reaction. Once the reaction started, 2-bromo thiophene (95 gm 0.58 mol) was added to maintain reflux which was then continued for 2 hours and then cooled to 45 ° C. Then sulfur (19.66 gm, 0.614 mole) was added maintaining the temperature below 50 ° C and stirring continued for 2 hours. Then triethylamine hydrochloride (84 gm, 0.611 moles) was added at 45 ° C and stirring was continued for 1 hour. A mixture of triethylamine (80 gm, 0.79 mole) and protonic acid (63 gm 0.733 mole) in THF (200 ml) was then added at 45 ° C. The mixture was refluxed for 18 to 20 hours. The pH was adjusted to 2 to 2.5 by 6 N HCl at 0o at 15 ° C. The compound of formula (III) was extracted with MDC and concentrated to dryness to give the title compound (123 gm, 100%). 1 H NMR (CDC123) d 1.35 (d, 3 H, J = 6.9 Hz, CH 3), 2.48 (dd, 1 H, J = 8.0 J = 16.1 Hz, CH 2) 2.77 (dd, 1 H, J = 16.1 Hz, CH 2 ) 3.36-3.42 (m, 1 H, CH) 7.03 (dd, 1 H, J = 3.4 J = 5.3 Hz, 3-H) 7.20 (dd, 1 H, J = 1.2 J = 3.4 Hz, 4-H) 7.43 (dd, 1 H, J = 1.2 Hz, J = 5.3 Hz, 2-H) EXAMPLE 2 Preparation of 5,6-dihydro-4H-6-methylthienor-2,3-bltiopyran-4-one (IV) To a solution of the product from example 1 (123 gm 0.609 5 mmol) in MDC (1845 ml) and DMF (10 ml) was added thionyl chloride (54.35 ml, 0.73 mol) dropwise and the mixture was stirred at room temperature. Reflux 37 to 40 ° C for 2 hours. The mixture was cooled to -10 ° C and a solution of SnCl (39.12 ml, 0.33 mol) in MDC was added dropwise maintaining the * temperature below 0 ° C. The reaction was stirred at 0 ° C for 1 hour and Then it was added dropwise (500 ml) keeping the temperature below 10 ° C. The layers separated. The aqueous phase was extracted with MDC and the organic layers were washed with water followed by saturated bicarbonate solution, finally with brine. The MDC layer was then stirred with silica gel (100 gm), filtered and washed by MDC. The organic layer was dried with 15 anhydrous sodium sulfate. Finally the organic layer was completely concentrated to obtain the title compound (91 mg, 81.1%) 1 H NMR (CDCl 3) d 1: 48 (d, 3 H, J = 6.9 Hz, CH 3) 2.69 (dd, 1 H, J = 11.4 J = 16.8 Hz, CH2) 2.88 (dd, 1 H, J = 3.2 J = 16.8 Hz, CH2) 3.80 (t, 1 H, CH) 7.01 (d, 1 H, J = 5.5 Hz, 3-H) 7.46 (d, 1 H, j = 5.5 Hz, 2-H).

EXAMPLE 3 Preparation of 5,6-dihydro-4-HI-6-methylthienof2,3-b-thiopyran-4-one-2-sulfonamide (V) To a stirred solution of chlorosulfonic acid (196.9 ml, 2.96 moles), thionyl chloride (71.67 ml, 0.987 moles) is slowly added at a temperature of 0 ° C to 10 ° C. The mixture was stirred at 30 ° C to 32 ° C for 3 hours and then cooled to 0 ° C. The compound prepared in Example 2 (91 gm, 0.494 moles) was added slowly at room temperature. 0 ° C to 5 ° C. The mixture was then stirred at a temperature of 0 to 5 ° C for one hour and the temperature was then raised to 25 to 30 ° C and maintained for 5 to 10 hours. MDC (1000 ml) was then added and the reaction mass was quenched using 700 gm of ice below the temperature of 20 ° C. The lower organic layer was separated. The aqueous layer was extracted with MDC and mixed with the main organic layer which was washed with cold water. The organic layer was concentrated to obtain a sticky mass (130 gm) which was then dissolved in THF (100 ml), to which was added (150 ml) cold liquid ammonia liquor. This was stirred for two hours and water with ice (2000 ml) was added. This was then stirred for 3 hours and filtered and washed with water, and dried to obtain the title compound (V) (65 gm, 50%). 1H NMR (DMSO d-6) d 1.51 (d, 3H, J = 6.9Hz, CH3) 2.70 (dd, 1 H, J = 11.4 J = 16.8Hz, CH2) 2.93 (dd, 1 H, J = 3.2 J = 16.8Hz, CH2) 3.80-4.0 (bm, 1 H, CH) 4.62-4.80 (bm, 1 H, CH) 7.32 (bs, 2H, NH2) 7.84 (d, 1 H, J = 5.5Hz, 3- H) EXAMPLE 4 Preparation of 5,6 dichidro ^ H ^ -hydroxy-β-methylthienor- ^ - bltiopyran ^ -sulfonamide (VI) To a suspension of the product of Example 3 (65 gm, 0.247 mol) in methanol (455 ml) was added sodium borohydride (7.03 gm, 0.185 mol) and the resulting mixture was stirred for 2 hours at 25 to 30 ° C. The methanol was concentrated from the reaction mixture to obtain a sticky mass. Water (1000 ml) was added to the sticky mass and the mixture was stirred for 0.5 hrs and the pH adjusted to 6.5 to 7.0 by acetic acid. The stirring was then carried out for 1 hour at 20 to 25 ° C: The product obtained was filtered and washed with water. The cake was sucked to remove as much water as possible and dried to obtain the title compound (64.4 gm, 99%).

EXAMPLE 5 Preparation of 5,6-dihydro-4H-4-hydroxy-6-methyl-triene-2,3-bltiopyran-2-sulfonamide-7,7-dioxide (VII) To a product suspension of example 4 (64.4 gm, 0.242 mole) in acetic acid (320 ml) sodium perborate (83.48 gm, 0.545 mole) was added and the resulting mixture was stirred for one hour at 25 to 30 ° C, then heated to a temperature of 60 to 65 ° C and kept for 3 hours. The acetic acid was concentrated from the reaction mixture to obtain a sticky mass, which was dissolved in water (400 ml). The product was extracted with ethyl acetate, The organic layer was concentrated to maintain the inner volume 100 ml and then cooled to 0 to 5 ° C and stirred for 2 hours. The product was filtered and washed with chilled ethyl acetate. The cake was sucked off to remove as much ethyl acetate as possible and dried to obtain the title compound (55 gm, 76.27%). H NMR (DMSO d-6) d 1.49 (d, 3 H, CH 3) 2.42 (m, 2 H, CH 2) 3.55 (m, 1 H, 6-H) 4.60-4.90 (m, 1 H, 4-H) 7.51 (bs, 2H, NH2) 7.69 (bs, 1 H.3-H) EXAMPLE 6 Preparation of 5,6-dichidro-4H-4-acetylamino-6-metitienor-2,3-bltiopyran-2-sulfonamide-7,7-dioxide (HIV) A solution of the product of example 5 (55 gm, 0.185 mol) in acetonitrile (715 ml) was cooled to 0 to 5 ° C and sulfuric acid (167.5 ° C, 3.144 mol) was added dropwise maintaining the temperature 0 to 5 ° C. The temperature was allowed to rise to 25 to 30 ° C. The mixture was stirred for 25 to 27 hrs. The reaction mixture was added to the mixture of water and ethyl acetate below 5 ° C and the pH of the reaction mixture was adjusted to 7.5 by a 50% solution of sodium hydroxide. The sodium sulfate salt was filtered and washed with ethyl acetate. The organic layer was separated. The aqueous layer is extracted with ethyl acetate. The organic layer was concentrated to obtain a sticky mass as the title compound (VIII) (50 gm, 91.6%). 1 H NMR (DMSO d-6) d 1.47 (d, 3 H, CH 3) 1.96 & 2.01 (s, 3H each, COCH3) 2.30-2.60 (m, 2H, CH2) 3.70-3.85 (m, 1 H.CH) 5.20-5.30 (m, 1 H, CH) 7.44 & 7.88 (s, 2H, NH2) 7.59 (s, 1 H, 3-H).

EXAMPLE 7 Preparation of 5,6-hydro-4H-4-ethylamino-6-methyl-triene-2,3-bl thiopyran-2-sulfonamide-7,7-dioxide (IIX) To a solution of borane dimethyl sulphide complex (52.59 ml, 0.546 moles) and THF (108 ml) the product of example 6 (50 gm, 0.148 moles) in THF (80 moles) was added at 0 to 5 ° C. The temperature was allowed to rise to 25 to 30 ° C and the mixture was stirred for 10 hours. The reaction mixture was added to 1 N sulfuric acid (190 ml) at 0 to 5 ° C and stirred for 1 hour. The pH was adjusted to 7 with a 50% sodium hydroxide solution and stirred for one hour and then the product was extracted with ethyl acetate. The ethyl acetate layer was concentrated to obtain a sticky mass as the compound of Title (1 X) (39.5 gm, 82.41%) EXAMPLE 8 Preparation of Trans 5.6 dichydro-4H-4-ethylamino-6-methylthienor-2,3-b] thiopyran-2-sulfonamide-7,7 dioxide (X) A product solution of Example 7 (39.5 gm, 0.132 mol) in ethyl acetate (426 ml) was cooled to 0 to 5 ° C and ethanolic HCl (20 ml) was added and stirred for 3 hours at 0 ° C. at 5 ° C. The product was precipitated, filtered and washed with cooled ethyl acetate. The cake was sucked to remove as much methyl acetate as possible and dried to obtain the compound (21 gm). The product was suspended in ethyl acetate (210 ml), refluxed for 1 hour, then cooled to 10 ° C. The product was filtered and washed with chilled ethyl acetate. The cake was suctioned to remove as much ethyl acetate as possible and dried to the hydrochloride salt of the title compound (18 gm). The salt then reacted with the saturated sodium bicarbonate solution and the mixture was extracted with ethyl acetate. The organic extract was dried, filtered and concentrated to dryness to generate the title compound (X) (15 gm, 37.98%).

EXAMPLE 9 Preparation of hydrochloride of 5, dihydro-4H-4- (S) -ethylamino-6- (S) -methyl-ene [2,3-b1-thiopyran-2-sulfonamide-7,7-dioxide (I) A mixture of the compound of example 8 (15 gm 0.0465 moles) and di-p-toluyl-D-tartaric acid monohydrate (4.55 gm, 0.01125 moles) in n-propanol (1600 ml) was heated to boiling and the hot solution filtered with pad with filter aid with carbon layer. The filtrate was concentrated by boiling to a volume of about (400 ml) and allowed to crystallize. After resting the next day the crystals were filtered and removed and the material crystallized twice more from n-propanol (400 ml) to generate a 2: 1 salt of free base to acid. The combined mother liquors of this crystallization were stored for stage B. The salt was then treated with a saturated solution of sodium bicarbonate and the mixture extracted with ethyl acetate. The organic extract was dried, filtered and concentrated dry to generate (3.2 gm) of free base. The hydrochloride salt was prepared from 5.6 N HCl ethanol and crystallized from methanol-sopropanol to generate (2.83 gm) of (+) isomer, SOR 8.23 (C 0.9 methanol) M.P. 2.83-2.85 ° C. The combined mother liquor treated with a saturated solution of sodium bicarbonate and the mixture extracted with ethyl acetate. The organic extracts were dried, filtered and concentrated to dryness. The residue treated with di-p-toluyl-D-tartaric acid monohydrate (4.55 gm, 0.01125 mol) in n-propanol (1600 ml) and separated isomer with the procedure described above to give the compound of title (I) (3.75 gm, 22.48%) SOR = -8.34 (C1, methanol) M.P. 283 to 285 ° C.

Claims (34)

NOVELTY OF THE INVENTION CLAIMS

1. - A process for preparing 5,6-dihydro-4- (S) - (ethylamino) -6- (S) methyl-4H-thieno [2,3b] thiopyran-2-sulfonamide-7,7-dioxide hydrochloride formula (I) NH 0) the process comprises (a) reacting the compound of formula II wherein X is halo with magnesium metal and treating the Grignard reagent generated in a solvent in situ with sulfur, triethylamine hydrochloride, crotonic acid and a suitable base for obtain the compound of formula III p (b) reacting the compound of formula III with a chlorinating agent to obtain an acid chloride, followed by subjecting the acid chloride to cyclization in the presence of a Lewis acid to obtain a compound of formula IV; (c) reacting the compound of formula IV with a mixture of acid chlorosulfonic acid and a chlorinating agent to form a sulfonyl chloride of formula XX, extract the sulfonyl chloride in a chlorinated solvent, wash with water, dry and evaporate the chlorinated solvent to obtain the compound of formula V SCYNH. (d) reducing the compound of formula V to obtain the compound of formula SOJNH, VI (e) oxidizing the compound of formula VI to obtain the compound of formula Vile; Vü (f) subjecting the compound of formula VII to a Ritter reaction to obtain the compound of formula VIII (g) reducing the compound of formula VIII to obtain the compound of formula IX (h) converting the compound of formula IX to the acid addition salt thereof of formula XXI and recrystallizing the enriched salt from a solvent and then converting the salt of formula XXI to the compound of formula X X (i) reducing the compound of formula X in the compound of formula I.

2. - The process according to claim 1, further characterized in that in step (a), the organic solvent is selects from the group consisting of ethers, cyclic ethers and hydrocarbon aromatic.

3. - The process according to claim 1, further characterized in that the organic solvent used in step (a) is tetrahydrofuran.

4. The method according to claim 1, further characterized in that step (a) is carried out in the presence of a base selected from the group consisting of organic alkylamine and pyridine.

5. - The method according to claim 1, further characterized in that the base is trialkylamine.

6. The method according to claim 1, further characterized because the base is triethylamine.

7. The method according to claim 1, further characterized in that in the compound of formula II X is a halo selected from the group consisting of Cl, Br and I.

8. - The method according to claim 1, further characterized in that step (a) is carried out at a temperature in the range from 0 ° C to 70 ° C.

9. The process according to claim 1, further characterized in that in step (b) the organic solvent is a non-polar aprotic solvent.

10. The method according to claim 9, further characterized in that the non-polar aprotic solvent used is a chlorinated solvent.

11. The process according to claim 10, further characterized in that the chlorinated solvent is MDC.

12. The process according to claim 1, further characterized in that the Lewis acid in step (b) is selected from the group consisting of AICI3, AnCI2 and SnCl.

13. The process according to claim 1, further characterized in that the Lewis acid in step (b) is SnCl.

14. The process according to claim 1, further characterized in that the sulfonyl chloride of formula XX is dissolved in step (c) in an organic solvent selected from the group consisting of ether and ketone.

15. The process according to claim 1, used in step (c), further characterized in that the organic solvent is tetrahydrofuran.

16. The process according to claim 1, further characterized in that in step (c) the sulfonyl chloride of formula XX is dissolved in an organic solvent and then treated with ammonia followed by chlorination with a chlorinating agent selected from the group which consists of POCI3, PCI5, PCI3 and SOCI2 and in the presence of a chlorination solvent selected from the group consisting of CHCI3, MDC, and EDC.

17. The method according to claim 16, further characterized in that the chlorinating agent is SOCI2.

18. The process according to claim 16, further characterized in that the chlorination solvent is MDC.

19. The process according to claim 1, further characterized in that in step (d) the reduction is carried out using sodium borohydride in the presence of a solvent and at a temperature in the range of 0 ° C to 40 ° C.

20. The process according to claim 19, further characterized in that the solvent is a lower aliphatic alcohol.

21. The process according to claim 20, further characterized in that the lower aliphatic alcohol is methanol.

22. The process according to claim 1, further characterized in that in step (c) the compound of formula VI is oxidized with sodium perborate in the presence of acetic acid at 20 ° C to 70 ° C.

23. The method according to claim 1, further characterized in that in step (f) the Ritter reaction of the compound of formula VII is carried out in a strong acid with acetonitrile at 10 ° C to 40 ° C.

24. The process according to claim 23, further characterized in that the strong acid is selected from the group consisting of sulfuric acid and a mixture of concentrated sulfuric acid and fuming sulfuric acid.

25. The process according to claim 1, further characterized in that in step (g), the reduction is carried out using borane dimethisulfide complex in an organic solvent selected from ether and cyclic ether.

26. The process according to claim 1, further characterized in that the organic solvent used in step (g) is tetrahydrofuran.

27. The process according to claim 1, further characterized in that in step (h), the organic solvent is selected from the group consisting of a ketone, an ester, a dipolar aprotic solvent, lower aliphatic alcohol, aliphatic hydrocarbon and aromatic hydrocarbon.

28. The process according to claim 27, further characterized in that the ester is ethyl acetate.

29. The process according to claim 1, further characterized in that the acid used for the formation of salt in the step (h) is a mineral acid selected from the group consisting of HCl, H2SO4, HNO3, and HBr dissolved in a lower aliphatic alcohol.

30. The process according to claim 29, further characterized in that the acid is ethanolic HCl.

31. The process according to claim 1, further characterized in that the organic solvent used for recrystallization in step (h) is selected from the group consisting of a ketone, an ester, a dipolar aprotic solvent, lower aliphatic alcohol, hydrocarbon aliphatic and aromatic hydrocarbon.

32. The process according to claim 31, further characterized in that the organic solvent is selected from an ester, lower aliphatic alcohol and mixtures thereof.

33. The process according to claim 32, further characterized in that the organic solvent is selected from ethyl acetate, ethanol and mixtures thereof.

34. The process according to claim 1, further characterized in that the compound of formula X is reduced using di-p-toluyl-L-tartarate and di-p-toluyl-D-tartarate.