Sign In to Follow Application
View All Documents & Correspondence

An Improved Process For Resolution Of Tamsulosin Using Binaphthyldiyl Phosphates (Bpa)

Abstract: The invention disclosed in this application relates to an improved process for the resolution of a racemic mixture of 5-[2-[2-ethoxyphenoxy) ethylamino] propyl]-2-methoxy benzene sulfonamide (tamsulosin) employing BPA either S or R form to obtain enantiomerically hoghly pure R and S-isomer

Get Free WhatsApp Updates!
Notices, Deadlines & Correspondence

Patent Information

Application #
Filing Date
07 October 2004
Publication Number
25/2007
Publication Type
INA
Invention Field
BIOTECHNOLOGY
Status
Email
Parent Application
Patent Number
Legal Status
Grant Date
2008-04-25
Renewal Date

Applicants

DIVI'S LABORATORIES LIMITED
7-1-77/E/1/303, DIVI TOWERS, DHARAM KARAN ROAD, AMEERPET, HYDERABAD - 500 016,

Inventors

1. BOLNENI NAGESWARA RAO
7-1-77/E/1/303, DIVI TOWERS, DHARAM KARAN ROAD, AMEERPET, HYDERABAD - 500 016,
2. MUTYALA KRISHNAJI RAO
7-1-77/E/1/303, DIVI TOWERS, DHARAM KARAN ROAD, AMEERPET, HYDERABAD - 500 016,
3. ALLUPATI PADMANAV PATRO
7-1-77/E/1/303, DIVI TOWERS, DHARAM KARAN ROAD, AMEERPET, HYDERABAD - 500 016,
4. AMBADIPUDI UDAYALAKSHMI
7-1-77/E/1/303, DIVI TOWERS, DHARAM KARAN ROAD, AMEERPET, HYDERABAD - 500 016,
5. MUTYALA VEERAIAH
7-1-77/E/1/303, DIVI TOWERS, DHARAM KARAN ROAD, AMEERPET, HYDERABAD - 500 016,
6. GUNDU RAO PADAKANDALA
7-1-77/E/1/303, DIVI TOWERS, DHARAM KARAN ROAD, AMEERPET, HYDERABAD - 500 016,

Specification

Filed of Invention: The invention relates to an improved process for the resolution of tamsulosin using binaphthyldiyl phosphates (bpa). The present invention particularly relates to an improved process of resolving a racemic mixture of 5-[2-[2-(2-ethoxyphenoxy) ethylamino] propyl]-2-methoxy benzene sulfonamide, commonly known as tamsulosin. Background The compound tamsulosin (structure- of the f9ormula I given below) is a new type of highly selective a -adrenoceptor antagonist, clinically useful for patients with urinary obstruction due to benign prostatic hyperplasia (BPH) and in cardiac insufficiency. The racemic compound and its applications are revealed in the European Patent no 0034432, US patent no 4373106 and US patent no 4868216. Although there is a chiral center in the molecule (indicated by *), in none of these patents there is any mention of the optical isomers. The US patent no 4772475 also claims a controlled release formulation using the racemic tamsulosin as the active ingredient. In all these patents only the tamsulosin hydrochloride salt has been considered for therapeutic applications. The compound should obviously exhibit two optical isomers but are not reported in any of these patents. The US application no 2003/0109752 and the WO- patent no 03/037850 reveal method of obtaining solid racemic tamsulosin base in two polymorphic forms. The US patent no 4703063 claims several "sulfamoyl-substituted phenethylamine derivatives" represented by a general formula in Claim 1 of the said Patent. The dependent claim 6 makes a general claim for racemic compounds of all the analogs of claim 1. Similarly claims 8 to 10 make general claim for all optically active compounds of claim 1. The claim 14 dependent on claim 1 spells out the chemical name of tamsulosin, without mentioning the optical isomer. This racemic compound is described in example 20 only as its hydrochloride. As per example 20 and the scheme of its preparation in column 26 of the body of the patent, this compound v^as prepared by a non-stereospecific route resulting in a racemic compound only. There is neither a method of resolution nor a stereospecific synthetic route described for any compound claimed in the said patent. The US patent no 4731478 claims the optical isomers of tamsulosin, biological activity of only the (-) isomeric form is revealed. The two Examples namely, 33 (a) and 33 (b) in this patent, describe a method of stereospecific synthesis of the optical isomers. The stereospecific synthesis consists of condensing a chirally active intermediate amine, (R ) (-) isomer as in Example 33 (a) or (S) (+) isomer as in Example 33 (b), with the achiral bromo intermediate to yield the corresponding chiral base and converting the same to its hydrochloride salt. Although the Example states that " crude crystals of (R) (-)-5'[2[2'(o-ethoxy phenoxy) ethylamino]-2-methylethyl]-2-methoxy benzene sulfonamide.... " this base was not characterized further but converted to its salt, namely the hydrochloride. The hydrochloride was characterized only with its melting point, elemental analysis and optical rotation. Although the claims are exclusively for the optically active tamsulosin base (not hydrochloride) and specifically for (-) isomer of tamsulosin base (not hydrochloride), there is neither an Example nor a process described for the preparation of the pure "optically active" tamsulosin base. No characteristics of the "optically active" tamsulosin base are given anywhere in this patent or related patents by the same inventors. Even the specific optical rotation of the claimed (-) tamsulosin free base is not recorded. It is therefore evident that the applicants of the said patent failed to actually isolate and characterize the pure free bases of the two enantiomers of tamsulosin. No process for resolution of the racemic tamsulosin has also been mentioned. No equivalent Indian patent could be located. The European Patent no 0257787 describes in Example 4 the preparation of (R) -tamsulosin by condensing the chiral intermediate R (-) 5-[(2-aminopropyl)-2-methoxy benzene sulfonamide, with the achiral intermediate 2-(2-ethoxyphenoxy)-ethyl bromide exactly as described in the US patent no 4731478 patent. The same stereospecific synthetic process is also claimed. However, there is no mention of any resolution process for the racemic compound. The US patent no 5391825 is similar to the US patent no 4731478 in several aspects. The Examples 33(a) and 33(b) in both these patents reveal a method of preparing the optically active isomers as hydrochlorides by synthesis using the appropriate chiral intermediate. However, the claims are limited to the achiral intermediate only. The US patent no 5447958 claims the (R) tamsulosin as a compound and its application in pharmaceutical compositions. The method of its preparation as hydrochloride is given in Example 33(a) by synthesis using the chiral interinediate as in other US patents cited earlier. No equivalent patents have been filed in India. The WO- patent no 03/035608 describes the same synthetic route to the (R) tamsulosin as hydrochloride, however by improved conditions of reaction. In none of these patents a resolution process for obtaining the required (R) isomer from its racemic form has been mentioned. In none of these patents characteristics of the free bases are mentioned. It is thus evident that the pure R & S isomers were never isolated by any of the earlier investigators. Although none of the patents mentioned above provide any biological data supporting the use of the (R) isomer in preference to the racemic form, the publication by Honda.K.and Nakagawa, C. in J.Pharm.Exp. Therap. 239, 512 (1986) suggests the advantage of (R) isomer over the (S) isomer and the racemic form of tamsulosin. The US patent application no 2003/0109752 and its co-application WO- patent no 03/037850 (PCT/NL02/00657) are the only filed applications for resolving a racemic mixture of tamsulosin base. The racemic free base may be obtained directly by synthesis or the racemic salt may be converted to free racemic base followed by partial purification as camphor sulfonate addition salt, which is enriched in the 'R'-isomer. The scheme is outlined in the Chart 1 shown below: Chart -I Racemijc tamsulosin h3rdrDchlonde salt T II + III ^^^^ Racemic tamsulosin free base N-PTiiif5ed solid racemic free base (I) CH-CH3X 1.30 - 1.33 (3H, t, -CH2 -CH3), 3.89 (3H, s, -OCH3X 4.15 - 4.36 (10 H, 4-CH2, -CH, -NH), 7.61 (2H, s, -NH2X 6.8 - 7.5 (7H, m, Ar-H). The ^^C - NMR spectrum exhibited signals as expected, in particular at 5 values: 56.34 (-OCH3), 14.93 (-OCH2CH3), 17.29 (-CH.CH3), 54.59 (-CH.CH3), 64.11 (-OCH2.CH3), 44.51 (-NH.CH2.CH2.CH2.O-X 67.25 (-NH.CH2.CH2.O-), 39.53 (-CH2.CH-), 165.35 (COOH oxalate). Element analysis: C=53.64 % (Calcd.53.49%), H=6.57% (Calcd.6.62%), N=5.89% (Calcd.5.95%) and S=6.58% (Calcd.6.79%) and corresponds to the hydrate, M.Wt. 471.53, C21H29N2O7S.H2O. The ES-mass spectrum signal at m/z = 409 corresponded to mass of free base. The XRD trace shows strong peaks at 2 theta values: 20.36, 22.33, 14.8, and 13.74 in that sequence as shown in Fig.2. The DSC thermogram of pure salt exhibited a sharp peak at 180.2°C as shown in Fig.3. These data confirm the structure of the oxalate salt of racemic tamsulosin. (b). Preparation of fumarate salt of tamsulosin: The fumarate sah of racemic tamsulosin was prepared in a similar manner as described in (a) above, by using 13.12 gm (0.2 eq) of fumaric acid in place of oxalic acid. The purified sah showed a melting range of 200 -202°C and a chemical purity (HPLC) of 98.89 %. (c). Preparation of maleate salt of racemic tamsulosin : The maleate salt of racemic tamsulosin was prepared in a similar manner as described in (a) above, by using 13.12 (0.5 gm) of maleic acid in place of oxalic acid and ethyl acetate in place of acetone. The purified sah showed a melting range of 155 - 159°C and a chemical purity (HPLC) of 98.5 %. (d). Preparation of salicylate salt of racemic tamsulosin: The salicylate salt of racemic tamsulosin was prepared in a similar maimer as described in (a) above, by using 32.48 gm (1.04 eq) of salicylic acid in place of oxalic acid and dichloromethane in place of acetone. The purified sah showed a melting range of 47 -52°C and a chemical purity (HPLC) of 98.41 %. (e). Preparation of tartrate salt of racemic tamsulosin: The tartrate salt of racemic tamsulosin was prepared in a similar manner as described in (a) above, by using 16.97 gm (0.5 eq) of (+) tartaric acid in place of oxalic acid and ethyl acetate in place of acetone. The purified salt showed a melting range of 197 -199°C and a chemical purity (HPLC) of 98.5 %. EXAMPLE -2 Resolution of oxalate salt of racemic tamsulosin with (S) - (+)-l,r-binaphthyl-2,2'-diyl hydrogen phosphate (S -BPA): (a) Preparation of R-tamsulosin-S-BPA salt: Racemic oxalate salt of tamsulosin (10 gm, 21.2 mmol) obtained by the process described in Example 1 and S-BPA (7.4 gm, 21.2 mmol) were taken in a mixture of acetone (331 mL) and water (15 mL). The mixture was stirred at 50 -55°C for 25 mins, cooled to 27 -30°C and stirred for 5 hrs. The R-tamsulosin-S-BPA sah formed was collected by filtration and washed with acetone (20 mL). The combined filtrate and washings were reserved for recovery of the S-isomer.( see step ( d) below) It was dried at 80°C for 2 hrs and then at 110°C for 5 hrs to afford 5 gm of (R ) -tamsulosin - (S)-BPA salt, exhibiting optical rotation, [af'^D = +268.33° (C = 0.35, methanol) and a chiral purity of 96.88 % R-isomer with 3.12 % of S-isomer (chiral HPLC) The infra red spectrum substantially corresponds to the structure of the diastereomeric R-tamsulosin S-BPA salt as shown in Fig.4. Its identity was proved by ^H-NMR, ^^C-NMR and ^^P-NMR spectra as shown in Fig.5. For further characterization of the salt the differential scanning calorimetry (DSC) and X-ray diffractogram have been recorded as shown in Fig.6 &7 respectively . The XRD trace indicates amorphous nature of the salt. (b). Conversion of R-tamsulosin -S-BPA salt to R-tamsulosin free base: R-Tamsulosin -S-BPA salt (5 gm) obtained by the process described in step (a) above was suspended in water (100 mL) an4 stirred for 10 mins at 25 - 30°C. The suspension was adjusted to pH 10.5 with 15 % aqueous ammonia solution and then stirred at 45 -50°C for 30 mins. After allowing the suspension to ambient temperature it was extracted with ethyl acetate (6 x 100 mL).The aqueous phase and water washings were combined and reserved for recovery of S-BPA. The combined extracts were washed with water (3 X 100 mL) then with brine solution (2 x 100 mL) and dried over anhydrous sodium sulphate. The dried extract (organic layer) was filtered and concentrated in vacuum to give solid material, which after drying at 50°C for 2 hrs yielded 2.45 gm (90.8%) of R-tamsulosin free base. It shows specific optical rotation of [af^u = -15.88° ±1° (C=0.35, methanol), 99.04 % ee of R-isomer by chiral HPLC and 99.56 area % chemical purity by HPLC. Pure R-isomer base obtained after conversion to hydrochloride salt and re-liberated by alkaline treatment shows m.p. 131-133°C. It was further characterized by elemental analysis : C = 58.86 % (Calcd.58.80%), H=6.89% (Calcd. 6.91 %), N =6.88 % (Calcd .6.86 %) and S=7.79 % (Calcd. 7.84 %) for C20H28N2O5S (Mol.wt: 408.51), infrared spectrum as shown in Fig.8, ^H-NMR and ^^C -NMR spectra as shown in Fig. 9 & 10, ES-Mass spectrum (M^ peak at m/z 409), DSC (Fig. 11) and XRD as shown in Fig. 12 traces. (c). Conversion of R-tamsulosin free base into (R ) - tamsulosin hydrochloride : (R ) - (-) -Tamsulosin free base (2.45 gm) obtained in step (b) above was taken in 70 mL methanol, heated to 45 °C under stirring. Then it was treated with methanolic hydrochloric acid. The acid solution was concentrated in vacuum and residue suspended in 30 mL acetone. The solid material was collected by filtration, washed with acetone and dried at 50°C for one hour to afford 2.6 gm (97.4 %) of tamsulosin hydrochloride comprising 98.76 % ee of R-isomer by HPLC, optical rotation [a]\ = -4.32° (C=0.35, methanol). On crystallization from methanol white crystalline solid of R-tamsulosin hydrochloride of 99.4 % ee of R-isomer (by chiral HPLC), 99.94 % (area %) chemical purity by HPLC, and mehing point: 231 - 233°C (DSC) was obtained. Its identity was established by ^H-NMR, ES-Mass and IR spectra. Its XRD trace exhibited intense peaks at 2 theta values 11.13°, 16.71° and 22.33° (in that sequence). (d). Isolation of S-tamsulosin Free base: 24 The filtrate set aside in step (a) above was freed from acetone in vacuum and the residue treated with water (100 mL). The pH of the mixture was adjusted to 10.5 with 15 % aqueous ammonia solution, heated at 45 - 50°C under stirring for 30 mins. After allowing the mixture to cool to ambient temperature, it was extracted with ethyl acetate (6 x 100 mL). The combined extracts were washed with water (3 x 100 mL). The aqueous layer and water washings were combined and reserved for recovery of S-BPA (see step (e) below ). The organic phase was then washed with brine solution (2 x 100 mL) and dried over anhydrous sodium sulfate. The dried extract was filtered and concentrated in vacuum to yield an off white solid which after drying at 50°C for 2 hrs afforded 4.9 gm of tamsulosin free base of 66.9 % ee of S-isomer (by chiral HPLC) and of 92.87 % D chemical purity (by HPLC, area %), melting range : 118-124°C, optical rotation : [a] = + 12.42° ± 1° (C=0.35, methanol). (e). Recovery of S-BPA from S-tamsulosin -S-BPA salt: The aqueous layer reserved in step (d) was taken and its pH adjusted to 2 with hydrochloric acid (100 mL). The mixture was stirred for 2 hrs at ambient temperature. Material formed was filtered and washed with water (75 mL). The off white material collected was dried at 60°C, to afford to 4.2 gm of S-BPA of optical rotation [a]^^D = +516.12° (C=1.35 methanol), melting point: > 300°C. In a similar manner fiimarate, maleate, salicylate and tartrate salts of racemic tamsulosin could be resolved using S-BPA as resolving agent, to obtain R-tamsulosin free base. EXAMPLE-3 Resolution of oxalate salt of racemic tamsulosin with R-BPA : (a). Preparation of S-tamsulosin -R-BPA salt: Racemic oxalate salt of tamsulosin (3.0 gm, 6.36 mmol) obtained by the process described in Example 1 and R-BPA (2.21 gm, 6.35 mmol) were taken in a mixture of acetone (110 mL) and water (5.8 mL). The mixture was stirred at 50 -55°C for 25 minutes then cooled to 27 - 30°C and stirred for 5 hrs. The formed salt was collected by filtration and washed with acetone (10 mL). The filtrate and washings were combined and reserved for recovery of R-tamsulosin.( see step (d) below ) The salt was dried at 80°C for 2 hrs and then at 110°C for 5 hrs to afford 1.5 gm (31 %) of S-tamsulosin -R-BPA sah of optical rotation [af^u = -270.16° (C=0.35, methanol). The sah was characterized by study of infrared spectrum as shown in Fig. 13 and ^H-NMR, *^C -NMR and "^'P-NMR spectra as also by DSC as shown in Fig. 14 and XRD as shovra in Fig. 15 traces. (b). Conversion of S-tamsulosin -R-BPA salt to S-tamsulosin free base : S-Tamsulosin -R-BPA saU (1 gm) obtained in step (a) above was suspended in water (20 mL) and stirred for 10 mins at 25 - 30°C. The suspension was adjusted to pH 10.5 with 15 % aqueous ammonia solution and then stirred at 45 - 50*^C for 30 mins. After allowing the suspension to ambient temperature it was extracted with ethyl acetate (6 X 20 mL). The extracts were washed with water (3 x 20 mL), then brine solution (2 x 20 mL). The organic solvent extracts were combined, dried over anhydrous sodium sulphate, filtered, concentrated in vacuum and the residue dried at 50°C for 2 hrs to afford to 0.49 gm (90.8 %) of S-tamsulosin fi-ee base of 99.06 % ee of S-isomer by chiral HPLC and m.p. 122 - 126°C. Pure S-isomer base obtained after conversion to hydrochloride and reliberation by alkaline treatment shows m.p. 126 -128°C and specific optical rotation [af^x^ = 13.77+ 1° (c=0.35 in MeOH). The S-tamsulosin free base was further characterized by its infra red spectrum as shown in Fig. 16, H-NMR, C - NMR and ES-mass spectra as also by DSC as shown in Fig. 17 and XRD as shown in Fig. 18 traces. (c). Conversion of S-tamsulosin free base to S-tamsulosin hydrochloride : Tamsulosin free base (0.385 gm) obtained step (b) above was taken into methanol (11 mL), heated to 45°C under stirring and treated with methanolic hydrochloride. The solution was concentrated in vacuum, the residue suspended in acetone (20 mL), filtered, washed with acetone and dried at 50°C for one hour to afford 0.325 gm (77.5 %) of S-tamsulosin hydrochloride of 99.03 % ee of S-isomer by chiral HPLC. After recrystallisation from methanol S-tamsulosin hydrochloride of 99.54 % ee could be obtained. Melting point: 228 - 230°C. The IR absorbance spectrum is shown in Fig. 19. (d). Recovery of R-tamsulosin free base : The filtrate set aside in step (a) was freed from acetone in vacuum and the residue was treated with water (60 mL). The mixture was adjusted to pH 10.5 with 15 % aqueous ammonia solution, and heated at 45 - 50°C under stirring for 30 mins. After allowing the mixture to ambient temperature, it was extracted with ethyl acetate (6 x 50 mL). The combined extracts were washed with water (3 x 50 mL), then with brine solution (2 x 50 mL). The filtrate and aqueous washings were combined and reserved for recovery of S-tamsulosin free base (see below). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residual off white solid material was dried at 50°C for 2 hrs to afford 1-.3 gm of enriched tamsulosin free base of 57.8 % ee of R-isomer (by chiral HPLC). Tamsulosin free base (0.5 gm) containing 57.8 % of R-isomer obtained as above was treated with same equivalent of S-BPA in acetone-water mixture and stirred for about 30 mins and cooled. The R-tamsulosin-S-BPA salt formed was collected by filtration and washed with acetone affording 0.35 gm (38%) of R-tamsulosin -S-BPA salt of optical rotation [a] D = +267.3° (C= 0.35, methanol). Then it was suspended in water, treated with 15 % aqueous ammonia to decompose the salt. The freed tamsulosin base was extracted with ethyl acetate, the extract washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to yield R-tamsulosin fi"ee base. The aqueous phases contain ammonium salts of S-BPA, suitable for recovery of S-BPA and recycling. Recovery of S-tamsulosin free base : The aqueous phase reserved in (d) above contains S-tamsulosin -S-BPA salt. It was treated with 15 % ammonia solution to adjust pH to about 10.5 and stirred for 30 mins at about 45°C. The mixture was cooled and extracted with ethyl acetate, the ethyl acetate extract was dried over anhydrous sodium sulfate, filtered and concentrated to recover of S-tamsulosin free base. Example -4 Resolution of racemic tamsulosin free base with S-BPA : (a). Preparation of R-tamsulosin -S-BPA salt: Racemic tamsulosin free base (5 gm, 12.2 mmol) and S-BPA (4.24 gm, 12.2 mmol) were taken in a mixture of acetone (194 mL) and water (6,3 mL). The mixture was stirred at 50 -55°C for 25 mins and the clear solution stirred at 25 - 30°C overnight. The formed sah was collected by filtration and washed with acetone (20 mL). The combined filtrate and washings was reserved for recovery of S-tamsulosin fi'ee base.(see step ( c ) below) The saU was dried at 80°C for 2 hrs and then at llO^C for 5 hrs to afford 3.9 gm (42.1 %) of R-tamsulosin -S-BPA salt with an optical rotation of [a]\ = + 267.5° (C = 0.35, methanol). (b). Conversion of R-tamsulosin -S-BPA salt to R-tamsulosin free base : R-Tamsulosin -S-BPA salt (3 gm) obtained in step (a) above was suspended in water 77 mL and stirred for 10 mins at 25 - 30°C. The suspension was adjusted to pH 10.5 with 15 % aqueous ammonia solution and then stirred at 50°C for 30 mins. After allowing the suspension to ambient temperature it was extracted with ethyl acetate (5 x 77 mL). The extracts were combined and washed with water (3 x 77 mL). The aqueous phase and washings were combined and reserved (See (c) below) for recovery of S-tamsulosin fi-ee base. The organic phase was washed with brine solution (2 x 77 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The solid residue was dried at 50°C for 2 hrs to afford 1.4 gm (86 %) of R-tamsulosin free base of 98.35 % ee of R-isomer. Melting point: 118 - 120°C, chemical purity 99.24 area %. (c). Recovery of S-tamsulosin free base: The filtrate set aside in the steps (a) & (b) above, was freed from remaining acetone in vacuum. The residue was adjusted to pH 10.5 with 15 % aqueous ammonia solution and heated at 45 - 50°C under stirring for 30 mins. After allowing the mixture to ambient temperature, it was extracted with ethyl acetate (5 x 100 mL). The combined extracts were washed with water (3 x 100 mL) and then with brine solution (2 x 100 mL). The organic layer was separated, dried over anhydrous sodium sulphate. The dried extract was filtered and concentrated in vacuum to give solid material. The off white solid material was collected and dried at 50°C for 2 hrs to afford 2.2 gm of tamsulosin free base containing 84.12 % ee of S-isomer by chiral HPLC (Fig.23) and chemical purity by HPLC of 98.17 area % (fig-24). Melting range: 120 - 124°C. EXAMPLE -5 Resolution of racemic tamsulosin free base with R-BPA: (a). Preparation of S-tamsulosin -R-BPA salt: Racemic tamsulosin free base (5 gm, 12.2 mmol) and R-BPA (4.24 gm, 12.2 mmol) were taken in a mixture of acetone (194 mL) and water (6.3 mL). The mixture was stirred at 50 -55°C for 25 mins and the clear solution stirred at 25 - 30°C ovemight. The formed salt was collected by filtration, washed with acetone (20 mL) and dried at 80°C for 2 hrs and then at 110°C for 5 hrs to afford 3.8 gm (41 %) of S-tamsulosin-R-BPA salt of optical rotation [a]\ : -265.9° C (C= 0.35, methanol). (b). Conversion of S-tamsulosin -R-BPA salt to S-tamsulosin free base : S-Tamsulosin -R-BPA salt (3 gm) obtained in step (a) above was suspended in water (77 mL) and stirred for 10 mins at 25 - 30°C. The suspension was adjusted to pH 10.5 with 15 % aqueous ammonia solution and then stirred at 50°C for 30 mins. After allowing the suspension to ambient temperature, it was extracted with ethyl acetate (5 x 77 mL). The combined extract was washed with water (3 x 77 mL) and then with brine solution (2 X 77 mL). The organic solvent extract was dried over anhydrous sodium sulphate, filtered and concentrated in vacuum. The residue was dried at 50°C for 2 hrs to afford 1.35 gm (83.4%) of S-tamsulosin free base of 98.1 % ee of S-isomer. (c). Conversion of S-tamsulosin free base to S-tamsulosin hydrochloride : S-Tamsulosin ft'ee base (1.35 gm) obtained in step (b) above was taken into methanol (52 mL) and treated with methanolic hydrochloric acid under stirring. The solution was concentrated in vacuum and residue suspended in acetone (19 mL). The solid material was collected by filtration, washed with acetone and dried at 50°C for one hour to afford 1.32 gm (89.8 %) of S-tamsulosin hydrochloride of ee 99.03 % and chemical purity of 99.54 %. Melting point of 229 - 231° C. EXAMPLE -6 Conversion of R -tamsulosin free base to R-tamsulosin salts: (a). R-Tamsulosin oxalate salt: (R ) -Tamsulosin free base (11 gm, 26.93 mmol) and acetone (85 mL) were taken and stirred at reflux temperature for 15 mins. In an another flask oxalic acid (1.68 gm, 13.33 mmol) and acetone (20 mL) were taken and stirred at reflux temperature to get clear solution. The oxalic acid solution was added slowly to the tamsulosin solution, stirred the mixture at reflux temperature for 20 mins, cooled slowly to room temperature and continued for 30 mins. The precipitate formed was filtered under vacuum and washed with acetone (20 mL), Off white solid material was collected and dried in hot air oven at 60*^C for 3 hrs to afford 11.3 gm of (R ) - tamsulosin oxalate sah with melting range 180 - 183.5°C, chemical purity by HPLC : 99.98% and 100 % of (R ) -tamsulosin oxalate salt (chiral HPLC). DSC : 178.8 - 180.3° (peak split); XRD : 20.3, 21.7, 23.0, 15.6,18.5,12.4, 26.4,17.9,12.7 & 16.5 (2 theta values in decreasing order of intensity). (b). R-Tamsulosin fumarate salt: (R ) -Tamsulosin free base (13 gm, 31.82 mmol) and acetone (371 mL) were taken and stirred at reflux temperature to get clear solution. Fumaric acid (1.85 gm, 15.94 mmol) was dissolved in acetone (520 mL) at reflux temperature, and added slowly into the solution of tamsulosin at 40 -45'^C. The mixture was stirred at reflux temperature for 20 mins, cooled to room temperature and stirred for 2 hrs. The precipitate formed was filtered under vacuum, washed with acetone (20 mL), the off white material collected, and dried in hot air oven for 3 hrs to afford 13.3 gm of (R) tamsulosin ftimarate sah. Melting range 191.6-194.2°C, chemical purity by HPLC: 96.24% and 100 % of (R) -tamsulosin fiimarate sah (chiral HPLC). DSC: 192.5° (sharp); XRD: 22.4, 15.3, 25.8, 19.1, 20.7, 10.3, 22.8, 11.5, 21.0, 12.3 (2 theta values in decreasing order of intensity). (c). R-Tamsulosin tnaleate salt: (R ) -Tamsulosin free base (12 gm, 29.383 mmol) was dissolved in ethyl acetate (514 mL) at reflux temperature. Maleic acid (1.7 gm, 14.65 mmol) was dissolved in ethyl acetate (257 mL) separately at reflux temperature, and added slowly to the solution of tamsulosin at 40 -45 °C. The mixture was stirred at reflux temperature for 20 mins, then cooled to room temperature and stirred for 2 hrs. The precipitate was filtered under vacuum, washed with ethyl acetate (20 mL) and the off white solid was collected and dried in hot air oven at 60°C for 3 hrs to afford 10 gm of (R ) -tamsulosin maleate salt. Melting range 128.4 - 131.3°C, and chemical purity by HPLC: 98.14 % and 100 % of (R) -tamsulosin maleate sah (chiral HPLC). DSC: 113.3 - 120.9° (peak 116.8°); XRD: 15.3, 23.9, 21.4, 18.6, 19.6, 23.1, 14.6 and 22.8 (2 theta values in decreasing order of intensity). (d). R-Tamsulosin tartrate salt: (R) -Tamsulosin free base (3.5 gm, 8.57 mmol) was dissolved in ethyl acetate (150mL) at reflux temperature. (+) -Tartaric acid (0.65 gm, 4.33 mmol) was dissolved in ethyl acetate (100 mL) separately at reflux temperature and added slowly to the solution of tamsulosin at 40 -45°C. The mixture was stirred at reflux temperature for 20 minutes, then cooled to room temperature and stirred for 2 hrs. The precipitate was filtered under vacuum, washed with ethyl acetate (15 mL), the off white sold collected and dried in hot air oven at 60°C to afford 3.3 gm of (R) - tamsulosin (+) -tartrate salt of melting range 179.5 - 182.7°C, chemical purity by HPLC : 99.93% and 100 % of (R) -tamsulosin (+) tartrate salt (chiral HPLC). DSC: 179-180.7^ (sharp); XRD: 14.9, 11.5,22.2,25.3,20.4, 19.3, 22.9, 20.1, 25.9 & 10.2 (2 theta values in decreasing order of intensity). Advantages of the present invention: • Resolution of racemic tamsulosin is achieved with high enantiomeric excess (ee) v^ith a single resolution. • Both racemic tamsulosin free base and its salts can be directly employed for resolution with either of the resolving agents. • The resolving agents are recoverable and reusable thereby making the process economical. • The chirally pure R or S tamsulosin free bases or their salts of greater than 99 % ee can be prepared for use in pharmaceutical compositions. • Higher purities of the hydrochloride salt are easily achieved from the free base of 99 % ee without fiirther purification. • The invention resuhs in novel isomers and their salts. We Claim: 1. An improved process for the resolution of racemic tamsulosin base of racemic tamsulosin and its pharmaceutically acceptable salts , which comprises (i). mixing the racemic mixture of tamsulosin base oroneof its salts and S (+)-binaphthyldiyl phosphate in equimolar proportions in an organic solvent or a mixture of an organic solvent and water, (ii) maintaining the resulting mixture at a temperature in the range of 20° to 60°C for a period in the range of 2 to 10 hours, (iii). filtering the solid R-tamsulosin-S- binaphthyldiyl phosphate salt formed, (iv). liberating the R-tamsulosin free base by basification and recovering the free tamsulosin base by filtration and extraction with organic solvents and if desired, (v). converting the R-tamsulosin so obtained to a pharmaceutically acceptable salt by conventional methods, (vi). recovering the S-tamsulosin or its salt from the filtrate obtained in step (iii) above and (vii). recovering the chiral resolving agent -(S)- binaphthyldiyl phosphate used in the process from the mother liquors obtained in steps (iv) or (vi) by conventional methods. 2. An improved process for the resolution of racemic tamsulosin base of racemic tamsulosin and its pharmaceutically acceptable salts , which comprises (i) mixing the racemic mixture of tamsulosin base or one of its salts and R-binaphthyldiyl phosphate in an organic solvent or a mixture of an organic solvent and water, (ii) maintaining the mixture at a temperature in the range of 20°C to 60°C for a period in the range of 2 to 10 hrs. (iii) filtering the solid S-tamsulosin-R- binaphthyldiyl phosphate sah formed and reserving the mother liquor by filtration and extraction with an organic solvent to recover R-tamsulosin free base by liberating from its salt by basification, filtration and extraction with an organic solvent and (i) if desired converting the solid S-tamsulosin-R- binaphthyldiyl phosphate salt so obtained to its pharmaceutically acceptable salts by conventional methods and (ii) recovering the resolving agent R-binaphthyldiyl phosphate by conventional methods. 3. An improved process as claimed in claim 1 wherein the base used in step (iv) for basification is selected from bases such as alkali hydroxides or carbonates , preferably ammonium hydroxide. 4. A process as claimed in claim 1 wherein the organic solvent used in step (i) or (a) is selected from ethers, esters, hydrocarbons and ketones preferably acetone. 5. A process as claimed in claims 1 & 2 wherein the organic solvent used for extraction in step (iv) (claim 1) or step (ii) (in claim 2) is selected from ethers, esters and hydrocarbons preferably ethyl acetate. 6. A process as in claims 1 & 2 wherein the racemic tamsulosin salt used is selected from the group oxalate, fumarate, maleate, salicylate or tartrate. 7. An improved process for the resolution of racemic tamsulosin base of racemic tamsulosin and its pharmaceutically acceptable salts substantially as herein described, with reference to the Examples.

Documents

Application Documents

# Name Date
1 1033-che-2004-abstract.pdf 2011-09-03
1 1033-che-2004-form 5.pdf 2011-09-03
2 1033-che-2004-claims.pdf 2011-09-03
2 1033-che-2004-form 3.pdf 2011-09-03
3 1033-che-2004-correspondnece-others.pdf 2011-09-03
3 1033-che-2004-form 19.pdf 2011-09-03
4 1033-che-2004-correspondnece-po.pdf 2011-09-03
4 1033-che-2004-form 1.pdf 2011-09-03
5 1033-che-2004-drawings.pdf 2011-09-03
5 1033-che-2004-description(complete).pdf 2011-09-03
6 1033-che-2004-description(complete).pdf 2011-09-03
6 1033-che-2004-drawings.pdf 2011-09-03
7 1033-che-2004-correspondnece-po.pdf 2011-09-03
7 1033-che-2004-form 1.pdf 2011-09-03
8 1033-che-2004-correspondnece-others.pdf 2011-09-03
8 1033-che-2004-form 19.pdf 2011-09-03
9 1033-che-2004-claims.pdf 2011-09-03
9 1033-che-2004-form 3.pdf 2011-09-03
10 1033-che-2004-form 5.pdf 2011-09-03
10 1033-che-2004-abstract.pdf 2011-09-03

ERegister / Renewals

3rd: 24 Jun 2008

From 07/10/2006 - To 07/10/2007

4th: 24 Jun 2008

From 07/10/2007 - To 07/10/2008

5th: 24 Jun 2008

From 07/10/2008 - To 07/10/2009

6th: 24 Jun 2008

From 07/10/2009 - To 07/10/2010

7th: 09 Mar 2009

From 07/10/2010 - To 07/10/2011

8th: 28 Jan 2011

From 07/10/2011 - To 07/10/2012

9th: 18 Jan 2012

From 07/10/2012 - To 07/10/2013

10th: 22 Jan 2013

From 07/10/2013 - To 07/10/2014

11th: 31 Jan 2014

From 07/10/2014 - To 07/10/2015

12th: 06 Apr 2015

From 07/10/2015 - To 07/10/2016