Novel polymorphic form of Tiotropium Bromide
Field of the invention
The present invention relates to a simple and efficient method for the preparation of stable anhydrous form B of substantially pure (1a,2p,4β,5a,7β)-7-[(hydroxydi-2-thienylacteyl)oxy]-9,9-dimethyl-3-oxa-9-azaniatricyclo[3.3.1.02'4] nonane-bromide i.e. Tiotropium bromide having Formula I, with a purity level of 99.99% and which is substantially free of other impurity.

Background of the invention
Tiotropium bromide is highly effective antichlorinegic and therefore has therapeutic benefit against COPD (chronic obstructive pulmonary diseases) or asthma. It is best used as inhalant and packed as powder in capsule or used as aerosol with propellant gas.
US5610163 (EP418716) first time disclosed a method for synthesis of Tiotropium bromide (Scheme I) which comprises;
Scheme I


the reaction of Scopine with methyl dithienyl glycolate in presence of sodium as base to give scopine dithienyl glycolate which is further reacted with methyl bromide in anhydrous methylene chloride to get Tiotropium bromide.
US6747153 disclosed a process for the preparation of tiotropium bromide (Scheme II)
wherein compound of Formula V or its acid addition salt or hydrates thereof is reacted with formamide-acetal of Formula VI to give compound of Formula VII which on further decarboxylation gives ester of Formula VIII which is reacted with methyl-di-(2-thienyl) glycolate of Formula III to give tropenol ester of formula IX which is epoxidised to give scopine of Formula IV which is quaternized to give desired product of Formula I.
US6747154 discloses a process for the preparation of tiotropium bromide by condensation of quaternary Scopine derivative with methyl dithenylglycolate (Scheme III)

US66110849 discloses a process for the preparation of tiotropium bromide going1 through tropenol intermediate (Scheme IV) *


wherein compound of Formula X is reduced to form acid addition salt of compound of Formula XII using Zn in presence of activating metal salt preferred iron or copper salts and further reacted with formula III to give tropenol ester of formula IV, which can be oxidized to give formula IV which on further quarternisation give Tiotropium bromide of Formula I.
Tiotropium bromide is known to exist in anhydrous form disclosed in US6608055, US2005143410, US2006246009, WO2006117299, CN1634921 and US6777423, US6908928, CN1733761, US2004002510, US2007015785 disclosing the monohydrate form.
The monohydrate can be prepared form the anhydrous form by dissolving it in the suitable solvent thereof at elevated temperature.
The aim of the present invention is to provide new anhydrous form of tiotropium bromide and an alternative method for preparing the same which is simple, non-aggressive and can be used for commercial manufacture of tiotropium bromide.
Detail description of the drawing
Figure I: XRPD of crystalline anhydrous Tiotropium bromide before micronisation.
Detail description of the invention
The present invention relates to a stable anhydrous form B of tiotropium bromide and the substantially free of other impurities.
The present invention also provides a method for manufacturing the said anhydrous form B of tiotropium bromide which process can be best illustrated by the scheme V given below.


which process comprises
• conversion of scopine hydrochloride to scopine free base with suitable base in suitable
solvent
• condensation of the scopine free base with methyl di (2-thienyl) glycolate in presence of sodium metal to give Scopine di-(2-thienyl) glycolate
• quaternization of Scopine di-(2-thienyl) glycolate with appropriate quaternising agent like alkyl halide in a suitable solvent to give Tiotropium Bromide (Crude).
• recrystallization in methanol to give Tiotropium Bromide.
The process wherein the free base formation of scopine hydrochloride is carried out in the presence of suitable base such as ammonia in gaseous or liquid state, most preferably ammonia in gaseous form.
The condensation of scopine free base with di(2-thienyl)glycolate is carried out in the presence of base selected from a group consisting of sodium metal, sodium methylate, sodium ethylate, sodium hydride and as such being used as catalyst, most preferably sodium metal.
The process wherein the condensation is carried out in the presence of solvent selected from a group consisting oPfrom toluene, xylene or heptane, most preferably toluene. *

The process wherein the recrystallisation of scopine dithienyl glycolate is carried out in the presence of solvent selected from a group consisting of water, methanol, toluene or acetonitrile, most preferably being water.
The process wherein the quarternisation is carried out in the presence of alky 1 halide preferably methyl bromide.
The process wherein the quarternisation to give crude tiotropium bromide is carried out in the presence of solvent selected from dimethylformamide, acetonitrile or methylene chloride most preferably dimethylformamide.
The process wherein the recrystallisation of crude tiotropium bromide is carried out in the presence of solvent selected from a group consisting of methanol, ethanol or propanol and most preferably methanol.
The present invention also provides a pharmaceutically acceptable active ingredient which is substantially pure of the impurity with a purity level of 99.99% and impurity level of less than 0.1%.
The impurity being the unreacted starting material as Scopine dithienyl glycolate of formula IV
and the side product of formula XIII a dimer of methyl dithienyl glycolate namely 2-oxo-l,l-dithiophen-2-ylpropyl hydroxy(dithiophen-2-yl)acetate and preparation thereof which comprises

• Refluxing Methyl di-(2-thienyl)-glycolate in toluene in the presence of sodium methoxide for 4-5hrs
• Distilling of the toluene layer
• and isolation of the desired product.

The tiotropium bromide obtained from the process explained above is of anhydrous form has a moisture content of less than 0.5%, with essentials bands of IR as shown in table I

The X-ray structural analysis carried out showed that the crystalline anhydrous tiotropium bromide form B has a simple monoclinic cell structure with the following dimensions a=17.99746A, b=11.281470A, c=15.218900A, α=90°, (3=104.74°, γ=90°and V=2987.536A3.
Anhydrous polymorphic form B of Tiotropium bromide which can be characterised by the XRD peaks at 8.71,11.67,12.92,13.94,15.5,16.4,17.16,19.44, 20.16,21.71, 23.27, 24.05,24.68 and 25.25.
The examples are provided to illustrate particular aspects of the disclosure and do not limit the scope of the present invention as defined by the claims.
EXAMPLE Example 1: Preparation of tiotropium bromide
Step I: Preparation of scopine free base
To scopine hydrochloride (250gm) in toluene (750mL) was added gaseous ammonia and the pH was adjusted to 9-10 and the reaction mass was stirred at 25-30°C for 2 hrs. The reaction mass was filtered and the filtrate was distilled off to obtain the title compound.
Step,2: Preparation of Scopine di-(2-thienyi) glycolate.

To the scopine free base obtained form the step I above in toluene (750.0mL) was added methyl di-(2-thienyl)-glycolate (50.0gm) and the reaction mixture was stirred for complete dissolution. Further sodium metal was added into the reaction mass in two lots (5.13gm) at 80-90°C and simultaneously the toluene layer was distill off, the reaction mass was cooled to 45-50°C and stirred till complete distillation of the excess toluene. The reaction mass was swapped with methanol, the methanol layer was distilled off, the reaction mass was cool and taken in demineralised water (188mL) and stirred for 2 hrs at 25-30°C. The product thus obtained was filtered off under vacuum. The wet cake was dissolved in a mixture of methylene chloride (940mL) and demineralised water (940 mL) and the pH of the reaction mixture was adjusted to 2.0 with hydrochloric acid and the reaction mass was stirred for 2 hrs for complete precipitation. The compound thus isolated was filtered and the layers were separated. The aqueous layer and the compound isolated above were taken in methylene chloride and the pH was adjusted to 7.0-8.0 with saturated sodium carbonated solution. The two layers were separated and the organic layer was given carbon treatment and filtered. The filtrate was distilled off and the reaction mass was swapped with methanol. The methanol layer was distilled off and the compound was taken in demineralised water, stirred for 2 hrs, filtered and dried until the moisture content was less than 0.5%. (Weight: 112.00g, Yield: 40%)
Step 3: Quaternization of Scopine di-(2-thienyl) glycolate
The compound obtained from the step 2 above was taken in dimethylformamide and stirred for complete dissolution at 25-30°C, followed by the addition of methyl bromide and stirring was continued for 48hrs at 25-30°C. 200-250mL of the solvent was distilled off under vacuum the reaction mass was cooled to 15-20°C to form the product. The crystals were filtered and washed with chilled dimethylformamide and acetonitrile. The compound was dried until the moisture content was less than 0.5% (Weight: 98.9g, Yield: 80%)
Step 4: Recrystallization of crude tiotropium bromide
The compound (98.9g) obtained form the step 3 above was taken in methanol (lOOOmL) and
stirred at 55-60° until complete dissolution, the reaction mass was treated with activated
carbon, filtered and 750-800mL of the filtrate was distilled at 40°C. The reaction mixture was
cooled to 5-10°C and stirred for 2 hrs at the same temperature, filtered and dried for 24hrs
under vacuum to obtain the title compound. (Weight: 74.0g. Yield: 740%. HPLC nuritv:
99.93%)

Example 2: Preparation of \(2.2-dithiophen-2-vlpropanoyl) oxyl(dithiophen-2-yl)acetic acid
To methyl di-(2-thienyl)-glycolate (5.0gm) in toluene (250mL) was added sodium metal (0.45g) at 80°C and the reaction mixture was stirred for 4 hrs at the same temperature. The reaction mixture was cooled and filtered. The filtrate was distilled off to obtain the compound. (Yield: 4.0g)

CLAIMS
1. Substantially pure anhydrous form B of tiotropium bromide with a purity of 99.9% with an impurity level less than 0.1%.
2. Anhydrous crystalline form B of tiotropium bromide having a monoclinic crystal lattice with the parameters as a=17.99746A, b=l 1.281470A, c=15.218900A, α=90°, β=104.74°,γ=90° and V=2987.536A3 as determined by X-ray structural analysis.
3. Anhydrous crystalline form B of tiotropium bromide characterised by XRD having following peaks 8.71,11.67,12.92,13.94,15.5,16.4,17.16,19.44,20.16,21.71,23.27, 24.05,24.68 and 25.25 at ± 0.20.
4. A process for preparing the crystallographically pure anhydrous Form B of (la,2P,4p,5a,7β)-7-[(hydroxydi-2-thienylacteyl)oxy]-9,9-dimethyl-3-oxa-9-azaniatricyclo[3.3.1.02,4]nonane-bromide which comprises:

• conversion of scopine hydrochloride to scopine free base with suitable base in suitable solvent
• condensation of the scopine free base with methyl di-(2-thienyl) glycolate in presence of sodium metal to give Scopine di-(2-thienyl) glycolate
• quaternization of Scopine di-(2-thienyl) glycolate with appropriate quaternising agent in a suitable solvent to give Tiotropium Bromide (Crude)
• recrystallization in methanol to get anhydrous polymorphic form B of tiotropium bromide.

5. The process according to claim 4, wherein the scopine hydrochloride is converted to free base in the presence of suitable base selected from ammonia in gaseous and liquid form, most preferably ammonia gas.
6. The process according to claim 4, wherein the condensation is carried out in the presence of suitable base selected from a group comprising of sodium metal, sodium methylate, sodium ethylate and sodium hydride, most preferably sodium metal.
7. The process according to claim 4, wherein the condensation is carried out in the presence of solvent selected from a group comprising of toluene, xylene and heptane most preferably toluene.
8. The process according to claim 4, wherein the recrystallistaion of Scopine dithienyl glycolate is carried out in the presence of solvent selected from a group comprising of water, methanol, toluene and acetonitrile most preferably water.

9. The process according to claim 4, wherein the quarternisation of Scopine dithienyl glycolate is carried in the presence of alkylating agent such as methyl bromide.
10. The process according to claim 4, wherein the quaternization of Scopine dithienyl glycolate is carried in the presence of suitable solvent selected from a group comprising of dimethylformamide, acetonitrile and methylene chloride most preferably dimethylformamide.
11. The process according to claim 4, wherein the recrystallistaion of scopine dithienyl glycolate is carried out in the presence of solvent selected a group comprising of from methanol, ethanol and propanol.
12. A compound of Formula XIII
13. A process for making the compound of Formula XIII which comprises

• Refluxing Methyl di-(2-thienyl)-glycolate in toluene in the presence of sodium methoxide for 4-5hrs
• distilling of the toluene layer
• and isolation of the desired product.