CLIAMS:1. A process for preparing 1-Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-1-(3-phenoxypropyl)-, bromide, (3R)- (Formula-I) comprising

Formula-I
(a) Reacting Methyl hydroxy (dithiophen-2-yl) acetate with (3R)-1-azabicyclo[2.2.2]octan-3-ol in presence of metalalkoxide and solvent;
(b) Isolating (R)-1-azabicyclo[2.2.2]oct-3-ylhydroxy(dithiophen-2-yl)acetate;
(c) Reacting 1-azabicyclo[2.2.2]oct-3-ylhydroxy(dithiophen-2-yl)acetate with 1-bromo phenoxy propane in presence of mixture of polar-aprotic solvent and non-polar solvent and
(d) Isolating 1-Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-1-(3-phenoxypropyl)-, bromide, (3R)-.

2. The process according to claim 1, where in the metalalkoxide is sodium methoxide.

3. The process according to claim 1, wherein the solvent is selected from linear or cyclo alkane.

4. The process according to claim 3, wherein the linear or cycloalkane solvent is selected from pentane, hexane, heptane, cyclopentane, cyclohexane,cycloheptane.

5. A process for purification of 1-Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-1-(3¬phenoxypropyl)-, bromide, (3R)- comprising;
(a) Dissolving 1-Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-1-(3¬phenoxypropyl)-, bromide, (3R)- in a first solvent with heating;
(b) Treating with charcoal;
(c) Precipitating with second solvent with cooling and
(d) Isolating 1-¬Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-1-(3¬phenoxypropyl)-, bromide, (3R)-.

6. The process according to claim 5, wherein the first solvent and second solvent may be same or different.

7. The process according to claim 5, wherein the first solvent and second solvent are selected from the group consisting of polar aprotic solvent such as dimethylformamide, acetone, acetonitrile, dimethyl sulfoxide, ethyl acetate, tetrahydrofuran, dimethylacetate and polar protic solvent such as methanol, ethanol, nitromethane, isopropanol, n-butanol, formic acid, Acetic acid, Water.

8. A process for preparing crystalline form-I of 1-Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-1-(3¬phenoxypropyl)-, bromide, (3R)- comprising;
(a) Dissolving 1-Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-1-(3- phenoxypropyl)-, bromide, (3R)- in a first solvent with heating;
(b) Treating with charcoal;
(c) Precipitating with a second solvent with cooling and
(d) Isolating pure 1-Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-1-(3¬phenoxypropyl)-, bromide, (3R)-.

9. The process according to claim 8, wherein the first solvent and second solvent may be same or different.

10. The process according to claim 8, wherein the first solvent and second solvent are selected from the group consisting of polar aprotic solvent such as dimethylformamide, acetone, acetonitrile,dimethyl sulfoxide, ethyl acetate, tetrahydrofuran, dimethylacetate and polar protic solvent such as methanol, ethanol, nitromethane, isopropanol, n-butanol, formic acid, Acetic acid, Water.

11. The process according to claim 8, wherein the temperature for step (a) and step (c) is 60-80° C and 0-5° C respectively.

12. A novel crystalline form-I of 1-Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-1-(3-phenoxypropyl)-, bromide, (3R)- .

13. The crystalline form-I according to claim 12, characterized by XPRD pattern with at least one characteristic peak (expressed in 2?) at 7.88, 13.28, 13.95, 14.03, 20.77, 21.09, 23.34, 24.49, 25.97, 26.37, 29.49, 31.21±0.2.
14. A process for preparing impurity - S-isomer of 1-azabicyclo[2.2.2]oct-3-ylhydroxy(dithiophen-2-yl)acetate and 1-Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-1-(3¬phenoxypropyl)-, bromide, (3R)- (Formula-VII & VI) comprising

Formula-VI Formula-VII
(a) Reacting Methyl hydroxy (dithiophen-2-yl) acetate with (3S)-1-azabicyclo[2.2.2]octan-3-ol in presence of metalalkoxide and solvent;
(b) Distilling solvent and degassing completely and
(c) Isolating intermediate- (S)-1-azabicyclo[2.2.2]oct-3-ylhydroxy(dithiophen-2-yl)acetate;
(d) Reacting (S)-1-azabicyclo[2.2.2]oct-3-ylhydroxy(dithiophen-2-yl)acetate with 1-bromo phenoxy propane in presence of mixture of polar-aprotic solvent and non-polar solvent and
(e) Isolating impurity S-isomer of 1-Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-1-(3¬phenoxypropyl)-, bromide, (3R)- .

15. The process according to claim 14, where in the metalalkoxide is sodium methoxide.

16. The process according to claim 14, wherein the solvent is selected from linear or cyclo alkane.

17. The process according to claim 14, wherein the linear or cycloalkane solvent is selected from pentane, hexane, heptane, cyclopentane, cyclohexane,cycloheptane.

18. The process according to any of the preceding claims, wherein the purity ofMethyl hydroxy (dithiophen-2-yl) acetate and 1-Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-1-(3¬phenoxypropyl)-, bromide, (3R)- is 99.82% and more than 99.9% respectively. ,TagSPECI:FORM 2
THE PATENTS ACT 1970
(39 of 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule13)
1. TITLE OF THE INVENTION:

“An advantageous process for preparing 1-Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-1-(3¬phenoxypropyl)-, bromide, (3R)- and its novel crystalline form-I”

2. APPLICANT:

(a) NAME: HARMAN FINOCHEM LIMITED

(b) NATIONALITY: Indian Company incorporated under the Indian
Companies Act, 1956

(c) ADDRESS: 107, Vinay Bhavya Complex, 159–A , C.S.T. Road, Kalina,
Mumbai - 400098, Maharashtra, India.

3. PREAMBLE TO THE DESCRIPTION:
The following specification particularly describes the invention and the manner in which it is to be performed:

FIELD OF INVENTION:
The present invention relates to an industrially feasible process for preparation of 1-Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-1-(3¬phenoxypropyl)-, bromide, (3R)- and its novel crystalline form-I.

BACKGROUND OF INVENTION:
1-¬Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-1-(3¬phenoxypropyl)-, bromide, (3R)- , quaternary ammonium compound, is s an anticholinergic agent with specificity for muscarinic receptors and prescribed for treatment for chronic obstructive pulmonary disease (COPD).

Formula-I
1-Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-1-(3-phenoxypropyl)-, bromide, (3R)- is marketed under the trade namesTudorzaPressair in the US, EkliraGenuair in the UK, and TudorzaGenuair in Canada, licensed to Menarini under the brand name BretarisGenuair for majority of EU member states.
PCT application WO 01/04118 A2, US patents US 6,750,226 B2 and US 7,109,210 B2 disclose 1-Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-1-(3-phenoxypropyl)-, bromide, (3R)- and its pharmaceutically acceptable anion of a mono or polyvalent acid and also discloses process for preparing the same as depicted in scheme-I.

Scheme-1
Prior arts WO 01/04118 A2, US patents US 6,750,226 B2 and US 7,109,210 B2 describes the process for preparing (Furan-2-yl)hydroxyphenylacetic acid 1-azabicyclo[2.2.2]oct-3(R)-yl Ester and 3(R)-(2-Furan-2-yl-2-hydroxy-2-phenyl acetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane, Bromide in methods c and a which are similar derivatives of (R)-1-azabicyclo[2.2.2]oct-3-ylhydroxy(dithiophen-2-yl)acetate and 1-Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-1-(3-phenoxypropyl)-, bromide, (3R)-. In US’226, example- 37 describes the process for preparing 1-Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-1-(3-phenoxypropyl)-, bromide, (3R)- according to methods c and a.

Prior art methods a and c are depicted in scheme- I a.

Scheme-I a

According to method c, reaction of (Furan-2-yl)-hydroxy-phenylacetic acid methyl ester with 3-(R)-hydroxy-1-azabicyclo[2.2.2]octane in presence of sodium hydride (60% dispersion in mineral oil), toluene to obtain mixture of diasteroisomers which is further crystallized about four times with acetonitrile to get pure (Furan-2-yl)hydroxyphenylacetic acid 1-azabicyclo[2.2.2]oct-3(R)-yl ester is described.

The major drawback of the said process involves in the use of highly flammable and hazardous compounds like sodium hydride (60% dispersion in mineral oil). NaH is very difficult and impractical to handle at industrial scale due to its high flammable nature. Moreover it is insoluble in organic solvent. Because of the insolubility of NaH, all reactions involving NaH occur at the surface of the solid. This results in lower yield and purity.
Another drawback of the prior art process is that it involves four time crystallization to get pure (Furan-2-yl)hydroxyphenylacetic acid 1-azabicyclo[2.2.2]oct-3(R)-yl Ester which makes the process costly, time consuming, tedious and lengthy. Moreover the four time crystallization also results mixture of diastereomers and thus affects the yield of 1-Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-1-(3-phenoxypropyl)-, bromide, (3R)- and hence this process is commercially not viable.

According to method a, reaction of (Furan-2-yl)hydroxyphenylacetic acid 1-azabicyclo[2.2.2]oct-3(R)-yl Ester with 3-phenoxy propyl bromide in presence of mixture of acetonitrile and chloroform to yield 3(R)-(2-Furan-2-yl-2-hydroxy-2-phenyl acetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane, Bromide as a mixture of diastereomers.

In the light of the above drawbacks, there is a need in the art to provide cost-effective, safe and commercially viable process for preparing 1-Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-1-(3-phenoxypropyl)-, bromide, (3R)- and novel crystalline form.

The main object of the present invention is to provide a process that does not involve highly flammable compounds which are difficult to handle. The process disclosed in the current invention involves cheaper reactants, solvents as compared to prior art which makes the process cost effective. More over the process does not involve more than one time purification and the purification process does not involve any costly technique/equipment, however, carried out with solvents which are industrially feasible. Due to less crystallization steps and higher solubility of reactants in organic solvents the present invention results in the product with higher yield and purity over prior art.

SUMMARY OF THE INVENTION:
The present invention provides the process for preparation of 1-Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-1-(3-phenoxypropyl)-, bromide, (3R)- (Formula-I) and its novel crystalline form-I.

Formula-I
In one aspect, the present invention describes the process for purification of intermediate methyl hydroxyl (dithiophen-2-yl) acetate which comprises;
(a) Dissolving methyl hydroxy (dithiophen-2-yl) acetate in non-polar solvent under heating;
(b) Treating with charcoal;
(c) Precipitating with non-polar solvent and
(d) Isolating pure methyl hydroxyl (dithiophen-2-yl) acetate.
In another aspect, the instant invention discloses the process for preparing (R)-1-azabicyclo[2.2.2]oct-3-ylhydroxy(dithiophen-2-yl)acetate from Methyl hydroxy (dithiophen-2-yl) acetate which comprises;
(a) Reacting Methyl hydroxy (dithiophen-2-yl) acetate with (3R)-1-azabicyclo[2.2.2]octan-3-ol in presence of metal alkoxide and solvent;
(b) Distilling solvent and degassing completely and
(c) Isolating (R)-1-azabicyclo[2.2.2]oct-3-ylhydroxy(dithiophen-2-yl)acetate.
In a further aspect, the present invention discloses the process for preparing 1-Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-1-(3-phenoxypropyl)-, bromide, (3R)- from (R)-1-azabicyclo[2.2.2]oct-3-ylhydroxy(dithiophen-2-yl)acetate which comprises,
(a) Reacting 1-azabicyclo[2.2.2]oct-3-ylhydroxy(dithiophen-2-yl)acetate with 1-bromo phenoxy propane in presence of mixture of polar-aprotic solvent and non-polar solvent and
(b) Isolating 1-Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-1-(3-phenoxypropyl)-, bromide, (3R)-.
In one another embodiment the present invention provides the process for purification of 1-Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-1-(3-phenoxypropyl)-, bromide, (3R)- which comprises;
(a) Dissolving 1-Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-1-(3-phenoxypropyl)-, bromide, (3R)- in polar aprotic solvent with heating;
(b) Treating with charcoal;
(c) Precipitating with polar aprotic solvent with cooling and
(d) Isolating 1-Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-1-(3-phenoxypropyl)-, bromide, (3R)- .
In one another aspect, the instant invention provides process for purification of 1-Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-1-(3-phenoxypropyl)-, bromide, (3R)- which comprises;
(a) Dissolving 1-Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-1-(3-phenoxypropyl)-, bromide, (3R)- in polar aprotic solvent with heating;
(b) Treating with charcoal;
(c) Precipitating with polar protic solvent with cooling and
(d) Isolating pure 1-Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-1-(3-phenoxypropyl)-, bromide, (3R)-.
In one another embodiment the instant invention provides process for purification of 1-Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-1-(3-phenoxypropyl)-, bromide, (3R)- which comprises;
(a) Dissolving 1-Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-1-(3-phenoxypropyl)-, bromide, (3R)- in polar protic solvent with heating;
(b) Treating with charcoal;
(c) cooling and
(d) Isolating pure 1-Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-1-(3-phenoxypropyl)-, bromide, (3R)-.
The invention further encompasses a novel crystalline form, which is designated herein below as Form-1 and process for preparation thereof.
Accordingly, in one aspect, the present invention provides the process for preparing novel crystalline form-I of 1-Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-1-(3-phenoxypropyl)-, bromide, (3R)- which comprises;
(a) Dissolving 1-Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-1-(3-phenoxypropyl)-, bromide, (3R)- in polar aprotic solvent with heating;
(b) Treating with charcoal;
(c) Precipitating with polar aprotic solvent with cooling and
(d) Isolating 1--Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-1-(3-phenoxypropyl)-, bromide, (3R)-.
In one another embodiment the instant invention provides process for preparing novel crystalline form-I of 1-Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-1-(3-phenoxypropyl)-, bromide, (3R)- which comprises;
(a) Dissolving 1-Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-1-(3-phenoxypropyl)-, bromide, (3R)- in polar aprotic solvent with heating;
(b) Treating with charcoal;
(c) Precipitating with polar protic solvent with cooling and
(d) Isolating pure 1-Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-1-(3-phenoxypropyl)-, bromide, (3R)-.
In one another embodiment the instant invention provides process for preparing novel crystalline form-I of 1-Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-1-(3-phenoxypropyl)-, bromide, (3R)- which comprises;
(a) Dissolving 1-Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-1-(3-phenoxypropyl)-, bromide, (3R)- in polar protic solvent with heating;
(b) Treating with charcoal;
(c) cooling and
(d) Isolating pure 1-Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-1-(3-phenoxypropyl)-, bromide, (3R)-.
In one aspect the present invention discloses the process for preparing impurity, i.e. s-isomer of 1-Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-1-(3-phenoxypropyl)-, bromide, (3R)- (formula-VI) and its intermediate- (S)-1-azabicyclo[2.2.2]oct-3-ylhydroxy(dithiophen-2-yl) (formula-VII) which comprises;

Formula-VI Formula-VII
(a) Reacting Methyl hydroxy (dithiophen-2-yl) acetate with (3S)-1-azabicyclo[2.2.2]octan-3-ol in presence of metalalkoxide and solvent;
(b) Distilling solvent and degassing completely and
(c) Isolating intermediate- (S)-1-azabicyclo[2.2.2]oct-3-ylhydroxy(dithiophen-2-yl)acetate;
(d) Reacting (S)-1-azabicyclo[2.2.2]oct-3-ylhydroxy(dithiophen-2-yl)acetate with 1-bromo phenoxy propane in presence of mixture of polar-aprotic solvent and non-polar solvent and
(e) Isolating impurity S-isomer of 1-Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-1-(3-phenoxypropyl)-, bromide, (3R)-.

BRIEF DESCRIPTION OF FIGURES:
Fig.1 shows the XPRD pattern of 1-Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-1-(3-phenoxypropyl)-, bromide, (3R)- crystalline form-I in Methanol, prepared as per example 17

Fig.2 shows the XPRD pattern of 1-Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-1-(3-phenoxypropyl)-, bromide, (3R)- crystalline form-I in DMF/IPA prepared as per example 15

Fig.3 shows the XPRD pattern of 1-Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-1-(3-phenoxypropyl)-, bromide, (3R)- crystalline form-I in DMF/Acetone prepared as per example 12
Fig.4 shows the XPRD pattern of 1-Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-1-(3-phenoxypropyl)-, bromide, (3R)- crystalline form-I in DMAc/Acetone prepared as per example 14

Fig.5 shows the XPRD pattern of 1-Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-1-(3-phenoxypropyl)-, bromide, (3R)- crystalline form-I in EA/Methanolprepared as per example 13

Fig.6 shows the XPRD pattern of 1-Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-1-(3-phenoxypropyl)-, bromide, (3R)- crystalline form-I in DMSO/Acetoneprepared as per example 16

DETAILED DESCRIPTION OF THE INVENTION:
The instant invention provides an efficient, advantageous and economical process for preparing 1-Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-1-(3-phenoxypropyl)-, bromide, (3R)- (Formula-I)and its novel crystalline form-I.

Formula-I
In one embodiment, the present invention describes the process for purification of intermediate methyl hydroxyl (dithiophen-2-yl) acetatewhich comprises;
(a) Dissolving methyl hydroxyl (dithiophen-2-yl) acetate in non-polar solvent underheating;
(b) Treating with charcoal ;
(c) Precipitating with non-polar solvent and
(d) Isolating pure methyl hydroxyl (dithiophen-2-yl) acetate.
Accordingly, the non-polar solvent is selected from the group consisting of Toluene, cyclohexane, Dichloromethane, Hexane, 1,4-Dioxane, Chloroform, Diethyl ether.
For above said process, the heating temperature is 50-55?C.
The process for purification isdepicted in the following reaction Scheme II

Scheme-II
In another embodiment, the instant invention discloses the process for preparing(R)-1-azabicyclo[2.2.2]oct-3-ylhydroxy(dithiophen-2-yl)acetate from Methyl hydroxy (dithiophen-2-yl) acetate which comprises;
(a) Reacting Methyl hydroxy (dithiophen-2-yl) acetate with (3R)-1-azabicyclo[2.2.2]octan-3-ol in presence of metalalkoxide and solvent;
(b) Distilling solvent and degassing completely and
(c) Isolating (R)-1-azabicyclo[2.2.2]oct-3-ylhydroxy(dithiophen-2-yl)acetate.
The reaction scheme for preparing (R)-1-azabicyclo[2.2.2]oct-3-ylhydroxy(dithiophen-2-yl)acetateis given in Scheme III.

Scheme III

In above process the term metalalkoxide refers to sodiummethoxide (sodium methylate).The term solvent refers to linear or cycloalkane is selected from the group consisting of pentane, hexane, heptane, cyclopentane, cyclohexane,cycloheptane.
According to above process, the reaction is carried out at 80 to 85?C.
In the present invention while sodium methoxide reacting with linear or cycloalkane solvent, methanol layer is separated which can be discarded easily, the removal of which helps to protect the reaction from hydrolysis of Methylhydroxy (dithiophen-2-yl) acetate. Thus the rate of reaction, yield and purity increases which makes the present invention cost-effective over the teachings of prior art. Therefore there is no need to purify the final product four times as described in prior art US’226.

In one embodiment the present invention discloses the process for preparing 1-Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-1-(3-phenoxypropyl)-, bromide, (3R)- of formula I from (R)-1-azabicyclo[2.2.2]oct-3-ylhydroxy(dithiophen-2-yl)acetate which comprises,
(a) Reacting 1-azabicyclo[2.2.2]oct-3-ylhydroxy(dithiophen-2-yl)acetate with 1-bromo phenoxy propane in presence of mixture of polar-aprotic solvent and non-polar solvent and
(b) Isolating 1-Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-1-(3-phenoxypropyl)-, bromide, (3R)-.
The reaction scheme for preparing 1-Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-1-(3-phenoxypropyl)-, bromide, (3R)- is given in Scheme IV.

Scheme-IV
The polar-aprotic solvent is selected from the group consisting of acetonitrile,dimethylsulfoxide, dimethylformamide, acetone, ethyl acetate, tetrahydrofuran. The non-polar solvent is selected from the group consisting of Chloroform,Dichloromethane, Toluene, Hexane, 1,4-Dioxane, Diethyl ether.According to above process the reaction temperature is 25 to 30?C.
In one another embodiment the present invention provides the process for purification of 1-Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-1-(3-phenoxypropyl)-, bromide, (3R)- which comprises;
(a) Dissolving 1-Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-1-(3-phenoxypropyl)-, bromide, (3R)- in polar aprotic solvent with heating;
(b) Treating with charcoal;
(c) Precipitating with polar aprotic solvent with cooling and;
(d) Isolating 1-Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-1-(3-phenoxypropyl)-, bromide, (3R)-.
In above said process polar aprotic solvent is selected from the group consisting of dimethylformamide, acetone, acetonitrile,dimethyl sulfoxide, ethyl acetate, tetrahydrofuran, dimethylacetate.
The heating temperature is 70-80?C and cooling temperature ranges from 0-5?C.
In one another embodiment the instant invention provides process for purification of 1-Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-1-(3-phenoxypropyl)-, bromide, (3R)- which comprises;
(a) Dissolving 1-Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-1-(3-phenoxypropyl)-, bromide, (3R)- in polar aprotic solvent with heating;
(b) Treating with charcoal;
(c) Precipitating with polar protic solvent with cooling and
(d) Isolating pure 1-Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-1-(3-phenoxypropyl)-, bromide, (3R)-.
The polar aprotic solvent is selected from the group consisting of ethyl acetate, dimethylformamide, acetone, acetonitrile,dimethyl sulfoxide, ,tetrahydrofuran. The polar protic solvent is selected from the group consisting of methanol, ethanol, nitromethane, isopropanol, n-butanol, formic acid, Acetic acid, Water. The heating temperature is 60-75?C and cooling temperature ranges from 0-5?C.
In one another embodiment the instant invention provides process for purification of 1-Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-1-(3-phenoxypropyl)-, bromide, (3R)- which comprises;
(a) Dissolving 1-Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-1-(3-phenoxypropyl)-, bromide, (3R)- in polar protic solvent with heating;
(b) Treating with charcoal;
(c) cooling and;
(d) Isolating pure 1-Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-1-(3-phenoxypropyl)-, bromide, (3R)-.
The polar protic solvent is selected from the group consisting of methanol, ethanol, nitromethane, isopropanol, n-butanol, formic acid, Acetic acid, Water. The heating temperature is 60-65?C and cooling temperature ranges from 0-5?C.

The invention further encompasses a novel crystalline form, which is designated herein below as Form-1 and process for preparation thereof.

Accordingly, in one another embodiment the present invention provides the process for preparing novel crystalline form-I of 1-Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-1-(3-phenoxypropyl)-, bromide, (3R)- which comprises;
(a) Dissolving 1-Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-1-(3-phenoxypropyl)-, bromide, (3R)- in polar aprotic solvent with heating;
(b) Treating with charcoal;
(c) Precipitating with polar aprotic solvent with cooling and
(d) Isolatingnovel crystalline form-I of1-Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-1-(3-phenoxypropyl)-, bromide, (3R)-.

In above said process polar aprotic solvent is selected from the group consisting of dimethylformamide, acetone, acetonitrile,dimethyl sulfoxide, ethyl acetate, tetrahydrofuran, dimethylacetate.
The heating temperature is 70-80?C and cooling temperature ranges from 0-5?C.
In one another embodiment the instant invention provides process for preparing novel crystalline form-I of 1-Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-1-(3-phenoxypropyl)-, bromide, (3R)- which comprises;
(a) Dissolving 1-Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-1-(3-phenoxypropyl)-, bromide, (3R)- in polar aprotic solvent with heating;
(b) Treating with charcoal;
(c) Precipitating with polar protic solvent with cooling and
(d) Isolating pure crystalline form-I of 1-Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-1-(3-phenoxypropyl)-, bromide, (3R)-.
The polar aprotic solvent is selected from the group consisting of ethyl acetate, dimethylformamide, acetone, acetonitrile ,dimethyl sulfoxide, tetrahydrofuran. The polar protic solvent is selected from the group consisting of methanol, ethanol, nitromethane, isopropanol, n-butanol, formic acid, Acetic acid, Water. The heating temperature is 60-75?C and cooling temperature ranges from 0-5?C.

In one another embodiment the instant invention provides process for preparing novel crystalline form-I of 1-Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-1-(3-phenoxypropyl)-, bromide, (3R)- which comprises;
(a) Dissolving 1-Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-1-(3-phenoxypropyl)-, bromide, (3R)- in polar protic solvent with heating;
(b) Treating with charcoal;
(c) cooling and
(d) Isolating pure 1-Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-1-(3-phenoxypropyl)-, bromide, (3R)-.

The polar protic solvent is selected from the group consisting of methanol, ethanol, nitromethane, isopropanol, n-butanol, formic acid, Acetic acid, Water. The heating temperature is 60-65?C and cooling temperature ranges from 0-5?C.

The novel crystalline form-I according to the present invention is characterised by PXRD with peaks at 2? values by at least one characteristic peak (expressed in 2?) at 7.88, 13.28, 13.95, 14.03, 20.77, 21.09, 23.34, 24.49, 25.97, 26.37, 29.49, 31.21±0.2.

In one aspect the present invention discloses the process for preparing impurity, i.e. s-isomer of 1-Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-1-(3-phenoxypropyl)-, bromide, (3R)- (formula-VI) and its intermediate- (S)-1-azabicyclo[2.2.2]oct-3-ylhydroxy(dithiophen-2-yl) (formula-VII) which comprises;

Formula-VI Formula-VII
(a) Reacting Methyl hydroxy (dithiophen-2-yl) acetate with (3S)-1-azabicyclo[2.2.2]octan-3-ol in presence of metalalkoxide and solvent
(b) Distilling solvent and degassing completely and
(c) Isolating intermediate- (S)-1-azabicyclo[2.2.2]oct-3-ylhydroxy(dithiophen-2-yl)acetate.
(d) Reacting (S)-1-azabicyclo[2.2.2]oct-3-ylhydroxy(dithiophen-2-yl)acetate with 1-bromo phenoxy propane in presence of mixture of polar-aprotic solvent and non-polar solvent and;
(e) Isolating impurity S-isomer of 1-Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-1-(3-phenoxypropyl)-, bromide, (3R)-.

In above process, the term metal alkoxide refers to sodium methoxide (sodium methylate).The term solvent refers to linear or cyclo alkane is selected from the group consisting of pentane, hexane, heptane, cyclopentane, cyclohexane,cycloheptane. According to above process, the reaction is carried out at 80 to 85?C.

The polar-aprotic solvent is selected from the group consisting of acetonitrile,dimethyl sulfoxide, dimethylformamide, acetone, ethyl acetate, tetrahydrofuran. The non-polar solvent is selected from the group consisting of Chloroform, Dichloromethane, Toluene, Hexane, 1,4-Dioxane, Diethyl ether. According to above process the reaction temperature is 25 to 30?C.

The following examples, which include preferred embodiments, will serve to illustrate the practice of this invention, it being understood that the particulars shown are by way of example and for purpose of illustrative discussion of preferred embodiments of the invention.

Examples:
Example-1: Purification of Methyl hydroxy (dithiophen-2-yl) acetate
To the 3 lit toluene added 1.0 kg methyl hydroxy (dithiophen-2-yl) acetate at 25-30°C and heatedupto 50-55°C till clear solution. Added activated charcoal and stirred for 30min. Filtered the reaction mass through Hyflo bed and washed the bed with 2 lit Hot Toluene. To the filtrate added 9 lit Cyclohexane at 35-40° C.Stirred for 30 min at 35-40° C and 1 hr at 0 - 5 ° C. Filtered the reaction mass and washed the bed with 1 lit chilled Cyclohexane.Dried the product at 30-40° C for 3 hrsto get 85% titled product.
HPLC purity:99.82%~ 99.9%.

Example-2: Preparation of 1-azabicyclo[2.2.2]oct-3-ylhydroxy(dithiophen-2-yl)acetate
To the 10 lit Cyclohexane added 0.638 kg (3R)-1-azabicyclo[2.2.2]octan-3-ol and 0.266 kg Sodium Methoxide Powder and heated upto 80-85° C. Simultaneously distilled out slowly 5.0 lit Cyclohexane and added 5.0 lit Cyclohexane and again distilled out by azeotrophically slowly 8.0 lit. Added 8.0lit L Fresh Cyclohexane and stirred for 3-4 hr at 80-85° C. Added 1.0 kg of methyl hydroxy (dithiophen-2-yl) acetate lot wise over a period of 20-30 min. Stirred and maintained for 3-4 hrs at 80-85° C. Cyclohexane Distilled out and degased completely under vacuum at below 85° C.Added 10. L DM-Water at 25-30° C and stirred for 1hr. Filtered and washed with 2.0 L DM water and slurry washed with 4.0lit Cyclohexane two time. Filtered the product, suck dried and washed with 1.0 L Cyclohexane and suck dried for 10-15 min to get 89.05% titled product.
HPLC purity: 97.68%

Example 3: Preparation of 1-Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-1-(3-phenoxypropyl)-, bromide, (3R)-
To the mixture of 6.0 L Chloroform and 4.0 L Acetonitrile added 1.0 kg (R)-1-azabicyclo[2.2.2]oct-3-yl hydroxyl(dithiophen-2-yl)acetate at 25-30 °C and Stirred for 5 -10 min . Added 3.270 kg 1-bromo phenoxy propane and stirred for 72 hrs.Filtered and washed with 2 T x 2.0 L Ethyl acetate to get 70-75% titled compound.
HPLC purity:99.15%

Example-4: Purification of 1-Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-1-(3-phenoxypropyl)-, bromide, (3R)-
To the 12.0 lit DMF added 1.0 kg of Crude 1-Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-1-(3-phenoxypropyl)-, bromide, (3R)- and heated to 70-80° C till clear solution. Added 0.150 kg of Activated carbon at 70-80° and stirred it for 10-15 min. Filtered through Hyflo bed and washed with 3.0 L hot DMF at 70-80° C. To the filtrate mother liquor added slowly 25.0 L Acetone and cooled to 0-5° C. Stirred for 30 min and filtered the solid product and washed with 10.0 L hot Acetone. Dried product under vacuum at 25-30° C to get 87% titled compound.
HPLC purity: 99.85%

Example 5:Purification of 1-Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-1-(3-phenoxypropyl)-, bromide, (3R)-
To the 25.0 L Ethyl acetate added 1.0 kg of 1-Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-1-(3-phenoxypropyl)-, bromide, (3R)- and heated upto 65-75°C.Added 31.0 L Methanol and stirred till clear solution. Again added 5.0 L Ethyl acetate ,Slowly cooled to 0-5° C.Stirred for 1 hr and filtered the solid and washed with 1.0 L chilled Ethyl acetate. Dried wet product under vacuum at 80-85° C for 6 hours to get 65% title compound.
HPLC purity: 99.93%

Example 6: Purification of 1-Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-1-(3-phenoxypropyl)-, bromide, (3R)-
To the 12.0 lit Dimethyl acetamide added 1.0 kg of Crude 1-Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-1-(3-phenoxypropyl)-, bromide, (3R)- and heated upto 70-80° C till clear solution. Added 0.150 kg of Activated carbon and stirred for 10-15 min. Filtered through Hyflo bed and washed with 3.0 L hot Dimethyl acetamide at 70-80° C. To the filtrate mother liquor added slowly 25.0 L Acetone and cooled to 0-5° C. Stirred for 30 min .Filtered the solid product and washed with 10.0 L hot Acetone. Dried product under vacuum at 25-30° C to get 94% titled compound.
HPLC purity: 99.80%
Example 7: Purification of 1-Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-1-(3-phenoxypropyl)-, bromide, (3R)-
To the 12.0 lit DMF was added 1.0 kg of Crude 1-Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-1-(3-phenoxypropyl)-, bromide, (3R)- and heated to 70-80° C till clear solution.Added 0.150 kg of Activated carbon and stirred for 10-15 min. Filtered through Hyflo bed and washed with 3.0 L hot DMF at 70-80° C. To the filtrate mother liquor added slowly 25.0 L Isopropyl alcohol and cooled to 0-5° C. Stirred for 30 min and filtered the solid product and washed with 10.0 L hot Isopropyl alcohol. Dried product under vacuum at 25-30° C to get 84% titled compound.
HPLC Purity: 99.81%

Example 8: Purification of 1-Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-1-(3¬phenoxypropyl)-, bromide, (3R)-
To the 3.5 L Dimethyl Sulfoxide added 1.0 kg of Crude 1-Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-1-(3-phenoxypropyl)-, bromide, (3R)- and heated upto 50-55° C till clear solution. Added 0.150 kg of Activated carbon at 50-55°C and stirred for 10-15 min. Filtered through Hyflo bed and washed with 0.5 L hot Dimethyl Sulfoxide at 50-55° C. To thefiltrate mother liquor slowly added 20.0 L Acetone at 50-55°C and stirred for 60 min at 50-55°c. Cooled it to 25-30° C. Filtered the solid product andwashed with 10.0 L hot Acetone. To the wet solid, charged 10 L acetone and stirred for 60 min at 40-50°C. Filtered the solid at 25-30° C andwashed with 10.0 L Acetone. Dried product under vacuum at 25-30° C to get 80% titled compound.
HPLC Purity: 99.96%

Example 9:Purification of 1-Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-1-(3-phenoxypropyl)-, bromide, (3R)-
To the 25.0 L Methanol added 1.0 kg 1-Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-1-(3phenoxypropyl)-, bromide, (3R)- and heated upto 60-65°C. Stirred clear solution for 5-10 min at 60-65°C. Charged 50 g charcoal and stirred for 10-15 min at 60-65°C. Slowly cooled to 25-30° C. Stirred for 12-15 hr and cooled to 0-5°C. Filtered the solid and washed with 1.0 L chilled Methanol. Dried wet product under vacuum at 80-85° C for 6 hours to get 80% titled compound.
HPLC Purity: 99.94%
Example 10: Preparation of (S)-1-azabicyclo[2.2.2]oct-3-ylhydroxy(dithiophen-2-yl)acetate
To the 10 L Cyclohexane added 0.638 kg (3S)-Azabicyclo Compound and 0.266 kg Sodium Methoxide Powder and heatedupto 80-85° C. Simultaneously 5.0 lit Cyclohexane distilled out slowly and added 5.0 lit Cyclohexane and again distilled out by azeotrophically slowly 8.0 lit. Added 8.0lit L Fresh Cyclohexane andstirred for 3-4 hr at 80-85° C. Added 1.0 kg of methyl hydroxy (dithiophen-2-yl) acetate lot wise over a period of 20-30 min. Stirred and maintained for 3-4 hrs at 80-85° C. Cyclohexane distilled out and degased completely under vacuum at below 85° C.Added 10. L DM-Water at 25-30° C stirred for 1hr. Filtered and washed with 2.0 L DM water and slurry washed with 4.0lit Cyclohexane two time. Filtered the product, sucked dry and washed with 1.0 L Cyclohexane and sucked dry for 10-15 min to get 80% titled compound.
HPLC Purity: 90.42%

Example 11: Preparation of 1-Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-1-(3-phenoxypropyl)-, bromide, (3R)-
To the mixture of 6.0 L Chloroform and 4.0 L Acetonitrile added 1.0 kg (S)-1-azabicyclo[2.2.2]oct-3-yl hydroxyl(dithiophen-2-yl)acetate at 25-30 °C and Stirred for 5 -10 min . Added 3.270 kg 1-bromo phenoxy propane and Stirred for 72 hrs.Filtered and washed with 2 T x 2.0 L Ethyl acetate to get 85% yield of titled compound.
HPLC Purity: 95.00%

Example-12: Preparation of crystalline form-I of 1-Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-1-(3-phenoxypropyl)-, bromide, (3R)-
To the 12.0 lit DMF added 1.0 kg of Crude 1-Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-1-(3-phenoxypropyl)-, bromide, (3R)- and heated to 70-80° C till clear solution.Added 0.150 kg of Activated carbon at 70-80° and stirred it for 10-15 min. Filtered through Hyflo bed and washed with 3.0 L hot DMF at 70-80° C.To the filtrate mother liquor added slowly 25.0 L Acetone and cooled to 0-5° C. Stirred for 30 min and filtered the solid product and washed with 10.0 L hot Acetone. Dried product under vacuum at 25-30° C to get 87% titled compound.
HPLC purity: 99.85%
Example 13:Preparation of crystalline form-I of 1-Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-1-(3-phenoxypropyl)-, bromide, (3R)-
To the 25.0 L Ethyl acetate added 1.0 kg of 1-Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-1-(3-phenoxypropyl)-, bromide, (3R)- andheatedupto 65-75°C.Added 31.0 L Methanol and stirred till clear solution.Again added 5.0 L Ethyl acetate ,Slowly cooled to 0-5° C.Stirred for 1 hr and filtered the solid and washed with 1.0 L chilled Ethyl acetate.Dried wet product under vacuum at 80-85° C for 6 hours to get 65% title compound.
HPLC purity: 99.93%

Example 14:Preparation of crystalline form-I of 1-Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-1-(3-phenoxypropyl)-, bromide, (3R)-
To the 12.0 lit Dimethyl acetamide added 1.0 kg of Crude 1-Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-1-(3-phenoxypropyl)-, bromide, (3R)- and heated upto 70-80° C till clear solution. Added 0.150 kg of Activated carbon and stirred for 10-15 min. Filtered through Hyflo bed and washed with 3.0 L hot Dimethyl acetamide at 70-80° C. To the filtrate mother liquor added slowly 25.0 L Acetone and cooled to 0-5° C. Stirred for 30 min .Filtered the solid product and washed with 10.0 L hot Acetone. Dried product under vacuum at 25-30° C to get 94% titled compound.
HPLC purity: 99.80%

Example 15: Preparation of crystalline form-I of 1-Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-1-(3-phenoxypropyl)-, bromide, (3R)-
To the 12.0 lit DMF was added 1.0 kg of Crude 1-Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-1-(3-phenoxypropyl)-, bromide, (3R)- and heated to 70-80° C till clear solution.Added 0.150 kg of Activated carbon and stirred for 10-15 min. Filtered through Hyflo bed and washed with 3.0 L hot DMF at 70-80° C. To the filtrate mother liquor added slowly 25.0 L Isopropyl alcohol and cooled to 0-5° C. Stirred for 30 min and filtered the solid product and washed with 10.0 L hot Isopropyl alcohol. Dried product under vacuum at 25-30° C to get 96%.
HPLC Purity: 99.81%

Example 16: Preparation of crystalline form-I of 1-Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-1-(3-phenoxypropyl)-, bromide, (3R)-
To the 3.5 L Dimethyl Sulfoxide added 1.0 kg of Crude 1-¬Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-1-(3-phenoxypropyl)-, bromide, (3R)- and heated upto 50-55° C till clear solution. Added 0.150 kg of Activated carbon at 50-55°C and stirred for 10-15 min. Filtered through Hyflo bed and washed with 0.5 L hot Dimethyl Sulfoxide at 50-55° C. To the filtrate mother liquor slowly added 20.0 L Acetone at 50-55°C and stirred for 60 min at 50-55°c. Cooled it to 25-30° C. Filtered the solid product and washed with 10.0 L hot Acetone. To the wet solid , charged 10 L acetone and stirred for 60 min at 40-50°C. Filtered the solid at 25-30° C andwashed with 10.0 L Acetone. Dried product under vacuum at 25-30° C to get 80% titled compound.
HPLC Purity: 99.96%

Example 17:Preparation of crystalline form-I of 1-Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-1-(3-phenoxypropyl)-, bromide, (3R)-
To the 25.0 L Methanol added 1.0 kg 1-¬Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-1-(3¬phenoxypropyl)-, bromide, (3R)- and heated upto 60-65°C.Stirred clear solution for 5-10 min at 60-65°C.Charged 50 g charcoal and stirred for 10-15 min at 60-65°C. Slowly cooled to 25-30° C.Stirred for 12-15 hr and cooled to 0-5°C. Filtered the solid and washed with 1.0 L chilled Methanol. Dried wet product under vacuum at 80-85° C for 6 hours to get 80% titled compound.
HPLC Purity: 99.94%