FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of 3-[(2-Cyclopentyl-2-hydroxy-2-phenylacetyl)oxy]-1,1-dimethyl pyrrolidinium bromide of Formula I

BACKGROUND OF THE INVENTION
3-[(2-Cyclopentyl-2-hydroxy-2-phenylacetyl)oxy]-l ,1-dimethyl pyrrolidinium bromide, commonly known as Glycopyrrolate, which is being marketed under the trade name Robinul. This drug is a potent anticholinergic useful in the treatment of peptic ulcer. This drug is effective at extremely low concentrations. Glycopyrrolate is a quaternary ammonium compound which prevents its passage through lipid membrane and therefore does not induce undesirable side effects such as dizziness, restlessness, irritability, disorientation, depression.
Glycopyrrolidinium bromide was first disclosed in US 2,956,062. This patent describes the synthesis of Glycopyrrolidinium bromide which is shown below:


The above mentioned process utilizes sodium metal which is very hazardous and undesirable in industrial scale operations.
US 3,691,198 describes a process to prepare l-hydrocarbyl-3-halopyrrolidine, which is an intermediate in the preparation of Glycopyrrolidinium bromide. The process comprises, cyclizing cis-l,4-dihalobutene with a primary amine (methylamine) to give 1-hydrocarbyl-
"X "X
A -pyrroline. This is reacted with 1-hydrocarbyl-A -pyrroline and cone, aqueous hydrogen halide solution was added at a temperature from ~100°C to ~140°C to recover the 1-hydrocarbyl-3-halo pyrrolidine.
Journal of Medicinal and Pharmaceutical Chemistry Vol 2, No. 5 (1960) 523-540 discloses the synthesis and purification of derivatives of 3-pyrrolidinols. In most cases where the possibility of diastereomers existed, only a single compound was isolated, however, both forms of l-ethyl-3-pyrrolidyl a-phenylcyclohexaneglycolate were obtained. This publication also discloses a method for crystallization and purification of quaternary salt using mixture of butanone-methanol.
WO 2004/054971 Al discloses a procedure for the isolation of (R,R) or S,S configuration Glycopyrronium salts of stereoisomers and their thienyl derivatives analogues of R,S or S,R
•3

configuration. It also claims isolation and recrystallisation of diastereomeric mixtures, specifically glycopyrinium bromide.
OBJECTIVES OF INVENTION
The objective of the present invention is to develop a new improved process for the
preparation of 3-[(2-Cyclopentyl-2-hydroxy-2-phenylacetyI)oxy]-1,1 -dimethyl
pyrrolidinium bromide with high purity and high yield.
SUMMARY OF INVENTION
Accordingly, the present invention provides an improved process for the preparation of 3-[(2-Cyclopentyl-2-hydroxy-2-phenylacetyl)oxy]-1,1-dimethyl pyrrolidinium bromide of Formula I



using an aqueous base in an organic solvent,
d) isolating the compound of Formula IV,
e) esterifying the compound of Formula IV using methanolic HCl in an inert organic solvent
to give a compound of Formula III,

g) hydrogenating the mixture of compounds of Formula VI a and Formula VI b using a
catalyst in an organic solvent to give compound of Formula VI a, h) quartemizing the compound of Formula VI a with methyl bromide in isopropyl alcohol
to give a compound of Formula I and isolating the compound of Formula I.
DETAILED DESCRIPTION OF THE INVENTION
The present invention describes a new improved process for the preparation of Glycopyrrolidinium bromide without using high vacuum distillation for purification.

The compound of Formula II and cyclopentyl bromide are reacted with magnesium under Barbier conditions in an inert organic solvent to give compound of Formula III. The inert organic solvents are selected from tetrahydrofuran, n-hexane, n-heptane, toluene or mixture thereof, preferably tetrahydrofuran. After completion of the reaction, reaction mixture is diluted with water and extracted with toluene, concentrated to give a residue containing the compound of Formula III as an oily mass. This oily mass is treated with aqueous base in an organic solvent to give compound of Formula IV. The aqueous base can be selected from sodium hydroxide, potassium hydroxide, preferably sodium hydroxide. The organic solvent employed is selected from methanol, ethanol, isopropyl alcohol, preferably methanol. The pH of the aqueous layer was adjusted to 1.8-2.2 with HCl to precipitate the product. Finally, the product obtained was filtered and further purified by recrystallization from acetonitrile. The compound of Formula III is insitu hydrolysed to give compound of Formula IV.
The compound of Formula IV is esterified by using methanolic HCl in inert organic solvent selected from toluene, xylene, hexane, cyclohexane, preferably toluene to give a compound of Formula III. The Glycopyrrolate hydroxy acid of Formula IV is dissolved in toluene and subjected to esterification using methanolic HCl at ambient temperature. After completion of the reaction, reaction mixture is cooled to 20-25°C and product was extracted into toluene. The toluene extract is washed with sodium bicarbonate and concentrated under reduced pressure to give compound of Formula III. Normally in the prior-art process thionyl chloride is used for esterification. However, in the present process methanolic HCl is used. The tedious job of distilling off excess thionyl chloride is avoided there by making the process less hazardous.
The compound of Formula III is transesterified with a compound of Formula V by using a base like sodium methoxide in presence of inert organic solvent selected from toluene, xylene, heptane, preferably n-heptane to give a mixture of compounds of Formula VI a and Formula VI b. After completion of the reaction, reaction mass is diluted with aqueous hydrochloric acid, washed with toluene and adjusted pH of the aqueous layer to 9.0-9.2 with aqueous ammonia. The product was extracted into toluene and thereafter toluene was

evaporated to give a mixture of compounds of Formula VI a and Formula VI b. This condensation was performed using sodium methoxide in place of strong bases like Na metal or sodium hydride, which are hazardous to handle.
During the above mentioned condensation of compound of Formula III with compound of Formula V, a mixture of two products are obtained Viz compounds of Formula VI a and VI b. The compound of Formula VI b is a by product and difficult to remove by crystallization. In order to solve this problem the inventors thought that instead of eliminating this compound by purification methods that are difficult, it is all the more advantageous to convert this impurity back to compound of Formula VI a. So the same solution of Formula VI a and VI b was hydrogenated using a catalyst in a solvent selected from Ci-e alcohols, Ci. 6 alkyl acetates or mixtures thereof. The CpCe alcohol is selected from the group consisting of methanol, ethanol, propanol and isopropanol, preferably in methanol at 20-30°C with a pressure of 40-60 psi. The catalyst is selected from palladium, platinum, rhodium, ruthenium and raney nickel, preferably palladium on carbon. After completion of the reaction, the catalyst was removed by filtration and filtrate concentrated under reduced pressure to yield compound of Formula VI a in quantitative yield.
The compound of Formula VI a is further quartemized to its bromide salt using methyl bromide. The compound of Formula VI a is dissolved in isopropyl alcohol and treated with a solution of methyl bromide. After completion of the reaction, the reaction mass was stirred to complete the crystallization. The precipitated product was filtered and washed with isopropyl alcohol and dried under reduced pressure to obtain Glycopyrrolidinium bromide. In prior art procedures the quartemization of compound VI a usually takes about nine days. However, in the present process of the invention quartemization is usually completed in 4-5 hrs.
The crude methyl bromide quartemary salt is fiarther purified by dissolving in methanol at 60°C. To this hot solution, methyl ethyl ketone was slowly added and the reaction temperature cooled to 30°C and stirred for 3 hrs to complete crystallization. Filtration and drying yielded pure product.

Example-1
Preparation of (2RS)-2-Cyclopentyl-2-hydroxy-2-phenyiacetic acid (Glycopyrrolate
hydroxy acid)
Magnesium turnings (llOg, 4.58 mol) were suspended in dry tetrahydrofuran (150 ml) under nitrogen atmosphere and heated the contents to 35-40°C. Catalytic amount of iodine (~lg) was added followed by a portion of solution (30 ml) from a mixture of methyl phenyl glyoxylate (500g, 3.05 mol) and cyclopentylbromide (545 g, 3.67 mol) in dry tetrahydrofiiran (2850 ml). After initiation, remaining quantity of reactants mixture was added at 35-40°C in ~90 min. Reaction was monitored by qualitative HPLC. After completion of reaction, reaction mass was added slowly to chilled water and thereafter neutralized the reaction mass with acetic acid. Product was extracted into toluene and then concentrated. The concentrated mass thus obtained was dissolved in methanol (500 ml) and 15% w/w aqueous sodium hydroxide solution (1000 ml) was added to it. Reaction mass was stirred at 20-25°C and monitored by qualitative HPLC analysis. After completion of reaction, reaction mass was diluted with DM water (3000 ml) and washed with toluene. Thereafter, pH of the aqueous layer was adjusted to 1.8 to 2.2 with concentrated hydrochloric acid at 20-30°C to precipitate the product. The product was filtered and washed with DM water. Filtered product (wet) was added to acetonitrile (850 ml) and heated to 70-75°C to obtain a clear solution. DM water (3000 ml) was added to the above solution at 70-75°C. Reaction mass was cooled slowly to 20-25°C and stirred for 2 hrs. Product was filtered and washed with DM water (2x500 ml) and dried at 60-65°C under reduced pressure (~20mm Hg) till water content is < 0.5% w/w (by KF).
Yield: 260 g; Chromatographic purity: 95.68%, water content: 0.24% w/w by KF titration Melting range: 135-142°C.
'H NMR (DMS0-d6), in 6ppm : 1.16-1.58 (m. 8H), 2.82-2.85 (m, IH), 5.30 (bs, IH); 7.20-7.61 (m, 5H); 12.91 (bs, IH).

Example 2
Preparation of methyl (2RS)-2-Cyclopentyi-2-hydroxy-2-phenylacetate
(Glycopyrrolate hydroxy ester)
Glycopyrrolate hydroxy acid (200g, 0.91 mole) was suspended in toluene (1000 ml) and added hydrogen chloride solution in methanol (500 ml, 18-22% w/w) at 20-25°C. Thereafter, reaction mass was heated to 55°C and stirred at 55-60°C and monitored by qualitative HPLC analysis. After completion of reaction, reaction mass was cooled to 20-25°C and transferred slowly into chilled water. Product was extracted into toluene (2x600ml) and washed with 5% w/w aqueous sodium bicarbonate solution (lx400ml) followed by DM water (400 ml) at 20-25°C. The washed toluene layer was concentrated at 50-65°C under reduced pressure varying from 200 mm to 20 mm of Hg to obtain the title compound.
Yield: 204 g. Chromatographic purity: 96.45 % .
'H NMR (DMS0-d6) in 6ppm: 1.14-1.57 (m, 8H), 2.79-2.87 (m, IH); 3.63 (s, 3H), 5.69 (s,
IH), 7.18-7.26 (dd, 2H), 7.30-7.35 (t, IH), 7.54 -7.57 (d, 2H).
Example 3
Preparation of (3RS)-3-[(2RS)-(2-Cyclopentyl-2-hydroxy-2-phenylacetyl)oxy]-l-
methylpyrrolidine (Desmethyl glycopyrrolate)
Glycopyrrolate hydroxy ester (185g, 0.79mol) and l-methyl-3-pyrrolidinol (103.80g, 1.02 mole) were added to n-heptane (3000ml). Subsequently, ~1000ml of n-heptane was removed by distillation at atmospheric pressure to remove traces of moisture. After cooling to 30-35°C, sodium methoxide (6.50g, 0.12mol) was added under nitrogen atmosphere and then heated the contents to boiling while distilling out the azeotrope. The amount of solvent distilling out was replaced by simultaneous addition of n-heptane to maintain the volume of the reaction mass and monitored trans-esterification by qualitative HPLC. After completion of reaction, reaction mass was cooled to 10-15°C and ~10% w/w aqueous hydrochloric acid solution (370ml) was added to it. Reaction mass was washed with toluene (2 X 350ml). Toluene (750ml) was added to washed aqueous layer and pH was adjusted to 9.0-9.2 at 15-

20°C. with aqueous ammonia solution. Product was extracted into toluene and the combined toluene extracts were washed with DM water, and concentrated at 40-50°C under reduced pressure varying fi-om 200mm to 20mm of Hg to get title product.
Yield: 166.5g; Chromatographic purity: 95.89%; Assay (% w/w, by titrimetry): 96.41. Desmethyl glycopyrrolate (165g, 0.54mole) having alkene desmethyl glycopyrrolate was dissolved in methanol (1000ml) and hydrogenated using palladium on carbon (8.0g) at 20-30°C/ 40-60 psi. After completion, catalyst was removed by filtration and filtrate was concentrated under reduced pressure to get the title compound as oily mass. Yield: 164g; Chromatographic purity: 97.35%; Assay (% w/w, by titrimetry): 98.0. 'H NMR (DMS0-d6) in Sppm: 1.22-1.56 (m,9H); 2.05-2.15 (m, IH); 2.02-2.22 (d,3H); 2.24-2.26 (m, IH); 2.30-2.45 (m,lH); 2.58-2.62 (m, 2H); 2.84 (bt, IH); 5.02-5.07 (bt, IH); 5.61 (s, IH); 7.21-7.26 (t, IH), 7.30-7.35 (t, 2H), 7.55-7.58 (d, 2H).
Example 4
Preparation of (3RS)-3-[(2RS)-(2-CycIopentyl-2-hydroxy-2-phenyIacetyl)oxy]-l,l-
dimetbylpyrrolidinium bromide
A solufion of Desmethylglycopyrrolate (150g, 0.49mole) in isopropyl alcohol (750ml) was treated with a solution of methyl bromide in t-butyl methyl ether (25% w/w, 470g) at 25-30°C. After completion of reaction (monitored by HPLC), the reaction mass was stirred for 4h to complete the crystallization. The product was filtered under nitrogen atmosphere and washed with isopropyl alcohol (2x75ml). Thereafter, the product was dried at 40-50°C, under reduced pressure (~20mm Hg).
Yield: 78g; Chromatographic purity: 99.61%; Glycopyrrolate diastereoisomer content: 9.03%.

Example 5 Purification
Glycopyrrolate crude (75g,) was heated in methanol (60 ml) at 50-60°C to obtain a clear solution. Ethyl methylketone (750ml) was added slowly maintaining temperature between 50-60°C. Thereafter, the contents were cooled slowly to 25-30°C and stirred for 3h to complete the crystallization. The product was filtered and washed with ethyl methylketone (2x75ml). Finally the product was dried to constant weight at 50-55°C under reduced pressure (~20mm Hg).
Yield: 60g; Chromatographic purity: 99.92%; Glycopyrrolate diastereoisomer content:
0.27%.
'HNMR(DMSO-d6)in5ppm: 1.19-1.60 (m,8H); 2.05-2.11 (m, IH); 2.61-2.68 (m, IH);
2.89-2.94(m,lH); 3.11(s,3H); 3.18(s, 3H); 3.50-3.63 (m,2H); 3.67-3.74 (m, IH); 5.38(bs,
IH); 5.83 (s,lH); 7.24-7.29 (t, IH); 7.33-7.38 (t, 2H); 7.58-7.61 (d, 2H).
NMR(DMS0-d6) (proton decoupled) in 8ppm: 26.5, 26.9, 26.9, 27.5, 30.5, 47.5, 52.8,
53.4, 64.7, 70.0, 73.6, 80.1, 126.5, 128.1, 128.8, 143.0, 174.3.

WE CLAIM
l)An improved process for the preparation of 3-[(2-cyclopentyl-2-hydroxy-2-phenylacetyl)oxy]-l,l-dimethylpyrrolidinium bromide of Formula I

using an aqueous base in an organic solvent,
d) isolating the compound of Formula IV,
e) esterifying the compound of Formula IV using methanolic HCl in an inert organic solvent to give a compound of Formula III,


g) hydrogenating the mixture of compounds of Formula VI a and Formula VI b using a
catalyst in an organic solvent to give compound of Formula VI a, h) quartemizing the compound of Formula VI a with methyl bromide in isopropyl alcohol
to give a compound of Formula I.
2) The process according to claim 1, wherein the condensation of compound of Formula II
with cyclopentyl bromide is carried out in inert organic solvents selected from tetrahydro
furan, n-hexane, n-heptane, toluene or mixture thereof, preferably tetrahydrofuran.
3) The process according to claim 1, wherein the compound of Formula III is hydrolysed to
compound of Formula IV using aqueous base like sodium hydroxide, potassium
hydroxide, preferably sodium hydroxide.
4) The process according to claim 3, wherein the hydrolysis is carried out in organic
solvents selected from methanol, ethanol, isopropanol, preferably methanol.
5) The process according to claim 1, wherein the esterification is carried out in inert
organic solvents selected from toluene, xylene, hexane, cyclohexane, preferably toluene.
6) The process according to claim 1, wherein the transesterification of compound of
Formula III with compound of Formula V is carried in inert organic solvents selected
from toluene, xylene, heptane, preferably heptane.

7) The process according to claim 1, wherein the hydrogenation is carried out using palladium, platinum, rhodium, ruthenium, raney nickel, preferably palladium.
8) The process according to claim 1, wherein hydrogenation is carried out in alcohols
selected from methanol, ethanol, isopropanol, n-butanol, preferably methanol.
9) The process according to claim 1, wherein the compound of Formula I is recrystallized
by dissolving in methanol and precipitating it by the addition of methyl ethyl ketone.