Claims:We CLAIM

1. An one pot process for preparing Glycopyrronium bromide having enantiomeric purity more than 95%, when measured by HPLC, the process comprising:
a) contacting methyl alpha cyclo mandelate and 1-methyl-3-pyrrolidinol in heptane,
b) treating the reaction mixture with saturated solution of methyl bromide in isopropyl alcohol,
c) removing solvent to get residue added aqueous solution of methyl ethyl ketone 1:4 (v/v) in residue,
d) reflux the reaction mixture to get clear solution,
e) isolate the product after cooling the reaction mass.

2. The process for purification of Glycopyrronium bromide comprising the steps of
a) dissolution of Glycopyrronium bromide in aqueous solution of methyl ethyl ketone,
b) heating to reflux to get clear solution,
c) cool to below 30°C and isolation of Glycopyrronium bromide having enantiomeric purity 99.95%, when measured by HPLC.

3. The process of claim 2 wherein, step c) cooling temperature is -5 to 5 deg C.

4. The process of claim 2 wherein aqueous methyl ethyl ketone, water ratio is in the range 1: 1 to 1:5 (volume / volume) with respect to methyl ethyl ketone.

5. The process of claim 3, wherein aqueous methyl ethyl ketone, water ratio is 1:4 (volume/volume) with respect to methyl ethyl ketone.

6. A Glycopyrronium bromide of enantiomeric purity 99.9% having melting point 194-196 deg C.

7. A Glycopyrronium bromide obtained by the process of, recrystallization from aqueous methyl ethyl ketone has enantiomeric purity 99.95% when measured by HPLC.

8. A Glycopyrronium bromide obtained by the process of, has HPLC purity is 99.95% or more.

9. A process of claim 6 wherein the ratio of water and methyl ethyl ketone in aqueous methyl ethyl ketone is (1:4 volume/volume)
, Description:Field of the Invention

The invention relates to a process for the preparation and purification of Glycopyrronium bromide having enantiomeric purity more than 95%, when measured by HPLC. The invention also relates to a novel process for the purification of Glycopyrronium bromide. The Glycopyrronium bromide obtained by the process of the present invention is more than enantiomeric purity 99.95%, when measured by HPLC.

Background of the Invention

Glycopyrrolate, chemically known as 3[(cyclopentylhydroxyphenylacetyl)oxy]-1,1 dimethyl pyrrolidinium bromide is an anticholinergic that helps to control conditions such as peptic ulcers that involve excessive stomach acid production. The injectable form of glycopyrrolate is also used to reduce saliva, nasal, lung, and stomach secretions and to help control heart rate during surgery. Glycopyrrolate is structurally represented as formula (I).

Formula-I

Various processes for the preparation of Glycopyrronium bromide (I) are described in the prior art literature.

EP2417106 discloses the preparation of glycopyrrolate using cyclopentyl mandelic acid and methyl pyrrolidinol in the presence carbonyldiimidazole.

EP 18506041 discloses the process for the preparation of glycopyrrolate rich in R,S and S,R diastereoisomers using solvents such as acetone, methyl ethyl ketone and methanol.

Similarly, EP 2607351 describes continuous alkylation of cyclic tertiary amines, in particular process for quaternization of cyclic tertiary amines.

US20090005577 discloses a process for the preparation of glycopyrrolate by reaction of methyl ester of cyclopentyl mandelic acid with n-methyl pyrrolidinol followed by repeated crystallization.

EP 3237378 describes a process for preparing Glycopyrronium bromide which comprises glycopyrrolate base with 5-nitroisophthalic acid in acetone water mixture (4:1) followed by purification with acetone and water mixture and further conversion to Glycopyrronium bromide using methyl bromide.

The process of the preparations Glycopyrrolate disclosed in the art have following disadvantages such as the prior art process involve the use of expensive reagents such as carbonyldiimidazole. It provides poor yields due to increase in the number of steps and repeated recrystallizations. The prior art process involve the use of multiple solvents and is provides low purity of the Glycopyrrolate. Isolation and handling of glycopyrrolate base are very dangerous and associated with many safety hazards.

The inventors of the present application have found a cost effective and eco-friendly process for the preparation of Glycopyrronium bromide. Also, a process is disclosed in the present invention, wherein Glycopyrronium base is not isolated. The invention also addresses the purification issues and repeated recrystallizations.

Summary of the Invention

The present invention relates to a process for preparation of Glycopyrronium bromide comprises the step of
a) a process for preparation of Glycopyrronium bromide without isolation of Glycopyrronium base and
b) a novel process for the purification of Glycopyrronium bromide that comprises of dissolving Glycopyrronium bromide in methyl ethyl ketone or aqueous solution of methyl ethyl ketone and its isolation.

Detailed description of the invention

The present invention relates to a process for the preparation and purification to Glycopyrronium bromide.

The process of the invention is disclosed in Scheme (1) below.


Scheme 1: Process for the Preparation of Glycopyrrolate
One of the embodiments of the present invention relates to the process for the preparation of glycopyrrolate as depicted in Scheme (1). The process involves the reaction of methyl cyclopentyl mandelate with N-methyl pyrrolidinol in heptane in presence of sodium metal.

The methanol formed was removed by applying Dean and Stark assembly. Sodium metal is added in the reaction at regular interval and continued the reaction at reflux temperature till the completion of reaction which takes place about 4-8 hours.

Another embodiment of the present invention is related to the process for the preparation of Glycopyrronium bromide, which is prepared by reaction of glycopyrrolate in the solution of heptane with methyl bromide followed by quaternization. The Glycopyrrolate base is taken in heptane and cooled to -10 to 0 deg C temperature followed by methyl bromide solution in Isopropyl alcohol is added. The reaction mixture temperature is maintained to about 60 deg till reaction reached on completion. After completion of the reaction the solvent is removed to obtained residue. The residue is dissolved in the aqueous solution of methyl ethyl ketone. Reflux the reaction mixture to get clear solution. The reaction mixture is cooled to -5 - 10 deg C to isolate the product.

The present invention provide a one pot process for preparing Glycopyrronium bromide having enantiomeric purity more than 99%, when measured by HPLC. The process includes step following steps:
a) contacting methyl alpha cyclo mandelate and 1, methyl-3-pyrrolidinol in heptane,
b) treating the reaction mixture with saturated solution of methyl bromide in isopropyl alcohol,
c) removing solvent to get residue added aqueous solution of methyl ethyl ketone 1:4 (v/v) in residue,
d) reflux the reaction mixture to get clear solution,
e) isolate the product after cooling the reaction mass.

Yet another embodiment of the present invention is related to the process for the purification of Glycopyrronium bromide using mixture of methyl ethyl ketone and water. The Glycopyrronium bromide is dissolved in the aqueous solution of methyl ethyl ketone. Reflux the reaction mixture to get clear solution. The reaction mixture is cooled to -5 - 10 deg C and isolated product is filtered and dried, the product enantiomeric purity is 95.5% more, when measured by HPLC.

The product is isolate from the reaction mixture by the common technique known through prior art such as filtration under reduced pressure and centrifugation. The isolated product is dried in vacuum drier, tray drier and rotavapor drier.

In another embodiment the Glycopyrronium bromide having enantiomeric purity less than 95% prepared by any process known through various prior art like United States patent US 2,956,062 can be purified to enantiomeric purity 99.5% or more, when measured by HPLC.

By crystallization of Glycopyrronium bromide with aqueous solution of methyl ethyl ketone and isolate the improved purity material.

The aqueous solution of methyl ethyl ketone may contain water ratio is in the range 1: 1 to 1:5 (volume / volume). The preferred water content in methyl ethyl ketone is 1:4.

Another embodiment of the invention wherein the enantiomeric purity of the Glycopyrronium bromide is more than 95% and HPLC purity is 99.9% or more, when measured by HPLC.

Another embodiment of the invention wherein the Glycopyrronium bromide of enantiomeric purity 99.9% having melting point 194-196 deg C.

Another embodiment of the invention wherein Glycopyrronium bromide purify in the mixture water and methyl ethyl Ketone has enantiomeric purity 99.9% or more, when measured by HPLC.

The aforementioned process for the preparation and purification of Glycopyrrolate has the following advantages:
i) increased yields,
ii) use of less expensive reagents such as CDI,
iii) decrease in time cycle,
iv) increased purity and,
v) simple reaction conditions
vi) single step purification

The principles, preferred embodiments, and modes of operation of the present invention have been described in the foregoing examples. The invention, which is intended to be protected herein, however, is not to be construed limited to the particular forms disclosed, since these are to be regarded as illustrative rather than restrictive. Variations and changes may be made by those skilled in the art, without departing from the spirit of the invention.

Examples

Example 1: Preparation of Glycopyrronium Bromide:

Methyl alpha cyclopentyl mandelate (100 gm) was added to 1-methyl-3-pyrrolidinol (55gm) in heptane (1.2 L) and refluxed in a dean Stark assembly. The Sodium (1 gm) is added in four aliquots at reflux temperature. After the completion of the reaction, the mixture was cooled and washed with water. The Organic layer cooled to -5°C and isopropyl alcohol (500ml ) saturated with methyl bromide was added to the reaction mixture under stirring. The reaction mixture was further stirred at 50 to 55°C for an hour. The solvents were distilled and under reduced pressure.
Yield: 85 gm
HPLC Purity: 93%
Enantiomeric Purity: 88%

Example 2: Recrystallization Process 1
Glycopyrronium bromide (85 gm) was dissolved in a mixture of aqueous solution methyl ethyl ketone (water: methyl ethyl ketone ratio, 1:4) and refluxed. After a clear solution was obtained the reaction mixture was cooled gradually to 0-5°C and stirred for 2 hour. The solid was filtered and washed with methyl ethyl ketone: water and dried under reduced pressure in vacuum oven.
Yield: 33 gm.
HPLC Purity: 99.9%
Enantiomeric purity: 95.0%

Example 3: Recrystallization Process 2
Glycopyrronium bromide (30 gm, enantiomeric purity 95%) was dissolved in a 300 ml aqueous mixture methyl ethyl ketone (water: methyl ethyl ketone ratio, 1:5 (v/v)) and refluxed to get a clear solution. After completion of stirring for 2 hour the reaction mixture was cooled gradually to 0-5°C and stirred for 1 2 hour for complete crystallization. The crystallized was solid washed with aqueous methyl ethyl ketone were dried under reduced pressure in vacuum oven.
Yield: 25 gm.
HPLC Purity: 99.95%
Enantiomeric Purity: 99.95%