DESC:FORM 2
THE PATENTS ACT, 1970
(39 OF 1970)
&
THE PATENTS RULE, 2003
COMPLETE SPECIFICATION
[See section 10, Rule 13]
A PROCESS FOR THE PREPARATION OF UMECLIDINIUM BROMIDE AND INTERMEDIATES THEREOF;

GBR LABORATORIES PVT. LTD., AN INDIAN COMPANY, WHOSE ADDRESS IS HNO 5-7-209/2, SRIPURAM COLONY, BN REDDY NAGAR, VANASTHALIPURAM, HYDERABAD-500070, TELANGANA, INDIA
AND
RACHANA PHARMA TECH, AN INDIAN COMPANY, WHOSE ADDRESS IS FLAT NO 404, B-BLOCK, SURYA TOWERS, ROAD NO-2, SNEHAPURI COLONY, NACHARAM, HYDERABAD - 500076, TELANGANA, INDIA

THE FOLLOWING SPECIFICATION PARTICULARLY DESCRIBES THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED.
FIELD OF THE INVENTION
This disclosure relates to an improved process for the preparation of umeclidinium bromide.
BACKGROUND OF THE INVENTION
Umeclidinium is a long-acting muscarinic antagonist (LAMA) used as maintenance treatment for symptoms of chronic obstructive pulmonary disease (COPD). It is used as an inhalation monotherapy or as a fixed-dose combination product with the long-acting beta2-agonist vilanterol. COPD is a progressive obstructive lung disease characterized by shortness of breath, cough, sputum production, and chronically poor airflow with a forced expiratory volume in 1 second (FEV1) of less than 80%. By blocking the M3 muscarinic receptor which is highly expressed in airway smooth muscle of the lungs, umeclidinium inhibits the binding of acetylcholine and thereby opens up the airways by preventing bronchoconstriction. Its use has been shown to provide clinically significant, sustained improvements in lung function.
The objective of COPD therapy is mainly towards instant relief, symptoms reduction, as well as decreased risk of future adverse health events. Bronchodilators are essential for management in COPD. The choice between beta2-agonists, anticholinergic agents, theophylline, or combination therapy depends on availability of these drugs and patient response. Two long-acting anticholinergic agents are approved for the long-term maintenance treatment of bronchospasm associated with COPD: tiotropium bromide and aclidinium bromide are the well known agents for effective treatment of respiratory disorders. .
The known processes of synthesis of umeclidinium bromide include lithium reagent, bromobenzene, chlorobenzene and other benzene halides as the starting material and requires long reaction times or solvents. The preparation of umeclidinium bromide becomes difficult on commercial scale via route of synthesis disclosed in art.
Accordingly there is need of a synthetic, eco-friendly, non- hazardous and cost effective process for the preparation of umeclidinium bromide and intermediates with high yield and purity thereof that overcomes the above mentioned drawbacks of the prior art.
Summary of the invention:
In one aspect, described herein is a process for preparation of umeclidinium bromide and intermediates thereof. The process for preparation of umeclidinium bromide comprises the steps of:
i. mixing 4-bromoquinuclidine with a predefined quantity of a metal and a catalyst in a solvent to obtain a mixture of 4-bromoquinuclidine of Formula 2;
ii. reacting the mixture of 4-bromoquinuclidine of Formula 2 with benzophenone in the solvent, to form an intermediate of Formula 3;

iii. forming quaternary salt of Formula 1 by;
a. mixing the intermediate of Formula 3 in a solvent mixture; and
b. reacting with ((2-bromoethoxy)methyl)benzene to form a white solid quaternary salt of Formula 1.

The process further comprises the step of pouring the reaction mixture of step (i) upon adding benzophenone into ice water; extracting with ethyl acetate; and separating the organic layer. The organic layer in concentrated in vacuum and is crystallized to obtain the purified product of Formula 3. Step (i) is conducted at an ambient temperature. The solvent in step (ii) (a) is a mixture of acetonitrile and chloroform. The metal in step (i) is a magnesium metal. The catalyst in step (i) is iodine. Further, the solvent in step (i) is tetrahydrofuran (THF). However, it is to be noted that in alternative embodiments, the type of metal and type of catalyst may vary. The quaternary salt of Formula 1 has a purity of between 98 % to 100% and the yield of umeclidinium bromide is about 20 % to 25%.
Detailed description of the invention:
The foregoing objects of the present invention are accomplished and the problems and shortcomings associated with the prior art, techniques and approaches are overcome by the present invention as described below in the preferred embodiments.
All materials used herein were commercially purchased as described herein or prepared from commercially purchased materials as described herein.
Although specific terms are used in the following description for sake of clarity, these terms are intended to refer only to particular structure of the invention selected for illustration in the drawings and are not intended to define or limit the scope of the invention.
References in the specification to “preferred embodiment” means that a particular feature, structure, characteristic, or function described in detail thereby omitting known constructions 20 and functions for clear description of the present invention.
In general aspect, the present invention provides a process for preparation of umeclidinium bromide and intermediates thereof. The process of the present invention is a synthetic, eco-friendly, non- hazardous and cost effective process.
In an embodiment, provided herein is a process for preparation of umeclidinium bromide and intermediates thereof. The process comprises:
i. mixing 4-bromoquinuclidine with a predefined quantity of a metal and a catalyst in a solvent to obtain a mixture of 4-bromoquinuclidine of Formula 2;
ii. reacting the mixture of 4-bromoquinuclidine, of Formula 2 with benzophenone in a solvent, to form an intermediate of Formula 3;

iii. forming quaternary salt of Formula 1 by;
a. mixing the intermediate of formula 3 in a solvent mixture; and
b. reacting with ((2-bromoethoxy)methyl)benzene to form a white solid quaternary salt of Formula 1.

At an initial step of the Grignard’s reaction, 4-bromoquinuclidine is stirred with a metal and a catalyst in a solvent to obtain a mixture of 4-bromoquinuclidine. Step (i) is initiated at a temperature range of 70 oC to 80 oC. The reaction of mixture of 4-bromoquinuclidine of Formula 2 with benzophenone is initiated at ambient temperature of 25 oC for a predefined period of time. The solution of benzophenone in the solvent is added in portions over a predefined period of time. The reaction is conducted in aprotic solvents such as chloroform, dichloromethane (DCM), dichloroethane, acetonitrile, toluene, tetrahydrofuran (THF) and dimethyl ether and the like, preferably in THF.
Upon completion of addition of benzophenone, the reaction mixture was poured into ice water and extracted with ethyl acetate. The intermediate of Formula 3 is mixed with solvent mixture of acetonitrile and chloroform before reacting with ((2-bromoethoxy)methyl)benzene. The pure form of white solid quaternary salt of Formula 1 was obtained by washing the resulting residue with diethyl ether.
Advantageously, the process is conducted under mild conditions to obtain a pure form of quaternary salt of Formula 1. The quaternary salt of Formula 1 has a purity of about 98 % to 100%. The yield of umeclidinium bromide of Formula 1 is about 20 % to 25%.
In some embodiments of the reaction, the metal is selected from magnesium,
zinc, indium, and lithium.
In some embodiments of the reaction, the catalyst is selected from iodine, ultrasound, and heat.
In some embodiments of the reaction, the solvents are selected from chloroform, dichloromethane, dichloroethane, acetonitrile, toluene, tetrahydrofuran (THF), dimethyl ether, and a combination thereof.
The reaction scheme of preparing compound of Formula 1 is represented below:

EXAMPLES
The following examples illustrate the invention, but are not limiting thereof.

Example 1: Grignard reaction of 4-bromoquinuclidine (1)
To a mixture of 4-bromoquinuclidine (1) (2.0 equiv), Mg metal (2.0 equiv) and a catalytic amount of iodine (0.05 equiv) in THF (15 mL) was stirred over a period of 30 min at 0 °C. To this mixture, a solution of benzophenone (2) (1 equiv) in THF was added in portions over a period of 30 min. Upon completion of addition of benzophenone, the reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was separated and concentrated in vacuum. The resulting residue was purified by crystallization to obtain the pure product (3).

Example 2: Quaternary salt formation
To an intermediate (3) (1 equiv), mixture of acetonitrile and chloroform (10 mL, 2:3) and ((2-bromoethoxy)methyl)benzene (4) was added. The mixture was stirred at room temperature for 35 to 48h. The solvents, acetonitrile and chloroform were evaporated, and the resulting residue was washed with diethyl ether to obtain a pure form of quaternary salt of (5) as a white solid.

The process for the preparation of umeclidinium bromide advantageously avoids multiple numbers of steps of synthesis. The process shows increase in % yield of umeclidinium bromide by about 20 % to 25%. The process for the preparation of umeclidinium bromide advantageously involves simplified steps and advantageously avoids use of expensive reagents, solvents, chemicals, and the like. Further, the process for the preparation of umeclidinium bromide saves the processing time avoids use of hazardous chemicals. The process of the present invention is suitable for the preparation of umeclidinium bromide on commercial scale, thereby reducing the manufacturing cost by around 20% to 30%.
The foregoing description of specific embodiments of the present invention has been presented for purposes of illustration and description. They are not intended to be exhaustive or to limit the present invention to the precise forms disclosed, and obviously many modifications and variations are possible in light of the above teaching.
The embodiments were chosen and described in order to best explain the principles of the present invention and its practical application, to thereby enable others, skilled in the art to best utilize the present invention and various embodiments with various modifications as are suited to the particular use contemplated.
It is understood that various omission and substitutions of equivalents are contemplated as circumstance may suggest or render expedient, but such are intended to cover the application or implementation without departing from the spirit or scope of the present invention.

,CLAIMS:We claim:
1. A process for preparation of umeclidinium bromide comprising:
i. mixing 4-bromoquinuclidine with a predefined quantity of a metal and a catalyst in a solvent to obtain a mixture of 4-bromoquinuclidine of Formula 2;
ii. reacting 4-bromoquinuclidine, of Formula 2 with benzophenone in a solvent, to form an intermediate of Formula 3;

iii. forming quaternary salt of Formula 1 by;
a. mixing the intermediate of Formula 3 in a solvent mixture; and
b. reacting with ((2-bromoethoxy)methyl)benzene to form a white solid quaternary salt of Formula 1.

2. The process as claimed in claim 1, further comprises the step of :
i. pouring the reaction mixture of step (i) upon adding benzophenone into ice water;
ii. extracting with ethyl acetate; and
iii. separating the organic layer.
3. The process as claimed in claim 2 further comprises concentrating the organic layer in vacuum and crystallizing the purified product of Formula III.
4. The process as claimed in claim 1, wherein the metal in step (i) is a magnesium metal, catalyst in step (i) is iodine and the solvent in step (i) is tetrahydrofuran (THF).
5. The process as claimed in claim 1, wherein step (i) is conducted at a temperature range of 70 oC to 80 oC.
6. The process as claimed in claim 1, wherein the solvent in step (ii) (a) is a mixture of acetonitrile and chloroform.
7. The process of claim 1, wherein the quaternary salt of Formula 1 has a purity of 98% to 100%.
8. The process of claims 1 to 7, wherein the yield of umeclidinium bromide is about 20% to 25%.

Dated this 8th day of March, 2017.

For GBR Laboratories Pvt. Ltd. and Rachana Pharma Tech
by their Agent

(ANAND GOPALKRISHNA MAHURKAR) (IN/PA 1862),
KRISHNA & SAURASTRI ASSOCIATES LLP