DESC:Field of the Invention:
The present invention relates to the process for the preparation of Umeclidinium bromide and to the process for the preparation of intermediates used in the preparation of umeclidinium bromide.

Background of the Invention:
Umeclidinium bromide (I), is an effective anticholinergic agent and has been used in the treatment of respiratory diseases such as asthma or chronic obstructive pulmonary diseases (COPD). Umeclidinium chemically known as 4-[hydroxy(diphenyl)methyl]-1-[2-(phenylmethyl)oxy]ethyl]-1-azoniabicyclo[2.2.2.]octane bromide is a long acting muscarinic antagonist used in treatment of airflow obstruction in patients with COPD.

(I)
WO 2005/104745 discloses the preparation of umeclidinium bromide wherein the yield key intermediate ethyl 1-(2-chloroethyl) piperidine-4-carboxylate is lower due to formation of dimer by-product. WO 2014/027045 discloses an alternative process for preparation of ethyl 1-(2-chloroethyl) piperidine-4-carboxylate. This process requires high temperature during the process and use of highly corrosive and toxic reagents like thionyl chloride. WO 2016/071792 discloses a process for preparation of ethyl 1-(2-chloroethyl)piperidine-4-carboxylate which involve the use of methanolic-aqueous acidic conditions which are not suitable to obtain product in high purity. WO 2011/029896 discloses an alternative process for the preparation of umeclidinium bromide which involves lengthy synthetic route and additional protection and deprotection steps.

Thus there is a long felt need to develop a more efficient process for the preparation of umeclidinium bromide. The process needs to overcome the disadvantages of the prior art processes like formation of dimer leading to poor yields, use of toxic reagents, use of extreme reaction conditions, use of lengthy and longer synthetic routes etc.

Summary of the invention:
The present invention provides a process for preparing umeclidinium bromide which involves the steps of:
a) reacting ethyl isonipecotate (II) with 1-2 disubstituted haloethane in the presence of an organic base and a solvent to form ethyl 1-(2-haloethyl)piperidine-4-carboxylate (III) or a salt thereof;
b) reacting ethyl 1-(2-haloethyl)piperidine-4-carboxylate (III) or a salt thereof with a base in the presence of solvent to form ethyl 1-azabicyclo[2.2.2]octane-4-carboxylate (IV);
c) reacting 1-azabicyclo[2.2.2]octane-4-carboxylate (IV) with phenyl lithium in the presence of solvent to form 1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (V);
d) reacting 1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (V) with ((2-bromoethoxy)methyl)benzene (VI) in a solvent to form umeclidinium bromide;
e) optionally recrystallizing umeclidinium bromide from a suitable solvent;
f) optionally micronizing umeclidinium bromide to obtain a product with a desired particle size.

Detailed Description of the invention:
The present invention provides an alternative process for the preparation of umeclidinium bromide as depicted in Scheme (I) below:

The present invention provides a process for preparing umeclidinium bromide which involves the steps of:
a) reacting ethyl isonipecotate (II) with 1-2 disubstituted haloethane in the presence of an organic base and a solvent to form ethyl 1-(2-haloethyl)piperidine-4-carboxylate (III) or a salt thereof;
b) reacting ethyl 1-(2-haloethyl)piperidine-4-carboxylate (III) or a salt thereof with a base in the presence of solvent to form ethyl 1-azabicyclo[2.2.2]octane-4-carboxylate (IV);
c) reacting 1-azabicyclo[2.2.2]octane-4-carboxylate (IV) with phenyl lithium in the presence of solvent to form 1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (V);
d) reacting 1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (V) with ((2-bromoethoxy)methyl)benzene (VI) in a solvent to form umeclidinium bromide;
e) optionally recrystallizing umeclidinium bromide from a suitable solvent;
f) optionally micronizing umeclidinium bromide to obtain a product with a desired particle size.

Step a of the present invention is carried out by reacting ethyl isonipecotate (II) with 1,2 disubstituted haloethane in the presence of an organic base and a solvent, at a temperature between 20-50°C to form ethyl 1-(2-haloethyl)piperidine-4-carboxylate (III). Optionally thereafter removing salt by conventional techniques and isolating the product ethyl 1-(2-haloethyl)piperidine-4-carboxylate (III).

The 1-2, disubstituted haloethane may be 1,2 dibromoethane, 1,2 dichloroethane, 1-bromo-2-chloro ethane, 1-bromo-2-iodo ethane or 1-chloro-2-iodo ethane.

The solvent used in step a may be selected from the group consisting of ketones such as acetone, esters such as ethyl acetate, cyclic ethers such as tetrahydrofuran; non-polar solvents such as n-heptane; water or mixtures thereof.

The organic base used in step a may be selected from the group consisting of organic bases such as amines like triethyl amine, pyridine, N-N-diisopropylethylamine, 4-(dimethylamino)pyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).

Step b of the present invention is carried out by reacting ethyl 1-(2-haloethyl)piperidine-4-carboxylate (III) or a salt thereof with a base in the presence of solvent at a temperature between 20-80°C to form ethyl 1-azabicyclo[2.2.2]octane-4-carboxylate (IV).

The solvent used in step b may be selected from the group consisting cyclic ethers such as tetrahydrofuran; aromatic solvents such as toluene; ethers such as dibutyl ether ; cyclohexane etc; or mixtures thereof. The most preferred solvent is tetrahydrofuran.

The base used in step b is selected from KHMDS, LiHMDS and NaHMDS.

The step c of the present invention is carried out by reacting reacting 1-azabicyclo[2.2.2]octane-4-carboxylate (IV) with phenyl lithium in the presence of solvent at a temperature of about -40 to 25°C to form 1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (V);

Step d of the present invention is carried out by reacting 1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (V) with ((2-bromoethoxy)methyl)benzene (VI) in a solvent, at temperature of 20-80°C to form umeclidinium bromide;

The solvent used in step d may be selected from the group consisting cyclic ethers such as tetrahydrofuran; aromatic solvents such as toluene; or mixtures thereof. The most preferred solvent is tetrahydrofuran. The product can be isolated by conventional known techniques like filtration and dried preferably under vacuum with a purity of > 98.9%.

Step e, the recrystallization of umeclidinium bromide can be done in group of solvents comprising of alcohols such as methanol, ethanol propanol, butanol, isobutanol, protic solvents such as water, ester solvents such as ethyl acetate, halogenated solvents such as dichloromethane, hydrocarbons such as hexane, heptane; nitriles such as acetonitrile or mixtures thereof.

Umeclidinium bromide obtained from the present invention can be micronized using conventional techniques to obtain the material with a desired particle size for the inhalation.

The following examples are provided to illustrate the process of the present are not intended to be construed as limitations of the present invention.

Examples

Example 1: Ethyl 1-(2-chloroethyl)piperidine-4-carboxylate (III; X=Cl)
Ethyl isonipecotate (10gm) was added in acetone (100 ml). The reaction mixture was stirred followed by addition of DBU (14.5 ml). To the reaction mixture 1-bromo-2-chloro ethane (10.6 ml) was added and the reaction mixture was stirred at room temperature for a period of 7-10 hours. After completion of the reaction, water (50 ml) was added and the pH was neutralized using HCl solution. The product was extracted in ethyl acetate followed by removal of solvent to get title compound.
Yield: 8 gm

Example 2: Ethyl 1-azabicyclo[2.2.2]octane-4-carboxylate (IV)
KHMDS (60 ml) and tetrahydrofuran were added in a flask, to which a solution of ethyl 1-(2-chloroethyl)piperidine-4-carboxylate (10 gm in 20 ml tetrahydrofuran) was added under stirring. The reaction was stirred for 24 hours. After the completion of the reaction ethanol (5.0 ml) and acetic acid (3.0 ml) were added to the reaction mixture. To the reaction mixture, water (50 ml) and ethyl acetate (50 ml) were added and the product was isolated by removal of solvent.
Yield: 6 gm

Example 3: 1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (V)
Phenyl Lithium (120 ml solution (1.9 M in THF)) was charged in a flask and cooled to -30 °C. To this solution was added ethyl 1-azabicyclo[2.2.2]octane-4-carboxylate (10 gm). The reaction mixture was stirred for 16-20 hours. After completion, the reaction mixture was quenched with water and the product was isolated by filtration.
Yield: 10 gm

Example 4: Preparation of Umeclidinium bromide.
1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (10 gm) was added in tetrahydrofuran (100 ml) followed by addition of ((2-bromoethoxy)methyl)benzene (10.3 gm). The reaction mixture was heated to 50-60°C and maintained for 24-hours. After completion of the reaction, it was further cooled and the product was isolated by filtration.
Yield: 12 gm
Purity: 98.9%
,CLAIMS:1) A process for the preparation of umeclidinium bromide consisting the steps of
a) reacting ethyl isonipecotate (II) with 1-2 disubstituted haloethane in the presence of an organic base and a solvent to form ethyl 1-(2-haloethyl)piperidine-4-carboxylate (III) or a salt thereof;
b) reacting ethyl 1-(2-haloethyl)piperidine-4-carboxylate (III) or a salt thereof with a base in the presence of solvent to form ethyl 1-azabicyclo[2.2.2]octane-4-carboxylate (IV);
c) reacting 1-azabicyclo[2.2.2]octane-4-carboxylate (IV) with phenyl lithium in the presence of solvent to form 1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (V);
d) reacting 1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (V) with ((2-bromoethoxy)methyl)benzene (VI) in a solvent to form umeclidinium bromide;
e) optionally recrystallizing umeclidinium bromide from a suitable solvent;
f) optionally micronizing umeclidinium bromide to obtain a product with a desired particle size.

2) A process according to claim 1, wherein 1-2 disubstituted haloethane in step a is selected from a group consisting of 1,2 dibromoethane, 1,2 dichloroethane, 1-bromo-2-chloro ethane, 1-bromo-2-iodo ethane and 1-chloro-2-iodo ethane.

3) A process according to claim 1, wherein organic base used in step a is selected from a group consisting of amines like triethyl amine, pyridine, N-N-diisopropylethylamine, 4-(dimethylamino)pyridine, and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).

4) A process according to claim 1 wherein solvent used in step a is selected from a group consisting of ketones such as acetone, esters such as ethyl acetate, cyclic ethers such as tetrahydrofuran; non-polar solvents such as n-heptane; water and mixtures thereof.

5) A process according to claim 1, wherein step a is carried out at a temperature of 20-50°C.

6) A process of claim 1, wherein solvent used in step b is selected from a group consisting of cyclic ethers such as tetrahydrofuran; aromatic solvents such as toluene; ethers such as dibutyl ether ; cyclohexane and mixtures thereof.

7) A process of claim 1, wherein the base used in step b is selected from KHMDS, LiHMDS and NaHMDS.

8) A process according to claim 1, wherein step b is carried out at a temperature of 20-80°C.

9) A process according to claim 1, wherein step c is carried out at a temperature of -40 to 25°C.

10) A process of claim 1, wherein solvent used in step d is selected from a group consisting of cyclic ethers such as tetrahydrofuran; aromatic solvents such as toluene; and mixtures thereof.

11) A process of claim 1, wherein solvent used in step e is selected from a group consisting of alcohols such as methanol, ethanol propanol, butanol, isobutanol, protic solvents such as water, ester solvents such as ethyl acetate, halogenated solvents such as dichloromethane, hydrocarbons such as hexane, heptane; nitriles such as acetonitrile and mixtures thereof.

12) A process according to claim 1, wherein umeclidinium bromide is obtained with a purity greater than 98%.