T H E R E OF

This application claims priority to Indian Provisional Patent Application No. 201741005254 filed on 14 February 2017, which is incorporated herein in its entirety.

F ield of the invention:

The present invention relates to a process for preparation of aclidinium bromide and more particularly, to a process for preparing aclidinium bromide and intermediates thereof.

Background of the invention:

Chronic obstructive pulmonary disease (COPD) is mainly known by prolonged inflammatory changes that occur from exposure of the lungs and airway to noxious gas particles (e.g., tobacco smoke, occupational dust, and chemicals), resulting in airflow obstruction. COPD can be prevented and treated, however it causes significant extrapulmonary effects that contribute to disease severity. Over the past two decades, there has been a significant increase i n the preval ence of C O P D .

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 know agents for effective treatment of respiratory disorders. . Aclidinium is a synthetic anticholinergic agent that is used as an inhalant for treatment of acute bronchospasm due to respiratory disorders. It is an anticholinergic bronchodilator that is used in the management of chronic obstructive pulmonary disease. Aclidinium bromide is a white powder. Its molecular formula is C ₂₆ H ₃₀ NO ₄ S ₂ Br, and it has a molecular mass of 564.56. The chemical structure is

Many known processes of synthesis of aclidinium bromide involve esterifi cation, transesterificatioen and requires excess of the alkylation agent, long reaction times or chlorinated solvents. The preparation of aclidinium bromide on commercial scale becomes difficult via route of synthesis disclosed in art.

Accordingly there is a need in the art for efficient, eco-friendly, non- hazardous and cost effective methods of synthesis of pharmaceutical grade aclidinium bromide 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 synthesis of aclidinium bromide and intermediates thereof. The process for synthesis of aclidinium bromide comprises the steps of:

(i) acylating quinuclidinol of Formula 2 with methyl chlorooxoacetate to obtain an intermediate of Formula 3;

(ii) a Grignard reaction of the intermediate of Formula 3 with 2-bromothiophene to obtain an intermediate of Formula 4;

(iii) N-alkylating the intermediate of Formula 4 with (3- bronnopropoxy) benzene to obtain a compound of Formula 1.

In another aspect in the acylation step, quinuclidinol of Formula 2 is acylated with methyl oxalic acid monomethyl ester or dimethyl oxalate.

In yet another aspect, in the acylation step, quinuclidinol of Formula 2 is acylated with methyl oxalic acid monomethyl ester or dimethyl oxalate.

Acylation is conducted in dichloromethane at a temperature of 0 °C. Further, N-alkylation of the intermediate of Formula 4 is with (3-bromopropoxy)benzene. During N-alkylation the solvent is a mixture of acetonitrile and chloroform. By converting intermediate of Formula 4 to Formula 1 by N-alkylation of the intermediate of Formula 4 with (3- bromopropoxy) benzene, aclidinium bromide of Formula 1 is obtained.

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 and functions for clear description of the present invention. The present invention is illustrated with reference to the accompanying drawings, throughout which reference numbers indicate corresponding parts in the various figures.

Previously known methods for synthesis of aclidinium bromide comprised esterifi cation, transesterifi cation and required excess of the alkylation agent, long reaction times or chlorinated solvents. By contrast, described herein are processes wherein the preparation of aclidinium bromide is achieved by initially acylating quinuclidinol with methyl chlorooxoacetate or oxalic acid monomethyl ester followed by reactions with intermediates, as described in more detail in the Examples section.

In general aspect, the present invention provides a process for the preparation of aclidinium 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 aclidinium bromide. The process comprises:

(i) acylating quinuclidinol of Formula 2 with methyl chlorooxoacetate to obtain an intermediate of Formula 3;

(ii) a Grignard reaction of the intermediate of Formula 3 with 2-bromothiophene to obtain an intermediate of Formula 4;

(iii) N-alkylating the intermediate of Formula 4 with (3-bromopropoxy)benzene to obtain a compound of Formula 1.

In this embodiment, the solvents are selected from chloroform, dichloromethane, dichloroethylene, acetonitrile, toluene, tetrahydrofuran and dimethyl ether, and the like. The reaction of quinuclidinol (Formula 2) with methyl chlorooxoacetate is conducted at about 0 °C although other possible temperatures are readily apparent to one of skill in the art and are contemplated within the scope of embodiments described herein. The reaction is conducted in aprotic solvents such as dichloromethane (DC M), dichloroethane (DCE), chloroform, tetrahydrofuran (T H F) and the like, preferably in DCM. Other reagents may be used instead of methyl chlorooxoacetate including and not limited to oxalic acid monomethyl ester, dimethyl oxalate and the like.

The Grignard reaction of the intermediate of Formula 3 with 2-bromothiophene is initiated at ambient temperature, although other higher or lower temperatures will be readily apparent to one of skill in the art and are contemplated within the scope of embodiments described herein. In another embodiment, provided herein is a process for preparation of aclidinium bromide. The process comprises:

(i) acylating quinuclidinol of Formula 2 with oxalic acid monomethyl ester to obtain an intermediate of free base of Formula 3;

(ii) a Grignard reaction of the intermediate of free base form of Formula 3 with 2- bromothiophene to obtain an intermediate of Formula 4;

(iii) N-alkylating of the intermediate of Formula 4 with (3- bromopropoxy) benzene to obtain a compound of Formula 1.

In this embodiment, the solvents are selected from chloroform, dichloromethane, dichloroethylene, acetonitrile, toluene, tetrahydrofuran and dimethyl ether, and the like. The reaction of quinuclidinol (Formula 2) with methyl chlorooxoacetate is conducted at about 0 °C although other possible temperatures are readily apparent to one of skill in the art and are contemplated within the scope of embodiments described herein. The reaction is conducted in aprotic solvents such as dichloromethane (DC M), dichloroethane (DCE), chloroform, tetrahydrofuran (T H F) and the like, preferably in DCM. Other reagents may be used instead of methyl chlorooxoacetate including and not limited to oxalic acid monomethyl ester, dimethyl oxalate and the like.

The Grignard reaction of the intermediate of Formula 3 with 2-bromothiophene is initiated at ambient temperature, although other higher or lower temperatures will be readily apparent to one of skill in the art and are contemplated within the scope of embodiments described herein.

In yet another embodiment, provided herein is a process for preparation of aclidinium bromide. The process comprises:

(i) acylating quinuclidinol of Formula 2 with dimethyl oxalate to obtain an intermediate of free base of Formula 3;

(ii) a Grignard reaction of the intermediate of free base form of Formula 3 with 2- bromothiophene to obtain an intermediate of Formula 4;

(iii) N-alkylating of the intermediate of Formula 4 with (3- bromopropoxy) benzene to obtain a compound of Formula 1.

In this embodiment, the solvents are selected from chloroform, dichloromethane, dichloroethylene, acetonitrile, toluene, tetrahydrofuran and dimethyl ether, and the like. The reaction of quinuclidinol (Formula 2) with methyl chlorooxoacetate is conducted at about 0 °C although other possible temperatures are readily apparent to one of skill in the art and are contemplated within the scope of embodiments described herein. The reaction is conducted in aprotic solvents such as dichloromethane (DC M), dichloroethane (DCE), chloroform, tetrahydrofuran (T H F) and the like, preferably in DCM. Other reagents may be used instead of methyl chlorooxoacetate including and not limited to oxalic acid monomethyl ester, dimethyl oxalate and the like.

The Grignard reaction of the intermediate of Formula 3 with 2-bromothiophene is initiated at ambient temperature, although other higher or lower temperatures will be readily apparent to one of skill in the art and are contemplated within the scope of embodiments described herein. The reaction schemes of preparing compound of Formula 1 is represented below:

EXA M PL E S

T he f ol I owi ng exampl es i 11 ustrate the i nventi on, but are not I i miti ng thereof.

E xample 1A: Acylation of quinuclidinol with methyl chlorooxoacetate

To a stirred solution of (R)-quinuclidinol (1, 1 equiv) in dichloromethane was added methyl chlorooxoacetate (2, 1.1 equiv) at 0 °C under nitrogen atmosphere for 5 min. The resulting sol uti on was al lowed to sti r at room temperature for 12h. Solvent was removed under reduced pressure. This was followed by washing with diethyl ether to obtain the intermediate of Formula 3 in the form of white solid.

E xample 1 B: Acylation of quinuclidinol with oxalic acid monomethyl ester

To a stirred solution of (R)-quinuclidinol (1, 1 equiv) in dichloromethane was added oxalic acid monomethyl ester at 0 °C under nitrogen atmosphere for 5 min. The resulting solution was allowed to stir at room temperature for 12h. Solvent was removed under reduced pressure. This was followed by washing with diethyl ether to obtain the intermediate of free base form of Formula 3 in the form of white solid.

E xample 1 C : Acylation of quinuclidinol with dimethyl oxalate

To a stirred solution of (R)-quinuclidinol (1, 1 equiv) in dichloromethane was added dimethyl oxalate at 0 °C under nitrogen atmosphere for 5 min. The resulting solution was allowed to stir at room temperature for 12h. Solvent was removed under reduced pressure. This was followed by washing with diethyl ether to obtain the intermediate of free base form of Formula 3 in the form of white solid.

E xample 2: G rignard reaction of (3) with 2-bromothiophene (4)

To the suspension of 2-bromothiophene (4, 2.2 equiv) and Mg metal (2.2 equiv) in TH F (15 mL) was added 1,2-dibromoethane to initiate the reaction. The remaining solution was added over a period of 30 min. After stirring for 1 h, the intermediate of (3) was added in portions over a period of 20 min. Upon completion, the mixture was poured into ice water and extracted with ethyl acetate. The organic layer was separated and concentrated in vaccum. The crude product was further purified by flash column chromatography on silica gel (60-120 mesh) using MeOH/DC M (1/6, v/v) to obtain the intermediate (5).

E xample 3: N-Alkylation of (5) with (3-bromopropoxy)benzene

To a solution of intermediate of (5) (1 equiv) in acetonitrile and chloroform mixture (10 mL, 2:3) was added (3- bromopropoxy) benzene (6, 3 mmol). The resulting mixture was stirred at room temperature for 72h. The solvents were evaporated, and the residue was washed with diethyl ether to obtain the pure product (7) in the form of white solid.

The process for the preparation of aclidinium bromide shows increase in % yield of aclidinium bromide by about 70% to 90%. The process for the preparation of aclidinium bromide advantageously involves simplified steps and avoids use of expensive reagents, solvents, chemicals, and the like. The process of the present invention is suitable for the preparation of aclidinium bromide on commercial scale and advantageously avoids multiple numbers of steps of synthesis. The process of the present invention saves the overall processing time, avoids use of hazardous chemicals and also reduces the manufacturing cost by around 30% to 40 %.

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.