DESC:FIELD
The present disclosure relates to a process for the preparation of 2-(piperidin-4-yl)-1H-benzo[d]imidazole.
BACKGROUND
The background information hereinbelow relates to the present disclosure but is not necessarily prior art.
Bilastine is a non-sedating H1-antihistamine drug which is safe and effective for treating allergic rhinoconjunctivitis (sneezing, itchy nose, nasal secretion, nasal congestion, and red streaming eyes) and other forms of allergic rhinitis. It can also be used to treat itchy skin rashes (wheals or urticaria). The chemical name of Bilastine is 2-[4-[2-[4-[1-(2-ethoxyethyl) benzimidazol-2-yl]piperidin-1-yl]ethyl]phenyl]-2-methylpropionic acid and has the following chemical structure:

2-(piperidin-4-yl)-1H-benzo[d]imidazole is an important intermediate used in the preparation of Bilastine.

2-(piperidin-4-yl)-1H-benzo[d]imidazole
Conventionally, the process for preparing 2-(piperidin-4-yl)-1H-benzo[d]imidazole (Bilastine intermediate) utilizes polyphosphoric acid (PPA) which leads to the formation of thick mass and hence faces challenges during the isolation and purification process. Further, the neutralization of PPA with a base generates a higher amount of inorganic salts. It is also observed that the conventional processes are carried out at a high temperature, which leads to the formation of higher amounts of organic impurities hence are not feasible for commercial scale. The isolated material obtained via the conventional route has purity in the range of 60% to 70% and impurity in the range of 15% to 17%. Further, the use of polyphosphoric acid (PPA) is not environment friendly. Also, conventional processes for the preparation of 2-(piperidin-4-yl)-1H-benzo[d]imidazole uses high-cost chemical reagents such as 2, 3-Dichloro-5, 6-dicyano-1, 4-benzoquinone (DDQ), or lead (IV) acetate (Pb(OAc)4 in the reaction which are toxic and may lead to environmental hazards. Further, when the concentrated hydrochloric acid is used in the process, the reaction is required to maintain at a longer time period.
Therefore, there is felt a need to provide a process for preparing 2-(piperidin-4-yl)-1H-benzo[d]imidazole (Bilastine intermediate) that mitigates the drawbacks mentioned hereinabove or at least provide an alternate solution.
OBJECTS
Some of the objects of the present disclosure, which at least one embodiment herein satisfies, are as follows:
An object of the present disclosure is to ameliorate one or more problems of the prior art or to at least provide a useful alternative.
Another object of the present disclosure is to provide a process for the preparation of 2-(piperidin-4-yl)-1H-benzo[d]imidazole.
Yet another object of the present disclosure is to provide a process for the preparation of 2-(piperidin-4-yl)-1H-benzo[d]imidazole which involves the use of inexpensive and environment friendly reagents.
Another object of the present disclosure is to provide a process for the preparation of 2-(piperidin-4-yl)-1H-benzo[d]imidazole by using easily available reagents.
Still another object of the present disclosure is to provide a process for the preparation of 2-(piperidin-4-yl)-1H-benzo[d]imidazole which is commercially scaled up with reduced reaction time.
Other objects and advantages of the present disclosure will be more apparent from the following description, which is not intended to limit the scope of the present disclosure.
SUMMARY
The present disclosure relates to a process for the preparation of 2-(piperidin-4-yl)-1H-benzo[d]imidazole. The process comprises reacting o-phenylenediamine with an acid in a first fluid medium at a first predetermined temperature for a first predetermined time period to obtain a first reaction mixture. The first reaction mixture is reacted with a predetermined amount of isonipecotic acid in a second fluid medium at a temperature in the range of 120ºC to 140ºC for a second predetermined time period to obtain a second reaction mixture. The second reaction mixture is basified by using at least one base to obtain 2-(piperidin-4-yl)-1H-benzo[d]imidazole.
DETAILED DESCRIPTION
Embodiments are provided so as to thoroughly and fully convey the scope of the present disclosure to the person skilled in the art. Numerous details are set forth, relating to specific components, and methods, to provide a complete understanding of embodiments of the present disclosure. It will be apparent to the person skilled in the art that the details provided in the embodiments should not be construed to limit the scope of the present disclosure. In some embodiments, well-known processes, well-known apparatus structures, and well-known techniques are not described in detail.
The terminology used, in the present disclosure, is only for the purpose of explaining a particular embodiment and such terminology shall not be considered to limit the scope of the present disclosure. As used in the present disclosure, the forms "a,” "an," and "the" may be intended to include the plural forms as well, unless the context clearly suggests otherwise. The terms "comprises," "comprising," “including,” and “having,” are open ended transitional phrases and therefore specify the presence of stated features, integers, steps, operations, elements, modules, units and/or components, but do not forbid the presence or addition of one or more other features, integers, steps, operations, elements, components, and/or groups thereof. The particular order of steps disclosed in the method and process of the present disclosure is not to be construed as necessarily requiring their performance as described or illustrated. It is also to be understood that additional or alternative steps may be employed.
The terms first, second, third, etc., should not be construed to limit the scope of the present disclosure as the aforementioned terms may be only used to distinguish one element, component, region, layer or section from another component, region, layer or section. Terms such as first, second, third etc., when used herein do not imply a specific sequence or order unless clearly suggested by the present disclosure.
Bilastine is a second generation antihistamine compound for the treatment of allergic rhinoconjunctivitis and urticaria (hives).
Bilastine is represented as Formula (I)

Formula I
2-[4-[2-[4-[1-(2-ethoxyethyl) benzimidazol-2-yl]piperidin-1-yl]ethyl]phenyl]-2-methylpropionic acid
Chemical formula: C28H37N3O3
Molar mass: 463.622 g•mol-1
2-(piperidin-4-yl)-1H-benzo[d]imidazole is an important intermediate for the preparation of Bilastine.
Conventionally, the process for preparing 2-(piperidin-4-yl)-1H-benzo[d]imidazole (Bilastine intermediate) utilizes polyphosphoric acid (PPA) which leads to the formation of thick mass and hence faces challenges during the isolation and purification process. Further, the neutralization of PPA with a base generates a higher amount of inorganic salts. It is also observed that the conventional processes are carried out at a high temperature, which leads to the formation of higher amounts of organic impurities hence are not feasible for commercial scale. The isolated material obtained via the conventional route has purity in the range of 60% to 70% and impurity in the range of 15% to 17%. Further, the use of polyphosphoric acid (PPA) is not environment friendly. Also, conventional processes for the preparation of 2-(piperidin-4-yl)-1H-benzo[d]imidazole uses high-cost chemical reagents such as 2, 3-Dichloro-5, 6-dicyano-1, 4-benzoquinone (DDQ), or lead (IV) acetate (Pb(OAc)4 in the reaction which are toxic and may lead to environmental hazards. Further, when the concentrated hydrochloric acid is used in the process, the reaction is required to maintain at a longer time period.
There is a need for developing a relatively simple, less toxic, safe, commercially feasible process for the preparation of 2-(piperidin-4-yl)-1H-benzo[d]imidazole) that involves the use of inexpensive, environment friendly reagents.
The present disclosure relates to a process for the preparation of 2-(piperidin-4-yl)-1H-benzo[d]imidazole).
2-(piperidin-4-yl)-1H-benzo[d]imidazole) is represented by the formula (II):

Formula II
The process of the present disclosure is commercially viable, industrially advantageous, environment friendly, cost-effective and provides 2-(piperidin-4-yl)-1H-benzo[d]imidazole with comparatively better yield and purity.
A schematic representation for the process of preparation of (2-(piperidin-4-yl)-1H-benzo[d]imidazole) is as given below:

Scheme-I

Scheme-II

The present disclosure is related to the process for preparing 2-(piperidin-4-yl)-1H-benzo[d]imidazole.
The process is described in detail.
In a first step, o-phenylenediamine with an acid is reacted in a first fluid medium at a first predetermined temperature for a first predetermined time period to obtain a first reaction mixture.
Particularly, in the first step, o-phenylenediamine is mixed with the first fluid medium under stirring at a first predetermined temperature to obtain a mixture. To the mixture, an acid is added under stirring for a first predetermined time period to obtain a first reaction mixture. The first reaction mixture is filtered followed by washing with the first fluid medium to obtain a cake comprising o-phenylenediamine salt.
In accordance with an embodiment of the present disclosure, the first fluid medium is at least one selected from acetonitrile, and ethylene glycol. In an exemplary embodiment, the first fluid medium is acetonitrile. In another exemplary embodiment, the first fluid medium is ethylene glycol.
In accordance with an embodiment of the present disclosure, the first predetermined temperature is in the range of 0ºC to 5ºC. In an exemplary embodiment, the first predetermined temperature is 2ºC.
In accordance with an embodiment of the present disclosure, the acid is at least one selected from the group consisting of orthophosphoric acid, HCl and H2SO4. In an exemplary embodiment, the acid is orthophosphoric acid. In another exemplary embodiment, the acid is HCl.
In accordance with an embodiment of the present disclosure, the first predetermined time period is in the range of 2 hours to 6 hours, preferably 4 hours. In an exemplary embodiment, the first predetermined time period is 4 hrs.
In accordance with an embodiment of the present disclosure, a mole ratio of the o-phenylenediamine to the acid is in the range of 1:2.5 to 1:3.5. In an exemplary embodiment, the mole ratio of the o-phenylenediamine to the orthophosphoric acid is 1:3.
The schematic representation of the preparation of o-phenylenediamine salt in accordance with the present disclosure is given below as Scheme I.

Scheme I
In a second step, the first reaction mixture is reacted with isonipecotic acid at a temperature in the range of 120ºC to 140ºC for a second predetermined time period to obtain a second reaction mixture.
Particularly, in the second step, the cake (obtained after filtering the first reaction mixture) is mixed with a second fluid medium followed by adding a predetermined amount of isonipecotic acid and reacting at a temperature in the range of 120ºC to 140ºC for a second predetermined time period to obtain a second reaction mixture.
In accordance with an embodiment of the present disclosure, the second fluid medium is at least one selected from the group consisting of ethylene glycol, 2-methoxy ethanol, and 2-ethoxy ethanol. In an exemplary embodiment, the second fluid medium is ethylene glycol.
The second fluid medium having a boiling point of more than 120°C is desirable since the complete conversion of the reaction is done at a temperature more than 120ºC.
In an exemplary embodiment, the temperature is 125ºC. In another exemplary embodiment, the temperature is 135ºC.
In accordance with an embodiment of the present disclosure, the second predetermined time period is in the range of 12 hours to 24 hours, preferably 16 hours to 24 hours. In an exemplary embodiment, the second predetermined time period is 18 hours.
In a third step, the second reaction mixture is basified by using at least one base to obtain 2-(piperidin-4-yl)-1H-benzo[d]imidazole.
Particularly, in the third step, the second reaction mixture is cooled at room temperature followed by adding water and basified by using at least one base till the pH of the second reaction mixture is in the range of pH 8 to 14 to obtain a reaction mass. The reaction mass was filtered and washed with water to obtain 2-(piperidin-4-yl)-1H-benzo[d]imidazole.
The schematic representation of the preparation of 2-(piperidin-4-yl)-1H-benzo[d]imidazole in accordance with the present disclosure is given below as Scheme II.
Scheme II
In accordance with an embodiment of the present disclosure, the base is in an aqueous form. In accordance with an embodiment of the present disclosure, the base is at least one selected from the group consisting of sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, and calcium carbonate. In an exemplary embodiment, the base is sodium hydroxide solution.
In accordance with an embodiment of the present disclosure, a mole ratio of the o-phenylenediamine to the isonipecotic acid is in the range of 1:0.9 to 1:1.4. In an exemplary embodiment, the mole ratio of the o-phenylenediamine to the isonipecotic acid is 1:1. In another exemplary embodiment, the mole ratio of the o-phenylenediamine to the isonipecotic acid is 1:1.2. In still another exemplary embodiment, the mole ratio of the o-phenylenediamine to the isonipecotic acid is 1:1.3.
The optimum temperature and the specific ratio of –phenylenediamine, acid and isonipecotic acid are essential to produce 2-(piperidin-4-yl)-1H-benzo[d]imidazole with a purity of more than 94% and yield of more than 79%. The specific ratio of o-phenylenediamine to isonipecotic acid and the reaction temperature (more than 120oC) reduces the time period required for completing the reaction.
The reagents used in the process for preparing 2-(piperidin-4-yl)-1H-benzo[d]imidazole are easily available and relatively low in cost, rendering the process convenient with low production cost.
The process for the preparation of 2-(piperidin-4-yl)-1H-benzo[d]imidazole of the present disclosure has simple and convenient operations; environment friendly and suitable for industrial applications. Further, the process of the present disclosure provides an improved yield of the product with easy purification steps, low production costs, use less toxic, commercially feasible, and easily available reagents.
The purity of the so obtained product is in the range of 94% to 99%.
The foregoing description of the embodiments has been provided for purposes of illustration and is not intended to limit the scope of the present disclosure. Individual components of a particular embodiment are generally not limited to that particular embodiment but are interchangeable. Such variations are not to be regarded as a departure from the present disclosure, and all such modifications are considered to be within the scope of the present disclosure.
The present disclosure is further described in light of the following experiments which are set forth for illustration purpose only and not to be construed for limiting the scope of the disclosure. The following experiments can be scaled up to industrial/commercial scale and the results obtained can be extrapolated to the industrial scale.
EXPERIMENTAL DETAILS:
Experiment 1:
Preparation of 2-(piperidin-4-yl)-1H-benzo[d]imidazole in accordance with the present disclosure:
25g of o-phenylenediamine and 231 ml of acetonitrile were charged in a reactor under stirring at 2ºC for 4 hrs to obtain a mixture. 69.31g of ortho-phosphoric acid was added to the mixture under stirring to obtain a first reaction mixture. The reaction mixture was then filtered and washed with acetonitrile to obtain a cake.
The so obtained cake was added to 125 ml ethylene glycol followed by adding 35.85 g (0.28mol) of isonipecotic acid and heated to a temperature of 125°C for 18 hours and was further maintained at 125°C till the reaction was completed to obtain a second reaction mixture.
The so obtained second reaction mixture was cooled at room temperature followed by adding 100 ml of water and aqueous sodium hydroxide solution till the pH of the so obtained second reaction mixture turned into basic (pH=10) to obtain a reaction mass. The reaction mass was filtered and washed with water to obtain 2-(piperidin-4-yl)-1H-benzo[d]imidazole. The purity of 2-(piperidin-4-yl)-1H-benzo[d]imidazole was 98% and the yield was 85%.
Experiment 2:
Experiment 2 was carried out in a similar way as disclosed in experiment 1 except using HCl instead of orthophosphoric acid and ethylene glycol instead of acetonitrile i.e. both the steps of experiment 2 were carried out in ethylene glycol only. The purity of 2-(piperidin-4-yl)-1H-benzo[d]imidazole was 95% and the yield was 80%.
Experiment 3:
25g of o-phenylenediamine and 231 ml of acetonitrile were charged in a reactor under stirring at 2°C for 4 hrs to obtain a mixture. 69.31g of ortho-phosphoric acid was added to the mixture under stirring to obtain a first reaction mixture. The first reaction mixture was then filtered and washed with acetonitrile to obtain a cake.
The so obtained cake was added to 125 ml ethylene glycol followed by adding 29.89 g (0.23 mol) of isonipecotic acid and heated to a temperature of 125°C for 18 hours and was further maintained at 125°C till the reaction was completed to obtain a second reaction mixture.
The so obtained second reaction mixture was cooled at room temperature followed by adding 100 ml of water and sodium hydroxide solution till the pH of the so obtained second reaction mixture turned into basic (pH=10) to obtain a reaction mass. The reaction mass was filtered and washed with water to obtain 2-(piperidin-4-yl)-1H-benzo[d]imidazole. The purity of 2-(piperidin-4-yl)-1H-benzo[d]imidazole was 96 % and the yield was 58.06% (27g).
Experiment 4:
50g of o-phenylenediamine and 460 ml of acetonitrile were charged in a reactor under stirring at 2ºC for 4 hours to obtain a mixture. 138.69g of ortho-phosphoric acid was added to the mixture under stirring to obtain a first reaction mixture. The first reaction mixture was then filtered and washed with acetonitrile to obtain a cake.
The so obtained cake was added to 250 ml ethylene glycol followed by adding 77.6 g (0.60mol) of isonipecotic acid and heated to a temperature of 125°C for 18 hours and was further maintained at 125°C till the reaction was completed to obtain a second reaction mixture.
The so obtained second reaction mixture was cooled at room temperature followed by adding 200 ml of water and sodium hydroxide solution till the pH of the so obtained second reaction mixture turned into basic (pH=10) to obtain a reaction mass. The reaction mass was filtered and washed with water to obtain 2-(piperidin-4-yl)-1H-benzo[d]imidazole. The purity of 2-(piperidin-4-yl)-1H-benzo[d]imidazole was 98 % and the yield was 80% (74.4 g).
Experiment 5:
50g of O-phenylenediamine and 460 ml of acetonitrile were charged in a reactor under stirring at 2ºC for 4 hours to obtain a mixture. 138.69g of ortho-phosphoric acid was added to the mixture under stirring to obtain a first reaction mixture. The reaction mixture was then filtered and washed with acetonitrile to obtain a cake.
The so obtained cake was added to 250 ml ethylene glycol followed by adding 71.6 g (0.55 mol) of isonipecotic acid and heated to a temperature of 135°C for 18 hours and was further maintained at 135°C till the reaction was completed to obtain a second reaction mixture.
The so obtained second reaction mixture was cooled at room temperature followed by adding 200 ml of water and sodium hydroxide solution till the pH of the so obtained second reaction mixture turned into basic (pH=10) to obtain a reaction mass. The reaction mass was filtered and washed with water to obtain (2-(piperidin-4-yl)-1H-benzo[d]imidazole). The purity of 2-(piperidin-4-yl)-1H-benzo[d]imidazole was 96% and the yield was 81.1% (75.5 g).

Comparative Example 1:
50g of o-phenylenediamine and 460 ml of acetonitrile were charged in a reactor under stirring below 5ºC to obtain a mixture. 138.69 g of ortho-phosphoric acid was added to the mixture under stirring to obtain a first reaction mixture. The reaction mixture was then filtered and washed with acetonitrile to obtain a cake.
The so obtained cake was added to 250 mL ethylene glycol followed by adding 71.6 g (0.56mol) of isonipecotic acid at 80°C to 100°C and was further maintained at 80°C to100°C for 46 hours to obtain a second reaction mixture. The reaction does not comply.
The so obtained second reaction mixture was cooled at room temperature followed by adding 200 ml of water and sodium hydroxide solution till the pH of the so obtained second reaction mixture turned into basic (pH=10) to obtain a reaction mass. The reaction mass was filtered and washed with water to obtain 2-(piperidin-4-yl)-1H-benzo[d]imidazole. The purity of 2-(piperidin-4-yl)-1H-benzo[d]imidazole was 90% and the yield was 58% (54 g).
It is evident from the above examples that the enhanced yield and purity of 2-(piperidin-4-yl)-1H-benzo[d]imidazole were obtained where the mole ratio of o-phenylenediamine to isonipecotic acid is more than 1:1.1 and a temperature of above 120°C. The optimum temperature and the specific ratio are essential to produce 2-(piperidin-4-yl)-1H-benzo[d]imidazole with a purity of more than 94% and yield of more than 79%. The specific ratio of o-phenylenediamine to isonipecotic acid and the reaction temperature (more than 120oC) reduces the time period required for completing the reaction, in view of comparative example.
TECHNICAL ADVANCEMENTS
The present disclosure described hereinabove has several technical advantages including, but not limited to, the realization of a process for preparing 2-(piperidin-4-yl)-1H-benzo[d]imidazole, which
- provides a comparatively high purity and high yield of 2-(piperidin-4-yl)-1H-benzo[d]imidazole;
- employs inexpensive reagents and has industrial applicability; and
- is simple and environment friendly.
Throughout this specification, the word “comprise”, or variations such as “comprises” or “comprising, will be understood to imply the inclusion of a stated element, integer or step,” or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps.
The use of the expression “at least” or “at least one” suggests the use of one or more elements or ingredients or quantities, as the use may be in the embodiment of the invention to achieve one or more of the desired objects or results. While certain embodiments of the inventions have been described, these embodiments have been presented by way of example only, and are not intended to limit the scope of the inventions. Variations or modifications to the formulation of this invention, within the scope of the invention, may occur to those skilled in the art upon reviewing the disclosure herein. Such variations or modifications are well within the spirit of this invention.
The numerical values given for various physical parameters, dimensions and quantities are only approximate values and it is envisaged that the values higher than the numerical value assigned to the physical parameters, dimensions and quantities fall within the scope of the invention unless there is a statement in the specification to the contrary.
While considerable emphasis has been placed herein on the specific features of the preferred embodiment, it will be appreciated that many additional features can be added and that many changes can be made in the preferred embodiment without departing from the principles of the disclosure. These and other changes in the preferred embodiment of the disclosure will be apparent to those skilled in the art from the disclosure herein, whereby it is to be distinctly understood that the foregoing descriptive matter is to be interpreted merely as illustrative of the disclosure and not as a limitation.
,CLAIMS:WE CLAIM:
1. A process for the preparation of 2-(piperidin-4-yl)-1H-benzo[d]imidazole, said process comprising the following steps:
a. reacting o-phenylenediamine with an acid in a first fluid medium at a first predetermined temperature for a first predetermined time period to obtain a first reaction mixture;
b. reacting said first reaction mixture and a predetermined amount of isonipecotic acid in a second fluid medium at a temperature in the range of 120ºC to 140ºC for a second predetermined time period to obtain a second reaction mixture; and
c. basifying said second reaction mixture by using at least one base to obtain 2-(piperidin-4-yl)-1H-benzo[d]imidazole.
2. The process as claimed in claim 1, wherein said acid is at least one selected from the group consisting of ortho-phosphoric acid, HCl, and H2SO4.
3. The process as claimed in claim 1, wherein said first fluid medium is at least one selected from acetonitrile, and ethylene glycol.
4. The process as claimed in claim 1, wherein said first predetermined temperature is in the range of 0°C to 5°C.
5. The process as claimed in claim 1, wherein said first predetermined time period is in the range of 2 hours to 6 hours.
6. The process as claimed in claim 1, wherein said second fluid medium is at least one selected from the group consisting of ethylene glycol, 2-methoxy ethanol, and 2-ethoxy ethanol.
7. The process as claimed in claim 1, wherein said second predetermined time period is in the range of 12 hours to 24 hours.

8. The process as claimed in claim 1, wherein said base is at least one selected from the group consisting of sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, and calcium carbonate.
9. The process as claimed in claim 1, wherein the mole ratio of said o-phenylenediamine to said acid is in the range of 1:2.5 to 1:3.5.
10. The process as claimed in claim 1, wherein the mole ratio of said o-phenylenediamine to said isonipecotic acid is in the range of 1:0.9 to 1:1.4.
11. The process as claimed in claim 1, wherein said 2-(piperidin-4-yl)-1H-benzo[d]imidazole has a purity in the range of 94% to 99%.

Dated this 31st day of March, 2022

_______________________________
MOHAN RAJKUMAR DEWAN, IN/PA – 25
of R.K.DEWAN & CO.
Authorized Agent of Applicant

TO,
THE CONTROLLER OF PATENTS
THE PATENT OFFICE, AT MUMBAI