EARLIEST PRIORITY DATE:

This International Application claims priority from a Complete patent application filed in India having Patent Application No. 202121019207, filed on April 27, 2021, and titled “A METHOD FOR PREPARATION OF CHLORPHENIRAMINE MALEATE”.

FIELD OF INVENTION

Embodiment of the present disclosure relates to a method for preparation of chlorpheniramine maleate and more particularly to a novel less hazardous method of preparing the same.

BACKGROUND OF THE INVENTION

Histamine is an amine that is produced as part of a local immune response to cause inflammation. More particularly, as part of the immune response to foreign pathogens, histamine is produced by basophils and by mast cells. It is also known that it is histamine which is responsible for causing watery eyes, runny or blocked nose, sneezing, skin rashes, itching, etc during an allergic reaction.

Chlorpheniramine maleate is used as an antiallergic medication, when a body is exposed to any allergen such as pollen, animal dander, house dust, etc. The mechanism of action of chlorpheniramine maleate involves blocking the action of histamine to relieve these symptoms.

US2567245 discloses the hydrolysis & decarboxylation of 2-(4-chlorophenyl)-4- (dimethylamino)-2-(pyridin-2-yl) butanenitrile ( chlorphenamine impurity ) was performed by cooking with Sulfuric acid at 140°C to 150°C for 24 hours to obtain 3-(4- chlorophenyl)-N, N-dimethyl-3-pyridin-2-ylpropan-l -amine ( chlorphenamine base). The presently available processes are not safe and time consuming. Therefore, there is a need for an alternative safe, short duration and less hazardous process for obtaining 3-(4- chlorophenyl)-N, N-dimethyl-3-pyridin-2-ylpropan-l -amine ( chlorpheniramine maleate).

SUMMARY OF THE INVENTION

In accordance with an embodiment of the present invention, a method for preparation of chlorpheniramine maleate is discloses, wherein the method comprises of addition of a predetermined amount of an isopropyl alcohol and a maleic acid to obtain a mixture, heating the isopropyl alcohol and the maleic acid mixture at a predetermined temperature, adding the isopropyl alcohol and the maleic acid mixture to a (4-chlorophenyl)-N, N- dimethyl-3-pyridin-2-ylpropan-l-amine prepared by a predetermined process to obtain a reaction mass, heating the reaction mass at a temperature in the range of 60°C to 65°C for a predetermined period of time to isolate the product, cooling the isolated product at a temperature in the range of 10°C to 15°C and filtering and drying the isolated product to obtain a pure chlorpheniramine maleate.

In accordance with an embodiment of the present invention, wherein the predetermined process of preparing the (4-chlorophenyl)-N, N-dimethyl-3-pyridin-2-ylpropan- 1-amine comprises of condensing a predetermined amount of p-Chloro benzyl cyanide and a 2- Chloro pyridine using O-Xylene as solvent & condensing agent to form a (4- chlorophenyl) (pyridin-2-yl) ethanenitrile, obtained (4-chlorophenyl) (pyridin-2-yl) ethanenitrile is condensed insitu with a dimethyl aminoethyl chloride followed by addition of predetermined amount of methanol and distilled water to extract a 2-(4- chlorophenyl)-4-(dimethylamino)-2-(pyridin-2-yl) butanenitrile in O-xylene by a phase separation technique, decyanation of the 2-(4-chlorophenyl)-4-(dimethylamino)-2- (pyridin-2-yl) butanenitrile is carried out with a potassium hydroxide in O-xylene at a high temperature, addition of distilled water to extract the decyanated product into an organic layer by the phase separation technique, concentrating the O-Xylene layer to obtain brown coloured crude oil of (4-chlorophenyl)-N, N-dimethyl-3-pyridin-2- ylpropan-1 -amine; and collecting (4-chlorophenyl)-N, N-dimethyl-3-pyridin-2-ylpropan- 1 -amine by a high vacuum fractional distillation.

In accordance with an embodiment of the present invention, wherein the condensing agent is sodium amide.

In accordance with an embodiment of the present invention, wherein the pH of the reaction mass is in the range of 5.0 to 6.0.

In accordance with an embodiment of the present invention, wherein the predetermined time comprises of 60 minutes.

In accordance with an embodiment of the present invention, wherein the high vacuum fractional distillation is carried out at NLT 650 mmHg at a temperature in the range of 160°C to 180°C.

In accordance with an embodiment of the present invention, wherein the reaction is monitored by a gas chromatography.

In accordance with an embodiment of the present invention, wherein the high temperature is in the range of 140°C to 155°C at the time of decyanation.

To further clarify the advantages and features of the present disclosure, a more particular description of the disclosure will follow by reference to specific embodiments thereof, which are illustrated in the appended figures. It is to be appreciated that these figures depict only typical embodiments of the disclosure and are therefore not to be considered limiting in scope. The disclosure will be described and explained with additional specificity and detail with the appended figures. BRIEF DESCRIPTION OF THE DRAWINGS

The disclosure will be described and explained with additional specificity and detail with the accompanying figures in which: FIG. 1 illustrates a flow chart depicting process for preparing a chlorpheniramine maleate in accordance with an embodiment of the present disclosure.

FIG. 2 illustrates a flow chart depicting process for preparing (4-chlorophenyl)-N, N- dimethyl-3-pyridin-2-ylpropan-l-amine, in accordance with an embodiment of the present invention.

Further, those skilled in the art will appreciate that elements in the figures are illustrated for simplicity and may not have necessarily been drawn to scale. Furthermore, in terms of the construction of the device, one or more components of the device may have been represented in the figures by conventional symbols, and the figures may show only those specific details that are pertinent to understanding the embodiments of the present disclosure so as not to obscure the figures with details that will be readily apparent to those skilled in the art having the benefit of the description herein. DETAILED DESCRIPTION OF THE INVENTION

For the purpose of promoting an understanding of the principles of the disclosure, reference will now be made to the embodiment illustrated in the figures and specific language will be used to describe them. It will nevertheless be understood that no limitation of the scope of the disclosure is thereby intended. Such alterations and further modifications in the illustrated system, and such further applications of the principles of the disclosure as would normally occur to those skilled in the art are to be construed as being within the scope of the present disclosure. The terms "comprises", "comprising", or any other variations thereof, are intended to cover a non-exclusive inclusion, such that a process or method that comprises a list of steps does not include only those steps but may include other steps not expressly listed or inherent to such a process or method. Appearances of the phrase "in an embodiment", "in another embodiment" and similar language throughout this specification may, but not necessarily do, all refer to the same embodiment.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this disclosure belongs. The examples provided herein are only illustrative and not intended to be limiting.

In the following specification and the claims, reference will be made to a number of terms, which shall be defined to have the following meanings. The singular forms “a”, “an”, and “the” include plural references unless the context clearly dictates otherwise.

As used herein, the term “chlorpheniramine maleate” refers to a synthetic alkylamine derivative used in allergic reactions, hay fever, rhinitis, urticaria, and asthma, antihistamine. It acts as a competitive histamine HI receptor antagonist and displays anticholinergic and mild sedative effects as well. It is chemically designated as 3-(4- chlorophenyl)-N, N-dimethyl-3-pyridin-2-ylpropan- 1-amine.

According to an embodiment of the present invention, a method for preparation of chlorpheniramine maleate, the method comprises of addition of a predetermined amount of an isopropyl alcohol and a maleic acid to obtain a mixture, heating the isopropyl alcohol and the maleic acid mixture at a predetermined temperature, adding the isopropyl alcohol and the maleic acid mixture to a (4-chlorophenyl)-N, N-dimethyl-3-pyridin-2- ylpropan-1 -amine prepared by a predetermined process to obtain a reaction mass, heating the reaction mass at a temperature in the range of 60°C to 65°C for a predetermined period of time to isolate the product, cooling the isolated product at a temperature in the range of 10°C to 15°C and filtering and drying the isolated product to obtain a pure chlorpheniramine maleate.

According to an embodiment of the present invention, wherein predetermined process of preparing the (4-chlorophenyl)-N, N-dimethyl-3-pyridin-2-ylpropan- 1-amine comprises of condensing a predetermined amount of p-Chloro benzyl cyanide and a 2-Chloro pyridine using a condensing agent to form a (4-chlorophenyl) (pyridin-2-yl) ethanenitrile, obtained (4-chlorophenyl) (pyridin-2-yl) ethanenitrile is condensed insitu with a dimethyl aminoethyl chloride followed by addition of predetermined amount of methanol and distilled water to extract a 2-(4-chlorophenyl)-4-(dimethylamino)-2-(pyridin-2-yl) butanenitrile in O-xylene by a phase separation technique, decyanation of the 2-(4- chlorophenyl)-4-(dimethylamino)-2-(pyridin-2-yl) butanenitrile is carried out with a potassium hydroxide in O-xylene at a high temperature, addition of distilled water to extract the decyanated product into an organic layer by the phase separation technique, concentrating the O-Xylene layer to obtain brown coloured crude oil of (4-chlorophenyl)- N, N-dimethyl-3-pyridin-2-ylpropan-l -amine; and collecting (4-chlorophenyl)-N, N- dimethyl-3-pyridin-2-ylpropan-l-amine by a high vacuum fractional distillation.

According to an embodiment of the present invention, wherein the condensing agent is sodium amide.

According to an embodiment of the present invention, wherein the pH of the reaction mass is in the range of 5.0 to 6.0.

According to an embodiment of the present invention, wherein the predetermined time comprises of 60 minutes.

According to an embodiment of the present invention, wherein the high vacuum fractional distillation is carried out at NLT 650 mmHg at a temperature in the range of 160°C to 180°C. According to an embodiment of the present invention, wherein the reaction is monitored by a gas chromatography.

According to an embodiment of the present invention, wherein the high temperature is in the range of 140°C to 155°C at the time of decyanation.

FIG. 1 illustrates a flow chart depicting process for preparing chlorpheniramine maleate, in accordance with an embodiment of the present invention.

According to an embodiment of the present invention, at step 102, addition of a predetermined amount of an isopropyl alcohol and a maleic acid to obtain a mixture.

According to an embodiment of the present invention, at step 104, heating the isopropyl alcohol and the maleic acid mixture at a predetermined temperature.

According to an embodiment of the present invention, at step 106, adding the isopropyl alcohol and the maleic acid mixture to a (4-chlorophenyl)-/V, /V-dimethyl-3-pyridin-2- ylpropan-1 -amine prepared by a predetermined process to obtain a reaction mass.

According to an embodiment of the present invention, at step 108, heating the reaction mass at a temperature in the range of 60°C to 65°C for a predetermined period of time to isolate the product.

According to an embodiment of the present invention, at step 110, cooling the isolated product at a temperature in the range of 10°C to 15°C.

According to an embodiment of the present invention, at step 112, filtering and drying the isolated product to obtain a pure chlorpheniramine maleate. FIG. 2 illustrates a flow chart depicting process for preparing (4-chlorophenyl)-N, N- dimethyl-3-pyridin-2-ylpropan-l-amine, in accordance with an embodiment of the present invention.

According to an embodiment of the present invention, at step 202, condensing a predetermined amount of p-Chloro benzyl cyanide and a 2-Chloro pyridine using a condensing agent to form a (4-chlorophenyl) (pyridin-2-yl) ethanenitrile.

According to an embodiment of the present invention, at step 204, obtained (4- chlorophenyl) (pyridin-2-yl) ethanenitrile is condensed insitu with a dimethyl aminoethyl chloride followed by addition of predetermined amount of methanol and distilled water to extract a 2-(4-chlorophenyl)-4-(dimethylamino)-2-(pyridin-2-yl) butanenitrile in O- xylene by a phase separation technique. As used herein “phase separation” refers to a creation of two distinct phases from a single homogeneous mixture.

According to an embodiment of the present invention, at step 206, decyanation of the 2- (4-chlorophenyl)-4-(dimethylamino)-2-(pyridin-2-yl) butanenitrile is carried out with a potassium hydroxide in O-xylene at a high temperature.

According to an embodiment of the present invention, at step 208, addition of distilled water to extract the decyanated product into an organic layer by the phase separation technique.

According to an embodiment of the present invention, at step 210, concentrating the O- Xylene layer to obtain brown coloured crude oil of (4-chlorophcnyl)- A, A-dimcthyl-3- pyridin-2-ylpropan- 1 -amine.

According to an embodiment of the present invention, at step 212, collecting (4- chlorophenyl)- V, A-dimcthyl-3-pyridin-2-ylpropan-l -amine by a high vacuum fractional distillation. EXAMPLE 1

Preparation of (4-chlorophenyl)-N, N-dimethyl-3-pyridin-2-ylpropan-l -amine

In a reactor with inert atmosphere, 884 kg of p-Chloro Benzyl Cyanide & 596 kg of 2- Chloro Pyridine is added sequentially. To this, slurry mixture of 410kg Sodium Amide in 840 litre of O-Xylene is carefully added at 55°C to 60°C. After maintaining the reaction for 60 to 90 minutes, the solution of Dimethyl amino ethyl chloride is carefully added, wherein Dimethyl amino ethyl chloride can be prepared by chlorinating 2-(Dimethyl amino) ethanol using Thionyl chloride, as its Hydrochloride salt & basifying the salt by the common technique followed by extracting in O-Xylene. The reaction is monitored by gas chromatography during the maintaining period. The Methanol 50 litre was added followed by 2500 litre water addition. The 2-(4-chlorophenyl)-4-(dimethylamino)-2- (pyridin-2-yl) butanenitrile is extracted in O-Xylene by phase separation technique. Further reaction is heated to 140°C to 155°C with caustic Potash (Potassium hydroxide). The reaction conversion is monitored by gas chromatography. The reaction is brought to the room temperature & 2500 litre water was added followed by phase separation to extract the decyanated product into an Organic layer. The brown colored crude oil of (4- chlorophenyl)-N, N-dimethyl-3-pyridin-2-ylpropan-l -amine is obtained by concentrating the O-Xylene layer. The Pure fraction was collected by high vacuum fractional distillation at the vacuum NLT 650 mmHg at 160°C to 180°C.

EXAMPLE 2

Preparation of Chlorpheniramine Maleate

In a reactor, sequentially added 600 litre of Isopropyl alcohol & 168.0 - 180.0kg of Maleic Acid, on dry basis. This is heated to 50°C to 55°C to dissolve. In another reactor, sequentially added 450kg (4-chlorophenyl)-N, N-dimethyl-3-pyridin-2-ylpropan-l- amine, prepared by the method as described in Example-I. The maleic acid solution is transferred to the above solution to adjust pH to 5.0 to 6.0. The reaction was heated to 60°C to 65°C for 60 minutes. The maleate salt formed is isolated by chilling to 10°C to 15°C, followed by filtration and drying. The highly pure chlorpheniramine maleate is obtained with up to 570kg yield.

The chlorpheniramine maleate obtained using the process of present invention is cheaper, efficient and furthermore industrially safer to produce.

More specifically, in the present disclosure, the decyanation of 2-(4-chlorophenyl)-4- (dimethylamino)-2-(pyridin-2-yl) butanenitrile is performed by using Potassium hydroxide which is quite safe to handle rather than Sulfuric acid, considering an industrial safety. An additional advantage is that the reaction can be terminated for further work up in 3 to 4 hours of maintaining.

Overall, the present disclosure discloses a one pot synthesis of decyanation of 2-(4- chlorophenyl)-4-(dimethylamino)-2-(pyridin-2-yl) butanenitrile, which is synthesized by condensing p-Chloro benzyl cyanide with 2-Chloro pyridin by using sodium amide as a condensing agent to form (4-chlorophenyl)(pyridin-2-yl) ethanenitrile. The obtained (4- chlorophenyl)(pyridin-2-yl) ethanenitrile is further condensed insitu with dimethyl aminoethyl chloride. In the present disclosure, the cyanide group is removed by treating the nitrile with potassium hydroxide in xylene at a high temperature.

While specific language has been used to describe the disclosure, any limitations arising on account of the same are not intended. As would be apparent to a person skilled in the art, various working modifications may be made to the method in order to implement the inventive concept as taught herein.

The figures and the foregoing description give examples of embodiments. Those skilled in the art will appreciate that one or more of the described elements may well be combined into a single functional element. Alternatively, certain elements may be split into multiple functional elements. Elements from one embodiment may be added to another embodiment. For example, order of processes described herein may be changed and are not limited to the manner described herein. Moreover, the actions of any flow diagram need not be implemented in the order shown; nor do all of the acts need to be necessarily performed. Also, those acts that are not dependant on other acts may be performed in parallel with the other acts. The scope of embodiments is by no means limited by these specific examples.