DESC:RELATED PATENT APPLICATION(S)

This application claims the priority to and benefit of Indian Patent Application No. 201841040623 filed on October 28, 2018; the disclosures of which are incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to an improved process for the preparation of benznidazole and its crystalline Form M2.

BACKGROUND OF THE INVENTION

Benznidazole is an antiparasitic drug used in the treatment of Chagas disease caused by Trypanosoma cruzi. Benznidazole chemically known as N-benzyl-2-(2-nitro-1H-imidazol-1-yl) acetamide having the formula I as mentioned below,

Benznidazole first disclosed in US Patent No. 3679698 assigned to Hoffmann-La Roche Inc. and the preparation process of benznidazole as in this patent is mentioned below in Scheme-1,

The patent AR 097991 discloses the process for the preparation of benznidazole in Scheme-2 as mentioned below,


This process involves more number of steps and workup process for each intermediate and this makes the process difficult in large scale.

The PCT publication WO 2017205622 discloses the process for the preparation of benznidazole in Scheme-3 as mentioned below,

The European Journal of Medicinal Chemistry disclosed the similar reaction process in Scheme-4 as mentioned below,

Besides the availability of different methods for the preparation benznidazole in state of the art, there is a need for an improved process for the preparation of benznidazole that is economically significant.

The present invention overcomes the problems associated with the prior art by adopting a simple process, which provides benznidazole with good yield and purity. The process of the present invention is simple, safer and economically significant.

OBJECTIVE OF THE INVENTION

The object of the invention is to provide an improved process for the preparation of benznidazole.

Another object of the invention is to provide a process for the purification of benznidazole.

Yet another object of the invention is to provide a process for the preparation of crystalline form of benznidazole.

SUMMARY OF THE INVENTION

Accordingly, there is provided an improved process for preparing benznidazole of Formula I and its crystalline Form M2.

One aspects of the present invention provides the process for the preparation of benznidazole of Formula I, comprising the steps of

a) reacting the compound of Formula II

with nitro imidazole of Formula III

in presence of suitable base and suitable solvent selected form the group comprising alcoholic solvent, water or mixture thereof to provide the benznidazole compound of Formula I; and
b) optionally, purifying the benznidazole of Formula I using suitable alcoholic solvent or mixture thereof to provide crystalline benznidazole compound of Formula I.

In some embodiments, the base used in the above described process for preparation of benznidazole of Formula I is selected from the group comprising of sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide or potassium hydroxide; preferably potassium carbonate.
In some other embodiment, the alcoholic solvent used in the above described process for preparation of benznidazole compound of Formula I is selected from the group comprising of methanol, ethanol, propanol, isopropanol, butanol, isobutanol, ethylene glycol, benzyl alcohol, 1,4-butanediol, tert-butyl alcohol or mixture thereof.

In another aspect there is provided a process for the preparation of benznidazole of Formula I comprising the step of:

a) reacting the compound of Formula II

with nitro imidazole of Formula III

in presence of suitable aqueous base solution with small amount of iodides or bromides of alkali metal to provide the benznidazole compound of Formula I; and
b) optionally, purifying the benznidazole compound of Formula I using suitable organic solvent or mixture thereof to provide crystalline benznidazole compound of Formula I.

In some embodiment, the aqueous base solution in step (a) in the above described process for the preparation of benznidazole of compound of Formula I is selected from the group comprising the aqueous solution of sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide or potassium hydroxide; preferably aqueous solution of potassium carbonate or sodium bicarbonate.
In some embodiment, the iodides or bromides of alkali metal in the above described process for the preparation of benznidazole compound of Formula I is selected from the group comprising of iodides or bromides of sodium or potassium.

In some other embodiment, the organic solvent in step (b) is selected from the group comprising of acetone, methanol, ethanol, ethyl acetate, isopropanol, acetonitrile tetrahydrofuran, acetophenone, butanone, cyclopentanone, 2-pentanone, 3-pentanone, methyl isopropyl ketone, methyl isobutyl ketone, ethyl isopropyl ketone, 2-hexanone or its mixtures thereof, preferably acetone.

In yet another aspect of the invention, there is provided a process for purification of benznidazole of Formula I, said process comprising the steps of
a. providing a suspension or partial suspension of benznidazole in ethylacetate solvent;
b. slurring the obtained suspension or partial suspension of benznidazole for some time;
c. optionally facilitating the crystallization of benznidazole obtained in step (a) or step (b);
d. isolating the benznidazole obtained in the above steps; and
e. optionally, repeating the above steps.

Another aspect of the present invention provides a process for preparing a novel crystalline benznidazole Form M2, which exhibits a characteristic X-ray powder diffraction pattern with characteristic peaks expressed in d-values (Å): 7.41, 10.96, 16.17, 16.91, 21.94, 25.44, and 28.55 ± 0.2 degrees or which exhibits a characteristic X-ray powder diffraction pattern with characteristic peaks expressed in d-values (Å): 7.41, 10.96, 14.78, 16.17, 16.91, 17.78, 20.656, 21.94, 23.69, 23.87, 25.23, 25.44, 27.56, 28.55, and 35.93 ± 0.2 degrees; or which exhibits a characteristics X-ray powder diffraction pattern as exhibited in Figure 1; the process comprising:
a) dissolving the benznidazole compound of Formula I in methanol or acetone;
b) concentrating the reaction mixture obtained in step (a);
c) facilitating crystallization of benznidazole; and
d) isolating the pure benznidazole compound of Formula I.
BRIEF DESCRIPTION OF FIGURES

Figure 1: Illustrates the Powder X-ray Diffractogram (PXRD) of crystalline benznidazole Form M2 of Formula I.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides an improved process for preparing the benznidazole of Formula I and its crystalline Form M2.

One aspects of the present invention provides a process for the preparation of benznidazole of Formula I comprising the steps of

a) reacting the compound of Formula II

with nitro imidazole of Formula III

in presence of suitable base and suitable solvent selected form the group comprising alcoholic solvent, water or mixture thereof to provide the benznidazole compound of Formula I; and
b) optionally, purifying the benznidazole compound of Formula I using suitable alcoholic solvent or mixture thereof to provide crystalline benznidazole compound of Formula I.
According to this embodiment of the present invention may be carried out in suitable base selected from the group comprising of sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide or potassium hydroxide; preferably potassium carbonate.

According to this embodiment of the present invention may be carried out in suitable alcoholic solvents selected from the group comprising of methanol, ethanol, propanol, isopropanol, butanol, isobutanol, ethylene glycol, benzyl alcohol, 1,4-butanediol, tert-butyl alcohol or mixture thereof.

In another aspect there is provided a process for the preparation of benznidazole of Formula I comprising the step of:

a) reacting the compound of Formula II

with nitro imidazole of Formula III

in presence of suitable aqueous base solution with small amount of iodides or bromides of alkali metal to provide the benznidazole compound of Formula I; and
b) optionally, purifying the benznidazole compound of Formula I using suitable organic solvent or mixture thereof to provide crystalline benznidazole compound of Formula I.

According to this embodiment of the present invention may be carried out in aqueous base solution selected from the group comprising an aqueous solution of sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide or potassium hydroxide; preferably aqueous solution of potassium carbonate or sodium bicarbonate.

Unexpectedly the inventors of the present invention found that the reaction of N-benzyl-2-chloroacetamide of Formula II with nitro imidazole of Formula III in water provides high yield.

Surprisingly the inventors of the present invention found that the reaction of N-benzyl-2-chloroacetamide of Formula II with imidazole of Formula III in presence of catalytic amount of iodides or bromides of alkali metals increases the efficiency of the reaction and yield, makes the workup procedure easy and simple.

According to this embodiment, the said iodides or bromides of alkali metals is selected from the group comprising of potassium iodide, potassium bromide, sodium iodide, sodium bromide and like. Preferably potassium iodide.

In some embodiment, the aqueous base solution in step (a) in the above described process for the preparation of benznidazole of compound of Formula I is selected from the group comprising the aqueous solution of sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide or potassium hydroxide; preferably aqueous solution of potassium carbonate or sodium bicarbonate.

In some other embodiment, the organic solvent in step (b) is selected from the group comprising of acetone, methanol, ethanol, ethyl acetate, isopropanol, acetonitrile tetrahydrofuran, acetophenone, butanone, cyclopentanone, 2-pentanone, 3-pentanone, methyl isopropyl ketone, methyl isobutyl ketone, ethyl isopropyl ketone, 2-hexanone or its mixtures thereof, preferably acetone.

Yet another aspect of the present invention provides a process for purification of benznidazole of Formula I employing ethyl acetate. Preferably the process comprising the steps of;
a) providing a suspension or partial suspension of benznidazole in ethyl acetate solvent;
b) slurring the obtained suspension or partial suspension of benznidazole for some times;
c) optionally, facilitating the crystallization benznidazole obtained in step (a) or step (b);
d) isolating the benznidazole obtained in the above steps; and
e) optionally, repeating the above steps.

According to this invention, step (c) of the present invention may be carried out by known crystallization technique in the state of art.

According to this invention, step (d) of the present invention may be carried out by known isolation technique in the state of art.

Another aspect of the present invention provides a process for preparing a novel crystalline benznidazole Form M2, which exhibits a characteristic X-ray powder diffraction pattern with characteristic peaks expressed in d-values (Å): 7.41, 10.96, 16.17, 16.91, 21.94, 25.44, and 28.55 ± 0.2 degrees or which exhibits a characteristic X-ray powder diffraction pattern with characteristic peaks expressed in d-values (Å): 7.41, 10.96, 14.78, 16.17, 16.91, 17.78, 20.656, 21.94, 23.69, 23.87, 25.23, 25.44, 27.56, 28.55, and 35.93 ± 0.2 degrees; or which exhibits a characteristics X-ray powder diffraction pattern as exhibited in Figure 1; the process comprising:
a) dissolving the benznidazole compound of formula I in methanol or acetone;
b) concentrating the reaction mixture obtained in step (a);
c) facilitating crystallization of benznidazole; and
d) isolating the pure benznidazole compound of formula I.

According to this embodiment, step (a) of the present invention may be carried out in suitable alcoholic solvents selected from the group comprising of methanol, ethanol, propanol, isopropanol, butanol, isobutanol, ethylene glycol, benzyl alcohol, 1,4-butanediol, tert-butyl alcohol or its mixtures thereof, preferably methanol.

According to this embodiment, step (a) of the present invention may be carried out in ketone solvents selected from the group comprising of acetone, acetophenone, butanone, cyclopentanone, 2-pentanone, 3-pentanone, methyl isopropyl ketone, methyl isobutyl ketone, ethyl isopropyl ketone, 2-hexanone or its mixtures thereof, preferably acetone.

According to this embodiment, step (a) of the present invention may be carried out by heating in a temperature between 25-65°C preferably 40-65°C and more preferably 50-60°C.

According to this embodiment, step (a) of the present invention may be carried out charcoalizing by state in the art followed by filtration as in the state of art.

According to this invention, step (b) of the present invention may be carried out by concentrating at temperature between 45-65°C, preferably 52-57°C.

According to this invention, step (c) of the present invention may be carried out by known crystallization technique in the state of art.

According to this invention, step (d) of the present invention may be carried out by known isolation technique in the state of art.

The present invention is explained in detail with reference to the following examples described below, which are given for the purpose of illustration only and are not intended to limit the scope of the invention.

EXAMPLES

Example-1: Preparation of N-benzyl-2-chloroacetamide:
To a cooled mixture of benzylamine (25 g), sodium bicarbonate (25.2 g) and toluene (50 ml), chloroacetyl chloride (31.6 g) was slowly added at 0-10°C and maintained at the same temperature for two hours. The progress of the reaction was monitored by TLC. After completion of the reaction, methanol (25 ml) and water (100 ml) was added to the reaction mass and stirred. The resulted precipitate was filtered and washed with water (100 ml) and dried to obtain the titled product. Yield: 85%.
Example-2: Preparation of N-benzyl-2-chloroacetamide:
To a cooled mixture of benzylamine (200 g), sodium bicarbonate (203.8 g) and toluene (2800 ml), chloroacetyl chloride (221.3 g) was slowly added at 0-10°C then heated to 35°C and maintained for 4 hours. The progress of the reaction was monitored by HPLC. After completion of the reaction, the reaction mass was cooled to 0°C and maintained for 1 hour. The resulted reaction mass was filtered and washed with chilled toluene (200 ml). The obtained solid was slurried with water (3000 ml) and dried to obtain the titled product. Yield: 88%.

Example-3: Preparation of Benznidazole crude
To a mixture of 2-nitroimidazole (10 g), potassium carbonate (14.6 g) and ethanol (80 ml), N-benzyl-2-chloroacetamide (17 g obtained from Example-1) was added and heated to 78±2°C and maintained for 20 hours at the same temperature. The progress of the reaction was monitored by TLC. After completion of the reaction, reaction mass was concentrated under vacuum. Water (100 ml) was added to the concentrated reaction mass, then cooled to 10±5°C and maintained the same temperature for 1 hour. The resultant solid was filtered and washed with water (50 ml) and dried to obtain benznidazole. Yield: 87%.

Example-4: Preparation of Benznidazole crude:
To a mixture of 2-nitroimidazole (100 g), and aqueous potassium hydroxide solution (59.5 g in 1500 ml water), N-benzyl-2-chloroacetamide (170.5 g obtained from Example-2) and potassium iodide (1 g) was added and heated to 95±3°C and maintained for 15 hours at the same temperature. The progress of the reaction was monitored by HPLC. After completion of the reaction, reaction mass was cooled to 35°C then resulted solid was filtered and washed with water (500 ml). The obtained solid was slurried with water (1500 ml) followed by washing with ethyl acetate (500 ml) at 35°C and dried to obtain benznidazole. Yield: 91%.

Example-5: Purification of Benznidazole:
A mixture of benznidazole (10 g) and methanol (200 ml) was heated to 55±5°C till formation of clear solution. Activated charcoal 5% (0.5 g) was added to the clear solution and maintained the temperature for 1 hour. The resulted charcoal mixture was filtered over the hyflobed. The filtrate was concentrated under reduced pressure then cooled the reaction mass to 5±5°C and maintained the temperature for 2 hours. The resultant solid was filtered then washed with chilled methanol (20 ml) and dried to obtain the purified benznidazole. The obtained benznidazole is crystalline Form M2 characterized by XRPD as shown in Figure 1.Yield: 85%.

Example-6: Purification of Benznidazole
A mixture of benznidazole (100 gm) and acetone (2000 ml) was heated to 55±5°C till formation of clear solution. Activated charcoal 10% was added to the clear solution and maintained the temperature for 1 hour. The resulted charcoal mixture was filtered over the hyflobed. The filtrate was concentrated under reduced pressure then cooled the reaction mass to 5±5°C and maintained the temperature for 2 hours. The resultant solid was filtered, washed with chilled acetone (100 ml) and dried to obtain the purified benznidazole. The obtained benznidazole is crystalline Form M2 characterized by XRPD as shown in Figure 1.Yield: 93%.
,CLAIMS:
1. A process for the preparation of benznidazole of Formula I, comprising the steps of:

a) reacting the compound of Formula II

with nitro imidazole of Formula III

in presence of suitable base and suitable solvent selected form the group comprising alcoholic solvent, water or mixture thereof to provide the benznidazole compound of Formula I; and
b) optionally, purifying the benznidazole compound of Formula I using suitable alcoholic solvent or mixture thereof to provide crystalline benznidazole compound of Formula I.

2. The process as claimed in claim 1, wherein the base is selected from the group comprising of sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide or potassium hydroxide; preferably potassium carbonate.

3. The process as claimed in claim 1, wherein the alcoholic solvent is selected from the group comprising of methanol, ethanol, propanol, isopropanol, butanol, isobutanol, ethylene glycol, benzyl alcohol, 1,4-butanediol, tert-butyl alcohol or mixture thereof.

4. A process for the preparation of benznidazole of Formula I comprising the step of:

a) reacting the compound of Formula II

with nitro imidazole of Formula III

in presence of suitable aqueous base solution with small amount of iodides or bromides of alkali metal to provide the benznidazole compound of Formula I; and
b) optionally, purifying the benznidazole compound of Formula I using suitable organic solvent or mixture thereof to provide crystalline benznidazole compound of Formula I.

5. The process as claimed in claim 4, wherein the aqueous base solution in step (a) is selected from the group comprising the aqueous solution of sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide or potassium hydroxide; preferably aqueous solution of potassium carbonate or sodium bicarbonate.

6. The process as claimed in claim 4, wherein the iodides or bromides of alkali metal is selected from the group comprising of iodides or bromides of sodium or potassium.

7. The process as claimed in claim 4, wherein the organic solvent in step (b) is selected from the group comprising of acetone, methanol, ethanol, ethyl acetate, isopropanol, acetonitrile tetrahydro furan, acetophenone, butanone, cyclopentanone, 2-pentanone, 3-pentanone, methyl isopropyl ketone, methyl isobutyl ketone, ethyl isopropyl ketone, 2-hexanone or its mixtures thereof, preferably acetone.

8. A process for purification of benznidazole of Formula I, said process comprising the steps of
a. providing a suspension or partial suspension of benznidazole in ethylacetate solvent;
b. slurring the obtained suspension or partial suspension of benznidazole for some time;
c. optionally facilitating the crystallization of benznidazole obtained in step (a) or step (b);
d. isolating the benznidazole obtained in the above steps; and
e. optionally, repeating the above steps.

9. A process for preparation of benznidazole of Formula I characterized by X-ray diffraction pattern having significant peaks expressed as d-values (Å) at about 7.41, 10.96, 16.17, 16.91, 21.94, 25.44, and 28.55 ± 0.2 degrees, said process comprising the steps of
a. dissolving the benznidazole compound of Formula I in methanol or acetone;
b. concentrating the reaction mixture obtained in step (a);
c. facilitating crystallization of benznidazole; and
d. isolating the pure benznidazole compound of Formula I.

10. The process as claimed in claim 9, wherein the obtained benznidazole compound of Formula I is characterized by X-ray diffraction pattern having significant peaks expressed as d-values (Å) at about 7.41, 10.96, 14.78, 16.17, 16.91, 17.78, 20.656, 21.94, 23.69, 23.87, 25.23, 25.44, 27.56, 28.55, and 35.93 ± 0.2 degrees.