DESC:RELATED PATENT APPLICATION(S)

This application claims the priority to and benefit of Indian Patent Application No. 201841045389 filed on November 30, 2018; the disclosures of which are incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to a novel process for the preparation of Mebendazole, that is simple and economical significant in large scale.

BACKGROUND OF THE INVENTION

Mebendazole is used as an antiparasitic in humans and marketed in the name of Vermox for anthelmitinic infections. The chemical name of Mebendazole is N-(6-benzoyl-1H-benzimidazol-2-yl)-carbamic acid methyl ester represented by Formula-I.

Mebendazole is highly hydrophobic and exists in three different polymorphs based on crystallization conditions. The polymorphs A, B and C display distinct features in solubility, toxicity and therapeutic effects in anthelmintic applications. The Polymorph C is the most efficacious polymorph in anthelmintic use, can transform over time to the less effective polymorph A, especially with higher temperatures and humidity.

Mebendazole was first disclosed in the US Patent No. 3,657,267 as a broad spectrum benzimidazole anthelmintic. This patent discloses the process for preparing Mebendazole as mentioned in Scheme-1.

The US Patent No. 3,954,791 discloses the process for preparing a compound similar to Mebendazole as mentioned in Scheme-2.

The Indian Patent No. 173995 discloses the preparation of a compound similar to Mebendazole as mentioned in Scheme-3.

The Chinese Patent No. 102304090 discloses the process for the preparation of Fenbendazole, a compound similar to Mebendazole shown in Scheme-4.

The Chinese Patent No. 103242237 discloses the process for the preparation of Fenbendazole, a compound similar to Mebendazole as shown below in Scheme-5.

The Publication J.E. Cheong et al, European Journal of Medicinal Chemistry (2018) discloses the preparation of methyl(5-(4-(methyl(oxetan-3-yl)amino)benzoyl)-1H-benzo[d]imidazol-2-yl)carbamate involving the reaction of (3,4-diaminophenyl)(4-(methyl(oxetan-3-yl)amino)phenyl)methanone with 1,3-bis(methoxycarbonyl)-2-methyl-2-thiopseudourea in methanol in Scheme-6.

Besides the availability of different methods for the preparation Mebendazole in state of the art, there is a need for a novel process for the preparation of Mebendazole that is easy and economically significant in large scale.

OBJECTIVE OF THE INVENTION

The objective of the invention is to provide novel process for the preparation of Mebendazole that is easy and economically significant in large scale.

Another objective of the invention is to provide a process for the purification of Mebendazole.

SUMMARY OF THE INVENTION

Accordingly, there is provided an improved process for the preparation of Mebendazole.

The principle aspect of the present invention is provide a process for preparing Mebendazole of Formula-I,

said process comprising the step of: reacting 3,4-diaminobenzophenone of Formula-II with 1,3-bis(methoxycarbonyl)-2-decyl-2-thiopseudourea of Formula-III in a suitable solvent to obtain Mebendazole of Formula-I.

In some embodiment, the solvent used in the above described process for the preparing Mebendazole of Formula-I is selected from one or more alcoholic solvent. In some other embodiments, the said solvent is selected from methanol, ethanol, isopropanol and mixture thereof. In yet another embodiment, the said solvent is methanol.

In some embodiment, in said process for preparing Mebendazole of Formula-I the step of reacting 3,4-diaminobenzophenone of Formula-II with 1,3-bis(methoxycarbonyl)-2-decyl-2-thiopseudourea of Formula-III is carried out in presence of catalytic amount of hydrochloric acid.

In some embodiment, in said process for preparing Mebendazole of Formula-I the compound of Formula-II is reacted with the compound of Formula -III at a temperature in the range of 30-60?.

In some embodiment, the Mebendazole of Formula -I obtained in the above described process is further purified in suitable solvent selected from formic acid, methanol or dichloromethane. In some other embodiment the purification of Mebendazole of Formula-I obtained in the above described process is carried in formic acid.

In some embodiment, there is provided a process for the preparation of Mebendazole of Formula-I, wherein the Mebendazole of Formula-I obtained is having purity of 99.9% as determined by HPLC.

In some embodiment, there is provided a process for the purification of Mebendazole of Formula-I, wherein the solvent used is formic acid and the said purification process comprises the steps of:
a) dissolving Mebendazole in formic acid at 45-50°C to obtain a clear solution;
b) adding activated charcoal to the solution obtained in step (a) and stirring at 45-50°C for 1 hour;
c) filtering the solution obtained in step (b);
d) adding the filtrate obtained in step (c) to water under stirring; and
e) isolating the Mebendazole as crystalline solid.

BRIEF DESCRIPTION OF THE FIGURES

Figure-1: Illustrates the DSC graph of Mebendazole of Formula-I prepared from the Method-1 of Example-3.

Figure-2: Illustrates the X-Ray diffractogram of Mebendazole of Formula-I prepared from Method-1 of Example-3.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides an improved process for the preparation of Mebendazole.

The principle aspect of the present invention is provide a process for preparing Mebendazole of Formula-I,

said process comprising the step of: reacting 3,4-diaminobenzophenone of Formula-II with 1,3-bis(methoxycarbonyl)-2-decyl-2-thiopseudourea of Formula-III in a suitable solvent to obtain Mebendazole of Formula-I.

In some embodiment, the process of the present invention may be illustrated by the Scheme-7 as mentioned below.

In some embodiment, the compound 3,4-diaminobenzopheneone of Formula-II of the present invention is prepared by methods known in the state of art, preferably by the reduction of 4-amino-3-nitrobenzophenone using a reducing agent selected from Raney nickel, Sodium borohydride or Platinum, preferably Raney nickel, in presence of solvent or its mixtures selected from alcoholic solvent like methanol, ethanol, isopropanol, preferably methanol. Preferably the reduction is carried out at 8 kg H2 pressure and at temperature in the range of 40-70?, most preferably in the range of 50-55?.

In some embodiment, the solvent used in the present invention involving process for the preparing Mebendazole of Formula-I is selected from one or more alcoholic solvent. In some other embodiments, the said solvent is selected from methanol, ethanol, isopropanol and mixture thereof. In yet another embodiment, the said solvent is methanol.

In some embodiment, the reaction of 3,4-diaminobenzopheneone of Formula-II with 1,3-bis(methoxycarbonyl)-2-decyl-2-thiopseudourea of Formula-III is carried out at temperature in the range of 30-60?, preferably in the range of 40-45?.

In some embodiment, the reaction of 3,4-diaminobenzopheneone of Formula-II with 1,3-bis(methoxycarbonyl)-2-decyl-2-thiopseudourea of Formula-III is carried out in presence of catalytic amount of hydrochloric acid.

In still another embodiment of the invention, purification of the crude Mebendazole of Formula-I is carried out using specific solvents selected from formic acid, methanol and methylene dichloride to obtain specific polymorphic form of Mebendazole of Formula-I.

In some embodiment, the Mebendazole of Formula-I obtained in the above described process is further purified in suitable solvent selected from formic acid, methanol or dichloromethane. In some other embodiment the purification of Mebendazole of Formula-I obtained in the above described process is carried in formic acid.

In some embodiment, there is provided a process for the preparation of Mebendazole of Formula-I, wherein the Mebendazole of Formula-I obtained is having purity of 99.9% as determined by HPLC.

In some embodiment, there is provided a process for the purification of Mebendazole of Formula-I, wherein the solvent used is formic acid and the said purification process comprises the steps of:
a) dissolving Mebendazole in formic acid at 45-50? to obtain a clear solution;
b) adding activated charcoal to the solution obtained in step (a) and stirring at 45-50? for 1 hour;
c) filtering the solution obtained in step (b);
d) adding the filtrate obtained in step (c) to water under stirring; and
e) isolating the Mebendazole as crystalline solid.

In some embodiment, there is provided a process for the preparation of Mebendazole characterized by DSC as shown in Figure 1 and X-Ray diffractogram as shown in Figure 2.

The use of 1,3-bis(methoxycarbonyl)-2-decyl-2-thiopseudourea of Formula-III in the present invention replaces the use of 1,3-bis(methoxycarbonyl)-2-methyl-2-thiopseudourea that generates gas methyl mercaptan, a colorless, flammable gas with extremely strong and repulsive smell.

The reaction when carried out with 1,3-bis(methoxycarbonyl)-2-decyl-2-thiopseudourea of Formula-III generates decyl mercaptan a high boiling liquid soluble in methanol and other polar solvents that is easily removed by washings.

Further employs a novel intermediate 1,3-bis(methoxycarbonyl)-2-decyl-2-thiopseudourea of Formula-III in the reaction by replacing the use of toxic 1,3-bis(methoxycarbonyl)-2-methyl-2-thiopseudourea.

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 3,4-Diaminobenzophenone
100.0 g of 4-amino-3-nitrobenzophenone was stirred with 500.0 mL of methanol in an autoclave to get clear solution. To this solution 10.0 g of Raney nickel was added and 7-8 kg hydrogen pressure was applied. The reaction mass was then heated to 50-55? and stirred for 4-5 hours. The progress of the reaction was monitored by HPLC. After completion of the reaction, the reaction mass was filtered and filtrate was concentrated under reduced pressure till residual volume (100.0 mL). To the concentrated mass, 500 mL of water was added at 50-55? under stirring and then cooled to room temperature. The resultant solid was filtered and crystallized in 200 mL of hot xylene. The resultant yellow crystalline solid was filtered and dried at 60-70? under vacuum. Yield: 92-95%; HPLC purity: More than 99%.

Example-2: Preparation of crude Mebendazole
To a stirred solution of 100.0 g of 3,4-diaminobenzophenone in 1.0 L of methanol, 164.0 g of 1,3-bis(methoxycarbonyl)-2-decyl-2-thiopseudourea was added. Catalytic amount of aqueous hydrochloric acid (2 g) was added to the reaction mixture at 40-45? and stirred for 2-3 hours. The progress of the reaction was monitored by HPLC. After completion of the reaction, the reaction mass was filtered, washed with 100 ml of hot methanol and dried at 60-70? under vacuum. Yield: 95-97%; HPLC purity: More than 99.5%.

Example-3: Purification of Mebendazole crude
Method-1: 100.0 g of Mebendazole crude material dissolved in 300.0 mL of formic acid at 45-50? to get a clear solution. To the clear solution, 5% activated charcoal was added and kept stirring at 45-50? for 1.0 hour. The contents were filtered. The filtrate was slowly added into 1.0 L of water under fast stirring and stirred for 2 hours. The resultant crystalline solid was filtered, washed with 300 ml of water and dried at 60-70? till moisture content less than1.0%. Yield: 90-95 g; HPLC purity: 99.9%. The obtained Mebendazole is characterized by DSC as shown in Figure 1 and X-Ray diffractogram as shown in Figure 2.

Method-2: 100.0 g of Mebendazole crude material was suspended in 500 mL of methanol. Molar equivalent of sulphuric acid was added to the suspension at 50-60? and stirred to obtain a solution. 5% Activated charcoal was added to the solution and stirred for one hour at 50-60?. The contents were filtered; the filtrate was cooled to 0-10°C and maintained till the formation of solid. The resultant solid was filtered. The solid obtained by filtration was suspended in 1.0 L of water and then it was neutralized using aq. ammonia and stirred for 2.0 hours. The resultant solid was filtered, washed with 100 ml of water and dried at 60-70? till moisture content is less than 1.0%. Yield: 80-85 g.

Method-3: 100 g of product obtained from method-1 or method-2 was suspended in 500 mL of methylene dichloride and heated to reflux and stirred for 2-3 hours. The stirred solution was cooled to room temperature. The resultant solid was filtered and dried at 60-70? under reduced pressure to obtain 99.0 g of Mebendazole.
,CLAIMS:

1. A process for preparing Mebendazole of Formula-I,

said process comprising the step of: reacting 3,4-diaminobenzophenone of Formula-II with 1,3-bis(methoxycarbonyl)-2-decyl-2-thiopseudourea of Formula-III in a suitable solvent of to obtain Mebendazole of Formula-I.

2. The process for preparing Mebendazole of Formula-I as claimed in claim 1, wherein said suitable solvent is selected from one or more alcoholic solvent.

3. The process for preparing Mebendazole of Formula-I as claimed in claim 2, wherein said suitable solvent is selected from methanol, ethanol, isopropanol and mixture thereof.

4. The process for preparing Mebendazole of Formula-I as claimed in claim 3, wherein said suitable solvent is methanol.

5. The process for preparing Mebendazole of Formula-I as claimed in claim-1, wherein step of reacting 3,4-diaminobenzophenone of Formula-II with 1,3-bis(methoxycarbonyl)-2-decyl-2-thiopseudourea of Formula-III in a suitable solvent is carried out in catalytic amount of hydrochloric acid.

6. The process as claimed in claim 1, wherein the compound of Formula-II is reacted with the compound of Formula-III at a temperature in the range of 30-60?.

7. The process as claimed in claim 1, wherein the obtained Mebendazole of Formula-I is further purified in suitable solvent selected from formic acid, methanol or dichloromethane.

8. The process as claimed in claim 7, wherein the Mebendazole of Formula-I obtained is having purity of 99.9% as determined by HPLC.

9. The process as claimed in claim 7, wherein the solvent used for the purification process is formic acid.

10. The process as claimed in claim 9, wherein the purification process comprises the steps of:
a) dissolving Mebendazole in formic acid at 45-50? to obtain a clear solution;
b) adding activated charcoal to the solution obtained in step (a) and stirring at 45-50? for 1 hour;
c) filtering the solution obtained in step (b);
d) adding the filtrate obtained in step (c) to water under stirring; and
e) isolating the Mebendazole as crystalline solid.