DESC:FIELD OF THE INVENTION

The present invention relates to a novel process for the preparation of Clofazimine.

BACKGROUND OF THE INVENTION:

Clofazimine, is an antileprosy agent, having brand name Lamprene. Clofazimine is chemically known as 3-(p-chloroanilino)-10-(p-chlorophenyl)-2, 10-dihydro-2-isopropyliminophenazine and its structural formula is represented in Formula I.

Clofazimine is reported in US 2948726 and discloses synthesis of the same.
Organic Process Research & Development Volume 20 Issue 2 Pages 452-464; 2016 discloses a process for the preparation of Clofazimine precursor N-(4-Chlorophenyl)-2-nitroaniline comprising reacting 1-fluoro-2-nitrobenzene with 4-chloro-aniline in presence of lithium hexamethyl disilazane (LiHMDS) gives N-(4-chlorophenyl)-2-nitroaniline. Hydrogenation of N-(4-chlorophenyl)-2-nitroaniline with H2 and 2-methoxynaphtalene gives N-(4-Chlorophenyl)-2-nitroaniline, which is further converted into Clofazimine.
J. Chem.Research (S), 52-53; 1984 discloses reduction of 2-nitro-4-chlorodiphenylamine with 10% Pd-C in presence of glacial acetic acid, Ferric chloride and HCl solution gives of 3-(p-chloroanilino)-10-(p-chlorophenyl)-2.10-dihydro-2-iminophenazine hydrochloride, which on reaction with acetone, H2 pressure, platinum catalyst gives Clofazimine.
The present invention provides a novel process which is user friendly and results into highly pure compound.
OBJECT AND SUMMARY OF THE INVENTION:
The present invention provides a novel process for the preparation of Clofazimine.
In one object, the present invention provides a novel process for the preparation of Clofazimine comprising:
a) reacting an acid addition salt of imine compound of formula II with an iso-propyl amine; and
b) isolating Clofazimine.
In another object, the present invention provides an improved process for the preparation of an imine compound of formula II or its acid addition salt comprising:
a) reacting 2-fluoronitro benzene with p-chloroaniline to give N-(4-chlorophenyl)-2-nitroaniline;
b) reducing N-(4-chlorophenyl)-2-nitroaniline to give N-(4-chlorophenyl) benzene-1,2-diamine in presence of sodium sulfide and suitable solvent; and
c) converting N-(4-chlorophenyl) benzene-1,2-diamine into Imine compound of formula II or an acid addition salt.
In one more object, the present invention provides a novel acetic acid salt of formula II.

In another aspect, the present invention provides novel polymorph of acetate salt of imino compound of Formula II.

BRIEF DESCRIPTION OF THE DRAWINGS
Further aspects of the present disclosure together with additional features contributing thereto and advantages accruing there from will be apparent from the following description of embodiments of the disclosure which are shown in the accompanying drawing figures wherein:
Figure 1 shows a powder X-ray diffraction pattern of acetate salt of imino compound of Formula II.
Figure 2 shows 1HNMR of acetate salt of imino compound of Formula II.

DETAILED DESCRIPTION OF THE INVENTION:
The present invention provides a novel process for the preparation of Clofazimine.
The main aspect of the present invention is to provide a novel process for the preparation of Clofazimine comprising:
a) reacting an acid addition salt of imine compound of formula II with an iso-propyl amine; and
b) isolating Clofazimine.
The process of the present invention is represented in scheme-I.

In one embodiment, the imine compound of Formula II is reacted with isopropyl amine in a suitable solvent to give Clofazimine. As per the present invention, the imine compound of formula II is an acid addition salt. The acid addition salt of formula II is selected from acetic acid, propanoic acid, hexanoic acid, malonic acid, succinic acid, malic acid, tartaric acid, citric acid, oxalic acid, phosphoric acid, methane sulphonic acid and the like. Preferably acetic acid salt of Formula II.
In another embodiment, the suitable solvent for above reaction is selected from toluene, 1,4-dioxane, dichloromethane, ethyl acetate, tetrahydrofuran, acetone, dimethyl formamide, acetonitrile, dimethyl sulfoxide or mixtures thereof. Preferably toluene.
In another embodiment, the resulting clofazimine is recrystallized from a suitable solvent selected from methanol, ethanol, isopropyl alcohol, isopropyl acetate, acetone, dimethyl formamide, dimethyl sulfoxide, toluene and iso propyl ether. Preferably acetone.
In another aspect, the present invention provides an improved process for the preparation of an imine compound of formula II or its acid addition salt comprising:
a) reacting 2-fluoronitro benzene with p-chloroaniline to give N-(4-chlorophenyl)-2-nitroaniline;
b) reducing N-(4-chlorophenyl)-2-nitroaniline to give N-(4-chlorophenyl) benzene-1,2-diamine in presence of sodium sulfide and suitable solvent; and
c) converting N-(4-chlorophenyl) benzene-1,2-diamine into Imine compound of formula II or an acid addition salt.
The process of the present invention is represented in Scheme-II:

In one embodiment, 2-Fluoronitro benzene is reacted with p-chloroaniline in presence of a suitable solvent to give N-(4-chlorophenyl)-2-nitroaniline. The suitable solvent for the reaction is selected from toluene, 1,4-dioxane, dichloromethane, ethyl acetate, tetrahydrofuran, acetone, dimethyl formamide, acetonitrile, dimethyl sulfoxide, n-methlyl pyridine; or mixtures thereof. Preferably Dimethyl sulfoxide.
According to the present invention, N-(4-chlorophenyl)-2-nitroaniline is prepared by using excess moles of p-chloroaniline with 2-Fluoronitro benzene.
In one more embodiment, N-(4-chlorophenyl)-2-nitroaniline is reduced with sodium sulfide to give N-(4-chlorophenyl) benzene-1,2-diamine in presence of a suitable solvent. Optionally after reduction, N-(4-chlorophenyl) benzene-1,2-diamine is isolated as a salt selected from hydrochloric acid, phosphoric acid, hydrobromic acid and the like. Preferably hydrochloride salt. The suitable solvent for reduction is selected from methanol, ethanol, propanol, isopropyl alcohol, n-propanol, butanol, water or mixtures thereof. Preferably methanol and water.
It has been surprisingly found that, by carrying out reduction with sodium sulfide, the only selective nitro reduction was performed by which the halogen substituted on phenyl moiety doesn’t undergo dehalogenation and there is no probability of formation of dehalogenated impurity.
In an alternate embodiment, the reduction of N-(4-chlorophenyl)-2-nitroaniline is carried out by treating N-(4-chlorophenyl)-2-nitroaniline with Zn powder and acetic acid in a suitable solvent selected from dichlormethane, toluene, 1,4-dioxane, ethyl acetate, tetrahydrofuran, acetone, dimethyl formamide, acetonitrile, dimethyl sulfoxide or mixtures thereof. Preferably dichloromethane.
In one embodiment, N-(4-chlorophenyl) benzene-1,2-diamine hydrochloride is further converted into Imino compound of Formula II or its acid addition salt form by following the processes known in the art such as Journal of Chem. Research (S), 52-53; 1984.
According to the present invention, N-(4-chlorophenyl) benzene-1,2-diamine hydrochloride treated with anhydrous ferric chloride and acetic acid in presence of a suitable solvent to give hydrochloride salt of Imino compound of Formula II. The suitable solvent for the conversion is selected from methanol, ethanol, propanol, isopropyl alcohol, n-propanol, butanol, water or mixtures thereof.
In one more embodiment, the hydrochloride salt of Imino compound of formula II is further converted into its acid addition salt by treating hydrochloride salt of Imino compound of formula II in presence of a suitable base in a suitable solvent followed by treating with an acid. The suitable base is selected from ammonia, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate and the like. The suitable solvent is selected from methanol, ethanol, propanol, isopropyl alcohol, n-propanol, butanol, water or mixtures thereof. Preferably methanol.
The resulting Imino compound of formula II of above embodiment is reacted with an acid in suitable solvent to give an acid addition salt of Imino compound of formula II. The suitable acid addition salt is selected from acetic acid, malonic acid, succinic acid, malic acid, tartaric acid, citric acid, oxalic acid, methane sulphonic acid, phosphoric acid and the like. Preferably acetic acid salt of Formula II.
In one more embodiment, the above resulting acetic acid salt of imino compound of Formula II is further converted into Clofazimine, by treating acetate salt formula II with an isopropyl amine in presence of a suitable solvent selected from methanol, ethanol, propanol, isopropyl alcohol, n-propanol, butanol, water, dichloromethane, ethyl acetate, tetrahydrofuran, acetone, dimethyl formamide, acetonitrile, 1,4-dioxane, dimethyl sulfoxide or mixtures thereof. Preferably toluene.
Unexpectedly we found that, by using acetic acid salt of Imino compound of formula II in the preparation of Clofazimine enhances the purity of final compound. Specifically, when performing the condensation of acetic acid salt of Imino compound of formula II with isopropyl amine, acetate salts breaks the keto formation (keto impurity) at imine substitution, which interns enhances the formation of desired product with high yield. The structural formula of keto impurity is depicted below.

In one more embodiment, the resulting clofazimine is recrystallized from a suitable solvent selected from methanol, ethanol, isopropyl alcohol, isopropyl acetate, acetone, dimethyl formamide, dimethyl sulfoxide, toluene and iso propyl ether. Preferably acetone.
One more aspect of the present invention is to provide novel acetate salt of imino compound formula II.

Another aspect of the present invention is to provide a novel polymorph of acetate salt of imino compound of formula II.
In one embodiment, the present invention provides crystalline polymorph of acetate salt of imino compound of formula II. The crystalline acetate salt of imino compound of Formula II is measured on BRUKER D-8 Discover powder diffractometer equipped with a goniometer of ?/2? configuration and Lynx Eye detector. The Cu-anode X-ray tube was operated at 40 kV and 30 mA. The experiments were conducted over the 2? range of 2.0°-50.0°, 0.030° step size and 0.4 seconds step.
The novel polymorph of acetate salt of imino compound of formula II has been characterized by powder X-ray diffraction pattern having peaks 22.3, 22.6, 21.4, 16.3, 10.51, 6.0 ± 0.2° 2-theta. The acetate salt of imino compound of formula II may be further characterized by powder X-ray diffraction pattern as depicted in Figure 1.
Examples:
Example 1: N-(4-chlorophenyl)-2-nitroaniline
A mixture 100 g of 2-Fluoronitro benzene, 180.9 g of p-chloroaniline and 98 g of potassium carbonate in 2000 ml of dimethyl sulfoxide were stirred at about 100 °C for 48 hours. After completion of the reaction, the reaction mixture was cooled to ambient temperature and was added with water and continued stirring for 2-3 hours. The resulting precipitate was filtered, washed with water and suck dried. The wet material is washed with 10% aqueous methanol, filtered and dried to afford N-(4-chlorophenyl)-2-nitroaniline.
Yield: 150.0 g
Example 2: N-(4-chlorophenyl)-2-nitroaniline
1 mole equivalent of 2-Fluoronitrobenzene and 1 mole equivalent of para chloro aniline was added 15 volumes of water and stirred at 100 °C for 12-hrs. After completion of the reaction, reaction mass was cooled to room temperature and was added water slowly and further stirred for 2-hrs. The resulting solid was filtered and treated with aq methanol to get N-(4-chlorophenyl)-2-nitroaniline 0.3% yield w/w.

Example 3: N-(4-chlorophenyl)-2-nitroaniline
1 mole equivalent of 2-Fluoronitrobenzene and 1.16 mole equivalents of para chloro aniline were charged into 0.9 volumes of pyridine and the temperature was raised to 120 °C and stirred for 15-hrs. The reaction mixture was cooled to room temperature and reaction mass treated with 6N NaOH solution followed by extraction with MDC and concentrated to obtain a residue which consists 60-70% of N-(4-chlorophenyl)-2-nitroaniline product.
Example 4: N-(4-chlorophenyl)-2-nitroaniline
To 1 mole equivalent of 2-Fluoronitrobenzene, 0.96 mole equivalents of para chloro aniline, 1 mole equivalent of potassium carbonate was added 0.5 vol of DMF and the reaction mixture was stirred at 125-130°C for 5-hrs. The reaction mixture was cooled to room temperature and was added 10 volumes of water slowly and further stirred for 2-hrs. The obtained solid was filtered and treated with aq methanol to yield N-(4-chlorophenyl)-2-nitroaniline 0.5% w/w desired product.
Example 5: N-(4-chlorophenyl)-2-nitroaniline
To 1 mole equivalent of 2-Fluoronitrobenzene, 0.96 mole equivalent of para chloro aniline and 1.5 mole equivalents of potassium hydroxide was added 0.5 volumes of DMF and stirred at 125-130°C for 5-hrs. The reaction mass was cooled to room temperature and water was added slowly and stirred for 2-hrs. The obtained solid was filtered and treated with aq ethanol to yield N-(4-chlorophenyl)-2-nitroaniline 0.5% yield w/w
Example 6: N-(4-chlorophenyl)-2-nitroaniline
To 1 mole equivalent of 2-Fluoronitrobenzene and 2 mole equivalents of para chloro aniline was added 1 mole equivalent of potassium fluoride and stirred at 165-170°C for 6-hrs. The reaction mixture was cooled to room temperature and was treated with 3M HCl followed by aqueous methanol to yield N-(4-chlorophenyl)-2-nitroaniline 1.5% yield w/w.
Example 7: N-(4-chlorophenyl)-2-nitroaniline
To 1 mole equivalent of 2-Fluoronitrobenzene, 2 mole equivalents of para chloro aniline and 1 mole equivalent of potassium carbonate was added 2 volumes of DMSO and stirred at 110°C for 48-hrs. The reaction mixture was cooled room temperature and was stirred with water followed by aqueous methanol purification to give N-(4-chlorophenyl)-2-nitroaniline 1.45% yield w/w.
Example 8: N-(4-chlorophenyl)-2-nitroaniline
To 1 mole equivalent of 2-Fluoronitrobenzene, 2 mole equivalents of para chloro aniline and 1 mole equivalent of potassium carbonate was added 2 volumes of DMSO and stirred at 110°C for 48-hrs. The reaction mass was cooled to room temperature was a stirred with water followed by aqueous methanol purification to give N-(4-chlorophenyl)-2-nitroaniline 1.5% yield w/w.
Example 9: N-(4-chlorophenyl) benzene-1,2-diamine hydrochloride
To a mixture of 100 g of N-(4-chlorophenyl)-2-nitroaniline, 500 ml of methanol and 50 ml of water was added 210 g of sodium sulfide at 60°C. The reaction mixture maintained at same temperature and after completion of the reaction the reaction mixture was cooled to ambient temperature. 1000 ml of water was added to the reaction mixture and maintained for 2-3 hours and filtered. To the resulting crude was added 1000 ml of water and 100 ml of hydrochloride acid and is stirred for about 2-3 hours. The reaction mixture was filtered to isolate N-(4-chlorophenyl) benzene-1,2-diamine hydrochloride and dried.
Yield: 95 g.
Example 10: N-(4-chlorophenyl) benzene-1,2-diamine hydrochloride.
To a mixture of 10 g of N-(4-chlorophenyl)-2-nitroaniline, 10 ml of dichloromethane and 20 ml of acetic acid was slowly added 1.8 g of zinc powder at ambient temperature. The reaction mixture was maintained at 50 °C. after completion of the reaction, the reaction mixture was filtered and the the filtrate is concentrated under vacuum to afford N-(4-chlorophenyl) benzene-1,2-diamine which is further converted into N-(4-chlorophenyl) benzene-1,2-diamine hydrochloride in dichloromethane by adding concentrated HCl.
Yield: 95 g
Example 11: N-(4-chlorophenyl) benzene-1,2-diamine hydrochloride.
To N-(4-chlorophenyl)-2-nitroaniline was added methanol and Raney Nickel in autoclave vessel applied 3.0 Kg of pressure and stirred for 18-hrs at room temperature, filtration followed by concentration of the reaction mass results in purification on column chromatography yields N-(4-chlorophenyl) benzene-1,2-diamine 0.5 % w/w yield.
Example 12: N-(4-chlorophenyl) benzene-1,2-diamine hydrochloride.
To a mixture of 1 mole equivalent of N-(4-chlorophenyl)-2-nitroaniline and 5 volumes of methanol was added 1 volume of water, followed by addition of 6.7 mole equivalents of sodium sulfide flakes portion wise at about 60 °C and stirred for 1 hr. The reaction mass was cooled to ambient temperature and stirred for 2-hrs by adding water (10 Vol). The resulting slurry was filtered and washed with water to obtain N-(4-chlorophenyl) benzene-1,2-diamine, which upon treating with concentrated HCl in water results N-(4-chlorophenyl) benzene-1,2-diamine hydrochloride 0.9% w/w yield.
Example 13: 3-(p-chloroanilino)-10-(p-chlorophenyl)-2.10-dihydro-2-imino phenazine hydrochloride.
To a mixture of 178 g of anhydrous Ferric chloride, 2000 ml of water and 300 ml of acetic acid was added 100 g of N-(4-chlorophenyl) benzene-1,2-diamine hydrochloride in portions at ambient temperature. The reaction mixture was maintained for 24 hours and filtered. The resulting wet product was further slurred with water, filtered and dried to yield 3-(p-chloroanilino)-10-(p-chlorophenyl)-2.10-dihydro-2-iminophenazine hydrochloride.
Yield: 80.0 g
Example 14: 3-(p-chloroanilino)-10-(p-chlorophenyl)-2.10-dihydro-2-imino phenazine hydrochloride.
To a mixture of 295.150 g of ferric chloride hexahydrate, 2000 ml of water and 300 ml of acetic acid was added 100 g of N-(4-chlorophenyl) benzene-1,2-diamine hydrochloride in portions at ambient temperature. The reaction mixture was stirred for 24 hours and filtered. The resulting wet product was slurred in water, filtered and dried to yield 3-(p-chloroanilino)-10-(p-chlorophenyl)-2.10-dihydro-2-iminophenazine hydrochloride.
Yield: 80.0 g.
Example 15: 3-(p-chloroanilino)-10-(p-chlorophenyl)-2.10-dihydro-2-imino phenazine hydrochloride.
To a solution of 295.150 g of Ferric chloride hexahydrate in 2000 ml of water was added 100 g of N-(4-chlorophenyl) benzene-1,2-diamine hydrochloride in portions at ambient temperature. The reaction mixture is stirred for 24 hours and filtered. The resulting wet product was slurred in water, filtered and dried to afford 3-(p-chloroanilino)-10-(p-chlorophenyl)-2.10-dihydro-2-iminophenazine hydrochloride.
Yield: 75.0 g
Example 16: 3-(p-chloroanilino)-10-(p-chlorophenyl)-2.10-dihydro-2-iminophenazine acetate.
To a mixture of 100 g of Imino Piperazine Hydrochloride and 10% of Methanol in 1000 ml of Dichloromethane was added 150 ml of aqueous ammonia and stirred for 5-6 hours. After the completion of the reaction, 150 ml of acetic acid was added and continued stirring for 5-6 hours. The resulting precipitate was filtered. The resulting solid was slurred with water and filtered to isolate 3-(p-chloroanilino)-10-(p-chlorophenyl)-2.10-dihydro-2-iminophenazine acetate.
Yield: 70.0 g.
1H NMR (300 MHz, DMSO-d6) d 1.90 (3H, s), d 5.44 (1H, s), d 6.52 (1H, s), d 6.79 (1H, s), d 7.26-7.27 (2H, m), d 7.42-7.47 (4H, m), d 7.59-7.61 (2H, m), d 7.69 (1H, s), d 7.86-7.88 (2H, m), d 9.92 (3H, br).
Example 17: 3-(p-chloroanilino)-10-(p-chlorophenyl)-2,10-dihydro-2-iminophenazine acetate.
To a mixture of 100.0 g of Imino Piperazine Hydrochloride and 1000 ml of Dichloromethane was added 150 ml of aqueous ammonia and stirred for 5-6 hours. After completion of the reaction, 150 ml of acetic acid was added and continued stirring for an additional 5-6 hours. The resulting precipitate was collected by filtration and the wet material was slurred in water and filtered to isolate 3-(p-chloroanilino)-10-(p-chlorophenyl)-2.10-dihydro-2-iminophenazine acetate.
Yield: 60.0 g
Example 18: 3-(p-chloroanilino)-10-(p-chlorophenyl)-2.10-dihydro-2-iminophenazine acetate.
To a mixture of 100.0 g of Imino piperazine hydrochloride and 1000 ml of methanol was added 150 ml of aqueous ammonia and stirred for about 5-6 hours. After the completion of the reaction, 150 ml of acetic acid was added and continued stirring for an additional 5-6 hours. The resulting precipitate was collected by filtration and the wet material was slurred in water and filtered to isolate 3-(p-chloroanilino)-10-(p-chlorophenyl)-2.10-dihydro-2-iminophenazine acetate.
Yield: 75.0 g
Example 19: Clofazimine
100 g of 3-(p-chloroanilino)-10-(p-chlorophenyl)-2.10-dihydro-2-iminophenazine acetate was reacted with 144.4 g of isopropylamine in 10 volumes Toluene at 100 °C for 24 hours. After completion of the reaction, the reaction mass was washed with water and concentrated under vacuum to obtain clofazimine crude. The clofazimine crude was recrystallized from acetone to yield pure Clofazimine.
Yield: 80.0 g
Example 20: Clofazimine
100 g of Imino piperazine acetate was reacted with 144.4 g of isopropylamine in 10 volumes of 1,4-dioxane at 100°C for about 24 hours. After the completion of the reaction, the reaction mass was washed with water and concentrated under vacuum to yield crude Clofazimine. The obtained Clofazimine crude was recrystallized from acetone to afford pure Clofazimine.
Yield: 75.0 g
Example 21: Clofazimine
100 g of Imino piperazine acetate was reacted with 144.4 g of isopropylamine in 10 volumes of ethyl acetate at 100°C for about 24 hours. After the completion of the reaction, the reaction mass was washed with water and concentrated under vacuum to yield crude Clofazimine. The obtained clofazimine crude was recrystallized from acetone to afford pure Clofazimine.
Yield: 60.0 g
,CLAIMS:Claims:

1. A process for the preparation of Clofazimine comprising:
a) reacting an acid addition salt of imine compound of formula II with an iso-propyl amine; and
; and
b) isolating Clofazimine.

2. The process as claimed in claim 1, wherein the acid addition salt of Imine compound of Formula II is selected from acetic acid, propanoic acid, hexanoic acid, malonic acid, succinic acid, malic acid, tartaric acid, citric acid, oxalic acid, phosphoric acid, methane sulphonic acid

3. The process as claimed in Claim 2, where in the acid addition salt is acetic acid salt of Formula II.

4. A process for the preparation of an imine compound of formula II or its acid addition salt comprising:
a) reacting 2-fluoronitro benzene with p-chloroaniline to give N-(4-chlorophenyl)-2-nitroaniline;
b) reducing N-(4-chlorophenyl)-2-nitroaniline to give N-(4-chlorophenyl) benzene-1,2-diamine in presence of sodium sulfide and suitable solvent; and
c) converting N-(4-chlorophenyl) benzene-1,2-diamine into Imine compound of formula II or an acid addition salt.

5. The process as claimed in claim 4, wherein the N-(4-chlorophenyl)-2-nitroaniline is prepared by using excess moles of p-chloroaniline with 2-Fluoronitro benzene.

6. The process as claimed in claim 4, wherein the suitable solvent for reduction is selected from methanol, ethanol, propanol, isopropyl alcohol, n-propanol, butanol, water or mixtures thereof

7. The process as claimed in claim 4, wherein N-(4-chlorophenyl) benzene-1,2-diamine is reacted with ferric chloride and acetic acid in presence of a suitable solvent to give HCl salt of Imine compound of formula II.

8. The process as claimed in claim 7, wherein HCl salt of Imine compound of formula II is treated with acetic acid to give acetate salt of Imine compound of formula II.

9. A crystalline acetate salt of imino compound of formula II having X-ray diffraction pattern having peaks 22.3, 22.6, 21.4, 16.3, 10.51, 6.0 ± 0.2° 2-theta.

10. A crystalline acetate salt of imino compound of formula II of claim 10 characterized by a PXRD pattern as depicted in Figure 1.