A Process for Preparation of Oxyclozanide

Field of Invention

The present invention relates to a novel, cost-effective process for the preparation of Oxyclozanide, which is prepared by conversion of acid to acid chloride followed by condensation and purification to give Oxyclozanide with improved yield and purity.

Background of the Invention

Oxyclozanide is chemically known as 2,3,5-Trichloro-N-(3,5-dichloro-2- hydroxyphenyl)-6-hydroxybenzamide and it is represented by the following structural formula I. Oxyclozanide is a salicylanilide anthelmintic. It is used in the treatment and control of Fascioliasis in ruminants mainly domestic animals like cattle, sheep and goats.

Oxyclozanide was first disclosed in GB 1,048,084 by Imperial Chemical Industries Ltd. This patent describes a process for the preparation of Oxyclozanide, in which, 3, 5, 6- trichlorosalicylic acid was refluxed with thionyl chloride in dry benzene or in dry toluene. The resulting clear solution was reacted with 2-amino-4,6-dichlorophenol in presence of triethylamine and extracted with NaOH to obtain Oxyclozanide. The obtained oxyclozanide was further crystallised from glacial acetic acid. Another variant of the process describes the preparation of Oxyclozanide by condensing 3, 5, 6- trichlorosalicylic acid with 2-amino-4, 6- dichlorophenol in THF in presence of dicyclohexylcarbodiimide and further recrystallisation of the obtained Oxyclozanide by glacial acetic acid.

GB 1,139,989 discloses a process for the preparation of Oxyclozanide, in which 3,5,6- trichlorosalicylic acid and 2-amino-4,6-dichlorophenol was refluxed in xylene and phosphorus trichloride. The supernatant clear solution was cooled to give a precipitate of oxyclozanide which is isolated and crystallized from acetic acid.

The above prior art processes use highly toxic and expensive solvents and reagents like benzene, xylene, toluene and dicyclohexylcarbodiimide. The reaction in benzene and toluene is slow and gives poor yield of the product. Moreover, the prior art processes involves acetic acid crystallisation using high volumes (approximately 30 volume) of acetic acid. The use of such a huge volume of acetic acid adds to the cost of production significantly and makes the process costly and cumbersome.

Thus it is highly desirable to develop a process which overcomes most of the drawbacks of the prior art. The present inventors have developed a very cost effective and environment friendly process, which overcomes most of the drawbacks available in prior art process.

Summary of the Invention

The principal aspect of the present invention is to provide a process for the preparation of oxyclozanide comprising:

a) reaction of 3,5,6- trichlorosalicylic acid of formula IV with thionyl chloride in presence of monochlorobenzene and a catalytic amount of dimethyl formamide to obtain 3,5,6-trichloro-2-hydroxybenzoyl chloride of formula III;

b) condensation of 2-amino-4,6-dichlorophenol of formula II with 3,5,6-trichloro-2- hydroxybenzoyl chloride of formula III to obtain oxyclozanide of formula I; and

c) purification of oxyclozanide obtained above by sodium salt formation to obtain pure oxyclozanide of formula I.

The process of the present invention may be illustrated as in scheme below:

In another aspect, this invention provides a novel crystalline form of oxyclozanide which is very stable and has good free flowing property which is highly desirable for the formulation. This novel crystalline form is characterised by the powdered X-Ray diffractogram substantially as given in figure 1 and having 20 values 7.5671, 12.6078, 15.0963, 18.1899, 20.2204, 21.4609, 22.7224, 23.4031, 24.5909, 25.5150, 26.3445, 26.8252, 27.1302, 27.8032, 28.4600, 29.1724, 29.9720, 30.4604, 32.1202, 33.0221, 33.3309, 36.1832, 36.6940, 38.3810, 39.2989,41.7301,43.1901,43.5833,44.6187, 46.5727,47.2198,48.4619.

Brief Description of the Diagram/Figure

Figure 1: Represents X-Ray diffractogram of the novel crystalline form Oxyclozanide

Detail Description of the Invention

Accordingly in an embodiment of the invention 3,5,6- trichlorosalicylic acid of formula IV is dissolved in monochlorobenzene at the reflux temperature and treated with
thionyl chloride in presence of catalytic amount of dimethyl formamide in the temperature range of 60°C. to 80°C., preferably 70°C. to 75°C to form 3,5,6-trichloro-2-hydroxybenzoyl chloride of formula III. The obtained compound of formula III may be isolated and condensed or condensed insitu with 2-amino-4,6-dichlorophenol of formula II in monochlorobenzene in the temperature range of 130°C. to 135°C. In this reaction majority of monochlorobenzene is recovered easily and reused.

In another embodiment of the invention, the above Oxyclozanide of formula I is purified by dissolving it in water at pH in the range 11 to 13 preferably to 11.5- 12 using 20- 25% NaOH at room temperature. The reaction mass is stirred, filtered and the filtrate is diluted with water. The pH is further adjusted to 5.0-5.5 using acetic acid, stirred and filtered. The solid was washed with sodium dithionate solution and with DM water to obtain pure Oxyclozanide of formula I.

In yet another embodiment of the invention, the novel crystalline oxyclozanide of the present invention is very stable and highly desired for formulation due to its good free fiowing property. This novel crystalline oxyclozanide is represented by the X-ray diffractogram substantially as given in figure 1. The novel crystalline oxyclozanide is further characterised by its XRD 20 values 7.5671, 12.6078, 15.0963, 18.1899, 20.2204, 21.4609, 22.7224, 23.4031, 24.5909, 25.5150, 26.3445, 26.8252, 27.1302, 27.8032, 28.4600, 29.1724, 29.9720, 30.4604, 32.1202, 33.0221, 33.3309, 36.1832, 36.6940, 38.3810, 39.2989, 41.7301, 43.1901, 43.5833,44.6187,46.5727,47.2198,48.4619.

The present invention is advantageous over prior art, some of them are stated below:

1. The present invention avoids the use of class one solvent benzene and uses user friendly solvent monochlorobenzene for the conversion of acid to acid chloride which
makes the reaction very smooth, fast and gives higher yield.

2. The purification of Oxyclozanide in the present invention avoids the use of huge amount of (approximately 30 volumes) acetic acid and it is done by dissolving oxyclozanide in water and making sodium salt. The colour is controlled by Sodium dithionate. Thus making the purification easier, cheaper and environment friendly.

The present invention can be illustrated by the following examples, which are not to limit the scope of invention.

Example 1: Preparation of 23,5-trichloro-N-(3,5-dichloro-2-hydroxyplienyl)-6- hydroxybenzamide (I) [Oxyclozanide].

(a) Preparation of 3,5,6-trichloro-2-hydroxybenzoyl chloride
3,5,6- trichlorosalicylic acid (0.75kg) was refluxed with monochlorobenzene (1.8 L) at 130-135°C under stirring. A portion of monochlorobenzene was distilled out at atmospheric pressure at 130-135°C. Reaction mass was cooled to 35-40°C and DMF (0.0048 L) and thionylchloride (0.43kg) were added to it and heated to 70-75°C for 3 hrs. After completion of the reaction, excess of thionylchloride was distilled out at 100-102°C and reaction mass was cooled to 35-40°C to obtain 3,5,6-trichloro-2-hydroxybenzoyl chloride.

(b) Preparation of 2,3,5-Trichloro-N-(3,5-dichloro-2-hydroxyphenyl)-6-
hydroxybenzamide (I)

Fresh monochlorobenzene (1 L) was added to 3,5,6-trichloro-2-hydroxybenzoyl chloride obtained in step a) and reacted with 2-amino- 4, 6- dichlorophenol (0.50kg). The reaction mass was heated to 130-135°C under stirring for 8 hrs. After completion of reaction the temperature was brought down to 0-5 °C slowly. The solid was filtered, washed with monochlorobenzene, suck dried, further slurry washed with 5% aq. NaHCO3, water and dried do obtain oxyclozanide.

(c) Purification of Oxyclozanide using water

Oxyclozanide which is prepared in step b) was suspended in DM water under stirring for 10 minutes at 25-30°C under nitrogen. The pH was adjusted to 11.5- 12 using 20-25% NaOH at 25-30°C. The reaction mass was stirred to get a clear solution and filtered. The filtrate was diluted with DM water under stirring at 25-30°C. Again pH was adjusted to 5.0- 5.5 using acetic acid and the reaction mass stirred, filtered and washed with water. The solid was slurry washed with sodium dithionate solution and with DM water at 25-30°C. The compound was dried under vacuum at 75-80°C to obtain pure Oxyclozanide of formula I.

Yield of the pure Oxyclozanide = 1.00kg.

Example 2: Purification of Oxyclozanide using methanol and water
Oxyclozanide which is prepared in step b) was dissolved in DM water (10.4 L) and methanol (0.26 L) under stirring for 10 minutes at 25-30°C under nitrogen. The pH was adjusted to 11.5- 12 using 20-25% NaOH at 25-30°C. The reaction mass was stirred to get a clear solution and filtered. Sodium dithionate (0.049 kg) was added, stirred and heated to 45- 50 °C, charcolated, filtered through hyplo, washed with water and cooled to 10-15 °C. The pH was adjusted to 5.0-5.5 using acetic acid and the reaction mass stirred, filtered and washed with water. The solid was slurry washed with and with DM water at 25-30°C. The compound was dried under vacuum at 85-90°C to obtain pure Oxyclozanide of formula I.

Yield of the pure Oxyclozanide = 1.05kg.

We claim:

1. A process for the preparation of oxyclozanide comprising:

d) reaction of 3,5,6- trichlorosalicylic acid with thionyl chloride in presence of
monochlorobenzene to obtain 3,5,6-trichloro-2-hydroxybenzoyl chloride;

e) condensation of 2-amino-4,6-dichlorophenol with 3,5,6-trichloro-2-hydroxybenzoyl chloride in presence of a solvent to obtain oxyclozanide; and

f) purification of oxyclozanide obtained above by sodium salt formation to obtain pure oxyclozanide.

2. A process according to claim 1 wherein, 3,5,6- trichlorosalicylic acid is reacted with thionyl chloride in the presence of catalytic amount of dimethylformamide (DMF).

3. A process according to claim 1 wherein, 3,5,6- trichlorosalicylic acid is reacted with thionyl chloride at the temperature in the range of 60 °C to 80 °C.

4. A process according to claim 1 wherein, the condensation in step b) is carried out in monochlorobenzene.

5. A process according to claim 1 wherein, the condensation in step b) is carried out in the temperature range of 130°C. to 135°C.

6. A process according to claim 1 wherein, the purification in step c) is carried out in the solvent selected from the group comprising methanol, water and its mixture thereof

7. A process for purification of oxyclozanide comprising:

a) suspending oxyclozanide in water or aqueous methanol;

b) adjusting the pH in the range of 11.5 to 12;

c) filtering, diluting the filtrate with water and adjusting the pH to 5-5.5; and

d) slurry washing the obtained solid with sodium dithionate solution.

8. A crystalline oxyclozanide having X-ray diffractogram substantially as given in figure 1.

9. A crystalline oxyclozanide according to claim 8, which is further characterised by the powdered X-Ray diffractogram substantially as given in figure 1 and having 29 values 7.5671, 12.6078, 15.0963, 18.1899, 20.2204, 21.4609, 22.7224, 23.4031, 24.5909, 25.5150, 26.3445, 26.8252, 27.1302, 27.8032, 28.4600, 29.1724, 29.9720, 30.4604, 32.1202, 33.0221, 33.3309, 36.1832, 36.6940, 38.3810, 39.2989, 41.7301, 43.1901, 43.5833, 44.6187, 46.5727, 47.2198,48.4619.