IE63471B1 - Manufacture of a salicylanilide derivative - Google Patents

Description

Manufacture of a salicvlanilide derivative OfQ This invention relates to industrial scale manufacture of a salicylanilide derivative, more particularly 3'-chloro-4'-(pchlorophenoxy)-3,5-diiodosalicylanilide (Rafoxanide).

Rafoxanide is useful as a fasciolicide and anthelmintic and is particularly effective against liver fluke in domestic animals such as cattle and sheep.

U.K. Patent Specification No. 1,183,641 (Example 29) describes the preparation of Rafoxanide on a laboratory scale. In the latter Example Rafoxanide is prepared by refluxing a mixture of 4-amino2,4'-dichlorobiphenylether, diiodosalicylic acid and phosphorus trichloride in chlorobenzene for three hours, whereupon the mixture is decanted and the crude product allowed to settle out of solution upon cooling to room temperature. The latter process results in a yield of Rafoxanide of 37%. This process cannot be readily scaled up to industial scale manufacture.

U.K. Patent No. 1,219,500 describes a laboratory scale preparation of Rafoxanide and other salicylanilides covered by U.K. Patent No. 1,183,641 by diazotizing an appropriately substituted aminophenylthio- or aminophenoxy- salicylanilide with nitrous acid. In the case of Rafoxanide (Example 2) the yield obtained is not given.

It is an object of the present invention to provide an industrial scale process for the production of Rafoxanide in increased yield relative to prior methods.

Accordingly, the invention provides in one aspect a process for the manufacture of 3'-chloro-4'-(p-chlorophenoxy)-3,5diiodosalicylanilide, which comprises heating a mixture of 2-chloro-4aminophenyl-p-chlorophenyl ether, diiodosalicylic acid, an amine activating agent and an inert organic solvent under reflux, recovering a portion of the inert organic solvent by distillation and allowing the ? mixture to cool to a temperature in the range 65-85°C., adding a polar solvent under reflux conditions and refluxing the mixture for a period ♦ of less than 30min., followed by cooling and collection of the salicylanilide product.

Preferably, the amine activating agent is selected from an alkyl halophosphite, alkyl halophosphate, aryl halophosphate, a halophosphate acid, phosphorus oxychloride or phosphorus trichloride.

Most preferably, the amine activating agent is phosphorus trichloride.

The refluxing of the reactants prior to the removal of said portion of the inert organic solvent is preferably carried out for a period of 30-90min.

Further, preferably the amount of the inert organic solvent removed is at least half of the amount thereof initially added to the reaction vessel.

The preferred inert organic solvent is toluene.

The mixture is preferably cooled to a temperature in the range 70-80°C. following the distillation of the inert organic solvent.

Following the refluxing of the reactants with the polar solvent, the mixture is allowed to cool to ambient temperature and is preferably allowed to stand for several hours, whereupon the precipitated salicylanilide product is suitably collected by filtration and washing with said polar solvent. fe The preferred polar solvent is ethanol.

The 2-chloro-4-aminophenyl-p-chlorophenyl ether is preferably prepared by the reduction of 2-chloro-4-nitrophenyl-p-chlorophenyl ether.

The 2-chloro-4-aminophenyl-p-chlorophenyl ether may be reacted immediately with the other reactants without being isolated.

The 2-chloro-4-nitrophenyl-p-chlorophenyl ether is preferably prepared by by reacting p-chlorophenol and dichloronitrobenzene in a basic medium.

The process according to the invention is a streamlined process for the manufacture of Rafoxanide on an industrial scale and gives yields which are up to 10% or greater than yields previously obtained under somewhat comparable conditions.

The process according to the invention can be carried out substantially as a 'one pot' process, if required.

The invention also provides 3'-chloro-4'-(p-chlorophenoxy)-3,5diiodosalicylanilide whenever manufactured by a process hereinbefore specified.

As indicated above the manufacture of 3'-chloro-4'-(pchlorophenoxy)-3,5-diiodosalicylanilide in accordance with the invention is preferably carried out as depicted in Scheme 1.

Scheme 1 Preparation of 3'-chloro-4'-p-chlorophenoxy-3.5diiodosalicvlanilide (Rafoxanide) 2-chloro-4-aminophenyl-pchlorophenyl ether. 3’-chloro-4’-p-chlorophenoxy-3,5-diiodosalicylanilide The 2-chloro-4-aminophenyl-p-chlorophenyl ether is preferably obtained by reduction of 2-chloro-4-nitrophenyl-p-chlorophenyl ether. The reduction may be carried out by refluxing the nitro compound in the presence of iron powder and ammonium chloride as described in Preparation 2 hereafter or by hydrogenation of the nitro compound over Raney nickel in the presence of ethyl acetate, according to Scheme 2 and Scheme 3 respectively.

Scheme 2 Preparation of 2-chloro-4-aminophenyl-p-chlorophenyl 2-chloro-4-nitrophenylp-chlorophenyl ether 2-chloro-4-aminophenylp-chlorophenyl ether Scheme 3 Preparation of 2-chloro-4-aminophenyl-p-chlorophenyl ether h2 Ethyl Acetate NO2 -Cl Raney Nickel NH, 2-chloro-4-nitrophenylp-chlorophenyl ether 2-chloro-4-aminophenylp-chlorophenyl ether The preparation of the 2-chloro-4-nitrophenyl-p-chlorophenyl ether is suitably carried out by reaction of 3,4-dichloronitrobenzene 15 with p-chlorophenol in the presence of potassium hydroxide and xylene according to Scheme 4.

Scheme 4 Preparation of 2-chloro-4-nitrophenyl-p-chlorophenyl ether 3,4-dichloronitrobenzene KOH Xylene p-chlorophenol V no2 2-chloro-4-nitro phenyl -p-chlorophenyl ether The invention will be further illustrated by the following Preparations and Examples.

Preparation 1 Preparation of 2-chloro-4-nitrophenyl-p-chlorophenyl ether Potassium hydroxide (1.41 Kg.), p-chlorophenol (2.70 Kg.) and dichloronitrobenzene (4.2 Kg.) were added to a clean dry vessel fitted with a Dean & Stark receiver with reflux condenser, stirred and heated to reflux. The p-chlorophenol and dichloronitro benzene were melted before being added to the vessel. Water was removed by azeotropic distillation, allowing the vessel temperature to rise to 140°C. maximum. This temperature was maintained for 30 min., then the xylene was distilled off, initially at atmospheric temperature and finally under vacuum. When no more xylene was collected the vessel was cooled to 120°C. whilst maintaining stirring. Ethanol (25 1.) was added under reflux conditions the temperature was allowed to fall to 80°C. and refluxed for a further 30 min. Water (8.4 1.) was added slowly while maintaining reflux, and the refluxing was continued for a further 30 min. The reaction mixture was cooled to 0-5°C. and maintained at this temperature for 2 h. The yellow solid obtained was then filtered off and washed sequentially with aqueous ethanol (50%).

The product was then dried at 60°C. (yield 85%; m. . 106108°C.).

Preparation 2 Preparation of 2-chloro-4-aminophenyl-p-chlorophenyl ether To a refluxing mixture of ammonium chloride (2.7 Kg.) in water (100 1) containing iron powder (11.2 Kg.) 2-chloro-4nitrophenyl-p-chlorophenyl ether (14.2 Kg.) obtained in Preparation 1 was added portionwise over 2-3 h. The resulting mixure was refluxed for an additional 3 h., then cooled to 40-50°C.. Ethyl acetate (100 1.) was added over 30 min. and then the reaction mixture was cooled to 15-20°C. This mixture was filtered and the solids washed with ethyl acetate (20 1.). The aqueous phase was separated and re-extracted with ethyl acetate (301.). The combined extracts were washed with water (50 1.), then dried over anhydrous magnesium sulphate, filtered and the filtrate evaporated to dryness to give the desired aniline yield 9.8 Kg; (77%).

Example 1 Preparation of 3,-chloro-4,-(p-chlorophenoxy)-3-5-diiodosalicylanilide 2-Chloro-4-aminophenyl-p-chlorophenyl ether (28.9% in ethyl acetate) solution was charged to a one litre flask. The solution was heated to reflux and the ethyl acetate removed by atmospheric distillation. A vacuum was applied to remove any remaining ethyl 5 acetate. A change was made to reflux conditions, whereupon toluene (350 g.) followed by phosphorus trichloride (22.3g.) and > diiodosalicylic acid were added to the flask. The reactants were heated slowly to reflux (110°C.) and refluxed for lh. A change was then made to atmospheric conditions and a portion of the toluene (200 g.) removed. The mixture was then cooled to 70°C. and ethanol (65 g.) added under reflux conditions. The mixture was then heated back to reflux (84°C.) and refluxed for 10 min. The mixture was then cooled to room temperature, allowing the salicylanilide product to crystallise out, whereupon it was filtered off, washed first with toluene and then twice with ethanol to give a wet yield of 175.2 g. The wet salicylanilide was dried in an oven at 50°C. The fined yield obtained =123.9 g (49.8%).

On analysis the product, which was a light yellow crystalline powder, gave a melting point of 173-174 (ht 175-176) and when subjected to thin layer chromatography (tic) gave a single spot. An I.R. Spectrum was identical to the reference.

Example 2 Preparation of 3'-chloro-4’-(p-chlorophenoxy)-3.5diiodosalicvlanilide To a stirred solution containing 2-chloro-4-aminophenyl-pchlorophenyl ether (5.0 Kg.) obtained in Preparation 2, diiodosalicylic acid (7.7 Kg.) in toluene (50 1) was added phosphorus trichloride (1.1 Kg.) over a short period of time (5-20 min.). The resulting mixture _ s was heated at reflux for 75 min. Toluene (2.7 1.) was then recovered by distillation, the heat removed and the mixture cooled to 80°C. when ethanol (4.0 1.) was added slowly. The mixture was refluxed for 15 min, then cooled to ambient temperature for several hours. The precipitated solid was collected by filtration and washed with ethanol (11.).

The damp cake obtained was recrystallised from an ethanol toluene mixture (15 1. of 50:50 mixture) to give the title compound after washing with ethanol (1 1.) and drying at 50°C., yield 5.9 Kg.; (47.7%).

Claims (13)

1. A process for the manufacture of 3'-chloro-4'-(pchlorophenoxy)-3,5-diiodosalicylanilide, which comprises heating a mixture of 2-chloro-4-aminophenyl-p-chlorophenyl ether, diiodo salicylic acid, an amine activating agent and an inert organic solvent under reflux, removing a portion of the inert organic solvent by distillation and allowing the mixture to cool to a temperature in the range 65-85°C., adding a polar solvent under reflux conditions and refluxing the mixture for a period of less than 30min., followed by cooling and collection of the salicylanilide product.

2. A process according to Claim 1, wherein the amine activating agent is an alkyl halophosphite, alkyl halophosphate, aryl halophosphate, a halophosphate acid, phosphorus oxychloride or phosphorus trichloride.

3. A process according to Claim 1, wherein the amine activating agent is phosphorus trichloride.

4. A process according to any preceding claim, wherein the refluxing of the reactants prior to the removal of said portion of the inert organic solvent is carried out for a period of 30-90min.

5. A process according to any preceding claim, wherein the amount of the inert organic solvent removed is at least half the amount thereof initially added.

6. A process according to any preceding claim, wherein the inert organic solvent is toluene.

7. A process according to any preceding claim, wherein the mixture is cooled to a temperature in the range 70-80°C. following the distillation of the inert organic solvent.

8. A process according to any preceding claim, wherein the precipitated salicylanilide product is collected by filtration and washed with said polar solvent. ι

9. A process according to any preceding claim, wherein the 25 chloro-4-aminophenyl-p-chlorophenyl ether is prepared by the reduction of 2-chloro-4-nitrophenyl-p-chlorophenyl ether.

10. A process according to Claim 9, wherein the 2-chloro-4aminophenyl-p-chlorophenyl ether prepared is subjected to the process according to any one of Claims 1-8 without being isolated. 10

11. A process according to Claim 9 or 10, wherein the 2-chloro-4nitrophenyl-p-chloropheny 1 ether is prepared by reacting pchlorophenol and dichloronitrobenzene in a basic medium.

12. A process according to any preceding claim, which is carried out substantially as a one pot process.

13. 15 13. A process according to Claim 1, substantially as hereinbefore described with particular reference to the accompanying Preparations and Examples.