DESC:FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)

A PROCESS FOR THE PREPARATION OF 4-HYDROXYBENZOTHIOAMIDE

Vasudha Pharma Chem Limited
An Indian company having its registered office at
78/A, Vengalrao Nagar,
Hyderabad – 500038,
Telangana
India
The following specification particularly describes the nature of this invention and the manner in which it is to be performed:
A PROCESS FOR THE PREPARATION OF 4-HYDROXYBENZOTHIOAMIDE
FIELD OF THE INVENTION
The present application relates to a process for the preparation of 4-hydroxybenzothioamide and further relates to a process for the preparation of Febuxostat.
BACKGROUND OF THE INVENTION
4-hydroxybenzothioamide of the formula I:

is an important pharmaceutical intermediate, used in the synthesis Febuxostat.
There are many processes reported for the preparation of 4-hydroxybenzothioamide. The process reported in the literature is represented by the following reaction scheme:

Some of the reported reagents used for the conversion of compound of formula II to compound of formula I are thioacetamide; NaHS/H2S; Na2S/ H2S; thiourea; (NH4)2S; (C2H5O)2PS2H. The prior art methods are expensive, reactions are difficult to control, generates large amount of foul smelling toxic waste, requires large amount of solvent and found to be lower yields.
The process of the present invention has advantages of improved yield, simple, easy handling which afford a significantly greater yield. The process is also industrially scalable, cost effective which makes it highly suitable for industrial scale.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is an illustration of a powder X-ray diffraction (PXRD) pattern of crystalline form A of Febuxostat.
Figure 2 is an illustration of a powder X-ray diffraction (PXRD) pattern of crystalline form C of Febuxostat.
Figure 3 is an illustration of a powder X-ray diffraction (PXRD) pattern of crystalline form G of Febuxostat.
SUMMARY OF THE INVENTION
In the first embodiment the present application provides a process for the preparation of compound of formula I, comprising: reacting a compound of formula II with Phosphorous pentasulfide (P2S5) in the absence of a solvent and in the presence of an acid.

In the second embodiment the present application provides a process for the preparation of Febuxostat comprising: reacting a compound of formula II with Phosphorous pentasulfide (P2S5) in the absence of a solvent and in the presence of an acid, to produce compound of formula I;

and then converting compound of formula I to Febuxostat.
DETAILED DESCRIPTION OF THE INVENTION
In the aspects of the first embodiment, the present application provides a process for the preparation of compound of formula I, comprising: reacting a compound of formula II with Phosphorous pentasulfide (P2S5) in the absence of a solvent and in the presence of an acid,

In aspects, the conversion of compound of formula II may be performed in the presence of an acid. The acids includes but not limited to inorganic and organic acids. The acid may be selected from hydrochloric acid, sulphuric acid, polyphosphoric acid, orthophosphoric acid, formic acid, acetic acid, propionic acid, trifluoroaceticacid, methanesulphonic acid, ethanesulphonic acid, trifluoromethanesulphonic acid, p-toluenesulphonic acid, or mixture(s) thereof. Specifically, the acid may be an inorganic acid. More specifically, the acid may be orthophosphoric acid.
In aspects, the conversion of compound of formula II may be carried out for about 30 minutes to about 24 hours at about 0 °C to about 100 oC. Specifically, the conversion of compound of formula II may be carried out for about 1 hour to about 12 hours at about 60 °C to about 75 °C.
In the aspects of the second embodiment the present application provides a process for the preparation of Febuxostat, wherein the process comprises: converting a compound of formula II with Phosphorous pentasulfide (P2S5) in the absence of a solvent and in the presence of an acid to compound of formula I:

and then converting compound of formula I to Febuxostat.
In aspects, the conversion of compound of formula II may be performed in the presence of an acid. The acids includes but not limited to inorganic and organic acids. The acid may be selected from hydrochloric acid, sulphuric acid, polyphosphoric acid, orthophosphoric acid, formic acid, acetic acid, propionic acid, trifluoroaceticacid, methanesulphonic acid, ethanesulphonic acid, trifluoromethanesulphonic acid, p-toluenesulphonic acid or mixture(s) thereof. Specifically, the acid may be an inorganic acid. More specifically, the acid may be orthophosphoric acid.
In aspects, the conversion of compound of formula II may be carried out for about 30 minutes to about 24 hours at about 0 °C to about 100 oC. Specifically, the conversion of compound of formula II may be carried out for about 1 hour to about 12 hours at about 60 °C to about 75 °C.
In the aspects, Febuxostat may be prepared from compound of formula I by any known methods in the literature or may be prepared by the method mentioned in this application.
In the aspects, the Febuxostat obtained above, may be isolated in any of the known crystalline forms of Febuxostat or in amorphous form.
In the aspects, Febuxostat may be isolated as crystalline polymorphic Form A of Febuxostat.
In the aspects, Febuxostat may be isolated as crystalline polymorphic Form C of Febuxostat.
In the aspects, Febuxostat may be isolated as crystalline polymorphic Form G of Febuxostat.
DEFINITIONS
The following definitions are used in connection with the present application unless the context indicates otherwise.
The terms "about," "general, "generally," and the like are to be construed as modifying a term or value such that it is not an absolute. Such terms will be defined by the circumstances and the terms that they modify as those terms are understood by those of skill in the art. This includes, at very least, the degree of expected experimental error, technique error and instrument error for a given technique used to measure a value.
All percentages and ratios used herein are by weight of the total composition and all measurements made are at about 25 °C and about atmospheric pressure, unless otherwise designated. All temperatures are in degrees Celsius unless specified otherwise. As used herein, the terms "comprising" and "comprises" mean the elements recited, or their equivalents in structure or function, plus any other element or elements which are not recited. The terms "having" and "including" are also to be construed as open ended. All ranges recited herein include the endpoints, including those that recite a range between two values. Whether so indicated or not, all values recited herein are approximate as defined by the circumstances, including the degree of expected experimental error, technique error, and instrument error for a given technique used to measure a value.
Room temperature as used herein refers to ‘the temperatures of the thing close to or same as that of the space, e.g., the room or fume hood, in which the thing is located’. Typically, room temperature can be from about 20 °C to about 30 °C, or about 22 °C to about 27 °C, or about 25 °C.
The reaction time should be sufficient to complete the reaction which depends on scale and mixing procedures, as is commonly known to one skilled in the art. Typically, the reaction time can vary from about few minutes to several hours. For example the reaction time can be from about 10 minutes to about 24 hours, or any other suitable time period.
The isolation of the product may be accomplished by, among other things, extraction, concentration, precipitation, crystallization, filtration or centrifugation.
Suitable temperatures for isolation may be less than about 120 °C, less than about 80 °C, less than about 60 °C, less than about 40 °C, less than about 30 °C, less than about 20 °C, less than about 10°C, less than about 0 °C, less than about -10 °C, less than about -40 °C or any other suitable temperatures.
Washing of the obtained residue may be carried out using the solvents in which the product is sparingly soluble and by selecting a temperature that allows dissolving of impurities only and not the desired product. The solvents for washing may include, but are not limited to, water, ethyl acetate, acetone, methanol, ethanol. 1-propanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl-1-propanol, 1-pentanol, ethyleneglycol, propylene glycol, diethyl ether, ethyl methyl ether, tert-butyl methyl ether, tetrahydrofuran or 1,4-dioxane, methyl acetate, propyl acetate, butyl acetate, methyl ethylketone, methylisobutyl ketone, benzene, toluene, xylene, N,N-dimethylformamide or N,N-dimethylacetamide, acetonitrile, propionitrile, dimethylsulfoxide, diethylsulphoxide, or mixture(s) thereof.
Certain specific aspects and embodiments of the present application will be explained in more detail with reference to the following examples, which are provided for purposes of illustration only and should not be construed as limiting the scope of the present application in any manner.
EXAMPLES
Example 1: Preparation of 4-hydroxybenzothioamide
Ortho phosphoric acid (200 ml) and 4-hydroxybenzonitrile (100 gm) were charged into a round bottom flask at room temperature and stirred for 10-15 minutes. Raise the temperature of the reaction mass to 60 oC and then phosphorous pentasulphide (74 gm) was added and maintained for 4 hours. Water (1000 ml) was added at the same temperature, cooled to room temperature and maintained for 3 hours at the same temperature. Filtered and washed with water (500 ml) to get pure titled compound.

Example 2: Preparation of ethyl 2-(4-hydroxyphenyl)-4-methylthiazole-5- carboxylate.
Isopropanol (100 ml) and 4-hydroxybenzothioamide (25 gm) were charged into a round bottom flask at room temperature and stirred for 15 minutes. The reaction mass was cooled to 15 °C and ethyl-2-chloroacetoacetate (30 gm) was added for 1 hour at the same temperature. The temperature of the reaction mas was raised to 90 oC and stirred for 4 hours. The reaction mass was cooled to 10 oC and maintained for 3 hours at the same temperature and filtered to pure titled compound.

Example 3: Preparation of ethyl 2-(3-formyl-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate.
Polyphosphoric acid (2200 gm), orthophosporic acid (1100 gm) and ethyl 2-(4-hydroxyphenyl)-4-methylthiazole-5-carboxylate (550 gm) were charged into a round bottom flask at 50 °C and maintained for 1 hour. The temperature of the reaction mass was raised to 60 oC then hexamethylenetetramine (380 gm) was added slowly and temperature of the reaction mass was raised to 70 oC and maintained for 5 hours. Cooled to room temperature and the reaction mass was washed with water (1925 ml) and methanol (2750 ml) and dried to get pure titled compound.

Example 4: Preparation of ethyl 2-(3-cyano-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate.
N,N-dimethylformamide (1800 ml), ethyl 2-(3-formyl-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate (600 gm) and hydroxylamine hydrochloride (180 gm) were charged into a round bottom flask at room temperature. The temperature of the reaction mass was raised to 70 oC and stirred for 1 hour. Acetic anhydride (358.5 gm) was added lot-wise for 5 hours to the reaction mass with stirring at 90 oC. The reaction mass was stirred for 2 hours and cooled to room temperature. To the reaction mass water (6000 ml) was added and stirred for 2 hours and filtered the reaction mass and washed with water (600 ml) and dried at 70 oC for 12 hours to get the pure titled compound.

Example 5: Preparation of ethyl 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate.
N,N-dimethylformamide (1650 ml), ethyl 2-(3-cyano-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate (550 gm) were charged into a round bottom flask at room temperature and stirred for 15 minutes. Potassium carbonate (475 gm) was added to the reaction mass at same temperature and stirred for 30 minutes and raised the temperature of the reaction mass to 45 oC. Isobutyl bromide solution (442 gm in 550 ml of N,N-dimethylformamide) was added to the reaction mass at the same temperature and raised the temperature to 95 oC. The reaction mass was stirred for 6 hours at the same temperature and cooled to room temperature and water (5500 ml) was added and stirred for 3 hours. The reaction mass was filtered and washed with water (1100 ml) and filtered. The filtered wet compound was purified with ethylacetate (1650 ml) and dried at 65 oC for 10 hours to get the pure titled compound.

Example 6: Preparation of 2-(3-cyno-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid [FEBUXOSTAT CRUDE]
Acetone (5500 ml), ethyl 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate (550 gm) and sodiumhydroxide solution (176 gm in 2200 ml water) were charged into a round bottom flask at room temperature. The temperature of the reaction mass was raised to 40 oC and stirred for 6 hours and cooled to 5 oC. Now 15% HCl (550 ml of Concentrated HCl in 550 ml water) was added to the reaction and the temperature of the reaction mass was raised to 45 oC and stirred for 2 hours and filtered. Washed with aqueous acetone (acetone 275 ml + water 275 ml) and filtered to get titled compound.

Example 7: Preparation of crystalline Form-A of Febuxostat
Methylisobutylketone (1000 ml) and Febuxostat (100 gm) were charged into a round bottom flask at room temperature and heated to 110 oC. Water was completely removed from the reaction system azeotropically and treated with carbon. The reaction mass was filtered and washed with pre heated methylisobutylketone (200 ml) and filtered. From the filtrate was distilled out 700 ml of methylisobutylketone. Crystalline Febuxostat Form A (1 gm) seed was added lot wise between 114 oC to 105 oC. The reaction mass was cooled to 35 oC and stirred for 1 hour and further cooled to 5 oC. After stirring for 3 hours the reaction mass was filtered and washed with pre heated methylisobutylketone (50 ml) and dried under vacuum at 50 oC for 13 hours to give crystalline Form A of Febuxostat.

Example 8: Preparation of crystalline Form-C of Febuxostat
Acetone (1000 ml) and Febuxostat (100 gm) were charged into a round bottom flask at room temperature and heated to 55 oC and stirred for 1 hour. The reaction mass was cooled to 53 oC and Form C (500 mg) seed was added lot wise between 53 oC to 45 oC. The reaction mass was cooled to 35 oC and stirred for 1 hour and further cooled to 5 oC. After stirring for 3 hours the reaction mass was filtered and washed with pre cooled acetone (25 ml) and dried under vacuum at 45 oC for 12 hours to give crystalline Form C of Febuxostat.

Example 9: Preparation of crystalline Form-G of Febuxostat
Water (4400 ml) and Febuxostat (849 gm) were charged into a round bottom flask at room temperature. The temperature of the reaction mass was raised to 60 oC and stirred for 3 hours then cooled to room temperature and stirred for another 3 hours. The reaction mass was filtered and washed with water (550 ml) to give wet compound. The wet compound was dried under vacuum at 50 oC for 15 hours to give Form G of Febuxostat.
,CLAIMS:
We Claim:
1) A process for the preparation of compound of formula I, comprising: reacting a compound of formula II with Phosphorous pentasulfide (P2S5) in the absence of a solvent and in the presence of an acid.

2) A process for the preparation of Febuxostat comprising: reacting a compound of formula II with Phosphorous pentasulfide (P2S5) in the absence of a solvent and in the presence of an acid, to produce compound of formula I;

and then converting compound of formula I to Febuxostat.
3) The process according to claims 1 and 2, wherein the acid is selected from inorganic and organic acids.
4) The process according to claim 3, wherein the acid is selected from hydrochloric acid, sulphuric acid, polyphosphoric acid, orthophosphoric acid, formic acid, acetic acid, propionic acid, trifluoroaceticacid, methanesulphonic acid, ethanesulphonic acid, trifluoromethanesulphonic acid, p-toluenesulphonic acid and or mixtures thereof.
5) The process according to claim 3, wherein the acid is orthophosphoric acid.