FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patent Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
TITLE OF THE INVENTION
"PROCESS FO PREPARATION OF 2-(3-CYANO-4-
ISOBUTYLOXYPHENYL)-4-METHYL-5-
THIAZOLECARBOXYLIC ACID AND INTERMEDIATES
THEREOF"
We, CADILA HEALTHCARE LIMITED, a company incorporate under the Companies Act, 1956, of Zydus Tower, Satellite Cross Road, Ahmedabad 380015, Gujarat, India.
The following specification particularly describes the invention and the manner in which it is to be performed:

The present invention relates to the process for the preparation of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid, "Febuxostat" (1) and intermediates thereof. In particular the present invention relates to the process for the preparation of 3-(substituted-4,5-dihydrooxazol-2-yl)-4-isobutoxybenzothioamide (4) and its use for the preparation of Febuxostat (1). This compound has an action of regulating biosynthesis of uric acid in vivo and can be used as a therapeutic agent for hyperuricemia. BACKGROUND OF THE INVENTION
The following discussion of the prior art is intended to present the invention in an appropriate technical context and allow its significance to be properly appreciated. Unless clearly indicated to the contrary, however, reference to any prior art in this specification should be construed as an admission that such art is widely known or forms part of common general knowledge in the field.
The common name of 2-(3-cyano-4-isobutyloxyphenyl)-4-methy1-5-thiazolecarboxylic acid (1) is Febuxostat, mainly is used for the treatment of hyperuricemia.

US 5,614,520 discloses the process for the preparation of Febuxostat (1) i.e. 2-arylthiazole derivative or pharmaceutically acceptable salt thereof for treating diseases selected from consisting of gout or hyperuricemia and diseases associated with a production of interleukin. US '520 discloses several prior arts for the synthesis of 2-arylthiazole derivatives.
Febuxostat can be prepared as per the known procedures as described in Organic Reactions, Vol. 6, 367-409 (1951), or Heterocyclic Compounds, Vol. 34 (1978). The arylthiazoles can be prepared by the process as disclosed in scheme-1.

Scheme-]
Hal represents a halogen atom, and Ra represents a C1-4 alkyl group. Rl, R2 and R3 are defined in the specfication.

JP patent 06345724 discloses method for preparation of 2-(3-cyanophenyl)thiazole derivative. The title compound or a pharmacologically acceptable salt thereof is prepared by reacting 888 mg 4-nitrobenzonitrile and 703 mg KCN at 100° in DMSO for 40 min and cooled and 2.9 g iso-Bu bromide and 410 mg K2C03 were added followed by stirring the mixture at 80°C for 8 h to give intermediate with 50% yield. The latter compound (590 mg) was stirred with 550 mg thioacetamide in 6 N HCl in DMF at 45° for 48 h and additional 2 mL HCl/DMF and 220 mg thioacetamide were added followed by stirring the mixture for 24 h to give arylthioacetamide derivative in 92% yield. A solution of the latter compound {400 mg) and 340 mg Et chloro-acetoacetate in EtOH was heated with stirring at 100° for 100 min to give Febuxostat.
Heterocycles Vol. 47, No. 2 (1998) p 857 discloses the process for the preparation of Febuxostat (1) by using 4-isobutoxy-l,3-benzenedicarbonitrile (8a).

The process parameters provided in Heterocycles discloses introduction of cyano group to 4-nitrobenzonitrile and converting it to 4-alkoxy-l,3-benzenedicarbonitrile in a one pot process. Further the obtained 4-alkoxy-l,3-benzenedicarbonitrile can be converted to Febuxostat (1) as shown in reaction scheme-2.


The process discloses in above prior arts has serious drawbacks. The compound 4-alkoxy-l,3-benzenedicarbonitrile (8a) undergoes side reaction by the formation of byproduct of dimer impurity of (7b). The entire reaction pathway proceeds similar to the formation of Febuxostat (1) as shown above in the scheme-2a. Thus, the process provided in the prior art is not suitable for the formation of Febuxostat (1) in high yield and purity.

US Patent 6,225,474 B1 discloses the presence of five crystal polymorphs of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid, crystals A, B, C, D, and G and an amorphous form and a.method for producing them. The method for producing crystal polymorphs described here involves the production of each crystal polymorph by adding a predetermined mixed solvent of methanol and water to 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid, dissolving the resultant mixture by heating with stirring, cooling the mixture by the addition of water to obtain the predetermined methanol and water composition and temperature, then collecting crystals by filtration, and drying the crystals.
CN1275126, wherein the A crystalline substance is the relative crystal formation of stabilizing wherein, the brilliant methanolizing thing that be of D, and the G crystalline substance is the hydrate. This piece of patent all adopts the solvent system of methyl alcohol / water or isopropyl alcohol / water to carry out the crystallization, and can carry out the crystal formation.
China patent application 200610030935 discloses two kinds of new crystal formation I and II of 22-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid (1). These two kinds of crystal formations hygroscopicity under the high humility environment is lower, is suitable for and makes stable pharmaceutical preparations.
China patent application CN 101386605 discloses crystalline Form K of Febuxostat and CN 101474175 discloses high bioavailability with Febuxostat crystal C, H, I or J crystal form and the average grain diameter of the Febuxostat crystal form ranges from 3.5-10 μm, preferably 3.5-7.0 μm. CN 101412700 also discloses another novel crystalline form of Febuxostat obtained by recrystallization of Febuxostat in ethyl acetate.
Accordingly, there is a need for an improved process for the preparation of Febuxostat (1), which reduces the formation of byproduct as per reaction scheme-2a. Thus, the inventors of the present invention provides an improved process for the preparation of Febuxostat (I) by using novel intermediate 3-(substituted-4,5-dihydrooxazol-2-yl)-4-isobutoxybenzothioamide (4).
Thus, there remains a need in the art for an improved process of preparing Febuxostat (1) that eliminates the problems of the prior art on a commercial scale in a convenient and cost efficient manner. SUMMARY OF INVENTION
In one embodiment, there is provided a compound of formula (4)


wherein R1,R2,R3 and R4 each independently represents H, C1 to C8 alkyl, C5 to C10 cycloalkyl
or aryl, preferably R6 and R7 each independently represents H or C1 to Cg alkyl and even more

preterably, R1 and R2 both represent H, and R3 and R4 both r
in oneembofdiment, there is provided a method of preparing substantially pure

Febuxostat(l),
the process comprises:
(a) reacting compound of formula (4),

wherein R1, R2, R3 and R4 are as defined above,
with ethyl 2-chloroacetoacetate in a polar solvent to obtain ethyl 2-(3-substituted)-4-

isobutoxyphenyl)-4-methylthiazo1e-5-carboxylate(3);


(b) hydrolyzing ethyl 2-{3-(substituted)-4-isobutoxyphenyl)-4-methyl-thiazole-5-carboxylate (3)
with suitable base in a suitable organic solvent to obtain 2-(3-(substituted)-4-
isobutoxyphenyl)-4-methyl-thiazole-5-carboxylic acid (2);

(c) treating 2-(3-(substituted)-4-isobutoxyphenyl)-4-methyl-thiazole-5-carboxylic acid (2) of step (b) with acidic dehydrating agent to obtain Febuxostat (1); and
(d) optionally, recrystallizing Febuxostat (1) in suitable organic solvent to obtain substantially pure Febuxostat (1).
In another embodiment, there is there is provided an intermediate 2-(3-substituted)-4-isobutoxyphenyl)-4-methyl-thiazole-5-carboxylate(3),

wherein R1, R2, R3 and R4 are as defined above.
In another embodiment, there is there is provided an intermediate 2-(3-substituted)-4-isobutoxyphenyl)-4-methyl-thiazole-5-carboxylic acid (2)


(2) wherein R1, R2, R3 and R4 are as defined above.
In yet another embodiment, there is provided a method for the preparation of an intermediate 3-(substituted)-4-isobutoxybenzothioamide (4)

wherein R1, R2 ,R3 and R4 are as defined above, the process comprises:
(a) reacting methyl 5-cyano-2~hydroxybenzoate with isobutyl bromide in presence of base to
obtain methyl 5-cyano-2-isobutoxybenzoate of formula (9);

(b) reacting methyl 5-cyano-2-isobutoxybenzoate of formula (9) with thioacetamide in an
organic solvent to obtain methyl 5-carbamothioy!-2-isobutoxybenzoate of formula (8);

(c) hydrolyzing methyl 5-carbamothioyI-2-isobutoxybenzoate of formula (8) in presence of base
to obtain 5-carbamothioyl-2-isobutoxybenzotic acid (7);


(7)
(d) reacting acid of formula (7) with thionyl chloride in suitable hydrocarbon solvent to obtain acid chloride of formula (6) and in-situ reacting acid chloride (6) with 2-amino-2-methyl propanol in suitable hydrocarbon solvent in presence of co-solvent to obtain hydroxy amide of formula (5);
(e) subjecting hydroxy amide of formula (5) to ring closure reaction with suitable reagent to obtain an intermediate 3-(substituted)-4-isobutoxybenzothtoamide (4); and
(0 isolating 3-(substituted)-4-isobutoxybenzothioamide (4).
In still another embodiment, there is provided a method for preparing 3-(substituted)-4-isobutoxybenzothioamide (4),
wherein R1, R2, R3 and R4 are as defined above, the process comprises:
(a) reacting methyl 5-cyano-2-hydroxybenzoate with isobuty] bromide in presence of base to obtain methyl 5-cyano-2-isobutoxybenzoate of formula (9);


(b) hydrolyzing methyl 5-cyano-2-isobutoxybenzoate of formula (9) in presence of base to
obtain 5 -cyano-2- isobutoxybenzo ic acid (13);

(c) reacting acid of formula (13) with thionyl chloride in suitable hydrocarbon solvent to obtain
propanol in suitable hydrocarbon solvent in presence of co-solvent to obtain hydroxy amide of formula (11);
(g) subjecting hydroxy amide of formula (11) to ring closure reaction with suitable reagent to obtain an intermediate of formula (10);

(h) reacting compound of formula (10) with thioacetamide in an organic solvent to obtain 3-
(substituted)-4-isobutoxybenzothioamide of formula (4); and (i) isolating 3-(substituted)-4-isobutoxybenzothioamide (4).

In still another embodiment, there is provided a method for preparing 3-(substituted)-4-isobutoxybenzothioamide (4),
wherein R1, R2, R3 and R4 are as defined above, the process comprises:
(a) reacting 5-chloro-2-hydroxybenzoic acid with thionyl chloride in suitable hydrocarbon
solvent to obtain 5-chloro-2-hydroxybenzoyl chloride and in-situ reacting acid chloride with
2-amino-2-methyl propanol in suitable hydrocarbon solvent in presence of co-solvent to
obtain hydroxy amide of formula (18);

(b) subjecting hydroxy amide of formula (18) to ring closure reaction with suitable reagent to
obtain an intermediate of formula (17);

(c) reacting compound of formula (17) with sodium cyanide in suitable organic solvent to obtain
3-(substituted)-4-hydroxybenzonitrile of formula (16);

(d) reacting 3-(substituted)-4-hydroxybenzonitrile of formula (16) with isobutyl bromide in
presence of base to obtain 3-(substituted)-4-isobutoxybenzonitrile of formula (10);


(e) reacting 3-(substituted)-4-isobutoxybenzonitrile of formula (10) with thioacetamide in an organic solvent to obtain 3-(substituted)-4-isobutoxybenzothioamide of formula (4); and
(f) isolating 3-(substituted)-4-isobutoxybenzothioamide (4).
In yet another embodiment, there are provided novel intermediates for the preparation of Febuxostat (1) and their process for preparation.
DETAILED DESCRIPTION ON INVENTION
The present inventors have found that by using 5-chloro-2-hydroxybenzoic acid or methyl 5-cyano-2-hydroxybenzoate as starting materials, the formation of dimer impurity as shown in scheme-2a can be avoided. The desired reaction proceeds with no formation of byproducts as there is single nitrile substitution. Further, the inventors have also found that the use of novel intermediates for the preparation of key intermediates can be used without affecting the yield and purity. This significantly improves the process economics and commercial viability.
The isolation may include filtration, filtration under vacuum, centrifugation, and decantation. The product obtained may be further or additionally dried to achieve the desired moisture values. For example, the product may be dried in a tray drier, dried under vacuum and/or in a Fluid Bed Drier.
Optionally, the solution, prior to any solids formation, can be filtered to remove any undissolved solids, solid impurities and the like prior to removal of the solvent. Any filtration system and filtration techniques known in the art can be used. "Suitable solvent" means a single or a combination of two or more solvents.
"Substantially pure" means Febuxostat (1) prepared by the process of the present invention is substantially free from dimer impurities of formula (7b), (6b) and (lb) respectively. The impurities (7b), (6b) and (lb) individually are less than about 0.5% by area percentage of HPLC, preferably less than about 0.25%, more preferably less than about 0.1% by area percentage of HPLC.

Embodiments of the process may include one or more of following features. For example, the solution or suspension may be obtained by dissolving or pending Febuxostat in a suitable solvent. Alternatively, such a solution may be Obtained directly from a reaction mixture in a process in which Febuxostat is formed. The solvent containing Febuxostat may be heated to obtain a solution. It can be heated from about 30 °C to about reflux temperature of the solvent used, for example from about 30 °C to about 100°C.
The term "obtaining" includes dissolving, slurrying, stirring combination thereof. In one aspect, there is provided an intermediate of formula (4A)

wherein R represents a C2 to C5 alkylene group which may be substituted or substituted by one or more of the groups selected from C1 to C8 alkyl, C8 to C15 aryl C8-C15 heteroaryl, C3 to C10 cycloalkyl, C5 to C10 heterocycloalkyl, C7 to C10 aralkyl. C1-C6 alkoxy, or a C3 to C7 cycloalkyl group attached to the alkylene group via a spiro carbon atom, or the alkylene group may contain a C8-C15 aryl group fused to two alkylene carbon atoms.
Particularly preferred novel compounds of the present invention are the compounds of formula (4A) wherein R represents a C2 to C5 alkylene group, which may be unsubstituted or substituted by one or more of the groups selected from C5 to C10 cycloalkyl, C5 to Cl0 heterocycloalkyl, C7 to C10 aralkyl, C1 to C5 alkoxy, or a C5 to C7 cycloalkyl group attached to the alkylene group via a spiro carbon atom, or the alkylene group may contain C5-C15 aryl group fused to two alkylene carbon atoms.
The invention also provides the use of these novel compounds in the synthesis of Febuxostat (1).

Preferably, in the novel compounds of the present invention, R represents a C2 to C5 alkylene group substituted by C5 to Cg cycloalkyl, C1 to C6 alkoxy, or a benzene or naphthalene ring fused to two carbon atoms of the alkylene group.
In another aspect there is provided an intermediate of formula (4),

wherein R1, R2, R3 and R4 each independently represents H, C1 to C8 alkyl, C5 to C10 cycloalkyl or aryl. Preferably R6 and R7 each independently represent H or C1 to C8 alkyl and even more preferably, R1 and R2 both represent H, and R3 and R4 both represent methyl.
In still another aspect, there is provided a method of preparing substantially pure Febuxostat (1),
the process comprises:
{a) reacting 3-(substituted)-4-isobutoxybenzothioamide compound of formula (4),

wherein R1, R2, R3 and R4 are as defined above,
with ethyl 2-chloroacetoacetate in a polar solvent to obtain ethyl 2-(3-substituted)-4-
isobutoxyphenyl)-4-methylthiazole-5-carboxylate(3);


(b) hydrolyzing ethyl 2-(3-(substituted)-4-isobutoxyphenyl)-4-methyl-thiazole-5-carboxylate (3) with suitable base in a suitable organic solvent to obtain 2-(3-(substituted)-4-isobutoxyphenyl)-4-methyl-thiazole-5-carboxylic acid (2);

(c) treating 2-(3-(substituted)-4-isobutoxyphenyl)-4-methyl-thiazole-5-carboxylic acid (2) of step (b) with acidic dehydrating agent to obtain Febuxostat (1); and
(d) optionally, recrystallizing Febuxostat (1) in suitable organic solvent to obtain substantially pure Febuxostat (I).
In general procedure, the process for the preparation of Febuxostat (1) may include reacting 3-(substituted)-4-isoburoxybenzothioamide compound of formula (4) with ethyl 2-chloroacetoacetate in a polar organic solvent selected from aliphatic alcohols like methanol (MeOH), ethanol (EtOH), n-propanol, isopropanol (IPA), n-butanol, tert-amyl alcohol (t-AmOH); aliphatic ketones like acetone, methylethylketone (MEK), methylisobutyl ketone (MIBK), dimethylformamide (DMF), dimethylacetamide (DMAc), dimethylsulfoxide (DMSO), N-methylpyrrolidone (NMP) and the like, preferably isopropanol (IPA) to obtain ethyl 2-(3-substituted)-4-isobutoxyphenyl)-4-methy|thiazole-5-carboxylate(3).
Embodiments of the process may include that the reaction mixture is dissolved in a solvent system with optional heating to form a solution or suspension. The heated reaction mixture can be at about the boiling point of the solvent system, specifically about 25°C to about 100°C, more specifically about 50°C to about 80°C, yet more specifically about 75°C to about 85°C. The product can be isolated upon cooling at an ambient temperature. The isolated product can optionally be washed with IPA before drying.

The isolated product, novel compound ethyl 2-(3-substituted)-4-isobutoxyphenyl)-4-methylthiazole-5-carboxyfate (3) can further be hydrolyzed with suitable base selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydride, potassium tert-butoxide and the like, preferably sodium hydroxide.
In general procedure, the hydrolysis reaction may be done in a suitable solvent selected from aliphatic alcohols like methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-amyl alcohol aliphatic ketones like acetone, methyl ethyl ketone, methylisobutyl ketone, DMF, DMAc, DMSO, NMP, THF, 2rmethyl THF and the like, preferably THF, methanol or mixture thereof in appropriate proportion.
The hydrolysis reaction can be carried out at about the boiling point of the solvent system, specifically about 25°C to about 90°C, more specifically about 40°C to about 70°C, yet more specifically about 50°C to about 60°C.
Embodiments of the process may include removal of solvent mixture by distillation upon completion of the reaction. The residue thus obtained can be triturated with water. The aqueous solution can be washed with suitable organic solvent like ethyl acetate, toluene, and methylenedichloride etc., preferably ethyl acetate. The separated aqueous layer can be acidified with suitable mineral acid selected from hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid, preferably hydrochloric acid to adjust the pH of about 2.5-3.5. The isolated product can be filtered and washed with chilled water before drying to obtain 2-(3-(substituted)-4-isobutoxyphenyl)-4-methyl-thiazole-5-carboxylic acid (2).
According to further important aspect of the present invention, the novel compound 2-(3-(substituted)-4-isobutoxyphenyl)-4-methyl-thiazole-5-carboxylic acid (2) can be dehydrated with suitable acidic dehydrating agent. The suitable dehydrating agents comprise a halide or oxyhaJide compound of phosphorus or sulfur.
Thus, in accordance with a preferred embodiment of the process, the compound of formula (2), wherein R1, R2, R3 and R4 are as defined herein above, is subjected to reactions with PCl3, PCl5, POCl3 and SOCl2 or a combination of at least two reagents selected from PCI3, PC15, POCl3 and SOCl2.
Febuxostat (1) thus obtained by the process as discussed above can optionally be purified with a suitable organic solvent to obtain substantially pure Febuxostat (1). The suitable organic solvents selected for the purification of Febuxostat comprise of methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-amyl alcohol; aliphatic ketones like acetone, methylethylketone, methylisobutyl ketone; esters like ethyl acetate, n-butyl acetate, tert-butyl acetate, acetonitrile,

DMF, DMAc etc., and mixture thereof with water. Preferably, Febuxostat (1) can be purified in mixture of acetone and water or ethyl acetate.
In still another aspect, there is there is provided a novel intermediate 2-(3-substituted)-4-isobutoxyphenyl)-4-methyl-thiazole-5-carboxylate(3),

wherein R1, R2, R3 and R4 are as defined above.
In further aspect, there is there is provided another novel intermediate 2-(3-substituted)-4-isobutoxyphenyl)-4-methyl-thiazole-5-carboxylic acid (2)

wherein R1, R2, R3 and R4 are as defined above.
In further aspect, there is provided a method for the preparation of an intermediate 3-(substituted)-4-isobutoxybenzothioamide(4)

wherein R1, R2, R3 and R4 are as defined above, the process comprises:
(a) reacting methyl 5-cyano-2-hydroxybenzoate with isobutyl bromide in presence of base to obtain methyl 5-cyano-2-isobutoxybenzoate of formula (9);


(b) reacting methyl 5-cyano-2-isobutoxybenzoate of formula (9) with thioacetamide in an
organic solvent to obtain methyl 5-carbamothioyl-2-isobutoxybenzoate of formula (8);

(c) hydrolyzing methyl 5-carbamothioyl-2-isobutoxybenzoate of formula (8) in presence of base
to obtain 5-carbamothioyl-2-isobutoxybenzoic acid (7);

(d) reacting acid of formula (7) with thionyl chloride in suitable hydrocarbon solvent to obtain
acid chloride of formula (6) and in-situ reacting acid chloride (6) with 2-amino-2-methyl
propanol in suitable hydrocarbon solvent in presence of co-solvent to obtain hydroxy amide
of formula (5);

(e) subjecting hydroxy amide of formula (5) to ring closure reaction with suitable reagent to obtain an intermediate 3-(substituted)-4-isobutoxybenzothioamide (4); and
(f) isolating 3-(substituted)-4-isobutoxybenzothioamide (4).

Embodiments of the process include reacting methyl 5-cyano-2-hydroxybenzoate with isoburyl bromide in presence of base. Suitable base can be selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydride, potassium tert-butoxide and the like, preferably potassium carbonate.
In general, the process conditions includes reacting methyl 5-cyano-2-hydroxybenzoate with isobutyl bromide in presence of base in a suitable organic solvent like dimethylformamide, dimethylacetamide, N-methyl pyrrolidone, dimethylsulfoxide, THF, 2-methyl THF, methanol, ethanol, isopropanol, butanol, acetone, methylisobutyl ketone, toluene, xylene, ethylbenzene, hexane, cyclohexane, methylenedichloride and the like, preferably dimethylsulfoxide or toluene or mixture thereof.
In a generalized procedure, the reaction mixture is dissolved in a solvent system with optional heating to form a solution or suspension. The heated reaction mixture can be at about the boiling point of the solvent system, specifically about 40°C to about 150°C, more specifically about 60°C to about 130°C, yet more specifically about 700C to about 1200C.
Further embodiments include reacting obtained intermediate methyl 5-cyano-2-isobutoxybenzoate of formula (9) with thioacetamide in a suitable organic solvent selected from methanol, ethanol, isopropanol, butanol, tert-amyl alcohol, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, THF, 2-methyl THF, acetone etc., preferably dimethylformamide in the form of its hydrochloride.
In general, the reaction mixture can be heated at about the boiling point of the solvent system, specifically about 25°C to about 100°C, more specifically about 400C to about 80°C, yet more specifically about 50°C to about 60°C. After the completion of the reaction as monitored by TLC, the reaction mixture can be quenched in aqueous ammonia solution to adjust the pH of about 7.0 to 9.0 for isolating methyl 5-carbamothioyl-2-isobutoxybenzoate of formula (8). The isolated product can be optionally washed with chilled water.
Embodiments of the process further includes, hydrolyzing obtain methyl 5-carbamothioyl-2-isobutoxybenzoate of formula (8) with suitable base selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydride, potassium' tert-butoxide and the like, preferably sodium hydroxide to obtain 5-carbamothioyl-2-isobutoxybenzoic acid (7).
In a generalized procedure, the acid of formula (7) is converted to the corresponding acid chloride of formula (6) using thionyl chloride. Reaction of the acid chloride with amino alcohol, i.e. 2-methyl-2-aminopropanoI, forms an amide alcohol intermediate of formula (5). The reaction can be preferably carried out suitable hydrocarbon solvent selected from toluene,

xylene, ethylbenzene, cyclohexane, hexane, heptane and the like preferably toluene in presence of catalytic amount of co-solvent like DMF, N-methylpyrrolidohe, methanol, DMAc or THF preferably DMF.
Embodiments of the process further include insitu reaction of acid chloride (6) with amino alcohol, i.e. 2-methyl-2-aminopropanol, forms an amide alcohol intermediate of formula (5) in suitable hydrocarbon solvent selected from toluene, xylene, ethylbenzene, cyclohexane, hexane, heptane and the like preferably toluene in presence of catalytic amount of co-solvent like DMF, N-methylpyrrolidone, methanol, DMAc or THF preferably DMF. The reaction mixture can be maintained for about 30 minutes to about 3 hours till the completion of the reaction followed by addition of mineral acid like HC1 to adjust the pH of about 2-3 to isolate the amide alcohol of formula (5). The isolated product can be optionally washed with water.
According to further embodiments, the process include subjecting hydroxy amide of formula (5) to ring closure reaction by reaction with suitable reagent like sulfuric acid, thionyl chloride, phosphorus pentoxide etc, preferably thionyl chloride. In general, the reaction conditions may include reacting hydroxy amide of formula (5) with thionyl chloride in suitable organic solvent.
The solvent for reaction can be selected from toluene, xylene, methylene dichloride, ethylenedichloride, ethylbenzene, ethyl acetate, isobutyl acetate, tertbutyl acetate, n-butyl acetate, chlorobenzene and the like, preferably methylene dichloride. The process can include further addition of co-solvent for dilution like C1-4 alcohols, C2-6 ketones, amides, nitriles etc which comprises of methanol, ethanol, isopropanol, butanol, acetone, methylethylketone, methyl isobutyl ketone, DMF, DMAc, acetonitrile, NMP etc, preferably methanol.
In general procedures, the compound of formula (4) may be isolated by treating the reaction mixture after dilution by methanol, with an organic base like triethylamine, diisopropylethylamine, diisopropylamine, pyridine etc, preferably triethylamine to neutralize the mixture at pH of about 4-5. The excess of solvent can be removed by distillation under vacuum followed by addition of another hydrocarbon solvent to prepare the solution.
The hydrocarbon solvent can be selected from aromatic hydrocarbon like toluene, xylene, ethylbenzene, preferably toluene. The hydrocarbon solution is further treated with aliphatic hydrocarbon as an anti-solvent selected from cyclohexane, hexane, heptane, preferably heptane to precipitate the hovel intermediate 3-(substituted)-4-isobutoxybenzothioamide (4). The isolated product can be optionally washed with heptane before drying.
According to still further important aspect, there are provided methods for preparation of 3-(substituted)-4-isobutoxybenzothioamide (4) by changing the sequence of steps as described

herein above. Hence, according to still another embodiment, there is provided a method for preparing 3-(substituted)-4-isobutoxybenzothioamide (4),

wherein R1, R2, R3 and R4 are as defined above, the process comprises:
(a) reacting methyl 5-cyano-2-hydroxybenzoate with isobutyl bromide in presence of base to
obtain methyl 5-cyano-2-isobutoxybenzoate of formula (9);

(b) hydrolyzing methyl 5-cyano-2-isobutoxybenzoate of formula (9) in presence of base to
obtain 5-cyano-2-isobutoxybenzoic acid (13);

(c) reacting acid of formula (13) with thionyl chloride in suitable hydrocarbon solvent to obtain
acid chloride of formula (12) and in-situ reacting acid chloride (12) with 2-amino-2-methyl
propanol in suitable hydrocarbon solvent in presence of co-solvent to obtain hydroxy amide
of formula (11);

(11)
(d) subjecting hydroxy amide of formula (11) to ring closure reaction with suitable reagent to
obtain an intermediate of formula (10);

(e) reacting compound of formula (10) with thioacetamide in an organic solvent to obtain 3-(substituted)-4-isobutoxybenzothioamide of formula (4); and
(f) isolating 3-(substituted)-4-isobutoxybenzothioamide (4).
In still another embodiment, there is provided a method for preparing 3-(substituted)-4-isobutoxybenzothioamide (4),
wherein R1, R2, R3 and R4 are as defined above, the process comprises:
(a) reacting 5-chloro-2-hydroxybenzoic acid with thionyl chloride in suitable hydrocarbon
solvent to obtain 5-chloro-2-hydroxybenzoyl chloride and in-situ reacting acid chloride with
2-amino-2-methyl propanol in suitable hydrocarbon solvent in presence of co-solvent to
obtain hydroxy amide of formula (18);

(b) subjecting hydroxy amide of formula (18) to ring closure reaction with suitable reagent to
obtain an intermediate of formula (17);


(c) reacting compound of formula (17) with sodium cyanide in suitable organic solvent to obtain
3-(substituted)-4-hydroxybenzonitrile of formula (16);

(d) reacting 3-(substituted)-4-hydroxybenzonitrile of formula (16) with isobutyl bromide in
presence of base to obtain 3-(substituted)-4-isobutoxybenzonitrile of formula (10);

(e) reacting 3-(substituted)-4-isobutoxybenzonitrile of formula (10) with thioacetamide in an organic solvent to obtain 3-(substituted)-4-isobutoxybenzothioamide of formula (4); and
(f) isolating 3-(substituted)-4-isobutoxybenzothioamide (4).
Embodiments of the process include preparation of 3-(substituted)-4-isobutoxybenzothioamide (4) by selected key starting material as 5-chloro-2-hydroxybenzoic acid instead of methyl 5-cyano-2-hydroxybenzoate. The key starting material 5-chloro-2-hydroxybenzoic acid can be efficiently converted to 3-(substituted)-4-isobutoxybenzothioamide (4) by the reaction steps as described above.
The cyantion of compound of formula (17) with sodium cyanide can be done by the process known in the art, which is incorporated herein by reference. The remaining process parameters remains unchanged as described above only the process sequence is changed.
In yet another embodiment, there are provided novel intermediates for the preparation of Febuxostat (1) and their process for preparation.
Thus, in accordance with preferred embodiments, there is provided hydroxy amide of formula (5),


According to still another embodiment, there is provided hydroxy amide of formula (11)

According to the still preferred aspects, there is provided the novel intermediates of formula (10), (18), (17), and (16) as below.

In yet another aspect there is provided a process for the preparation of Febuxostat or pharmaceutically acceptable salts thereof, the process comprises:
(a) obtaining a solution or a suspension containing Febuxostat in water having alkaline pH;
(b) washing aqueous alkaline solution with one or more ester solvents;
(c) separating the aqueous layer containing Febuxostat;
(d) acidifying aqueous layer with mineral acid;
(e) isolating Febuxostat by filtration; and
(f) purifying Febuxostat in C2-6 ester solvents to obtain substantially pure Febuxostat.
In yet another aspect there is provided a process for the preparation of substantially pure Febuxostat (1) comprising: (a) converting a compound of formula (4A)


wherein R represents a C2 to Cs alkylene group which may l>e unsubstituted or substituted by one or more of the groups selected from: C1 to C6 alkyl, which may be unsubstituted or substituted by halo, C1 to C6 alkoxy, or C6 to C15 aryl; C3 to C10 cycloalkyl, which may be unsubstituted or substituted by halo, Ct to C6 alkyl, Q to C6 alkoxy, or C6 to C15 aryl; C5 to C10 heterocycloalkyl; C6 to C15 aryl, which may be unsubstituted or substituted by halo, C1 to C6 alkoxy, or C1 to C6 alkyl; C7 to C10 aralkyl; C1 to C6 alkoxy and heteroaryl; or the alkylene group can be substituted by one or more C3 to C7 cycloalkyl groups attached to the alkylene group via a spiro-carbon atom; or the alkylene group may contain a C6 to C15 aryl group fused to two alkylene carbon atoms; to a compound of formula (I):

by treating compound of formula (4A) with acidic dehydrating agent to obtain Febuxostat (1); and
(b) optionally, recrystallizing Febuxostat (1) in suitable organic solvent to obtain substantially pure Febuxostat (I).
According to further important aspect of the present invention, the novel compound (4A) can be dehydrated with suitable acidic dehydrating agent. The suitable dehydrating agents comprise a halide or oxyhalide compound of phosphorus or sulfur.
Thus, in accordance with a preferred embodiment of the process, the compound of formula (4A), wherein R1, R2, R3 and R4 are as defined herein above, is subjected to reactions with FCl3, PCl5, POCl3 and SOCl2 or a combination of at least two reagents selected from PC13, PCl5, POCl3 and SOCl2.

Febuxostat (1) thus obtained by the process as discussed above can optionally be purified with a suitable organic solvent to obtain substantially pure Febuxostat (1). The suitable organic solvents selected for the purification of Febuxostat comprise of methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-amyl alcohol; aliphatic ketones like acetone, methylethylketone, methylisobutyl ketone; esters like ethyl acetate, n-butyl acetate, tert-butyl acetate, acetonitrile, DMF, DM Ac etc., and mixture thereof with water. Preferably, Febuxostat (1) can be purified in mixture of acetone and water or ethyl acetate.
As se forth in the following schemes, the process of the invention for the preparation of chiral diol sulfones and dihydroxy acid HMG CoA reductase inhibitors involves the following chemical reactions.

Having thus described the invention with reference to particular preferred embodiments and illustrative examples, those in the art would appreciate modifications to the invention as described and illustrated that do not depart from the spirit and scope of the invention as disclosed in the specification. The Examples are set forth to aid in understanding the invention but are not intended to, and should not be construed to, limit its scope in any way. The examples do not include detailed descriptions of conventional methods. Such methods are well known to those of ordinary skill in the art and are described in numerous publications.

EXAMPLE 1: -
Preparation of methyl 5-cvano-2-isobutoxybenzoate (9):

100 g methyl 5-cyano-2-hydroxybenzoate, 1500 ml of toluene, 200 mL of dimethylformamide, 97.5 g of anhydrous potassium carbonate were taken in round bottom flask. The reaction mixture was heated to 100°C for 2 hours. The reaction mixture was cooled to 80°C and 231.7 g of Isobutyl bromide was added within 2 hours and stirred for overnight at 80°C. After completion of the reaction on TLC, the reaction mixture was cooled to 20°C and diluted with 3000 mL water. The reaction mixture was stirred for 2 hours at 15°C, filtered and washed with water. The product thus obtained was dried in fan dryer oven at 50°C to 55°C. The product was recrystallized in isopropanol to obtain 115 g (87%) methyl 5-cyano-2-isobutoxybenzoate. EXAMPLE 2: -Preparation of methyl 5-carbamothioyl-2-isobutoxybenzoate (8):

100 g of methyl 5-cyano-2-isobutoxybenzoate, 1200 mL dimethylformamide hydrochloride, 91.14 g of thioacetamide were taken in round bottom flask. The reaction mixture was heated to 60°C. The reaction mixture was maintained with stirring at 50°C to 60°C overnight. After the completion of the reaction on TLC, the reaction mixture was cooled to 25°C. The reaction mixture was quenched in 3500 mL aqueous ammonia solution and pH was adjusted to about 7.0 to 9.0. The reaction mixture was stirred for 2 hours, filtered and washed with chilled water to obtain methyl 5-carbamothioyl-2-isobutoxybenzoate (8) wet-cake. The product was dried in fan dryer over at 50°C to 55°C to obtain 101 g (88%) dried product. EXAMPLE 3: -Preparation of 5-carbamothioyl-2-isobutoxxbenzoic acid (7):


100 g of methyl 5-carbamothioyl-2-isobutoxybenzoate (8), 1000 mL of methanol and 18.7 g sodium hydroxide solution in 400 water were taken in round bottom flask at 25°C. The reaction mixture was heated at 60°C for about 1.5 hours. After the completion of reaction as monitored by TLC, the reaction mixture was distilled under vacuum to remove methanol. 1000 mL water was added to the residue at 55°C and stirred for 30 minutes. The reaction mixture was gradually cooled to 15°C. filtered and washed with water. The combined filtrate was washed with 1000 mL ethyl acetate. The aqueous layer was treated with IN HCl solution to adjust the acidic pH with stirring. The reaction mixture was filtered, washed with chilled water and dried in fan dryer oven at 500C to 55°C to obtain 85 g (85%) of 5-carbamothioyl-2-isobutoxybenzoic acid (7).
EXAMPLE 4: -Preparation of hydroxy amide of formula (5):

50 g 5-carbamothioyl-2-isobutoxybenzoic acid (7) was suspended in 5 volumes of toluene containing a catalytic amount of DMF. The mixture was heated to 70-80°C and 28.64 g thionyl chloride was added slowly to the mixture at less than 80°C. The mixture was heated for 1 hour at reflux. The resultant solution was concentrated by distillation at atmospheric pressure and cooled to about 75°C. Dimethylformamide was added slowly and the mixture was cooled to approximately 20CC. This solution was added at 15-20°C to a solution of 38.74 g 2-amino-2-methyl propanol in toluene 3 volumes. After the addition was complete, the solution was stirred for 30 minutes and the pH adjusted to 2-3 by slow addition of hydrochloric acid. The mixture was stirred at 15-20°C for one hour. The precipitated product was filtered off, washed with water, and dried at about 60°C under reduced pressure. EXAMPLE 5: -Preparation of hydroxy amide of formula (4):


100 g hydroxy amide (5) was suspended in 4 volumes of dichloromethane and 50.2 g of thionyl chloride was added at 20-25°C. After stirring for 1 hour at 20-25°C methanol was added, and the mixture stirred at ambient temperature for 30 minutes. Triethylamine was added to neutralize the mixture to pH 4-5. Water was then added, and the layers allowed to separate. The organic extracts were washed with water and the dichloromethane was distilled off before the addition of toluene. The resulting mixture was filtered at 60-70°C. Heptane was added and the solution heated to reflux. After cooling to 15-20°C the product 3-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)-4-isobutoxy- benzothioamide (4) was filtered off, washed with heptane and dried at 50°C under reduced pressure. EXAMPLE 6: -Preparation of hydroxy amide of formula (13):

100 g of methyl 5-cyano-2-isobutoxybenzoate (9), 750 mL of methanol and 21.43 g sodium hydroxide solution in 400 water were taken in round bottom flask at 25°C. The reaction mixture was heated at 60°C for about 1.5 hours. After the completion of reaction as monitored by TLC, the reaction mixture was distilled under vacuum to remove methanol. 500 mL water was added to the residue at 55°C and stirred for 30 minutes. The reaction mixture was gradually cooled to 15°C, filtered and washed with water. The combined filtrate was washed with 500 mL ethyl acetate. The aqueous layer was treated with IN HCl solution to adjust the acidic pH with stirring. The reaction mixture was filtered, washed with chilled water and dried in fan dryer oven at 50°C to 55°C to obtain 92 g (92%) of 5-cyano-2-isobutoxybenzoic acid (13). EXAMPLE 7: -Preparation of hydroxy amide of formula (11):


50 g 5-cyano-2-isobutoxybenzoic acid (13) was suspended in 5 volumes of toluene containing a catalytic amount of DMF. The mixture was heated to 70-80°C and 24.78 g thionyl chloride was added slowly to the mixture at less than 80°C. The mixture was heated for 1 hour at reflux. The resultant solution was concentrated by distillation at atmospheric pressure and cooled to about 75°C. Dimethylformamide was added slowly and the mixture was cooled to approximately 20°C. This solution was added at 15-20°C to a solution of 33.52 g 2-amino-2-methyl propanol in toluene 3 volumes. After the addition was complete, the solution was stirred for 30 minutes and the pH adjusted to 2-3 by slow addition of hydrochloric acid. The mixture was stirred at 15-20°C for one hour. The precipitated product was Filtered off, washed with water, and dried at about 60°C under reduced pressure. EXAMPLE 8: -Preparation of hydroxy amide of formula (10):

100 g hydroxy amide (11) was suspended in 5 volumes of dichloromethane and 49.75 g of thionyl chloride was added at 20~25°C. After stirring for 1 hour at 20-25°C methanol was added, and the mixture stirred at ambient temperature for 30 minutes. Triethylamine was added to neutralize the mixture to pH 4-5. Water was then added, and the layers allowed to separate. The organic extracts were washed with water and the dichloromethane was distilled off before the addition of toluene. The resulting mixture was filtered at 60-70°C. Heptane was added and the solution heated to reflux. After cooling to 15-20°C the product 3-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)-4-isobutoxy- benzonitrile was filtered off, washed with heptane and dried at 50°C under reduced pressure. EXAMPLE 9: -
Preparation of 3-(4,4-dimethyl,5-dihydrooxazol-2-yl)4-isobutoxybenzothioamid of formula (4):


100 g of 3-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)-4-isobutoxybenzonitrile, 800 mL dimethyl- formamide hydrochloride, 78.05 g of thioacetamide were taken in round bottom flask. The reaction mixture was heated to 60°C. The reaction mixture was maintained with stirring at 50°C to 60°C overnight. After the completion of the reaction on TLC, the reaction mixture was cooled to 25°C. The reaction mixture was quenched in 3500 mL aqueous ammonia solution and pH was adjusted to about 7.0 to 9.0. The reaction mixture was stirred for 2 hours, filtered and washed with chilled water to obtain 3-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)-4-isobutoxybenzothioamide (4) wet-cake. The product was dried in fan dryer over at 50°C to 55°C to obtain 96 g (85%) dried product. EXAMPLE 10: -Preparation of hydroxy amide of formula (18):

100 g 5-chloro-2-hydroxybenzoic acid was suspended in 10 volumes of toluene containing a catalytic amount of DMF. The mixture was heated to 70-800C and 86.16 g thionyl . chloride was added slowly to the mixture at less than 80°C. The mixture was heated for 1 hour at reflux. The resultant solution was concentrated by distillation at atmospheric pressure and cooled to about 75°C. Dimethyl formamide was added slowly and the mixture was cooled to approximately 20°C. This solution was added at 15-20°C to a solution of 77.47 g 2-amino-2-methyl propanol in toluene 5 volumes. After the addition was complete, the solution was stirred for 30 minutes and the pH adjusted to 2-3 by slow addition of hydrochloric acid. The mixture was stirred at 15-20°C for one hour. The precipitated product hydroxy amide (18) was filtered off, washed with water, and dried at about 60°C under reduced pressure. EXAMPLE 11:-Prcparation of 4-chloro-2-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)phenol of formula (17):

100 g hydroxy amide (18) was suspended in 5 volumes of dichloromethane and 61.02 g thionyl chloride was added at 20-25°C. After stirring for 1 hour at 20-25°C methanol was added, and the mixture stirred at ambient temperature for 30 minutes. Triethylamine was added to neutralize the mixture to pH 4-5. Water was then added, and the layers allowed to separate. The organic extracts were washed with water and the dichloromethane was distilled off before the addition of toluene. The resulting mixture was filtered at 60~70°C. Heptane was added and the solution heated to reflux. After cooling to 15-20°C the product 4-chloro-2-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)phenol was filtered off, washed with heptane and dried at 50°C under reduced pressure. EXAMPLE 12: -
Preparation of 3-(4,4-dimethyl-4,5-dihydrooxazol-2-yl-4-hydroxybenzonitrile of formula (16):

100 g of 4-chloro-2-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)phenol (17), 1500 mL of DMSO and 23.88 g of Sodium cyanide were taken in round bottom flask at 25°C. The reaction mixture was heated at 6o°C for about 15 hours. After the completion of reaction as monitored by TLC, the reaction mixture was distilled under vacuum to remove DMSO. 1000 mL water was added to the residue at 55°c and stirred for 30 minutes. The reaction mixture was gradually cooled to 15°C, filtered and washed with water. The combined filtrate was extracted with 500 mL ethyl acetate. The reaction mixture was distilled to obtain 95 g of 3-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)-4-hydroxybenzonitrile (16) The product thus obtained is recrystallized in methanol. EXAMPLE 13: -
Preparation of 3-(4,4-methyl]-4,5-dihydrooxazol-2-yl)-4-isobutoxybenzonitrile of formula (10):

100 g 3-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)-4-hydroxybenzonitrile, 1500 ml of toluene, 200 mL of dimethylformamide, 118.71 g of anhydrous potassium carbonate were taken in round bottom flask. The reaction mixture was heated to 100°C for 2 hours. The reaction

mixture was cooled to 80°C and 189.43 g of Isobutyl bromide was added within 3 hours and stirred for overnight at 80°C. After completion of the reaction on TLC, the reaction mixture was cooled to 20°C and diluted with 3000 mL water. The reaction mixture was stirred for 2 hours at 15°C, filtered and washed with water. The product thus obtained was dried in fan dryer oven at 50°C to 55°C. The product was recrystallized in isopropanol to obtain 115 g (91%) 3-(4,4-d imethyl-4,5 -d ihydrooxazol-2-y l)-4- isobutoxybenzon itri le. EXAMPLE 14: -Preparation of ethyl 2-(3-(4,4-dimethvl-4,5-dihvdrooxazol-2-yl)-4-isobutoxyphenyl)-4-
methyl- thiazole-5-carboxylate of formula (3): -

100 g of 3-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)-4-isobutoxybenzothioamide, 80.52 g of EthyI-2-chloroacetoacetate and 1000 mL isopropanol were taken in round bottom flask at 25°C. The reaction mixture was heated at 80°C for 8 hours. After completion of the reaction as monitored by TLC, the reaction mixture was cooled to 35°C and stirred for 2 hours. The reaction mixture was filtered, washed with isopropanol and dried to obtain 100 g (73%) of ethyl 2-(3-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)-4-isobutoxyphenyl)-4-methyl-thiazole-5-carboxylate.
EXAMPLE 15: -
Preparation of 2-(3-(4,4-dimethvl-4.5-dihvdrooxazol-2-yl)-4-isobutoxyphenyl)-4-
methylthiazole -5-carboxylic acid of formula (2): -

100 g of ethyl 2-(3-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)4-isobutoxyphenyl)-4-methyl-thiazole-5-carboxylate, 900 mL THF, 900 mL methanol and 400 mL sodium hydroxide solution (12.0 g) in water were taken in round bottom flask at 35°C. The reaction mixture was heated at 600C for 1.5 hours. After the completion of the reaction as monitored by TLC, THF and methanol solvents were distilled under vacuum at 55°C to 60°C. 1500 mL water was added to

the residue at 55°C and stirred for 30 minutes. The reaction mixture was gradually cooled to
20°C and filtered through hyflow bed. The filtrate was washed with 900 mL ethyl acetate
and separated aqueous layer was acidified with IN HCI to adjust the pH to 2.5-3.5. The reaction mixture was stirred for 2 hours, filtered and washed with chilled water. The product was dried in fan dryer oven at about 50°C to 55°C to obtain 85% 2-(3-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid. EXAMPLE 16: -Preparation of Febuxostat of formula (1): -

The 2-(3-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid (2) (1.5 molar equivalents) was dissolved in pyridine (5 volumes). The mixture was stirred at 20-25°C for 1 hour. Phosphoryl chloride (2 molar equivalents) was added and the mixture maintained with stirring for 4 hours. The reaction mixture was quenched with water, extracted into toluene and evaporated to dryness to obtain Febuxostat (52%). The product was recrystallized in isopropanol. EXAMPLE 17: -Purification of Febuxostat (1): -
50 g of Febuxostat and 2000 mL ethyl acetate at 25°C. The reaction mixture was heated to 80°C and stirred for 30 minutes and cooled gradually to 35°C. The reaction mixture was stirred for 2 hours and filtered and washed with ethyl acetate (500 mL) and dried in vacuum dryer oven at 55°C to 60°C to obtain 35 g of pure Febuxostat. Advantages of the Invention
1) The present invention provides novel intermediates for the synthesis of Febuxostat.
2) The present invention also provides novel process for the synthesis of Febuxostat.
3) The present invention provides Febuxostat substantially free from impurities.
4) The present invention provides cost effective, eco-friendly and industrially applicable process.

What is claimed is:
1. Febuxostat substantially free from dimer impurities of formula(7b),(6b)and(1b)

2. A novel intermediate compound of formula (4A)

wherein R represents a C2 to C5 alkylene group which may be substituted by one or more of the groups selected from C1 to C8 alkyl, C1 to C15 aryl,C8 to C15 heteroaryl, C3 to C10 cycloalkyl, C5 to C10 heterocycloalkyl, C7 to C10 aralakyl,C1 toC6 alkoxy, or a C3 to C7 cycloalkyl group attached to the alkylene group via a spiro carbon atom,or the alkylene group may contain a C8-C15 aryl group fused to two alkylene carbon atoms.
3. The novel intermediate compound of claim 2, wherein compound (4A) is compound of
formula (4),
wherein R1, R2, R3 and R4 each independently represents H,C1 to C8 alkyl,C5 to C10 cycloalkyl or aryl. Preferably R6 and R7 each independently represent H or C1 to C8 alkyl and even more preferably, R1 and R2 both represent H, and R3 and R4 both represent methyl,
4, A process for preparing substantially pure Febuxostat (1),


the process comprises:
(a) reacting 3-(substituted)-4-isobutoxybenzothioamide compound of formula (4),

wherein R1, R2,R3 and R4 are as defind as above,
with ethyl 2-chloroacetoacetate in a polar organic solvent to obtain ethyl 2-(3-substituted)-4-
isobutoxyphenyl)-4-methylthiazole-5-carboxylate (3);

(b) hydrolyzing ethyl 2-(3-(substituted)4-isobutoxyphenyl)-4methyl-thiazole-5-carboxylate (3)
with suitable base in a suitable organic solvent to obtain 2-(3-(substituted)-4-
isobutoxyphenyl)-4-methyl-thiazole-5-carboxylic acid (2);


(c) treating 2-(3-(substituted)-4-isobutoxyphenyl)-4-methyl-thiazole-5-carboxylic acid (2) of step (b) with acidic dehydrating agent to obtain Febuxostat (1); and
(d) optionally, recrystallizing Febuxostat (1) in suitable organic solvent to obtain substantially pure Febuxostat (1).

5. The process of claim 4 (a), polar organic solvent is selected from aliphatic alcohols like methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-amyl alcohol; aliphatic ketones like acetone, methylethylketone, methylisobutylketone, dimethylformamide, dimethyiacetamide, dimethyl- sulfoxide, N-methylpyrrolidone, preferably isopropanol.
6. The process according to claim 4 (b), wherein suitable base can be selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydride and potassium tert-butoxide, preferably sodium hydroxide.
7. The process according to claim 4 (b), suitable organic solvent is selected from aliphatic alcohols like methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-amyl alcohol aliphatic ketones like acetone, methylethylketone, methylisobutyl ketone, DMF, DMAc, DMSO, NMP, THF, 2-methyl THF and the like, preferably THF, methanol or mixture thereof in appropriate proportion.
8. The process of claim 4 (b), wherein hydrolysis reaction can be carried out at about 25°C to 90°C, more specifically at about 40°C to about 70°C, preferably at about 50°C to about 60°C.
9. The process of claim 4 (c), wherein acidic dehydrating agent comprises a halide or oxyhalide compound of phosphorus or sulfur such as PCl3, PCl5, POCl3 and SOCl2 or a combination of at least two reagents selected from PCI3, PCl5, POCl3 and SOCl2
10. The process of claim 4 (d), suitable organic solvent is selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-amyl alcohol; aliphatic ketones like acetone, methylethylketone, methylisobutyl ketone; esters like ethyl acetate, n-butyl acetate, tert-butyl acetate, acetonitrile, DMF, DMAc etc., and mixture thereof with water, preferably in mixture of acetone and water or ethyl acetate.
11. A novel intermediate 2-(3-substituted)-4-isobutoxyphenyl)-4-methyl-thiazole-5-carboxylic acid (2).


(2) wherein R1, R2, R3 and R4 each independently represents H, C1 to C8 alkyl, C5 to C10 cycloalkyl or aryl. Preferably R6 and R7 each independently represent H or C1 to C8 alkyl and even more preferably, R1 and R2 both represent H, and R3 and R4 both represent methyl.
12. A novel intermediate 2-(3-substituted)4-isobutoxyphenyl)-4-methyl-thiazole-5-carboxylate

wherein R|, R2, R3 and R4 are as defined in claim 11.
13. A process for the preparation of an intermediate 3-(substituted)-4-isobutoxybenzothioamide (4)
wherein R1, R2, R3 and R4 are as defined above. the process comprises: {a) reacting methyl 5-cyano-2-hydroxybenzoate with isobutyl bromide in presence of base to obtain methyl 5-cyano-2-isobutoxybenzoate of formula (9);

(b) reacting methyl 5-cyano-2-isobutoxybenzoate of formula (9) with thioacetamide in an organic solvent to obtain methyl 5-carbamothioyl-2-isobutoxybenzoate of formula (8);


(c) hydrolyzing methyl 5-carbamothioyl-2-isobutoxybenzoate of formula(8) in presence of base
to obtain 5-carbamothioyl-2-isobutoxybenzoic acid (7);

(d) reacting acid of formula (7) with thionyl chloride in suitable hydrocarbon solvent to obtain acid chloride of formula (6) and in-situ reacting acid chloride (6) with 2-amino-2-methyl propanol in suitable hydrocarbon solvent in presence of co-solvent to obtain hydroxy amide of formula (5);
(e) subjecting hydroxy amide of formula (5) to ring closure reaction with suitable reagent to obtain an intermediate 3-{substituted)-4-isobutoxybenzothioamide {4); and
(f) isolating 3-(substituted)-4-isobutoxybenzothioamide(4).

14. The process according to claim 13 (a), suitable base can be selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydride, potassium tert-butoxide and the like, preferably potassium carbonate.
15. The process according to claim 13 (b), wherein suitable organic solvent can be selected from suitable organic solvent selected from methanol, ethanol, isopropanol, butanol, tert-amyl alcohol, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, THF; 2-methyl THF, acetone etc., preferably dimethylformamide in the form of its hydrochloride.

16. The process according to claim 13 (c), wherein suitable base can be selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydride, potassium tert-butoxide and the like, preferably sodium hydroxide.
17. The process according to claim 13 (d), wherein suitable hydrocarbon solvent can be selected from toluene, xylene, ethylbenzene, cyclohexane, hexane, heptane and the like preferably toluene.
18. The process of claim 13 (d) co-solvent is selected from DMF, N-methylpyrrolidone, methanol, DMAc or THF preferably DMF.
19. The process according to claim 13 (f), wherein suitable reagent can be selected from sulfuric acid, thionyl chloride, phosphorus pentoxide etc, preferably thionyl chloride.
20. The process according to claim 13 (e), wherein suitable solvent for reaction can be selected from toluene, xylene, methylenedichioride, ethylenedichloride, ethylbenzene, ethyl acetate, isoburyl acetate, tertbutyl acetate, n-butyl acetate, chlorobenzene and the like, preferably methylene dichloride.
21. The process according to claim 20, wherein process includes further addition of co-solvent for dilution selected from C1-4 alcohols, C2-6 ketones, amides, nitriles etc which comprises of methanol, ethanol, isopropanol, butanol, acetone, methylethylketone, methylisobutyl ketone, DMF, DMAc, acetonitrile, NMP etc, preferably methanol.
22. The process according to claim 13 (e), wherein suitable reagent can be selected from sulfuric acid, thionyl chloride, phosphorus pentoxide etc, preferably thionyl chloride.
23. The process according to claim 13 (f), wherein compound of formula (4) can be isolated by treating the reaction mixture after dilution by methanol, with an organic base like triethylamine, diisopropylethylamine, diisopropylamine, pyridine etc, preferably triethylamine.
24. The process according to claim 23, wherein reaction further comprises of neutralization by addition of triethylamine at a pH of about 4-5.
25. The process according to claim 13 (f), wherein compound (4) is isolated by addition of hydrocarbon like toluene, xylene, ethylbenzene, preferably toluene followed by treating with aliphatic hydrocarbon as an anti-solvent selected from cyclohexane, hexane, heptane, preferably heptane to precipitate the novel intermediate 3-(substituted)-4-isobutoxybenzothioamide (4).
26. A method for preparing 3-(substituted)-4-isobutoxybenzothioamide (4),


wherein R1, R2, R3 and R4 are as defined above, the process comprises:
(a) reacting methyl 5-cyano-2-hydroxybenzoate with isobutyl bromide in presence of base to
obtain methyl 5-cyano-2-isobutoxybenzoate of formula (9);

(b) hydrolyzing methyl 5-cyano-2-isobutoxybenzoate of formula (9) in presence of base to
obtain 5-cyano-2-isobutoxybenzoic acid (13);

(c) reacting acid of formula (13) with thionyi chloride in suitable hydrocarbon solvent to obtain
acid chloride of formula (12) and in-situ reacting acid chloride (12) with 2-amino-2-methyl
propanol in suitable hydrocarbon solvent in presence of co-solvent to obtain hydroxy amide
of formula (11);

(d) subjecting hydroxy amide of formula (11) to ring closure reaction with suitable reagent to
obtain an intermediate of formula (10);

(e) reacting compound of formula (10) with thioacetamide in an organic solvent to obtain 3-(substituted)-4-isoburoxybenzothioamide of formula (4); and
(f) isolating 3-(substituted)-4-isobutoxybenzothioamide (4).
27. A method for preparing 3-(substituted)-4-isobutoxybenzothioamide (4),

wherein R1, R2, R3 and R4 are as defined above, the process comprises:
(a) reacting 5-chloro-2-hydroxybenzoic acid with thionyl chloride in suitable hydrocarbon
solvent to obtain 5-chloro-2-hydroxybenzoyl chloride and in-situ reacting acid chloride with
2-amino-2-methyl propanol in suitable hydrocarbon solvent in presence of co-solvent to
obtain hydroxy amide of formula (18);

(b) subjecting hydroxy amide of formula (18) to ring closure reaction with suitable reagent to
obtain an intermediate of formula (17);


(c) reacting compound of formula (17) with sodium cyanide in suitable organic solvent to obtain
3-(substituted)-4-hydroxybenzonitri[e of formula (16);

(d) reacting 3-(substituted)-4-hydroxybenzonitrile of formula (16) with isobutyl bromide in
presence of base to obtain 3-(substituted)-4-isobutoxybenzonitrile of formula (10);

(e) reacting 3-(substituted)-4-isobutoxybenzonitrile of formula (10) with thioacetamide in an organic solvent to obtain 3-(substituted)-4-isobutoxybenzothioamide of formula (4); and
(f) Isolating 3-(substituted)-4-isobutoxybenzothioamide (4).
28. A novel intermediate of hydroxy amide of formula (5),

wherein R1, R2, R3 and R4 are as defined above.
29. A novel intermediate of hydroxy amide of formula (11),


wherein R1, R2, R3 and R4 are as defined above.
30. A novel intermediate of formula (10), (16), (17) and (18).

31. A process for the preparation of Febuxostat or pharmaceutically acceptable salts thereof,
the process comprises:
(a) obtaining a solution or a suspension containing Febuxostat in water having alkaline pH;
(b) washing aqueous alkaline solution with one or more ester solvents;
(c) separating the aqueous layer containing Febuxostat;
(d) acidifying aqueous layer with mineral acid;
(e) isolating Febuxostat by filtration; and
(f) purifying Febuxostat in C2-6 ester solvents to obtain substantially pure Febuxostat.
32. A process for the preparation of substantially pure Febuxostat (1) comprising: converting a
compound of formula (4A)
wherein R represents a C2 to C5 alkylene group which may be unsubstituted or substituted by one or more of the groups selected from: C1 to C6 alkyl, which may be unsubstituted or substituted by halo, C1 to C6 alkoxy, or C6 to C15 aryl; C3 to C10 cycloalkyl, which may be unsubstituted or substituted by halo, C1 to C6 alkyl, C1 to C6 alkoxy, or C6 to C15 aryl; C5 to C10 heterocycloalkyl; C6 to C15 aryl, which may be unsubstituted or substituted by halo, C1 to

C6 alkoxy, or C1 to C6 alkyl; C7 to C10 aralkyl; C1 to C6 alkoxy and heteroaryl; or the alkylene group can be substituted by one or more C3 to C7 cycloalkyl groups attached to the alkylene group via a spiro-carbon atom; or the alkylene group may contain a C6 to C15 aryl group fused to two alkylene carbon atoms; to a compound of formula (I):

by treating compound of formula (4A) with acidic dehydrating agent to obtain Febuxostat (I); and optionally, recrystallizing Febuxostat (1) in suitable organic solvent to obtain substantially pure Febuxostat (1).
33. Use of novel intermediates of formula (5), (10), (11), (16), (17) and (18) for the preparation of Febuxostat (1).
34. Use of novel intermediate of formula (4A) for the preparation of Febuxostat (1).
35. Febuxostat of Formula (I) and its novel intermediates thereof substantially as herein described with reference to any of the embodiments of the invention illustrated in the accompanying drawings and/or examples.