Field of the Invention:

The present invention provides novel amine salts of 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid compound of formula-1 and its intermediates. It also relates to their use in the preparation of highly pure 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid compound of formula-1 and its intermediates. The present invention also provides the processes for the preparation of their amine salts.

Formula-1

2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid is commonly known as Febuxostat. It is an inhibitor of xanthine oxidase that is indicated for use in the treatment of hyperuricemia and gout.

Febuxostat was approved by the European Medicines and the U.S. Food and Drug Administration. Febuxostat is marketed by Takeda Pharmaceuticals with the brand names Adenuric (EU) and Uloric (US).

Background of the Invention:

2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid was first disclosed in US 5614520 patent. The disclosed synthetic process comprises of reacting the ethyl 2-(4-hydroxy)-3-nitrophenyl)-4-methyl-5-thiazolecarboxylate with l-bromo-2-methylpropane in presence of potassium carbonate in dimethyl formamide provides ethyl 2-(4-isobutoxy-3-nitrophenyl)-4-methylthiazole-5-carboxylate which is reduced with Pd/C and the obtained compound treated with sodium nitrite in water and followed by a mixture of cuprous cyanide and potassium cyanide provides ethyl 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylate. The obtained ethyl 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylate was hydrolyzed by treating with aqueous sodium hydroxide in a mixture of ethanol and tetrahydrofuran solvent provides 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid having melting range of 238 -239°C.

Heterocycles, Vol. 47, No. 2, 1998 discloses a process for the preparation of 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid which comprises of reacting 4-(2-methylpropoxy)-l,3-benzenedicarbonitrile in presence of hydrochloric acid with thioacetamide in dimethyl formamide provides 4-(2-methylpropoxy)-3-cyanobenzthioamide. It was reacted with 2-chloroacetoacetate in ethanol provides 2-(4-(2-methylpropoxy)-3-nitrophenyl)-4-methyl-5-thiazolecarboxylate which is further hydrolyzing with aqueous sodium hydroxide solution in a mixture of tetrahydrofuran and ethanol provides 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid which on further recrystallized from acetone provides a colorless crystals having the melting range of201-202°C.

JP10-045733 discloses a process for the preparation of 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid which comprises of reacting ethyl 2-(3-formyl-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate with hydroxyl amine in presence of formic acid and sodium formate provide ethyl 2-(3-cyano-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate. The obtained compound was reacted with l-bromo-2-methylpropane in presence of potassium carbonate provides ethyl 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylate, which on further hydrolysis with aq sodium hydroxide provides 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid.

In general, febuxostat prepared by the reported processes contain impurities like amide impurity, ethyl ester impurity and methyl ester impurity etc. It is important that any pharmaceutical compound or intermediate should free of impurities or if present they must be limited to the maximum level set by ICH guidelines. The purification technique of by recrystallisation of the compound from a suitable solvent such as the recrystallisation of febuxostat as disclosed in Heterocycles, Vol. 47, No. 2,1998 does not yields the desired purity. Hence it necessary to have an alternate purification technique for the preparation of highly pure febuxostat or its intermediate.

The present invention provides novel salts of febuxostat and its intermediates which are useful to prepare highly pure febuxostat or its intermediates.

Brief Description of the Invention:

The first aspect of the present invention is to provide novel amine salts of 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid compounds of general formula-2. The salts compound of general formula-2 are useful in the preparation of highly pure 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid compound of formula-1.

The second aspect of the present invention is to provide a process for the preparation of novel salts of 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid compound of general formula-2.

The third aspect of the present invention is to provide novel salts of 2-[3-formyl-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid compounds of general formula-4. The salts compound of general formula-4 are useful in the preparation of highly pure 2-[3-formyl-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid compounds of formula-3 as well as 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid, compound of formula-1.

The fourth aspect of the present invention is to provide a process for the preparation of novel salts of 2-[3-formyl-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid compounds of general formula-4.

The fifth aspect of the present invention is to provide novel amine salts of 2-[3-((hydroxyimino)methyl)-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylicacid compounds of general formula-6. The salt compounds of general formula-6 are useful in the preparation of highly pure 2-[3-((hydroxyimino)methyl)-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylicacid compound of formula-5 as well as 2-[3-cyano-4-(2-methyl propoxy)phenyl]-4-methylthiazole-5-carboxylic acid compound of formula-1.

The sixth aspect of the present invention provides a process for the preparation of novel salts of 2-[3-((hydroxyimino)methyl)-4-(2-methylpropoxy) phenyl]-4-methyl thiazole-5-carboxylicacid, compounds of general formula-6.

Detailed Description of the Invention:

As used herein the "suitable solvents" refers to wherever necessary, used in the present invention are selected from "ester solvents" like ethyl acetate, methyl acetate, isopropyl acetate; "ether solvents" like tetrahydrofuran, diethyl ether, methyl tert-butyl ether; "hydrocarbon solvents" like toluene, hexane, heptane and cyclohexane; "polar aprotic solvents" like dimethyl acetamide, dimethyl sulfoxide, acetonitrile; "ketone solvents" like acetone, methyl ethyl ketone, methyl isobutyl ketone; and "alcoholic solvents" like methanol, ethanol, n-propanol, isopropanol, n-butanol and isobutanol; "chloro solvents" like dichloromethane, chloroform and ethylene dichloride; polar solvents like water; and mixtures thereof.

As used herein the term "organic amines" refers to methyl amine, ethyl amine, di methyl amine, tri methyl amine, diethyl amine, tri ethyl amine n-propyl amine, isopropyl amine, n-butyl amine, tertiary butyl amine, (+/-)-sec-butyl amine, Octyl amine, 2-ethyl hexylamine, benzyl amine, a-methyl-benzylamine, phenyl ethylamine, dibenzylamine, N-methylbenzylamine, N,N-dimethylbenzylamine, N,N-diethyl benzyl amine, N-ethyl-N-methylbenzylamine, tribenzyl amine, cyclopentylamine, cyclohexyl amine, cycloheptylamine, N-methylcyclopentylamine, N-ethylcyclohexyl amine, N-ethyl cycloheptylamine, dicyclohexylamine, N,N-dimethylcyclo pentylamine, N,N-dimethyl cyclohexylamine, N,N-diethylcycloheptylamine and the like.

The first aspect of the present invention provides novel amine salts of 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid compound represented by the following general formula-2.

Formula-2 The suitable organic amine is selected from methyl amine, ethyl amine, di methyl amine, tri methyl amine, diethyl amine, tri ethyl amine, n-propyl amine, isopropyl amine, n-butyl amine, tertiary butyl, (+/-)-sec-butyl amine, Octyl amine, 2-ethyl hexylamine, benzyl amine, a-methyl-benzylamine, phenyl ethylamine, dibenzylamine, N-methylbenzylamine, N,N-dimethylbenzylamine, N,N-diethyl benzyl amine, N-ethyl-N-methylbenzylamine, tribenzyl amine, cyclopentylamine, cyclohexyl -amine, cycloheptylamine, N-methylcyclopentylamine, N-ethylcyclohexyl amine, N-ethyl cycloheptylamine, dicyclohexylamine, N,N-dimethylcyclo pentylamine, N,N-dimethyl cyclohexylamine, N,N-diethylcycloheptylamine and the like.

The second aspect of the present invention provides a process for the preparation of novel amine salts of 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid compound of general formula-2, which comprises of reacting the 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid compound of formula-1
Formula-1 with a suitable organic amine (as defined above) in a suitable solvent selected from ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, ketone solvents, alcoholic solvents, chloro solvents, polar solvents and also mixtures thereof, to provide corresponding amine salt of 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid compound of general formula-2.

The other embodiment of the present invention provides a methyl amine salt of 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid compound of formula-2a as a crystalline solid.

Formula-2a The crystalline compound of formula-2a of the present invention is characterized by it's powder x-ray diffractogram having the peaks at 8.89, 13.18, 14.33, 17.84, 18.92, 21.37, 21.76, 23.42, 24.76, 26.53, 26.93, 27.64, 28.95, 29.38, 31.67, 32.83 and 45.41 ± 0.2 degrees of 29. The crystalline salt compound of formula-2a is useful in the preparation of highly pure febuxostat compound of formula-1.

A process for the preparation of crystalline methylamine salt compound of formula-2a comprises of the following steps;

a) dissolving the crude 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid compound of formula-1 in a suitable solvent,

b) adding the methyl amine to the reaction mixture,

c) stirring the reaction mixture upto the completion of reaction,

d) filtering the precipitated solid,

e) washing the solid with a suitable solvent as defined above,

f) drying the compound to get the crystalline methyl amine salt of 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid compound of formula-2a.

The other embodiment of present invention provides tertiary butyl amine salt of 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid compound of formula-2b as a crystalline solid.

Formula-2b The crystalline tertiary butyl amine salt compound of formula-2b of the present invention is characterized by it's powder x-ray diffractogram having the peaks at 5.86, 8.03, 11.54, 13.91,16.08, 16.51, 17.37, 18.13, 19.74, 20.30, 21.35, 22.55, 23.76, 24.96, 26.07, 27.16, 28.51, 31.69 and 45.42 ± 0.2 degrees of 20. The crystalline salt compound of formula-2b is useful in the preparation of highly pure febuxostat compound of formula-1.

A process for the preparation of crystalline tertiary butylamine salt compound of formula-2b comprises of the following steps;

a) dissolving the crude 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid compound of formula-1 in a suitable solvent,

b) adding the tertiary butyl amine to the reaction mixture,

c) stirring the reaction mixture up to the completion of reaction,

d) filtering the precipitated solid,

e) washing the solid with a suitable solvent,

f) drying the compound to get the crystalline tertiary butyl amine salt of 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid compound of formula-2b.

The third aspect of the present invention provides novel amine salts of 2-[3-formyl-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid compounds of general formula-4 represented by the following structure

Formula-4

Wherein the organic amine is as defined above;

The novel amine salts compounds of general formula-4 are useful in the preparation of highly pure 2-[3-formyl-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid compound of formula-3 as well as febuxostat compound of formula-1.

The fourth aspect of the present invention provides a process for the preparation of novel amine salts of 2-[3-formyl-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid compound of general formula-4, which comprises of reacting the 2-[3-formyl-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid compound of formula-3,
Formula-3 with a suitable organic amine as defined above, in a suitable solvent to provide corresponding amine salt of 2-[3-formyl-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid compound of general formula-4.

The other embodiment of the present invention provides a methyl amine salt of 2-[3-formyl-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid compound of formula-4a as a crystalline solid.

Formula-4a

The crystalline methyl amine salt compound of formula-4a of the present invention is characterized by it's powder x-ray diffractogram having the characteristic peaks at 7.39, 8.59, 9.04, 12.39, 12.65, 13.76, 14.06, 14.77, 15.10, 17.10, 18.00, 20.87, 22.53, 23.30, 24.77, 25.26, 25.99, 26.68 and 32.11 ± 0.2 degrees of 20. The crystalline methyl amine salt compound of formula-4a is useful in the preparation of highly pure compound of formula-3 and compound of formula-1.

A process for the preparation of crystalline methylamine salt compound of formula-4a comprises of the following steps,

a) dissolving the crude 2-[3-formyl-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid compound of formula-3 in a suitable solvent,

b) adding the methyl amine to the reaction mixture,

c) stirring the reaction mixture up to the completion of reaction,

d) filtering the precipitated solid,

e) washing the solid with a suitable solvent,

f) drying the compound to get the crystalline methyl amine salt of 2-[3-formyl-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid compound of formula-4a.

The other embodiment of the present invention provides n-butyl amine salt of 2-[3-formyl-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid compound of formula-4b as a crystalline solid.

Formula-4b The crystalline n-butyl amine salt of 2-[3-formyl-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid compound of formula-4b of the present invention is characterized by it's powder x-ray diffractogram having the characteristic peaks at 5.73, 7.30, 8.06, 14.28, 15.51, 16.13, 18.13, 20.27, 24.40 and 26.19 ± 0.2 degrees of 29. The crystalline n-butyl amine salt compound of formula-4b is useful in the preparation of highly pure compound of formula-3 and compound of formula-1.

A process for the preparation of n-butylamine salt compound of formula-4b comprises of the following steps,

a) Dissolving the crude 2-[3-formyl-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid compound of formula-3 in a suitable solvent,

b) adding the n-butyl amine to the reaction mixture,

c) stirring the reaction mixture up to the completion of reaction,

d) filtering the precipitated solid,

e) washing the solid with a suitable solvent,

f) drying the compound to get the crystalline n-butyl amine salt of 2-[3-formyl-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid compound of formula-4b.

The fifth aspect of the present invention provides novel amine salts of 2-[3-((hydroxyimino)methyl)-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylicacid, compounds of general formula-6 having the following structural formula
Formula-6 The novel amine salts compounds of general formula-6 of the present invention are useful in the preparation of highly pure 2-[3-((hydroxyimino)methyl)-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylicacid compound of formula-5 as well as febuxostat compound of formula-1.
The sixth aspect of the present invention provides a process for the preparation of novel salts of 2-[3-((hydroxyimino)methyl)-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylicacid compound of general formula-6, which comprises of reacting the 2-[3-((hydroxyimino)methyl)-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylicacid compound of formula-5

Formula-5

with a suitable organic amine as defined above, in a suitable solvent to provide corresponding amine salt of 2-[3-((hydroxyimino)methyl)-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylicacid compound of general formula-6.

The other embodiment of the present invention provides methyl amine salt of 2-[3-((hydroxyimino)methyl)-4-(2-ethylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid compound of formula-6a as a crystalline solid.

Formula-6a The crystalline methyl amine salt of 2-[3-((hydroxyimino)methyl)-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid compound of formula-6a of the present invention is characterized by it's powder x-ray diffractogram having the characteristic peaks at 7.17, 7.58, 11.70, 14.36, 14.66,14.94, 16.63, 17.90, 18.96, 21.19, 23.55, 29.05, 29.61, 30.36, 31.68 and 45.41 ± 0.2 degrees of 20. The crystalline methyl amine salt compound of formula-6a of the present invention is useful in the preparation of highly pure compound of formula-5 and formula-1.

A process for the preparation of methylamine salt compound of formula-6a comprises of the following steps;

a) dissolving the crude 2-[3-((hydroxyimino)methyl)-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid of formula-5 in a suitable solvent,

b) adding the methyl amine to the reaction mixture,

c) stirring the reaction mixture upto the completion of reaction,

d) filtering the precipitated solid,

e) washing the solid with a suitable solvent,

f) drying the compound to get the crystalline methyl amine salt of 2-[3-((hydroxyimino)methyl)-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid compound of formula-6a.

The other embodiment of the present invention provides n-butyl amine salt of 2-[3-((hydroxyimino)methyl)-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid compound of formula-6b as a crystalline solid.

Formula-6b The crystalline n-butyl amine salt of 2-[3-((hydroxyimino)methyl)-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid compound of formula-6a of the present invention is characterized by it's powder x-ray diffractogram having the peaks at 6.33, 21.42, 23.61, 26.18, 27.30, 31.67 and 45.40 ± 0.2 degrees of 20. The crystalline n-butyl amine salt compound of formula-6b of the present invention is useful in the preparation of highly pure compound of formula-5 and formula-1.

A process for the preparation of n-butylamine salt compound of formula-6b of the present invention comprises of the following steps;

a) dissolving the crude 2-[3-((hydroxyimino)methyl)-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid compound of formula-5 in a suitable solvent,

b) adding the n-butyl amine to the reaction mixture,

c) stirring the reaction mixture upto the completion of reaction,

d) filtering the precipitated solid,

e) washing the solid with a suitable solvent,

f) drying the compound o get the crystalline n-butyl amine salt of 2-[3-((hydroxyimino)methyl)-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic
acid compound of formula-6b.

The novel amines salts compound of formula-4 and formula-6 of the present invention further converted into highly pure febuxostat compound of formula-1 by treating the salt compound of formula-4 or formula-6 with a suitable acid in a suitable solvent to provide corresponding highly pure compound of formula-3 or formula-5. The

The process described in the present invention was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention.

Examples:

Example 1: Preparation of methylamine salt of 2-[3-cyano-4-(2-methylpropoxy)
phenyl]-4-methylthiazole-5-carboxylic acid, compound of formula-2a.

To 10 gms of 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid added Ethyl acetate (10 ml) and cyclohexane (10 ml). Stirred the reaction mixture for 10 minutes. Added methanolic methyl amine (0.98 gms) to the reaction mixture and stirred for 3 hours. Filtered the precipitated solid and washed with cyclohexane (10 ml). Dried the obtained compound to get the title compound. MR: 185 - 190°C; Yield: 8 gms;

Example 2: Preparation of tertiary butyl amine salt of 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid compound of formula-lb.

To 10 gms of 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid added 70 ml of toluene. Stirred the reaction mixture for 10 minutes. Added tertiary butyl amine (2.3 gms) to the reaction mixture and stirred for 10 hours. Filtered the precipitated solid and washed with toluene (10 ml). Dried the obtained compound to get the title compound. MR: 225 - 230°C; Yield: 11.5 gms;

Example 3: Preparation of methylamine salt of 2-[3-formyl-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid, compound of formula-4a.

To 10 gms of 2-[3-formyl-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid added Ethyl acetate (10 ml) and cyclohexane (20 ml). Stirred the reaction mixture for 10 minutes. Added methanolic methyl amine (0.97 gms) to the reaction mixture and stirred for 3 hours. Filtered the precipitated solid and washed with 1:2 mixture of ethyl acetate and cyclohexane (10 ml). Dried the obtained compound to get the title compound. MR: 190 - 195°C; Yield: 9 gms said compound of formula-3 or formula-5 is converted in to highly pure febuxostat compound of formula-1 by the conventional methods.

The novel amine salts of compounds of general formula-2 of the present invention further converted into highly pure febuxostat compound of formula-1 by treating the salt compound of general formula-2 with a suitable acid in a suitable solvent to provide highly pure compound of formula-1

The suitable acid is selected from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and the like or organic acids such as acetic acid, trifluoro acetic acid, para toluene sulfuric acid, methane sulfonic acid and the like and the suitable solvent is selected from ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, ketone solvents, alcoholic solvents, chloro solvents, polar solvents and also mixtures thereof.

Example 4: Preparation of n-butyl amine salt of 2-[3-formyl-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid, compound of formula-4b.

To 10 gms of 2-[3-formyl-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid added 30 ml of toluene. Stirred the reaction mixture for 10 minutes. Added n-butyl amine (2.3 gms) to the reaction mixture and stirred for 10 hours. Filtered the precipitated solid and washed with toluene (10 ml). Dried the obtained compound to get the title compound. MR: 216 - 220°C; Yield: 5 gms

Example 5: Preparation of methylamine salt of 2-[3-((hydroxyimino)methyl)-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylicacid, compound of formula-6a.
To 10 gms of 2-[3-((hydroxyimino)methyl)-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylicacid added Ethyl acetate (10 ml) and cyclohexane (20 ml). Stirred the reaction mixture for 10 minutes. Added methanolic methyl amine (0.93 gms) to the reaction mixture and stirred for 3 hours. Filtered the precipitated solid and washed with 1:2 mixture of ethyl acetate and cyclohexane (10 ml). Dried the obtained compound to get the title compound. MR: 215-221°C; Yield: 7 gms

Example 6: Preparation of n-butyl amine salt of 2-[3-((hydroxyimino)methyl)-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylicacid, compound of formula-6b.
To 10 gms of 2-[3-((hydroxyimino)methyl)-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylicacid added 50 ml of toluene. Stirred the reaction mixture for 10 minutes. Added n-butyl amine (2.2 gms) to the reaction mixture and stirred for 10 hours. Filtered the precipitated solid and washed with toluene (10 ml). Dried the obtained compound to get the title compound. Yield: 9.5 gms MR:95-118°C

We Claim:

1. A process for the preparation of novel amine salts of 2-[3-cyano-4-(2-methylpropoxy) phenyl] -4-methylthiazole-5-carboxylic acid compound of general formula-2, which comprises of reacting the 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid compound of formula-1, with a suitable organic amine in a suitable solvent to provide corresponding amine salt of 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid compound of general formula-2.

2. A process for the preparation of crystalline organic amine salt compound of general formula-2 comprises of the following steps;

a) dissolving the crude 2-[3-cyano-4-(2-methylpropoxy) phenyl] -4-methylthiazole-5-carboxylic acid compound of formula-1 in a suitable solvent,

b) adding the organic amine to the reaction mixture,

c) stirring the reaction mixture upto the completion of reaction,

d) filtering the precipitated solid,

e) washing the solid with a suitable solvent,

f) drying the compound to get the crystalline organic amine salt of 2-[3-cyano-4-(2-methylpropoxy) phenyl] -4-methylthiazole-5-carboxylic acid compound of general formula-2.

wherein, the organic amine is selected from methyl amine and tertiary butylamine.

3. Novel amine salts of 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid compound of general formula-2,

Formula-2

wherein, R is selected from methyl, n-butyl and tertiary butyl.

4. A process for the preparation of novel amine salts of 2-[3-formyl-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid compound of general formula-4, which comprises of reacting the 2-[3-formyl-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid compound of formula-3, with a suitable organic amine in a suitable solvent to provide corresponding amine salt of 2-[3-formyl-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid compound of general formula-4.

5. A process for the preparation of crystalline organic amine salt compound of general formula-4 comprises of the following steps,

a) dissolving the crude 2-[3-formyl-4-(2-methylpropoxy)phenyl]-4-methyl thiazole-5-carboxylic acid compound of formula-3 in a suitable solvent,

b) adding the organic amine to the reaction mixture,

c) stirring the reaction mixture up to the completion of reaction,

d) filtering the precipitated solid,

e) washing the solid with a suitable solvent,

f) drying the compound to get the crystalline organic amine salt of 2-[3-formyl-
4-(2- methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid compound of
formula-4.

wherein, the organic amine is selected from methyl amine and n-butyl amine.

6. Novel amine salts of 2-[3-formyl-4-(2-methylpropoxy) phenyl] -4-methylthiazole 5-carboxylic acid compounds of general formula-4,

Formula-4 wherein, R1 is selected from methyl, n-butyl and tertiary butyl.

7. A process for the preparation of novel salts of 2-[3-((hydroxyimino)methyl)-4-(2-
methylpropoxy) phenyl]-4-rnethylthiazole-5-carboxylicacid compound of general
formula-6, which comprises of reacting the 2-[3-((hydroxyimino)methyl)-4-(2-

methylpropoxy) phenyl]-4-methylthiazole-5-carboxylicacid compound of formula-5, with a suitable organic amine in a suitable solvent to provide corresponding amine salt of 2-[3-((hydroxyimino)methyl)-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylicacid compound of general formula-6.

8. A process for the preparation of crystalline organic amine salt of general formula-6 comprises of the following steps;

a) dissolving the crude 2-[3-((hydroxyimino)methyl)-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid of formula-5 in a suitable solvent,

b) adding the organic amine to the reaction mixture,

c) stirring the reaction mixture upto the completion of reaction,

d) filtering the precipitated solid,

e) washing the solid with a suitable solvent,

f) drying the compound to get the crystalline organic amine salt of 2-[3-
((hydroxylimino) methyl)-4-(2-methylpropoxy) phenyl] -4-methylthiazole-5-
carboxylic acid compound of general formula-6.

wherein, the organic amine is selected from methyl amine and n-butyl amine.

9. Novel amine salts of 2-[3-((hydroxyimino)methyl)-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylicacid, compounds of general formula-6,

Formula-6 wherein, R2 is selected from methyl, n-butyl and tertiary butyl.

10. A process according to any of the proceeding claims, wherein the suitable organic
amine is selected from methyl amine, ethyl amine, dimethyl amine, trimethyl amine,
diethyl amine, triethyl amine, n-propyl amine, isopropyl amine, n-butyl amine,
tertiary butyl, (+/-)-sec-butyl amine, Octyl amine, 2-ethyl hexylamine, benzyl amine,
a-methyl-benzylamine, phenyl ethylamine, dibenzylamine, N-methylbenzylamine,
N,N-dimethylbenzylamine, N,N-diethyl benzyl amine, N-ethyl-N-methyl benzyl
amine, tribenzyl amine, cyclopentylamine, cyclohexyl-amine, cycloheptylamine, N-methylcyclopentylamine, N-ethylcyclohexyl amine, N-ethyl cycloheptylamine, dicyclohexylamine, N,N-dimethylcyclo pentylamine, N,N-dimethyl cyclo hexylamine, N,N-diethylcycloheptylamine; preferably methyl amine, n-butyl amine, tertiary butyl amine; and the suitable solvent is selected from ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, detone solvents, alcoholic solvents, chloro solvents; preferably ester solvents, hydrocarbon solvents.