DESC:FIELD OF INVENTION:
The present invention reports New Amine salts of Febuxostat and Novel process thereof. Furthermore, New Amine salts of Febuxostat of high purity are obtained in high yield and results highly pure Febuxostat which otherwise is very difficult to achieve without significant yield loss.
BACKGROUD OF INVENTION:
Febuxostat, sold under the brand names Uloric among others, is a medication used long-term to treat gout due to high uric acid levels. It is generally only recommended in those who cannot take allopurinol. When initially started, medications such as NSAIDs are often recommended to prevent gout flares. It is taken by mouth.
Common side effects include liver problems, nausea, joint pain, and a rash. Serious side effects include an increased risk of death as compared with allopurinol, Stevens-Johnson syndrome, and anaphylaxis. Use is not recommended during pregnancy or breastfeeding. It inhibits xanthine oxidase, thus reducing production of uric acid in the body.
Febuxostat was approved for medical use in the European Union in 2008 and in the United States in 2009. No generic version is available as of 2019, though one has been approved. In the United Kingdom a month of treatment costs the NHS about 24 pounds. In the United States the wholesale cost of a month's worth of medication is about US$320.
Febuxostat is used to treat chronic gout and hyperuricemia. Febuxostat is typically only recommended in those who cannot tolerate allopurinol. National Institute for Health and Clinical Excellence concluded that febuxostat is more effective than standard doses of allopurinol, but not more effective than higher doses of allopurinol.
Febuxostat is a non-purine-selective inhibitor of xanthine oxidase. It works by non-competitively blocking the molybdenum pterin center which is the active site on xanthine oxidase. Xanthine oxidase is needed to successively oxidize both hypoxanthine and xanthine to uric acid. Hence, febuxostat inhibits xanthine oxidase, therefore reducing production of uric acid. Febuxostat inhibits both oxidized as well as reduced form of xanthine oxidase because of which febuxostat cannot be easily displaced from the molybdenum pterin site.
Febuxostat was discovered by scientists at the Japanese pharmaceutical company Teijin in 1998. Teijin partnered the drug with TAP Pharmaceuticals in the US and Ipsen in Europe.
Ipsen obtained marketing approval for febuxostat from the European Medicines Agency in April 2008, Takeda obtained FDA approval in February 2009, and Teijin obtained approval from the Japanese authorities in 2011. Ipsen exclusively licensed its European rights to Menarini in 2009. Teijin partnered with Astellas for distribution in China and southeast Asia.
Febuxostat is chemically, 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methyl-5- thiazolecarboxylic acid and has the structural formula:

Febuxostat and its process were disclosed in U.S. patent rto. 5,614,520. Polymorphism is defined as "the ability of a substance to exist as two or more crystalline phases that have different arrangement and/or confrontations of the molecules in the crystal Lattice. Thus, in the strict sense, polymorphs are different crystalline structures of the same pure substance in which the molecules have different arrangements and/or different configurations of the molecules". Different polymorphs may differ in their physical properties such as melting point, solubility, X-ray diffraction patterns, etc.
Although those differences disappear once the compound is dissolved, they can appreciably influence pharmaceutically relevant properties of the solid form, such as handling properties, dissolution rate and stability. Such properties can significantly influence the processing, shelf life, and commercial acceptance of a polymorph. It is therefore important to investigate all solid forms of a drug, including all polymorphic forms, and to determine the stability, dissolution and flow properties of each polymorphic form. Polymorphic forms of a compound can be distinguished in the laboratory by analytical methods such as X-ray diffraction (XRD), Differential Scanning Calorimetry (DSC) and Infrared spectrometry (IR).
In EP0513379B1 Febuxostat is prepared from 4-hydroxy-3-nitrobenzaldehyde, according to the following scheme.

This particular process suffers from major drawbacks. Not only it is very long, including seven steps from the starting material to the final product, but, most importantly, it employs the use of cyanides, which are extremely toxic reagents. Cyanide salts are likely to generate hydrocyanide, which sets a high amount of risk in an industrial scale process.
In Japanese patent JP06345724A(JP2706037B) the intermediate ethyl ester of Febuxostat is prepared from p-cyano-nitrobenzene, in three steps. Febuxostat may, then, be prepared by alkaline hydrolysis. The use of extremely toxic potassium cyanide makes this process unsuitable for manufacturing purposes.
In Japanese patent JP3202607B Febuxostat ethyl ester is prepared, according to the scheme given below, through two similar routes. Route A uses flash column chromatography for the purification of the hydroxylamine reaction product, while Route B suffers from low yield and the use of chlorinated solvents for recrystallization. In addition, the reaction solvent is, in both cases, formic acid which causes severe skin burns and eye damage to humans. Formic acid is also corrosive towards metal-based materials of construction (MOC), like stainless steel and nickel alloys, limiting the options, essentially, to glass reactors or vessels. The drawbacks of using this solvent are also related to the high volumes of formic acid required per batch, which hinder the waste treatment.

Febuxostat can exist in different polymorphic Forms, which may differ from each other in terms of stability, physical properties, spectral data and methods of preparation.
PCT publication no. WO 2010/142653 disclosed a process for the preparation of febuxostat.
PCT publication no. WO 2011/031409 ('409 patent) disclosed a process for the preparation of febuxostat. According to the '409 patent also disclosed one-pot process for preparing of 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester.
According to the '409 patent, febuxostat can be prepared by hydrolyzing the 2-(3- cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester with sodium hydroxide in the presence of absolute ethanol or n-butanol.
U.S. patent no. 6,225,474 disclosed crystalline Form A, Form B, Form C, Form D, Form G and amorphous Form of febuxostat. PCT publication no. WO 2008/067773 disclosed crystalline Form H, Form I and Form J of febuxostat.
Crystalline Form I and Form II of febuxostat were disclosed in Chinese patent publication no. 101139325.
5 Chinese patent publication no. 101386605 disclosed a crystalline Form K of febuxostat, characterized by an X-ray powder diffraction pattern having peaks expressed as 2T at about 5.64, 7.80, 1 1.38, 1 1.70, 12.54, 12.74, 17.18 and 26.12 ± 0.2 degrees.
Chinese patent publication no. 101412700 disclosed a crystalline Form of febuxostat, characterized by an X-ray powder diffraction pattern having peaks expressed 10 as 2T at about 5.54, 5.66, 7.82, 11.48, 12.62, 16.74, 17.32, 18.04, 18.34, 20.40, 23.74, 25.76 and 26.04 ± 0.2 degrees.
Crystalline Form Q of febuxostat was disclosed in Chinese patent publication no. 101648926.
Chinese patent publication no. 101671315 disclosed a crystalline Form K of Febuxostat, characterized by an X-ray powder diffraction pattern having peaks expressed as 2T at about 4.82, 6.64, 6.88, 7.22, 11.74, 12.82, 13.28, 16.00, 16.50, 17.50, 20.98, 22.02, 23.00, 23.82, 24.70, 25.18, 25.84 and 26.68 ± 0.2 degrees.
Crystalline Form X, Form Y and Form Z of febuxostat were disclosed in Chinese patent publication no. 101684107.
An unpublished application, IN 2810/CHE/2010 assigned to Hetero research foundation discloses a crystalline Form HI and Form H2 of febuxostat.
As the above literature processes for the preparation of Febuxostat are not effective enough for the removal of critical impurities from Febuxostat without significant yield loss, therefore, there was a need to develop methodology to remove impurities from Febuxostat to get highly pure Febuxostat. To fulfill this requirement, Novel Amine salts of Febuxostat of high purity were prepared which ultimately resulted highly pure Febuxostat without significant yield loss. The X-Ray diffraction (XRD) study of some Amine salts of Febuxostat prepared using novel process thus developed, are also reported in this embodiment.
SUMMARY OF INVENTION:
The current invention provides novel amine salts of Febuxostat and method for the preparation thereof. It basically involves the preparation of dicyclohexylamine & cyclohexylamine salts of Febuxostat and its subsequent de-amination to get highly pure Febuxostat.
DETAILED DESCRIPTION OF THE INVENTION:
According to the first embodiment of the present invention, New Amine salts of Febuxostat are prepared using novel process which involves:
i. To crude or any form of Febuxostat in organic solvents comprises aliphatic esters like ethyl acetate, isopropyl acetate or aromatic hydrocarbons like Toluene, Xylene or aliphatic ketones like acetone, ethyl methyl ketone, diethyl ketone, dimethyl ketone, dipropyl ketone, dibutyl ketone or an aliphatic nitriles such as acetonitrile, propionitrile aliphatic alcohols like Methanol, ethanol or a mixture thereof at 50-60°C.
ii. Adding aliphatic amine selected from Dicyclohexylamine, Cycloxeylamine, tert-Butylamine, N,N-Diisopropylamine, Triethylamine etc with stirring at 50-60°C.
iii. Cooling the reaction mass to 10-20°C.
iv. Stirring for 1-3 hours to ensure complete crystallization.
v. Isolating Febuxostat Amine salt by filtration and drying of the wet cake at 50-60°C for 10-20 hours.
The above-mentioned invention is supported by the following non limiting examples.
Example 1:
10g of Febuxostat (HPLC Purity= 91.70%) was taken in Methanol (50ml) in a round bottom flask and heated to 50-60°C with stirring followed by addition of Dicyclohexylamine and stirred for 1-2 hrs. Then resulting mass was cooled to 10-20°C & stirred for 2-4 hours. The crystallized material was isolated by filtration and dried at 50-60°C for 10-25 hours to get 15g of Febuxostat Dicyclohexylamine salt having HPLC Purity= 99.90% (individual highest impurity = 0.05%).
Example 2:
10g of Febuxostat (HPLC Purity= 91.70%) was taken in Ethyl Acetate (50ml) in a round bottom flask and heated to 50-60°C with stirring followed by addition of Dicyclohexylamine and stirred for 1-2 hrs. Then resulting mass was cooled to 10-20°C & stirred for 2-4 hours. The crystallized material was isolated by filtration and dried at 50-60°C for 10-25 hours to get 15g of Febuxostat Dicyclohexylamine salt having HPLC Purity= 99.86% (individual highest impurity = 0.09%).
Example 3:
10g of Febuxostat (HPLC Purity= 91.70%) was taken in Methanol (50ml) in a round bottom flask and heated to 50-60°C with stirring followed by addition of Dicyclohexylamine and stirred for 1-2 hrs. Then resulting mass was cooled to 10-20°C & stirred for 2-4 hours. The crystallized material was isolated by filtration and dried at 50-60°C for 10-25 hours to get 15g of Febuxostat Cyclohexylamine salt having HPLC Purity= 99.44% (individual highest impurity = 0.22%).
Example 4:
10g of Febuxostat (HPLC Purity= 91.70%) was taken in Ethyl acetate (50ml) in a round bottom flask and heated to 50-60°C with stirring followed by addition of Cyclohexylamine and stirred for 1-2 hrs. Then resulting mass was cooled to 10-20°C & stirred for 2-4 hours. The crystallized material was isolated by filtration and dried at 50-60°C for 10-25 hours to get 15g of Febuxostat Cyclohexylamine salt.
Example 5:
Febuxostat Dicyclohexylamine salt (10g) was taken in Methanol (50ml) in a round bottom flask at 25-35°C with stirring followed by its treatment with hydrochloric acid and resulting mass was stirred for 2-4 hrs. Then resulting mass was then cooled to 10-20°C & stirred for 2-4 hours. The crystallized material was isolated by filtration and dried at 50-60°C for 10-25 hours to get 6g of Febuxostat having HPLC Purity= 99.90% (individual highest impurity = 0.05%).
,CLAIMS:WE CLAIM:
1. An improved process for preparation of Febuxostat which comprises:
I. adding aqueous caustic solution to Ethyl 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate or Febuxostat Ethyl ester in an aliphatic ketone selected from acetone, ethyl methyl ketone, diethyl ketone, dimethyl ketone, dipropyl ketone, dibutyl ketone or a mixture thereof;
II. heating the above to reflux with stirring at 50-60°C;
III. stirring the reaction mass for 2-6 hours at 50-60°C;
IV. cooling the reaction mass to 20-30°C;
V. adjusting the pH of reaction mass to 4-5 with dilute hydrochloric acid;
VI. isolating Febuxostat as wet cake by routine filtration; and
VII. drying of the wet cake at 50-60°C for 10-20 hours to get highly pure Febuxostat.

2. The process as claimed in claim 1 can control the formation of critical impurities which are formed by various processes of prior art involving hydrolysis using aliphatic alcohols or amide solvents and are difficult to reduce or remove.

3. A novel process for conversion of Febuxostat as claimed in claims 1 and 2 to its respective novel amine salt which comprises:
I. dissolving crude or any form of Febuxostat in an aliphatic ester selected from ethyl acetate, isopropyl acetate; or an aromatic hydrocarbon selected from toluene, xylene; or an aliphatic ketone selected from acetone, ethyl methyl ketone, diethyl ketone, dimethyl ketone, dipropyl ketone, dibutyl ketone; or an aliphatic nitrile selected from acetonitrile, propionitrile; or an aliphatic alcohol selected from methanol, ethanol or a mixture thereof at 50-60°C;
II. heating the reaction mass to 50-60°C;
III. adding aliphatic amine selected from Dicyclohexylamine, Cyclohexylamine, tert-Butylamine, N,N-Diisopropylamine, Triethylamine, benzylamine to reaction mass of step I) with stirring at 50-60°C;
IV. stirring the reaction mass at 50-60°C;
V. cooling the reaction mass to 10-20°C;
VI. stirring at 10-20°C for 1-3 hours to ensure complete crystallization;
VII. isolating the product as wet cake by routine filtration; and
VIII. drying of the wet cake at 50-60°C for 10-20 hours to get desired novel Febuxostat amine salt.
4. New Dicyclohexylamine, Cyclohexylamine, tert-Butylamine, N,N-Diisopropylamine, Triethylamine, benzylamine salts of Febuxostat.