IMPROVED PROCESS FOR THE PREPARATION OF FEBUXOSTAT
Field of the Invention
An improved and efficient process for the preparation of 2-[3-cyano-4-(2-
methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid (febuxostat) that is
substantially free from amide by-product is provided.
Background of the Invention
Febuxostat is a non-purine xanthine oxidase inhibitor known from U.S. Patent No.
5,614,520. It is chemically designated as 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-
methylthiazole-5-carboxylic acid having the structure as represented by Formula I .
Formula I
Febuxostat is marketed in the United States under the brand name Uloric and in
Europe under the brand name Adenuric® for the chronic management of hyperuricemia in
patients with gout. It works by non-competitively blocking the channel leading to the
active site on xanthine oxidase. Xanthine oxidase is needed to successively oxidate both
hypoxanthine and xanthine to uric acid. Hence, febuxostat inhibits xanthine oxidase,
therefore, reducing production of uric acid.
Processes for the preparation of febuxostat and intermediates thereof are disclosed
in U.S. Patent No. 5,614,520; Japanese Patent Nos. JP 2834971; JP 3202607; JP 2706037,
JP 10139770 and JP 3169735.
U.S. Patent No. 5,614,520 discloses preparation of febuxostat by hydrolysis of its
corresponding ester using sodium hydroxide. It has been observed that when hydrolysis is
carried out with sodium hydroxide, the cyano moiety also gets hydrolyzed along with ester
leading to the generation of amide by-product, a very potential impurity in febuxostat API.
The structure of the amide by-product is as shown below:
JP 2834971 describes preparation of febuxostat ester via formylation of a 4-
hydroxyphenyl substituted thiazole intermediate in the presence of an organic acid,
preferably with trifluoroacetic acid, and JP 3202607 describes preparation of febuxostat
ester via formylation of a 4-hydroxyphenyl substituted thiazole intermediate in the
presence of polyphosphoric acid. The work-up procedure for the isolation of product is
tedious requiring a number of steps.
The processes described in U.S. 5,614,520, JP 2706037, JP 10139770 and JP
3169735 involve the use of toxic metal cyanides for the preparation of febuxostat. The
use of metal cyanides is hazardous to health and is not recommended for an industrial
scale preparation.
Accordingly, there is a need for a process to synthesize febuxostat that is
substantially free of the amide by-product. The process should avoid long work-up
procedures and allow easy isolation of final product and also avoid the use of toxic metal
cyanides.
Summary of the Invention
The present invention provides an improved and efficient manufacturing method of
2-[3-cyano-4-(2-methylpropoxy)phenyl] -4-methylthiazole-5 -carboxylic acid (febuxostat)
that addresses many of the drawbacks of the prior art processes. Thus, it is suitable for
commercial-scale production. The process of the present invention does not involve the
use of hazardous cyanides. Also, the process makes use of methanesulfonic acid for
formylation, which allows easy isolation of the formylated product. In addition, the
febuxostat so synthesized is substantially free from the amide by-product. The control of
the formation of amide by-product was a challenge. The inventors of this patent
application found that this amide by-product could be controlled by selecting appropriate
base and solvent for the hydrolysis step.
Accordingly, the first aspect of the present invention provides a process for the
preparation of febuxostat of Formula I
Formula I
comprising the steps of:
(i) reacting 4-hydroxy thiobenzamide of Formula II
Formula II
with a compound of Formula III (wherein X is halogen and R is alkyl or
arylalkyl)
Formula III
to give a compound of Formula IV;
Formula IV
(ii) formylation of the compound of Formula IV with hexamethylene tetramine in
presence of an acid to give a compound of Formula V;
Formula V
(iii) reaction of the compound of Formula V with hydroxylamine hydrochloride to
give a compound of Formula VI;
Formula VI
(iv) alkylation of the compound of Formula VI with isobutyl halide of Formula
VII (wherein X is halogen)
Formula VII
a compound Formula VIII; and
Formula VIII
(v) hydrolysis of the compound of Formula VIII with a base selected from oxide
and hydroxide of barium to give febuxostat of Formula I.
In a second aspect, the present invention provides a process for the preparation of
febuxostat of Formula I
Formula I
comprising hydrolysis of the compound of Formula VIII (wherein R is ethyl)
Formula VIII where R is ethyl
with barium hydroxide octahydrate.
Other objects, features, advantages and aspects of the present invention will
become apparent to those of ordinary skill in the art from the following detailed
description.
Detailed Description of the Invention
Definitions
The following definitions apply to terms as used herein:
The term "alky!", unless otherwise specified, refers to a monoradical branched or
unbranched saturated hydrocarbon chain having from 1 to 20 carbon atoms. This term can
be exemplified by groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl,
sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, n-decyl, tetradecyl, and the like.
The term "arylalkyl", unless otherwise specified, refers to alkyl-aryl linked through
an alkyl portion (wherein alkyl is as defined above) and the alkyl portion contains 1-6
carbon atoms and aryl is as defined below. Examples of arylalkyl groups include benzyl,
ethylphenyl, propylphenyl, naphthylmethyl, and the like.
The term "halogen" or "halo'' or "halide" refers to fluorine, chlorine, bromine or
iodine.
The term "substantiallyfree from amide by-product" refers to limit of amide by¬
product in febuxostat of Formula I as less than or equal to 0.07%.
Various embodiments and variants of the present invention are described
hereinafter.
The reaction of a compound of Formula II with a compound of Formula III
(wherein X is halo and R is alkyl or arylalkyl) to give a compound of Formula IV can be
carried out in a solvent, for example, ethanol, methanol, denatured spirit (DNS), 2-
propanol, 2-methyl-2-propanol or the mixture(s) thereof, at a temperature of about 0°C to
about 250°C for about 15 minutes to about several days depending on type of reactant and
solvent selected.
In a particular embodiment, the reaction of compound of Formula II with a
compound of Formula III (wherein X is CI and R is ethyl) to give a compound of Formula
IV is carried out in denatured spirit (DNS) at a temperature of about 60°C to about 65°C
for a time period of about 2.5 hours.
The formylation of the compound of Formula IV with hexamethylene tetramine to
give a compound of Formula V can be carried out in presence of an acid selected from
methanesulfonic acid, trifluoroacetic acid, polyphosphoric acid, ethane sulphonic acid,
trifluoromethane sulphonic acid, />-toluene sulphonic acid, acetic acid, formic acid,
propionic acid, or mixture(s) thereof, optionally in the presence of a solvent, for example,
benzene, toluene, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, ethyl
acetate, methanol, ethanol, propanol, 2-propanol, diethylether, tetrahydrofuran, dioxane,
1,2-dimethoxyethane, dimethylformamide, dimethyl sulfoxide, or mixture(s) thereof, at a
temperature of about 0°C to about 250°C for about 15 minutes to about several days
depending on type of reactant, solvent and acid selected. After completion of the reaction,
the reaction mixture may be cooled. The isolation of product can be carried out by
addition of a solvent, for example, water and then optional extraction in a different
solvent, for example, ethyl acetate. In a particular embodiment, the formylation of
compound of Formula IV (wherein R is ethyl) is carried out with methanesulfonic acid at a
temperature of about 20°C to about 100°C for a time period of about 10 hours to about 14
hours.
In a particular embodiment, the formylation of compound of Formula IV is carried
out by adding hexamethylene tetramine to a solution of hydroxy phenyl thiazole ethyl
ester in methanesulfonic acid over an interval of about 30 minutes. The reaction mixture
may be heated at a temperature of about 70°C to about 80°C for a period of about 10 hours
to about 12 hours. The reaction mixture may be cooled to about 30°C. Isolation of the
product may be carried out by adding water, cooling to about 0°C to about 5°C and stirring
for about another 1 hour.
The conversion of the compound of Formula V to a compound of Formula VI can be
carried out with hydroxylamine hydrochloride, wherein formyl group reacts with
hydroxylamine initially to form oxime and then a cyano group. The reaction can be carried
out in a solvent, for example, formic acid, acetic acid, dichloromethane, dichloroethane,
chloroform, carbon tetrachloride, methanol, ethanol, 1-propanol, 2-propanol, toluene,
benzene, pyridine, ethyl acetate, diethylether, tetrahydrofuran, dioxane, 1,2-methoxyethane,
dimethylformamide, dimethyl sulfoxide, or mixture(s) thereof, in the presence of a base, for
example, sodium formate, potassium formate, sodium acetate, triethylamine, potassium
carbonate, caesium carbonate, sodium carbonate, sodium bicarbonate, pyridine or mixture(s)
thereof at a temperature of about 0°C to about 250°C for about 15 minutes to about several
days depending on type of reactant, solvent and base selected.
In a particular embodiment, the reaction of compound of Formula V (wherein R is
ethyl) with hydroxylamine hydrochloride to give a compound of Formula VI is carried out
using sodium formate as base and formic acid as solvent at a temperature of about 25°C to
about 125°C for a time period of about 7 hours to about 12 hours.
The alkylation of the compound of Formula VI with isobutyl halide of Formula VII
to give a compound of Formula VIII can be carried out in the presence of a base, for
example, potassium carbonate, sodium carbonate, caesium carbonate, sodium bicarbonate,
sodium hydride, a sodium ethoxide, sodium methoxide, potassium tert-butoxide,
triethylamine or pyridine, optionally in the presence of an additive agent, for example,
potassium iodide, sodium iodide or dimethylaminopyridine (DMAP), in a solvent, for
example, dimethylformamide, dimethylacetamide, ethyl methyl ketone, acetone, methyl
isopropyl ketone, methyl isobutyl ketone, methyl n-butyl ketone, methyl t-butyl ketone,
methyl isoamyl ketone, dimethyl sulfoxide, hexamethylphosphoric triamide,
tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol, dimethyl ether,
dichloromethane, dichloroethane, chloroform, carbon tetrachloride, toluene, ethyl acetate,
or mixture(s) thereof. The temperature of the reaction mixture may vary from about 0°C
to about 250°C and the time interval for carrying out the reaction may vary from about 15
minutes to about several days depending upon the solvent, additive agent, base and
reactants involved. In a particular embodiment, the isobutyl halide is isobutyl bromide,
the solvent is dimethylformamide, the temperature for carrying out the reaction is about
70°C to about 80°C and the time interval is about 7 hours to about 8 hours.
The hydrolysis of the compound of Formula VIII to give febuxostat of Formula I
can be carried out in the presence of a base, for example, alkali or alkaline earth metal
oxides and hydroxides selected from barium hydroxide octahydrate, barium oxide,
potassium hydroxide, magnesium hydroxide, lithium hydroxide or calcium hydroxide in a
solvent, for example, tetrahydrofuran (THF), water, ethanol, methanol, denatured spirit, 1-
propanol, 2-propanol, 1-butanol, dimethylformamide (DMF), dimethylacetamide (DMA),
ethyl methyl ketone, acetone, methyl isopropyl ketone, methyl isobutyl ketone, methyl nbutyl
ketone, methyl t-butyl ketone, methyl isoamyl ketone, dimethyl sulfoxide,
dichloromethane, dichloroethane, chloroform, carbon tetrachloride, toluene, ethyl acetate
or mixture(s) thereof at a temperature of about 0°C to about 250°C for about 15 minutes to
about several days depending on type of reactant, solvent and base selected. In a
particular embodiment, hydrolysis of compound of Formula VIII is carried out with
barium hydroxide octahydrate, barium oxide or lithium hydroxide monohydrate in a
solvent selected from tetrahydrofuran, ethanol, water, 2-propanol, methanol, denatured
spirit, or mixture(s) thereof. In another particular embodiment, the hydrolysis of
compound of Formula VIII (wherein R is ethyl) to give febuxostat of Formula I is carried
out with barium hydroxide octahydrate in tetrahydrofuran, ethanol, methanol, denatured
spirit and water. The temperature of the reaction may be about 55°C to about 70°C, more
particularly about 60°C to about 65°C. The time interval for carrying out the reaction may
be from about 30 minutes to about 3 hours, more particularly about 90 minutes to about
120 minutes. Upon completion of reaction, the temperature of the reaction mixture may
be cooled down to about 40°C to about 55°C. Dilution of the reaction mixture may be
carried out with a solvent such as ethyl acetate and water. pH of the reaction mixture may
be adjusted to 0.5-0.8 with an acid such as 6N HCl. The organic layer is separated and the
aqueous layer is extracted with ethyl acetate. The combined organic layer may be treated
with activated carbon, filtered and concentrated. The residue thus obtained may be
dissolved in a solvent selected from dichloromethane, dichloroethane, chloroform or
carbon tetrachloride, methanol, ethanol, 2-propanol, 1-propanol, 2-methyl-2-propanol, or
mixture(s) thereof. The solution may be cooled to about 0°C to about 10°C, more
particularly to about 0°C to about 5°C, stirred for about 1 hour, filtered, washed with a precooled
mixture of methanol and dichloromethane and dried under reduced pressure to
febuxostat.
The hydrolysis process of the present invention uses barium hydroxide octahydrate
and thereby provides febuxostat of very high chemical purity with very less amount of
amide by-product as compared to conventional hydrolyzing agents. The experimental
observations are tabulated in Table 1 as below.
Table 1
It has also been observed that the formation of amide by-product increases with
time in case of hydrolysis with conventional hydrolyzing agents such as sodium
hydroxide, whereas in case of the hydrolysis with barium hydroxide octahydrate, the
amide by-product does not increase with time as shown below in Table 2.
Table 2
In the present invention, reactants may interact with each other by different means,
for example, dissolving to give a solution, slurrying to form a suspension or making
colloids to give an emulsion.
In the present invention, isolation of the product may be accomplished by, among
other things, extraction, concentration, precipitation, crystallization, filtration or
centrifugation.
Washing of the obtained residue may be carried out using the solvents in which the
product is sparingly soluble and by selecting a temperature that allows dissolving of
impurities only and not the desired product. The solvents for washing may include, but
are not limited to, water, ethyl acetate, acetone, methanol, ethanol, 1-propanol, 2-propanol,
1-butanol, 2-butanol, 2-methyl- 1-propanol, 1-pentanol, ethylene glycol, propylene glycol,
diethyl ether, ethyl methyl ether, tert-butyl methyl ether, tetrahydrofuran or 1,4-dioxane,
methyl acetate, propyl acetate, butyl acetate, methyl ethyl ketone, methyl isobutyl ketone,
benzene, toluene, xylene, N,N-dimethylformamide or N,N-dimethylacetamide,
acetonitrile, propionitrile, dimethyl sulfoxide, diethyl sulphoxide, or mixture(s) thereof.
Extraction of the product is a method to separate compounds based on their relative
solubilities in two different immiscible liquids, usually water and an organic solvent, and
may be carried out using a separatory funnel. The extraction process in the present
invention may employ non-aqueous systems also depending upon the type of product.
Extraction process may be single stage or a multistage continuous process.
Separation and concentration method of the organic compound should be such that
allows minimum product decomposition and maximum product quality. The methods for
concentration employed in the present invention may involve any of the conventional
methods known in the art, for example, common distillation, distillation under reduced
pressure, through reverse osmosis membrane, prevaporation through a membrane,
hydrophilic ultrafiltration membrane, or a combination thereof.
Drying may be accomplished by any suitable method of drying such as drying
under reduced pressure, vacuum tray drying, air drying or a combination thereof. Drying
may be carried out at a temperature of about 45°C to about 70°C for about 10 hours to
about 2 days.
Filtration may be accomplished by any of the methods known in the art, for
example, by using biichner funnel, belt filter, rotary vacuum-drum filter, crossflow filters,
screen filter. Filtration may also be accompanied by filter aids, for example, diatomaceous
earth, kieselguhr, wood cellulose, perlite, etc. or a combination thereof.
Purification or refinement may be accomplished by combining suitable means,
such as processing by extraction, chromatography separation, activated carbon, florisil,
etc., and recrystallization.
In the foregoing section, embodiments are described by way of examples to
illustrate the processes of invention. However, these are not intended in any way to limit
the scope of the present invention. Several variants of the examples would be evident to
persons ordinarily skilled in the art which are within the scope of the present invention.
Non-limiting examples of the present invention are as follows.
Examples
Example 1: Synthesis of Ethyl 2-(4-HvdroxyphenvO-4-Methyl-5-Thiazol Carboxylate
A mixture of 4-hydroxy thiobenzamide (100 g, 0.653 mol) and ethyl 2-
chloroacetoacetate ( 118.3 g, 0.719 mol) in denatured spirit (DNS) (500 mL) was heated at
about 60°C to 65°C for about 2.5 hours. The reaction mixture was cooled to about 0°C to
5°C and stirred for about 1 hour at the same temperature. The solid obtained was filtered,
washed with denatured spirit and dried to obtain the title compound. (Yield: 156 g,
90.7%)
Example 2 : Synthesis of Ethyl-2-(3-Formyl-4-HvdroxyphenvD-4-Methyl-5-Thiazole
Carboxylate
Hexamethylene tetramine (134 g, 0.971 mol) was added to a solution of ethyl 2-(4-
hydroxyphenyl)-4-methyl-5-thiazol carboxylate (100 g, 0.38 mol) in methanesulfonic acid
(500 mL) slowly over a period of about 30 minutes. The reaction mixture was heated to
about 75°C and stirred for about 10 hours. After completion of reaction, the reaction
mixture was cooled to about 30°C and water was added to it. The reaction mixture was
further cooled to about 0°C and stirred for about 1 hour. The solid thus obtained was
filtered, washed with water and dried to give the title compound. (Yield: 80 g, 72.3%)
Example 3: Synthesis of ethyl-2-(3-cyano-4-hvdroxyphenvn-4-methyl-5-thiazole
carboxylate
Hydroxylamine hydrochloride (35.82 g, 0.515 mol) and sodium formate (46.73 g,
0.687 mol) were added to a solution of ethyl-2-(3-formyl-4-hydroxyphenyl)-4-methyl-5-
thiazole carboxylate (100 g, 0.343 mol) in formic acid (anhydrous, 300 mL) and the
reaction mixture was heated to a temperature of about 100°C for about 8 hours. After
completion of reaction, the reaction mixture was cooled to about 40°C and water was
added to it. The reaction mixture was cooled to about 25°C and stirred for about 1 hour.
The solid obtained was filtered, washed with water and dried. The solid was then
dissolved in acetone at about 50°C and water was added slowly over a period of about 30
minutes. The mixture was cooled to about 25°C and again stirred for about 1 hour. The
solid thus obtained was filtered, washed with acetone:water ( 1 :1) mixture and dried to
obtain the title product. (Yield: 85 g, 85.9%)
Example 4: Synthesis of Ethyl-2-(3-Cvano-4-Isobutyloxyphenyl)-4-Methyl-5-Thiazole
Carboxylate
Potassium carbonate (300 g, 2.17 mol) and isobutyl bromide (142.7 g, 1.041 mol)
were added to a solution of ethyl-2-(3-cyano-4-hydroxyphenyl)-4-methyl-5-thiazole
carboxylate (100 g, 0.347 mol) in dimethylformamide (300 mL), and the reaction mixture
was heated at a temperature of about 75°C for about 8 hours. After completion of reaction,
the reaction mixture was cooled to about 40°C and water was added. The reaction mixture
was further cooled to about 0°C and stirred for about 1 hour. The solid thus obtained was
filtered, washed with water and dried to give title compound. (Yield: 11lg, 92.9%)
Example 5 : Synthesis of 2-[3-Cvano-4-(2-Methyrpropoxy) Phenyl1-4-Methylthiazole-5-
Carboxylic Acid Febuxosta )
Aqueous barium hydroxide octahydrate solution (prepared by dissolving 55 g,
0.174 mol of barium hydroxide octahydrate in 350 mL water) was added to a solution of
ethyl-2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazole carboxylate (100 g, 0.29 mol)
in tetrahydrofuran (1000 mL) and denatured spirit (300 mL). The reaction mixture was
stirred at a temperature of about 60°C for about 90 minutes to about 120 minutes. After
completion of reaction, the mixture was cooled to a temperature of about 45°C and diluted
with ethyl acetate and water. The pH of the reaction mixture was adjusted to 0.5-0.8 with
6N HC1 at about 35°C. The organic layer was separated and the aqueous layer was
extracted with ethyl acetate. The combined organic layer was treated with activated
carbon (10 g) and filtered through hyflobed. The hyflobed was washed with ethyl acetate.
The combined filtrate was concentrated at a temperature of about 45°C under reduced
pressure. The residue thus obtained was dissolved in a mixture of dichloromethane (400
mL) and methanol (1000 mL) and the solution was cooled to about 0°C, stirred for about 1
hour. The solid thus obtained was filtered, washed with a precooled mixture of methanol
and methylene chloride, dried under reduced pressure to give febuxostat. (Yield: 8 1 g,
88%)
HPLC purity: 99.93%
Amide by-product: 0.07%.
We claim:
1. A process for the preparation of febuxostat of Formula I
Formula I
comprising the steps of:
(i) reacting 4-hydroxy thiobenzamide of Formula II
Formula II
with a compound of Formula III (wherein X is halogen and R is alkyl or
arylalkyl)
Formula III
to give a compound of Formula IV;
Formula IV
(ii) formylation of the compound of Formula IV with hexamethylene tetramine in
presence of an acid to give a compound of Formula V;
Formula V
(iii) reaction of the compound of Formula V with hydroxylamine hydrochloride to
give a compound of Formula VI;
Formula VI
(iv) alkylation of the compound of Formula VI with isobutyl halide of Formula
VII (wherein X is halogen)
H,C
H3C X
Formula VII
to give a compound Formula VIII; and
Formula VIII
(v) hydrolysis of the compound of Formula VIII with a base selected from oxide
and hydroxide of barium.
2. The process according to claim 1, wherein the hydrolysis is carried out in the
presence of barium oxide.
3. The process according to claim 1, wherein the hydrolysis is carried out in the
presence of barium hydroxide octahydrate.
4. A process for the preparation of febuxostat of Formula I
Formula I
comprising hydrolysis of the compound of Formula VIII (wherein R is ethyl)
Formula VIII where R is ethyl
with barium hydroxide octahydrate.
5. The process according to claim 4, wherein febuxostat of Formula I is substantially
free of amide by-product.
6. The process according to claim 4, wherein febuxostat of Formula I contains 0.07%
amide by-product.
7. The process according to claim 4, wherein in febuxostat of Formula I contains less
than 0.07% amide by-product.