Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
  • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
  • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
  • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

• the present invention relates to a novel preparation method for 2-(3-cyano-4-isobutoxyphenyl)- 4-methyl-l,3-thiazole-5-carboxylic acid (Febuxostat) via novel and high yielded conversion of a formyl group in to a cyano group.
• Febuxostat is an inhibitor of xanthine oxidase, which was discovered by the Japanese company Teijin Pharma Ltd and it is indicated for use in the treatment of hyperuricemia and chronic gout. Its chemical name is 2-(3-cyano-4-isobutoxyphenyl)-4-methyl- l,3-thiazole-5-carboxylic acid. It is marketed under the brand names Adenuric in Europe, Feburic in Japan and Uloric in USA and Canada.
• Febuxostat ethyl ester is prepared from 4-cyanophenol, through a five-step process.
• Febuxostat can be prepared from its respective ethyl ester via alkaline hydrolysis, as in the previous case.
• the process employs, in the final step, the use of palladium catalyst and, moreover, the reaction is performed at elevated temperatures (145 °C) for 48 hours, conditions that raise the energy cost and are, in general, difficult to transfer in industrial scale.
• the invention provides a process for the convertion of a formyl group of compound of formula II into a cyano group of compound of formula III, wherein R ⁇ is a hydrogen atom, an alkyl, alkenyl, or alkynyl group and R 2 is an alkyl, alkenyl, or alkynyl group, in the presence of ammonia and either oxygen and metal catalyst or iodine.
• Another object of this invention is to provide a novel process for the preparation of Febuxostat, exhibiting improved yield, safe reagents and industrially applicable techniques.
• a further object of the invention is a process for the production of Febuxostat, comprising the following steps: a) alkylation of compound of formula Ila where Ri is a hydrogen atom and R 2 is an alkyl, alkenyl, or alkynyl group, preferably an ethyl group to form a compound of formula lib where Ri is wo-butyl and R 2 is an alkyl, alkenyl, or alkynyl group, preferably an ethyl group; conversion of the formyl group of compound of formula lib to cyano group, to produce compound of formula Illb, in the presence of: i) ammonia, oxygen, and a metal catalyst, or, ii) ammonia and iodine;
• the transformation of the formyl group to cyano group in a compound of formula II, in either of the processes described above, is performed in the presence of i) ammonia, oxygen, and a metal catalyst or ii) ammonia and iodine.
• Another object of the present invention is a process, for the preparation of Febuxostat, comprising the conversion of the formyl group of compound of general formula II, to cyano group of compound of formula III, in the presence of: i) ammonia, oxygen and a metal catalyst, or, ii) ammonia and iodine, and subsequent conversion of the compound of general formula III to Febuxostat.
• Conversion of the compound of general formula III to Febuxostat is readily achieved when R 2 is other than hydrogen by removing the alkyl, alkenyl, or alkynyl group and, where Ri is other than z ' so-butyl, converting R t to so-butyl.
• Rj is a hydrogen atom, an alkyl, alkenyl, or alkynyl group and R 2 is an alkyl, alkenyl, or alkynyl group, preferably an ethyl group in the presence of ammonia and either oxygen and metal catalyst or iodine.
• the present invention also encompasses the preparation of Febuxostat or salts thereof, through this novel transformation, included in the process in the below scheme.
• the process is advantageous over prior art methods, due to the fact that it features high reaction yields, leads to compounds with chemical purities suitable for pharmaceutical purposes, uses more safe reagents and possesses characteristics suitable for industrialization.
• a particular object of the invention is to provide a process for the preparation of Febuxostat, comprising the following steps: a) alkylation of compound of formula Ila where Ri is a hydrogen atom and R 2 is an alkyl, alkenyl, or alkynyl group, preferably an ethyl group to compound of formula lib where Ri is an / ' so-butyl group and R 2 is an alkyl, alkenyl, or alkynyl group, preferably an ethyl group; conversion of the formyl group of compound of formula lib to cyano group, to produce compound of formula Illb, in the presence of : i) ammonia, oxygen and a metal catalyst, or, ii) ammonia and iodine;
• Suitable ester groups for preparation of Febuxostat are methyl, ethyl, propyl, /so-propyl, butyl, wo-butyl, tert-butyl preferably an ethyl ester group.
• the etherification reaction is performed with an isobutyl halide, preferably isobutyl bromide, in the presence of a base.
• the base can be an inorganic base.
• Preferable inorganic bases are metal hydroxides and carbonates. More preferable inorganic bases are potassium carbonate, sodium carbonate, lithium carbonate.
• the base may also be an organic base.
• Preferable organic bases are amines. More preferable organic bases are trimethylamine, triethylamine, diisopropylamine, diisopropylethylamine, NN-dimethylaminopyridine.
• the reaction is performed at temperatures that range between 25-100 °C. Preferable temperatures are 50-80 °C.
• Solvents suitable for the reaction are polar aprotic solvents.
• Preferable polar aprotic solvents are dimethylsulfoxide, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran, acetonitrile, acetone, t-butyl methyl ether.
• the conversion of the formyl group to cyano group is performed with ammonia, an oxygen source and a metal catalyst.
• a metal catalyst various compounds of metals may be used.
• Non-limiting examples of metals are copper, iron, zinc, tin, ruthenium, palladium, rhodium, iridium, silver, cobalt, nickel, manganese, molybenium, vanadium and rhenium.
• Preferred metals are copper, iron, ruthenium, palladium, iridium and silver. More preferred metals are copper, iron and ruthenium.
• Non-limiting examples of metal catalysts are oxides, hydroxides, salts of metals with the conjugated base of either strong acids, such as hydrohalides, sulfuric acid, nitric acid, or organic acids, such as triflic acid and acetic acid.
• the amount of ammonia used at the reaction may well vary, depending on the scale of the reaction and the conditions employed to it. Normally, at reactions involving such volatile reagents, the latter are used in great excess. Moreover, the amount of ammonia used in the reaction depends on the form in which the reagent is available. Non-limiting examples are aqueous solutions of ammonia and gaseous ammonia.
• the solvent can be a typical organic solvent.
• Preferable organic solvents are polar aprotic solvents.
• Preferable polar aprotic solvents are dimethylsulfoxide, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran, acetonitrile, acetone, /-butylmethylether.
• the temperature, at which the reaction is performed may range from room temperature to the boiling point of the respective solvent.
• step b is performed with ammonia and molecular iodine.
• typical organic solvents can be used, preferably polar aprotic solvents, as defined above.
• the amount of ammonia is according to the nature of the reagent, as defined above.
• the temperature at which the reaction is performed may range from 0 °C to the boiling point of the respective solvent.
• the hydrolysis of the ester may be performed under basic conditions.
• Such conditions involve a strong inorganic base.
• Preferable bases are metal oxides, hydroxides and carbonates. More preferable bases are alkali metal and alkaline earth oxides, hydroxides and carbonates. More preferable bases are sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, barium oxide, sodium carbonate, potassium carbonate and lithium carbonate.
• the reaction may be performed in a variety of solvents, depending mainly on the nature of the base used at it. Typical organic solvents suitable for this reaction are polar protic and aprotic solvents, as well as mixtures of them with water.
• Preferred polar aprotic solvents are tetrahydrofuran, acetone, t-butyl methyl ether, ethyl acetate.
• Preferred polar protic solvents are lower alcohols. More preferable solvents are methanol, ethanol, n-propanol and z ' sO-propanol.
• the reaction can be performed at room temperature to the boiling point of used solvent. Preferable temperature range is from 20 to 80 °C.
• Another object of the invention is to provide an alternate process for the preparation of Febuxostat, comprising the following steps:
• the metal catalyst used in step b is a copper catalyst, an iron catalyst, or a ruthenium catalyst.
• the metal catalyst is a copper catalyst.
• the copper catalyst may be selected from inorganic compounds and salts of copper, of oxidative state (I) or (II).
• Preferable compounds and salts are copper halides, copper nitrate, copper acetate, copper sulfate, copper triflate, copper oxide and their hydrates.
• the conversion of the formyl group of formula II to cyano group of formula III is carried out in the presence of ammonia, an oxygen source and a metal catalyst.
• the above described conversion is carried out in a polar aprotic solvent.
• Preferred aprotic solvents are dimethylsulfoxide, dimethylformamide, dimethylacetamide, N-methyl pyrrolidone and tetrahydrofuran.
• the above described conversion of the formyl group of formula II to cyano group of formula III is carried out in temperatures ranging from 20 °C to the boiling point of the solvent, wherein the reaction is performed.
• Preferable temperature range is 50-140 °C. More preferable temperature range is 60-120 °C. Even more preferable temperature range is 70-1 10 °C.
• said conversion of the formyl group of formula II to cyano group of formula III is performed under oxygen atmosphere.
• the percentage of the oxygen which is present in the reaction atmosphere may range from 1% to 100%. Preferable range is 5% to 100%. More preferable range is 20% to 100%.
• reaction time may vary depending on the percentage of oxygen present in the air supply, used in the reaction.
• the reaction time may also vary, depending on the pressure developed or applied to the reaction.
• the conversion of the formyl group of formula II to cyano group of formula III may also be achieved with ammonia and iodine.
• said conversion is carried out in a polar aprotic solvent.
• Preferred aprotic solvents are dimethylsulfoxide, dimethylformamide, dimethylacetamide, N-methyl pyrrolidone, acetonitrile and tetrahydrofuran.
• the above mentioned conversion of the formyl group of formula II to cyano group of formula III is carried out in temperatures ranging from 0 °C to the boiling point of the solvent, wherein the reaction is performed.
• Preferable temperature range is 0-100 °C. More preferable temperature range is 10-60 °C. Even more preferable temperature range is 10-40 °C.
• Another object of the present invention is a process for the preparation of Febuxostat, as described above, comprising the conversion of the formyl group of compound of formula II, to nitrile group of compound of formula III, comprising: i) ammonia, oxygen, and a metal catalyst, or, ii) ammonia and iodine, and subsequently converting the compound of formula III to Febuxostat.

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• Pain & Pain Management (AREA)
• Rheumatology (AREA)
• Physical Education & Sports Medicine (AREA)
• Thiazole And Isothizaole Compounds (AREA)
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• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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• 2014
  • 2014-07-30 CN CN201480044498.XA patent/CN105452228B/zh not_active Expired - Fee Related
  • 2014-07-30 JP JP2016532260A patent/JP6585044B2/ja active Active
  • 2014-07-30 WO PCT/EP2014/002079 patent/WO2015018507A2/en active Application Filing
  • 2014-07-30 ES ES14750307T patent/ES2772131T3/es active Active
• 2019
  • 2019-06-12 JP JP2019109184A patent/JP2019194203A/ja not_active Withdrawn

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