- A facile one-pot synthesis of 4-alkoxy-1,3-benzenedicarbonitrile
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2-(3-Cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxlic acid (TEI-6720) was prepared. The introduction of cyano group to 4-nitrobenzonitrile with KCN in dry DMSO followed by quenching with alkyl halide afforded the key intermediates, 4-alkoky-1,3-benzenedicarbonitriles, in good yield. The reaction was completed in dry DMSO, while no reaction occurred in dry DMF. This observation can be suggested by the participation of DMSO in the reaction.
- Hasegawa, Masaichi
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Read Online
- Synthesis, molecular docking, DFT study of novel N-benzyl-2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxamide derivatives and their antibacterial activity
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A series of febuxostat based new chemical entities was synthesized using microwave method and characterized by NMR, mass and FT-IR spectral studies. Molecular docking of febuxostat amide nucleus substitution compounds 8c (-7.91kcal/mol), 8g (-7.94 kcal/mol) exhibiting high binding energy against ALK receptors. Theoretical investigation of MEPs, HOMO, LUMO and energy gap of HOMO-LUMO were calculated by B3LYP/6-31G method. Among the tested compounds, methoxy substituted compound 8g showed highest antibacterial activity against S. aereus and B. subtilis.
- Sam Daniel Prabu,Lakshmanan, Sivalingam,Thirumurugan,Ramalakshmi,Arul Antony
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Read Online
- New preparation method of febuxostat intermediate
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The invention relates to a new preparation method of a febuxostat intermediate. The method includes: taking cheap 4-hydroxybenzaldehyde as an initial raw material, firstly preparing aldoxime from 4-hydroxybenzaldehyde and hydroxylamine hydrochloride, then adding a corresponding thio reagent, and preparing a compound 4-hydroxythiobenzamide (152A1-00) by Beckmann rearrangement reaction; utilizing one-pot process, adopting cheap 4-hydroxybenzaldehyde as an initial raw material, carrying out a series of reactions, and then performing cyclization with 2-halogenated ethyl acetoacetate to obtain ethyl 2-(4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate or different salt forms (152A2x) thereof; and using isobutyl sulfonate (152H1x) with more easily controllable quality to replace bromo-isobutane soas to prepare ethyl 2-(3-formyl-4-isobutoxyphenyl)-4-methyl-5-thiazolecarboxylate (152A4-00). In conclusion, the method provided by the invention is more beneficial to safe, simple and cost-efficientindustrial scale preparation of the febuxostat intermediate with higher purity.
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- Method for synthesizing febuxostat and intermediate thereof
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The invention relates to a method for synthesizing febuxostat and an intermediate thereof, specifically a method for synthesizing 2-(3-formyl-4-isobutoxy-phenyl)-4-methyl-thiazole-5-carboxylic acid ethyl ester. The method comprises the following steps: preparing 2-(3-formyl-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate; enabling the product obtained in the step (a) to react in DMF (Dimethyl Formamide) in the presence of potassium carbonate and bromo-isobutane, adding water and ethyl acetate for extraction, concentrating to obtain an organic layer, and recrystallizing with DMF to obtain 2-(3-formyl-4-isobutoxy-phenyl)-4-methyl-thiazole-5-carboxylic acid ethyl ester. The invention also relates to 2-(3-formyl-4-isobutoxy-phenyl)-4-methyl-thiazole-5-carboxylic acid ethyl ester and 2-(3-formyl-4-hydroxyphenyl)-4-methyl-5-thiazoleethyl formate and application thereof to the preparation of febuxostat. The method of the invention has excellent performance.
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- Febuxostat and intermediates and synthesis thereof
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The invention relates to febuxostat and intermediates and synthesis thereof, in particular to a method for synthesizing 2-(3-formyl-4-hydroxyphenyl)-4-methyl-5-thiazole ethyl formate, which comprisesthe following operation steps: (1) adding a reactant 2-(4-hydroxyphenyl)-4-methyl-5-thiazole ethyl formate into a mixture of polyphosphoric acid and methanesulfonic acid, and uniformly stirring the materials; (2) adding a Darf reaction reagent hexamethylenetetramine into the reaction mixture while stirring, continuously reacting, and cooling; and (3) adding saturated brine ice, separating out solid, filtering, cleaning the solid with water to-be-neutral, and drying to obtain the product. The invention also relates to 2-(3-formyl-4-hydroxyphenyl)-4-methyl-5-thiazole ethyl formate and to the usethereof for the preparation of febuxostat. The method has excellent performance.
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- Method for continuously preparing febuxostat
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The invention discloses a method for continuously preparing febuxostat. The method comprises the following steps: by taking a compound represented by a formula (II) as a raw material, carrying out anetherification reaction to obtain a compound solution represented by a formula (III), filtering, carrying out reduced pressure distillation on filtrate to recover excessive bromo-iso-butane, carryingout a cyanation reaction on the residual filtrate to obtain a compound solution represented by a formula (IV), adding an alkali, and carrying out an ester hydrolysis reaction to obtain the febuxostat(I). By optimizing the preparation process of febuxostat, the whole preparation of the febuxostat can be continuously produced, the prepared febuxostat is high in yield and good in purity, the use ofa large amount of acid solvents in the traditional process is avoided, the operation steps are simple, and the preparation method is particularly suitable for industrial production.
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- Preparation method of Febuxostat
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The invention provides a preparation method of Febuxostat, and belongs to the technical field of pharmaceutical synthesis. According to the method provided by the invention, with 2-(3-formyl-4-hydroxyphenyl)-4-methyl-thiazole-5-ethyl carboxylate as a raw material, the Febuxostat is synthesized through an isobutylation reaction, a cyanation reaction and a hydrolysis reaction. The synthesis route issimple; through aftertreatment of the product of each step of the reaction as well as refining for purification, crystal regulation and the like on crude products, the product purity and yield are remarkably improved, the cost is lowered, and the operation is easier and more reasonable; moreover, the preparation method provided by the invention has the advantages of mild reaction conditions and lower energy consumption and is more suitable for industrial production.
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- High purity febuxostat preparation method
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The invention relates to febuxostat preparation method, wherein the 2 - (3 - thiophene - 4 - hydroxy-phenyl) - 4 - methyl thiazole - 5 - carboxylic acid ethyl ester with isobutyl bromide after completion of the reaction, the reaction solution after treatment as follows: 1) adding purified water, separating out the first crystal; 2) a first crystal to purified water beating, get the secondary crystal; 3) the secondary crystal to 1: 1.2 - 2.0 mass ratio of ethanol - formic acid solution recrystallization, to obtain compound (2 - (3 - formyl - 4 - isobuoxy - phenyl) - 4 - methyl - thiazole - 5 - carboxylic acid ethyl ester (FBT - 1). Through the step of optimizing the reaction post, obviously improves the key intermediate purity and yield, thereby improving the purity of the final product febuxostat and yield.
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- New preparation method of febuxostat
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Belonging to the technical field of pharmaceutical synthesis, the invention in particular relates to a preparation method of a febuxostat intermediate I, a preparation method of a febuxostat intermediate II and application thereof, as well as a preparation method of a febuxostat product. The preparation method of the febuxostat product includes: preparing the febuxostat intermediate I and the febuxostat intermediate II, directly adding water and organic alkali into a solution of the febuxostat intermediate II, and carrying out hydrolysis reaction; at the end of the reaction, adjusting the pH to 6.0-7.0 with hydrochloric acid, adding water for crystallization, performing cooling and centrifugation to obtain a febuxostat crude product, and then performing further preparation to obtain the febuxostat product. The febuxostat finished product has high purity, the preparation method has high yield and is low in cost, solid-liquid separation is easy to realize, the residual solvent is easilyremoved in the finished product preparation step, and the method is convenient for "consistency evaluation" by a preparation manufacturer, has great market competition advantage, and is green and environmentally friendly.
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- A method for preparing [...]
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The invention discloses a method for preparing [...], relates to a pharmaceutical technical field of chemical synthesis, comprising the following steps: to adjacent bromobenzylcyanide as raw materials with the isobutyl alcohol in the etherification reaction under alkaline conditions, to obtain 2 - [...]; to hydrogen peroxide/hydrogen bromic acid system for the oxidation of bromide, 2 - [...] oxidation bromination reaction, to obtain 2 - isobuoxy - 5 - bromobenzylcyanide; the 2 - isobuoxy - 5 - bromobenzylcyanide with 2 - boric acid - 4 - methyl - 1, 3 - thiazole - 5 - carboxylic acid ethyl ester in Suziki coupling reaction, to obtain 2 - [3 - cyano - 4 - isobuoxy phenyl] - 4 - methyl thiazole - 5 - carboxylic acid ethyl ester; the 2 - [3 - cyano - 4 - isobuoxy phenyl] - 4 - methyl thiazole - 5 - carboxylic acid ethyl ester under basic condition to obtain [...]. The invention routes and novel and short synthetic route, requires only four-step reaction can be to obtain the target product, used in the preparation raw materials are cheap and easy to obtain, environmental protection, mild reaction conditions, the operation is convenient and controllable, the prepared [...] high purity, high yield.
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Paragraph 0034; 0042; 0050-0051; 0052; 0060-0061; 0062; 0070
(2019/02/13)
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- Preparation method of Febuxostat A crystal form
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The invention provides a preparation method of a Febuxostat A crystal form. The method comprises the following steps of 1, performing a hydrolysis reaction, wherein a compound shown in the formula (I)is dissolved into a non-protonic solvent, and then a so
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Paragraph 0042-0057
(2019/06/12)
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- Catalytic oxidative conversion of aldehydes into nitriles using NH3·H2O/FeCl2/NaI/Na2S2O8: A practical approach to febuxostat
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A novel approach to convert aldehydes into nitriles using NH3·H2O/FeCl2/NaI/Na2S2O8 has been developed. Both alkyl and aryl nitriles were obtained in good to excellent yields. Electron-withdrawing and electron-donating groups, such as fluoro, chloro, bromo, nitro, ester, cyano, trifluoromethyl and alkoxy were tolerated. Notably, febuxostat and its intermediate, ethyl 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methyl-5-thiazolecarboxylate, were obtained in excellent yields.
- Chen, Han,Sun, Sijia,Xi, Haoying,Hu, Kaifang,Zhang, Ning,Qu, Jingping,Zhou, Yuhan
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supporting information
p. 1434 - 1436
(2019/05/01)
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- Synthesis method of febuxostat and intermediate thereof
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The invention belongs to the technical field of chemical synthesis of drugs and relates to a synthesis method of febuxostat and an intermediate thereof. The febuxostat and the intermediate (II) thereof are finally obtained by the steps of taking a compound shown as a formula I as a raw material, taking ferrous chloride and an iodine reagent as catalysts, taking sodium persulfate as an oxidant andcarrying out chemical reaction on the substances and an ammonia source in an organic solvent. The formula is shown in the description, wherein R is selected from H and ethyl. The synthesis method disclosed by the invention has the advantages that the use of strongly corrosive reagents is avoided, reaction conditions are milder, the corrosion to equipment is greatly reduced and the industrial production is safer; as a catalyst, the ferrous chloride is low in price, easy to obtain and more environmentally friendly; by using catalytic amount of iodized salt to replace dose of elemental iodine, the production cost is greatly reduced and higher economy is realized.
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Paragraph 0071-0073
(2019/04/04)
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- Preparation method of febuxostat intermediate, and application thereof in preparation of febuxostat
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The invention provides a preparation method of a compound of structural formula II. The method comprises the following steps: 1) reacting a compound of structural formula VII under the action of an alkylating agent and an alkali to obtain a compound of structural formula VI; 2) reacting the compound of structural formula VI to obtain a compound of structural formula V; 3) reacting the compound ofthe structural formula V with urotropine under an acidic condition in the absence of a solvent to obtain a compound of structural formula IV; 4) reacting the compound of the structural formula IV withhydroxylamine hydrochloride in the presence of an alkali, and dehydrating the obtained reaction product to obtain a compound of structural formula III; and 5) performing a ring closing reaction on the compound of the structural formula III and the compound of the structural formula VIII to obtain the compound of structural formula II. The invention also provides an application of the preparationmethod in the synthesis of febuxostat. The method has the advantages of simplicity in operation, high yield, few side reactions and no highly toxic substances, and is suitable for industrial production as a novel method for preparing the febuxostat intermediate. R in the formulas is a C1-C4 alkyl group.
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- Process Development of Febuxostat Using Palladium- and Copper-Catalyzed C-H Arylation
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There is significant interest in the development of process routes for active pharmaceutical ingredients using C-H arylation methodology. An efficient and practical synthetic route for febuxostat (1), which is the first non-purine-type xanthine oxidase inhibitor, was established via palladium- and copper-catalyzed C-H arylation of thiazole with aryl bromide. The catalyst loading was reduced to 0.1 mol percent for the intermolecular C-H arylation, and a three-step synthesis produced febuxostat in 89percent overall yield with excellent selectivity.
- Dohi, Masahiko,Kato, Yoshiaki,Komiyama, Masato,Kurokawa, Masayuki,Minamizono, Kunio,Sato, Yoshinori,Teramoto, Mitsuru,Tsuchiya, Hideyoshi,Tsuchiya, Naoki,Yajima, Naoki
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p. 1306 - 1311
(2018/09/21)
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- Synthesis method of Febuxostat isomeride
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The invention relates to a synthesis method of Febuxostat isomeride. The method comprises the following steps: firstly ensuring that 2-(3-aldehyde-4- hydroxyphenyl)-4-methylthiazole-5-nonanoic acid-ethyl ester (a compound 1) taken as a raw material and bromobutane are reacted, so as to obtain a compound 2, secondly, performing oximation and dehydration on the compound 2, so as to obtain a cyan compound 3, and thirdly, performing hydrolysis on the compound 3, so as to obtain a compound 4.
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Paragraph 0024; 0068-0070; 0072; 0073
(2018/08/04)
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- Synthesis method for transforming impurity 3-formyl febuxostat into febuxostat
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The invention relates a synthesis method for transforming a main impurity 3-formyl febuxostat of febuxostat into the febuxostat. The synthesis method comprises the following steps: taking the 3-formylfebuxostat as a starting raw material, and carrying out chemical reaction in a nitrogen-containing reagent and an organic solvent of Bronsted acid; finishing transformation of a functional group by utilizing Schmidt reaction, so as to transform a formyl group into a cyano group, so as to finally obtain the febuxostat. The invention discloses the novel method for transforming the functional group,i.e., the formyl group, into the cyano group by taking the impurity 3-formyl febuxostat as the starting material to synthesize the febuxostat for the first time. The synthesis method has the characteristic of convenience for operation, simple synthesis technology, high yield and the like.
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Paragraph 0016-0035
(2020/09/20)
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- Novel method for transforming Febuxostat impurities into Febuxostat
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The invention relates to a synthetic method for transforming Febuxostat impurities into Febuxostat. The synthetic method is mainly characterized in that the Febuxostat is finally obtained by transformation of 3-amide Febuxostat or 3-hydroxamic acid Febuxo
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Paragraph 0016; 0017; 0018; 0019; 0020; 0021; 0022-0028
(2018/03/26)
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- Method for preparing Febuxostat through one-pot process
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The invention provides a method for preparing Febuxostat through a one-pot process. The method comprises the following steps: (1) preparing a compound III from a compound II, after a reaction is completed, carrying out direct concentrating and drying, and directly carrying out a subsequent reaction without treatment; (2) under the condition of the presence of an acid binding agent, allowing the compound III to react with bromo isobutane in an organic solvent so as to obtain a suspension of a compound IV, then carrying out filtering, subjecting a filter cake to pulping with water, and carrying out filtering so as to obtain a solid compound IV; and (3) subjecting the solid compound IV prepared in the step (2) to hydrolyzing so as to obtain a Febuxostat compound I, wherein a specific reaction formula is described in the specification.
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- Compound 2 - (3-aldehyde group-4-isobuoxy phenyl) - 4-methyl-thiazole-5-carboxylic acid ethyl ester and non-cloth rope Tanzania method for the preparation of
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The invention provides a preparation method of 2-(3-formyl-4-isobutoxy phenyl)-4-methyl thiazole-5-ethyl formate which is obtained by using 4-isobutoxy cyanophenyl as an initial raw material and through a series of reactions. The invention also provides a preparation method of febuxostat, which comprises the following steps: reacting 2-(3-formyl-4-isobutoxy phenyl)-4-methyl thiazole-5-ethyl formate with hydroxylamine hydrochloride under the action of a catalyst to obtain a compound with a structure as shown in formula (VIII); hydrolyzing the compound with the structure as shown in formula (VIII) under an alkaline condition, and performing acidification to obtain febuxostat. The preparation method of the invention prepares febuxostat without using cyanides, and is high in safety. The preparation methods of the invention are simple in operation and high in yield. Experiment results show that the yield of step (A) is up to 90%, the yield of step (B) is up to 85%, the yield of step (C) is up to 90%, the yield of step (D) is up to 90%, and the yield of step (E) is up to 97%.
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Paragraph 0071; 0103
(2016/10/09)
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- A 2- aryl residue nitrile method for the preparation of thiazole derivatives
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The invention discloses a novel intermediate (II) and a method for preparing a 2-arylnitrile-thiazole derivative (I) by a coupling reaction of the novel intermediate (II) and a compound shown in the formula (III). In the formulas, X represents Cl, Br or I, Y represents F, Cl, Br, I, N2, -OSO2Ra, -OCORa or -OSi(Ra)3, R1 represents C1-6 alkyl or C6-10 aryl, Ra represents C1-6 alkyl or C6-10 aryl, and the C1-6 alkyl or C6-10 aryl is independently and optionally replaced. The preparation method has the advantages of mild technical conditions, less impurities, simple processes, safety and controllability and low energy consumption and is especially suitable for industrial production. The invention also discloses a method for preparing the novel intermediate shown in the formula (II). The preparation method utilizes cheap materials, is free of separation purification and greatly reduces a reaction cost.
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Paragraph 0099; 0100
(2017/03/21)
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- SYNTHETIC METHOD OF FEBUXOSTAT
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Photo-reactive components (Xanthine Oxidase) [...] pharmacological of inhibition of the present invention refers to, hyperuricemia (Hyperuricemia) being treating agent containing lung north source tart (febuxostat) a method to efficiently manufacture fabricated from the same and relates in lung north source tart crystalline. First in the present invention an alkylation reaction reaction through optimization solvent base and of high yield ethyl 2 - (3-cyano-4-isobutoxy phenyl) - 5-methylthiazole via 2-chloro-5-4-making and hydroxylammonium carboxylates, in addition, hydrolysis reaction in addition base and reaction conditions by optimizing the reaction products have a 2 - (3-carbamoyl-4-isobutoxy phenyl) - 4-methylthiazole via 2-chloro-5-5-carboxylic acid by completely excluded generation without highly purified lung north source tart purity also it is possible to obtain high yield.. Furthermore, all of the reactants employed in the of the present invention manufacturing method in commercially glass for use as an anti- lung north source tart mild, parameters the reactor and which is useful for mass production. (by machine translation)
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Paragraph 0071; 0112; 0114
(2017/01/17)
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- A non-cloth rope Tanzania intermediate and its preparation method
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The invention provides a febuxostat intermediate and a preparation method thereof. The febuxostat intermediate is a chemical compound shown as the formula IV. The formula IV is described in the specification. The yield of febuxostat prepared by a method of preparing the febuxostat from the febuxostat intermediate and by the preparation method of the febuxostat intermediate is high and can be higher than 90%. The impurity of the febuxostat is high and can be higher than 99%. In addition, the preparation method of the febuxostat intermediate and the method of preparing the febuxostat from the febuxostat intermediate are free of highly toxic cyanide. A dehydrating agent used in the method is economic and environmental-friendly and is suitable for industrial production.
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- A method of preparing non-cloth rope Tanzania
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The invention provides a method of preparing febuxostat. The method includes subjecting a compound shown as the formula V to a hydrolysis reaction shown as follows under the existence of a hydrolysis catalyst, so as to obtain the febuxostat. The yield of the febuxostat obtained by a preparation method of a febuxostat intermediate and by a method of preparing the febuxostat from the febuxostat intermediate is high and can reach 90% or higher. The impurity of the febuxostat is high and can be higher than 99%. In addition, the preparation method of the febuxostat intermediate and the method of preparing the febuxostat from the febuxostat intermediate are free of highly toxic cyanide. A dehydrating agent used in the method is economic and environmental-friendly and is suitable for industrial production.
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- Facile one-pot transformation of arenes into aromatic nitriles under metal-cyanide-free conditions
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Electron-rich arenes bearing methyl or methoxy groups on the aromatic ring were treated with dichloromethyl methyl ether and ZnBr2, and then with molecular iodine and aq. ammonia to give the corresponding aromatic nitriles in good yields. Using this method, febuxostat was efficiently prepared from 4-bromophenol in four steps. The method can be used for the preparation of aromatic nitriles from arenes in one pot under metal-cyanide-free conditions. Various electron-rich arenes could be effectively converted into the corresponding aromatic nitriles in good yields, by treatment with ZnBr2 and dichloromethyl methyl ether, followed by reaction with molecular iodine and aq. ammonia.
- Tamura, Toshiyuki,Moriyama, Katsuhiko,Togo, Hideo
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p. 2023 - 2029
(2015/03/18)
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- A NOVEL PROCESS FOR THE PREPARATION OF FEBUXOSTAT
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The present invention relates to a novel preparation method for 2-(3-cyano-4-isobutoxyphenyl)- 4-methyl-1,3-thiazole-5-carboxylic acid (Febuxostat) via novel and high yielded conversion of a formyl group in to a cyano group.
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- Facile one-pot transformation of phenols into o-cyanophenols
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The treatment of phenols with paraformaldehyde in the presence of MgCl2 and Et3N in THF at 80 C, followed by reaction with molecular iodine and aq. ammonia at room temperature provided the corresponding o-cyanophenols in moderate to good yields. The present reaction is a one-pot transformation of phenols into o-cyanophenols using much less expensive reagents than are typically used; the reaction is free of both transition-metals and cyanide. The utility of this reaction was highlighted during our preparation of Febuxostat from p-bromophenol.
- Nakai, Yuhta,Moriyama, Katsuhiko,Togo, Hideo
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p. 6077 - 6083
(2015/03/30)
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- PROCESS FOR THE PREPARATION OF FEBUXOSTAT POLYMORPHS
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The present invention relates to polymorphic forms of Febuxostat and processes for the preparation of polymorphic forms of Febuxostat.
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Page/Page column
(2014/09/30)
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- PROCESS AND INTERMEDIATES FOR THE PREPARATION OF SUBSTITUTED 2-ARYLTHIAZOLE CARBOXYLIC ACIDS
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The present invention relates to processes and intermediates for the preparation of derivatives of 2-arylthiazole such as Febuxostat and its analogs. Febuxostat which is an inhibitor of xanthine oxidase, is used for the treatment of chronic hyperuricaemia
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Paragraph 0123-0126; 0130
(2014/08/19)
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- PROCESS FOR THE PREPARATION OF 2-ARYLTHIAZOLE DERIVATIVES
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The present invention relates an improved process for the preparation of 2-arylthiazole derivatives which are intermediates of Febuxostat and further conversion to Febuxostat or pharmaceutically acceptable salts thereof.
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- Direct oxidative conversion of methylarenes into aromatic nitriles
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A variety of methylarenes were successfully converted into the corresponding aromatic nitriles in good to moderate yields by the treatment with NBS or DBDMH in the presence of a catalytic amount of AIBN or BPO, followed by the reaction with molecular iodine in aq NH3 in a one-pot procedure. The present reaction is a useful and practical transition-metal-free method for the preparation of aromatic nitriles from methylarenes.
- Tsuchiya, Daisuke,Kawagoe, Yuhsuke,Moriyama, Katsuhiko,Togo, Hideo
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supporting information
p. 4194 - 4197
(2013/09/12)
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- STABLE CRYSTAL FORM OF FEBUXOSTAT AND PROCESS FOR THE PREPARATION THEREOF
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The invention relates to novel stable polymorphic form FC-1 of Febuxostat [2-[3-cyano- 4-(2-Methyl-propoxy)pheriyl]-4-methyl-5-thiazole carboxylic acid]. The invention also provides process for the preparation of novel stable polymorphic form FC-1 with >9
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Page/Page column 8
(2013/07/05)
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- PROCESS FOR THE PREPARATION OF FEBUXOSTAT POLYMORPHS
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The present invention relates to an improved process for the preparation of Febuxostat Form-K. The present invention also relates to a novel crystalline form Mi of Febuxostat.
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Page/Page column 18-19
(2013/06/06)
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- SUBSTANTIALLY PURE SALTS OF FEBUXOSTAT AND PROCESSES FOR PREPARATION THEREOF
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Substantially pure salts of febuxostat of Formula (IA): wherein Y is Na+, K+, Li+, Mg2+, Ca2+, Zn2+, Ba2+, Sr2+, choline, epolamine and N+(R)4 an
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Paragraph 0124; 0125
(2013/07/31)
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- IMPROVED PROCESS FOR THE PREPARATION OF FEBUXOSTAT
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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.
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- AN IMPROVED PROCESS FOR THE PREPARATION OF 2-ARYLTHIAZOLE DERIVATIVES
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The present invention relates an improved process for the preparation of 2- arylthiazole derivatives which are intermediates of Febuxostat and further conversion to Febuxostat or pharmaceutically acceptable salts thereof.
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- AN IMPROVED PROCESS FOR PREPARATION OF FEBUXOSTAT AND ITS POLYMORPHIC CRYSTALLINE FORM C THEREOF
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The present invention relates to process of preparation of 2-(3-cyano-4- isobutyloxyphenyl)-4-methyl-5-thiazole carboxylic acid (Febuxostat). The present invention in particular relates to an efficient and easily to operate scalable process of manufacturing of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazole carboxylic acid (Febuxostat) of Formula I and its crystalline polymorphic Form C.
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- PROCESS FOR FEBUXOSTAT
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The present invention provides a process for the preparation of 2-(4-hydroxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester. The present invention also provides a process for the preparation of 2-(3-formyl-4-hydroxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester. The present invention further provides novel crystalline Forms of febuxostat, processes for their preparation and pharmaceutical compositions comprising them. The present invention further provides febuxostat crystalline particles having a mean particle size of less than about 25 μm, the methods for the manufacture of said crystalline particles, and pharmaceutical compositions comprising said crystalline particles.
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- A NOVEL FEBUXOSTAT CRYSTALLINE FORM AND THE PROCESS FOR THE PREPARATION THEREOF
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The present invention relates to a crystalline form III of 2-(3-cyano-4-isobutyloxyphenyl)- 4-methyl-5-thiazolecarboxylic acid which shows the X-ray powder diffraction pattern of Figure 1, having characteristic peaks at a reflection angle 2 θ of about 3.0
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Page/Page column 4
(2012/05/04)
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- NOVEL PROCESS FOR THE PREPARATION OF FEBUXOSTAT
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Disclosed herein is a novel process for the preparation of 2-[3-cyano-4-(2- methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid and novel intermediates thereof.
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- PROCESSES FOR PREPARING FEBUXOSTAT
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Febuxostat can be prepared from the compound of the following formula (VI); Formula (VI) has been prepared in a one-pot process by combining a compound of the following formula (II); with an organic solvent, isobutyl halide and an inorganic base, to obtain a compound of the following formula (III); Formula III is optionally filtered before combining it with hydroxylamine base or hydroxylamine HCl. A water scavenger is added to obtain the compound of formula VI. Febuxostat can then be prepared, for example, by combining the compound of formula VI with one organic solvent and an alkali metal hydroxide.
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- PROCESS FOR THE PREPARATION OF 2-[3-CYANO-4-(2-METHYLPROPOXY)PHENYL]-4-METHYLTHIAZOLE-5-CARBOXYLIC ACID AND ITS PHARMACEUTICALLY ACCEPTABLE SALTS
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The present invention relates to novel and improved processes for the preparation of 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid compound of formula-1 and its pharmaceutically acceptable salts thereof. the present invention also provides the novel process for the preparation of crystalline forms of 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid compound of formula-1 and its intermediates.
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- Nickel-catalyzed C-H arylation of azoles with haloarenes: Scope, mechanism, and applications to the synthesis of bioactive molecules
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Novel nickel-based catalytic systems for the C-H arylation of azoles with haloarenes and aryl triflates have been developed. We have established that Ni(OAc)2/bipy/LiOtBu serves as a general catalytic system for the coupling with aryl bromides and iodides as aryl electrophiles. For couplings with more challenging electrophiles, such as aryl chlorides and triflates, the Ni(OAc)2/dppf (dppf=1,1′-bis(diphenylphosphino)ferrocene) system was found to be effective. Thiazoles, benzothiazoles, oxazoles, benzoxazoles, and benzimidazoles can be used as the heteroarene coupling partner. Upon further investigation, we discovered a new protocol for the present coupling using Mg(OtBu)2 as a milder and less expensive alternative to LiOtBu. Attempts to reveal the mechanism of this nickel-catalyzed heterobiaryl coupling are also described. This newly developed methodology has been successfully applied to the syntheses of febuxostat (a xanthine oxidase inhibitor that is effective for the treatment of gout and hyperuricemia), tafamidis (effective for the treatment of TTR amyloid polyneuropathy), and texaline (a natural product having antitubercular activity). Copyright
- Yamamoto, Takuya,Muto, Kei,Komiyama, Masato,Canivet, Jerome,Yamaguchi, Junichiro,Itami, Kenichiro
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supporting information; experimental part
p. 10113 - 10122
(2011/10/08)
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- PROCESSES FOR THE PREPARATION OF FEBUXOSTAT AND SALTS THEREOF
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There is provided a process for preparing febuxostat of formula (I) or a pharmaceutically acceptable salt thereof, the process comprising: condensing a compound of formula (A) with a compound of formula (B) to form an ester of febuxostat; hydrolyzing the ester of febuxostat to febuxostat, and optionally converting the febuxostat to a pharmaceutically acceptable salt thereof, wherein: R' is an activating group selected from boronic acid or lithium; R is selected from optionally substituted C1-4 alkyl or optionally substituted aryl; L is a leaving group selected from diazo, halo, -OSO2R", -OCOR" or -O-Si(R")3; and R" is selected from optionally substituted C1-4 alkyl or optionally substituted aryl.
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Page/Page column 28
(2011/07/07)
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- PREPARATION OF FEBUXOSTAT
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Processes for preparing febuxostat.
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Page/Page column 17
(2011/11/30)
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- Nickel-catalyzed biaryl coupling of heteroarenes and aryl halides/triflates
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Ni-based catalytic systems for the arylation of heteroarenes with aryl halides and triflates have been established. Ni(OAc)2/bipy is a general catalyst for aryl bromides/iodides, and Ni(OAc)2/dppf is effective for aryl chlorides/triflates. Thiazole, benzothiazole, oxazole, benzoxazole, and benzimidazole are applicable as heteroarene coupling partners. A rapid synthesis of febuxostat, a drug for gout and hyperuricemia, is also demonstrated.
- Canivet, Jerome,Yamaguchi, Junichiro,Ban, Ikuya,Itami, Kenichiro
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supporting information; experimental part
p. 1733 - 1736
(2009/08/15)
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- 2-arylthiazole derivatives and pharmaceutical composition thereof
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Pharmaceutical compositions for treating gout or hyperuricemia and containing a new categorized compound, i.e. 2-arylthiazole derivatives, as an active ingredient, are provided. The 2-arylthiazole derivatives in the present invention are represented by the following formula (I): STR1 wherein Ar is an unsubstituted or substituted pyridyl, thienyl, furyl, naphthyl or phenyl group; X is a hydrogen atom, alkyl group or carboxyl group which may be protected, and Y is a hydrogen atom, alkyl group, or a hydroxyl or carbonyl group which may be protected. Furthermore, novel compounds included in the 2-arylthiazole derivatives and pharmaceutically acceptable salts thereof are provided.
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