- Synthesis, structural elucidation and larvicidal activity of novel arylhydrazones
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The present study focuses on a series of novel hydrazones of 2- [3-cyano-4-(2-methylpropoxy)phenyl]-4-methyl-1,3-thiazole-5-carbohydrazide (5a-l) for their larvicidal activity against Anopheles arabiensis. The synthesis of the title compounds was achieved by the conventional reflux method, and structures of the novel compounds were ascertained by FT-IR, NMR (1H &13C), LC-MS, and elemental analysis. Compound (5l) was studied by single crystal X-ray diffraction for intra and intermolecular interactions. Title compounds (E)-2-(3-cyano-4-isobutoxyphenyl)-N'-(4-fluoro-3-phenoxybenzylidene)-4-methylthiazole-5-carbohydrazide (5a) and (E)-N'-(4-Chlorobenzylidene)-2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carbohydrazide (5g) emerged as promising larvicidal agents against Anopheles arabiensis.
- P, Nefisath,Dasappa, Jagadeesh Prasad,B, Haripriya,Chopra, Deepak,Venugopala, Katharigatta N.,Deb, Pran Kishore,Gleiser, Raquel M.,Mohanlall, Viresh,Maharaj, Rajendra,Shashiprabha,Poojary, Vishwanatha
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Read Online
- Febuxostat-based amides and some derived heterocycles targeting xanthine oxidase and COX inhibition. Synthesis, in vitro and in vivo biological evaluation, molecular modeling and in silico ADMET studies
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Various febuxostat derivatives comprising carboxamide functionalities and different substituted heterocycles were synthesized and evaluated for their biological activities as xanthine oxidase (XO) and cyclooxygenase (COX) inhibitors. All the tested compounds exhibited variable in vitro XO inhibitory activities (IC50 values 0.009–0.077 μM), among which the analog 17 has emerged as the most potent derivative (IC50 0.009 μM), representing nearly 3-times the potency of febuxostat (IC50 0.026 μM). The same analogs were further investigated for their in vitro COX-1 and COX-2 inhibitory activity, where fifteen analogs demonstrated recognizable COX-2 inhibitory potential (IC50 values range 0.04 – 0.1 μM), when correlated with celecoxib (IC50 0.05 μM), together with appreciable selectivity indices. Compounds 5a, 14b, 17, 19c, 19e and 21b that showed significant in vitro XO and/ or COX inhibitory potentials were further investigated for their in vivo hypouricemic as well as anti-inflammatory activities. Interestingly, the in vivo results were concordant with the collected in vitro data. Docking of compounds 5a, 14b, 17, 19c, 19e and 21b with the active sites of XO and COX-2 isozymes demonstrated superior binding profile compared with the reported ligands (febuxostat and celecoxib, respectively). Their docking scores were reasonable and cohering to a great extent with their corresponding in vitro IC50 values. Moreover, in silico computation of the predicted pharmacokinetic and toxicity properties (ADMET), together with the ligand efficiency (LE) of the same six compounds suggesting their liability to act as new orally active drug candidates with a predicted high safety profile.
- Rashad, Aya Y.,Kassab, Shaymaa E.,Daabees, Hoda G.,Abdel Moneim, Ahmed E.,Rostom, Sherif A.F.
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Read Online
- Pd/Cu-Catalyzed C-H/C-H Cross Coupling of (Hetero)Arenes with Azoles through Arylsulfonium Intermediates
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A highly efficient method for the selective formal C-H/C-H cross-coupling of azoles and (hetero)arenes was established through arylsulfonium intermediates under transition-metal catalysis, which produced a variety of 2-(hetero)aryl azoles in good to excellent yields. Advantages of the reaction included mildness, a good functional group tolerance, a wide range of substrates, a high regio- and chemoselectivity, one-pot procedures, and the late-stage functionalization of complex molecules without the use of oxidants, offering a promising strategy for the transition-metal-catalyzed C-H arylation of azoles.
- Lin, Zeng-Hui,Tian, Ze-Yu,Zhang, Cheng-Pan
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supporting information
p. 4400 - 4405
(2021/06/27)
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- 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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- 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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p. 619 - 626
(2020/02/06)
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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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- Improved method for synthesizing febuxostat key intermediate
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The invention relates to an improved cyanation reaction method for synthesizing febuxostat. According to the method, the feeding ratio of a compound II to hydroxylamine hydrochloride to sodium formateis 1:1.3:1.3, the amount of formic acid is 8-15 times by volume, the reaction temperature is 90-130 DEG C, the reaction time is 4-10 hours, after the reaction is finished, the temperature is reducedto 40-80 DEG C, an aftertreatment solvent is dropwise added into reaction liquid, after dropwise adding is finished, the temperature is reduced to 10-35 DEG C, fand iltering and drying are performed,so that an intermediate compound (III) with less than 0.10% of related substances.
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Paragraph 0022-0023
(2021/01/15)
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- 'One pot method' synthesis method for Febuxostat intermediate
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The invention belongs to the field of medicine synthesis and in particular relates to a 'one pot method' synthesis method for a Febuxostat intermediate 2-(3-cyan-4-isobutoxy phenyl)-4-methyl thiazole-5-ethyl formate. The method comprises the following steps: by taking 2-(4-hydroxy phenyl)-4-methyl thiazole-5-ethyl formate as an initial raw material, carrying out an etherification reaction on the compound with bromo-iso-butane under catalysis of an alkali, and carrying out solid-liquid separation so as to obtain filtrate; dropping phosphorus oxychloride into the filtrate, carrying out a stirring reaction, continuously stirring with ammonia water and elementary iodine, carrying out a quenching reaction after the reaction is completed, and carrying out extraction and organic phase concentration, thereby obtaining the Febuxostat intermediate. By adopting the method provided by the invention, the key intermediate of Febuxostat can be synthesized through serial operation of a one-pot method,purity requirements can be met without multiple times of purification in the process, in addition, a good yield is achieved, and the method is applicable to industrial large-scale production.
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Paragraph 0046; 0047; 0048; 0049; 0050; 0051; 0052-0055
(2019/04/04)
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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; 0048-0049; 0052; 0058-0059; 0062; 0068
(2019/02/13)
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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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- 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 0030-0070; 0074-0081
(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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- 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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- 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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- 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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Paragraph 0016; 0054
(2017/01/17)
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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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Page/Page column 15
(2015/02/25)
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- PROCESS TO PREPARE ETHYL 4-METHYL-2-(4-(2-METHYLPROPYLOXY)-3-CYANOPHENYL)-5-THIAZOLECARBOXYLATE
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Disclosed is a process for the preparation of Ethyl 4-methyl-2-(4-(2-methylpropyloxy)-3-cyanophenyl)-5-thiazolecarboxylate (I) the key intermediate for the preparation of [2-[3-cyano-4-(2-Methyl-propoxy)phenyl]-4-methyl-5-thiazole carboxylic acid (Febuxostat, I(A)) is approved under the trademark Uloric? by the US Food and Drug Administration for the treatment of hyperuricemia and gouty arthritis.
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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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Paragraph 0042
(2013/11/19)
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- METHOD FOR PRODUCING PHENYL-SUBSTITUTED HETEROCYCLIC DERIVATIVE BY MEANS OF COUPLING METHOD USING PALLADIUM COMPOUND
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The present invention provides a method for producing a xanthine oxidase inhibitor, which is a therapeutic agent for hyperuricemia, or intermediates of the same, said method being efficient and using a short process. The present invention is a novel coupling method for obtaining a compound represented by formula (3) by bringing about a coupling reaction between a compound represented by formula (1) and a compound represented by formula (2), in the presence of a palladium compound, a ligand capable of coordinating to the palladium compound, a base, a C1-C40 carboxylic acid, and at least one kind of additive.
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Paragraph 0316; 0317; 0318
(2013/06/28)
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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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Page/Page column 8
(2012/06/01)
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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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- 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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- 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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- PREPARATION OF FEBUXOSTAT
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Processes for preparing febuxostat.
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Page/Page column 14
(2011/11/30)
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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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Page/Page column 42-43
(2011/12/02)
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- PROCESS FOR PRODUCING PHENYL-SUBSTITUTED HETEROCYCLIC DERIVATIVE THROUGH COUPLING USING TRANSITION METAL CATALYST
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A process for efficiently producing, through few steps either a xanthine oxidase inhibitor, which is a therapeutic agent for hyperuricemia, or an intermediate therefore. The process is a novel coupling process which comprises subjecting a compound represented by formula (1) to coupling reaction with a compound represented by formula (2) in the presence of a transition metal compound to thereby obtain a compound represented by formula (3).
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Page/Page column 24
(2012/01/13)
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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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- 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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- A PROCESS FOR THE PREPARATION OF FEBUXOSTAT
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The present invention relates to a process for the preparation of Febuxostat, useful in the pharmaceutical field for the treatment of the hyperuricemia.
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Page/Page column 17-18
(2010/12/29)
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- 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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p. 857 - 864
(2007/10/03)
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