144060-53-7

Usage

Uses

Used in Pharmaceutical Industry:
Febuxostat is used as an antihyperuricemic agent for the treatment of hyperuricemia and chronic gout. It effectively lowers serum urate levels when administered at a dosage of 40-120 mg/day, managing hyperuricemia in patients with gout.
Used in Gout Management:
Febuxostat is used as a xanthine oxidase/xanthine dehydrogenase inhibitor for the chronic management of hyperuricemia in patients with gout. It helps in reducing serum uric acid concentrations below saturation levels, leading to crystal dissolution and eventual disappearance.
Used in Hyperlipidemia Treatment:
Febuxostat is also used as an antihyperlipidemic agent, contributing to the management of hyperlipidemia in patients.
Chemical Properties:
Febuxostat is a crystalline solid with the brand names Uloric and Adenuric.

Indications and Usage

Febuxostat is a new generation xanthine oxidase inhibitor developed by Tejin Co. (Japan,) used clinically for for long-term treatment of hyperuicemia (gout,) a new and highly effective non-purine selective inhibitor of xanthine oxidase. It is not recommended for gout patients without hyperuricemia.

Mechanisms of Action

The production of uric acid in the body is related to purine metabolism. In the last step of the production, hypoxanthine produces xanthine through the action of xanthine oxidoreductase (XOR), finally producing uric acid. Inhibiting the activity of this enzyme can effectively reduce the production of uric acid. Xanthine oxidase is the main enzyme promoting uric acid production. Through highly selective inhibition of oxidized and reduced xanthine oxidase, Febuxostat can reduce synthesis of uric acid, decreasing its concentration and effectively treating gout . Through liver metabolism, Xanthine oxidase does not rely on renal excretion, so patients with moderate to severe liver and kidney dysfunction do not need to reduce dosages. Febuxostat is a non-purine XOR inhibitor, so it is very safe.

Originator

Teijin (Japan)

Biochem/physiol Actions

Febuxostat is a potent non-purine xanithine oxidase inhibitor. Febuxostat is used in urate lowering therapies (ULTs) for the treatment of gout.

Clinical Use

Fabuxostat was discovered by Teijin Pharmaceuticals and licensed to TAP Pharmaceuticals (which is currently part of Takeda Pharmaceuticals) and was approved in the U.S. for the treatment of hyperuricemia in patients with gout. It is a once-daily non-purine based agent with potent inhibitory activity against xanthine oxidase. The safety profile of the drug also does not require dose adjustment for patients with mild to moderate renal or hepatic impairment. Febuxostat is the first new agent cleared for this indication in 40 years.

Synthesis

There are a number of routes available to prepare this agent as discussed in recent publications. The synthesis shown in Scheme 10 is a short and concise route and does not require the use of toxic reagents. Thus the commercially available and easily prepared 4-hydroxythiobenzamide (52) was reacted with ethyl bromoacetoacetate (53) in refluxing ethanol to provide the thiazole ester 54 in ≈60% yield after crystallization. The phenolic ester 54 was then treated with hexamethylenetetramine (HMTA) in polyphosphoric acid at 80 °C to provide the crude aldehyde 55 (74% conversion by HPLC). Reaction of phenol 55 and isobutyl bromide (56) in the presence of potassium carbonate with catalytic potassium iodide in DMF gave isobutyl ether 57 (64%, two steps). This ether was then converted in one pot to nitrile 58 in 93% by reacting the aldehyde with hydroxylamine hydrochloride and sodium formate in refluxing formic acid. Saponification of the ester 58 with aqueous sodium hydroxide provided fabuxostat (X).

Drug interactions

Potentially hazardous interactions with other drugs Azathioprine: avoid concomitant use, increased risk of neutropenia. Cytotoxics: avoid concomitant use with mercaptopurine. Theophylline: use with caution

Metabolism

Extensively metabolised by conjugation via the uridine diphosphate glucuronosyltransferase (UDPGT) enzyme system, and by oxidation via the cytochrome P450 isoenzyme system to form active metabolites. About 49% of a dose is excreted via the urine, and 45% via the faeces (12% as unchanged drug)

InChI:InChI=1/C16H16N2O3S/c1-9(2)8-21-13-5-4-11(6-12(13)7-17)15-18-10(3)14(22-15)16(19)20/h4-6,9H,8H2,1-3H3,(H,19,20)

Upstream product

• 1139901-88-4 tert-butyl 2-(3’-cyano-4’-isobutoxyphenyl)-4-methylthiazole-5-carboxylate 
• 208665-95-6 3-bromo-4-isobutoxybenzonitrile 
• 161798-03-4 2-(3-formyl-4-isobutyloxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester 
• 1271738-74-9 ethyl 2-[3-((hydroxyimino)methyl)-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylate 
• 1350352-70-3 2-[3-((hydroxyimino)methyl)-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid 
• 144649-99-0 5-bromo-2-methoxybenzonitrile 
• 40530-18-5 5-bromo-2-hydroxybenzonitrile 
• 14804-31-0 2-methyl-4-bromoanisole 
• 184970-28-3 4-bromo-2-(bromomethyl)-1-methoxybenzene 
• 40003-41-6 2-bromo-4-methyl-thiazole-5-carboxylic acid 
• 876918-32-0 (3-cyano-4-isobutoxyphenyl)boronic acid 
• 1429526-33-9 2-bromo-4-methylthiazole-5-carboxylic acid t-butyldimethylsilyl ester 
• 30752-23-9 4-bromophenyl iso-butyl ether 
• 1304385-08-7 4-iodophenyl isobutyl ether 

Downstream Products

• 923942-36-3 iso-butyl ester of febuxostat 

Relevant academic research and scientific papers

A facile one-pot synthesis of 4-alkoxy-1,3-benzenedicarbonitrile

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.

Synthesis, molecular docking, DFT study of novel N-benzyl-2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxamide derivatives and their antibacterial activity

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.

Method for continuously preparing febuxostat

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.

New preparation method of febuxostat intermediate

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.

Method for synthesizing febuxostat and intermediate thereof

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.

Febuxostat and intermediates and synthesis thereof

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.

A method for preparing [...]

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.

Preparation method of Febuxostat A crystal form

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

High purity febuxostat preparation method

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.

Preparation method of Febuxostat

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.