- Preparation method of Ataluren
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The invention discloses a preparation method of Ataluren. The preparation method comprises an addition step in which under an alkaline condition, 3-cyanobenzoate reacts with hydroxylamine hydrochloride by using a first mixed solvent to obtain an intermediate as shown in a formula III, a condensation step in which in a first organic solvent, a condensation reaction is conducted on the intermediate shown in the formula III and o-fluorobenzoic acid to obtain an intermediate shown in a formula IV, a cyclization step in which in a second organic solvent, catalyzing is conducted by using Lewis acid, and intramolecular dehydration is conducted on the intermediate in the formula IV to obtain an intermediate in a formula V, and an ester hydrolysis step in which under an alkaline condition, ester hydrolysis is conducted on the intermediate in the formula V by using a second mixed solvent to obtain the product. Cheap raw materials are subjected to addition, condensation, cyclization and ester hydrolysis, the reaction conditions are mild, the process is simple, the cost is low, and industrial production is facilitated. Meanwhile, the solvent in the reaction process can be basically recycled, the synthesis cost is low, and the reaction environment is good; in addition, the purification operation is simple, and the total yield and the product purity of the target compound Ataluren are high.
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- Method for preparing ataluren
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The invention discloses a method for preparing ataluren, (PTC124, a commodity name of ataluren) and belongs to the field of organic synthesis. The preparation method comprises the following steps: (1)reacting methyl m-cyanobenzoate with hydroxylamine hydrochloride in a lower alcohol or a mixed solvent of a lower alcohol and water to generate 3-(N-hydroxyamidino)-methyl benzoate; (2) carrying outO-acylation reaction between the 3-(N-hydroxyamidino)-methyl benzoate and o-fluorobenzoyl chloride in an organic solvent to obtain 3-((5-(2-fluorophenyl))-3-(1,2,4-oxadiazolyl)-methyl benzoate; (3) under the catalytic action of tetra-alkyl ammonium halide, carrying out cyclization to obtain 3-((5-(2-fluorophenyl))-3-(1,2,4-oxadiazolyl)-methyl benzoate; and (4) hydrolyzing to obtain ataluren. The synthesis method is a simple and efficient synthesis method of ataluren.
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- PROCESS FOR PREPARING ATALUREN AND ITS INTERMEDIATES
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The present invention provides processes for the preparation of ataluren. Intermediates for preparing ataluren are also provided.
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- Novel method for synthesizing Ataluren
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The invention discloses a novel method for synthesizing Ataluren. The method comprises the following steps that 1, a compound 2 reacts with hydroxylamine hydrochloride under the alkaline condition to obtain an intermediate 3; 2, in the presence of a reducing agent diethoxymethylsilane and bis(4-nitrobenzophenone)phosphate, a catalytic amount of triphenylphosphine and an equivalent amount of carbon tetrachloride and compound 4 react to obtain the target compound Ataluren (1). According to the method, the raw materials are easy to obtain, the synthesizing steps are brief, environmental friendliness is achieved, aftertreatment is convenient, and high industrial production value is achieved.
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Paragraph 0023; 0024
(2017/08/25)
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- Palladium-Catalyzed, Silver-Assisted Direct C-5–H Arylation of 3-Substituted 1,2,4-Oxadiazoles under Microwave Irradiation
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A direct C-5–H arylation of 3-substituted 1,2,4-oxadiazoles with aryl iodides in the presence of a palladium catalyst and silver acetate is reported. This method provides a rapid, reliable way to obtain versatile 3,5-diaryl-1,2,4-oxadiazole derivatives, which are common moieties of many biologically active molecules. The synthetic applications of this novel method have been demonstrated in the concise syntheses of Ataluren and a potent RET inhibitor Yhhu251. (Figure presented.).
- Li, Shan,Wan, Penghui,Ai, Jing,Sheng, Rong,Hu, Yongzhou,Hu, Youhong
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p. 772 - 778
(2017/03/11)
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- Oxdiazole compound solvate and preparation method thereof
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The present invention relates to the dimethyl sulfoxide solvate of 3-[5-(2-fluorophenyl)-[1,2,4]oxdiazole-3-yl]benzoic acid, wherein the dimethyl sulfoxide solvate has characteristics of good stability, high purity, excellent particle and excellent shape, and is suitable for pharmaceutical preparation applications. The present invention further relates to a preparation method of the dimethyl sulfoxide solvate, a pharmaceutical composition of the dimethyl sulfoxide solvate, and uses of the dimethyl sulfoxide solvate in preparation of drugs for treatment of genetic diseases.
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- Synthesis of benzoic acids containing a 1,2,4-oxadiazole ring
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A new approach to the synthesis of 4and 3-(5-R-1,2,4-oxadiazol-3-yl)benzoic acids via a selective oxidation of 5-R-3-tolyl-1,2,4-oxadiazoles with air oxygen in the presence of a catalytic system based on cobalt acetate was suggested. This synthesis allowed us to obtain the products in higher yields and with shorter sequence of steps as compared to the known procedures.
- Krasouskaya,Danilova,Baikov,Kolobov,Kofanov
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p. 142 - 145
(2015/10/05)
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- A metal-free tandem approach to prepare structurally diverse N-heterocycles: Synthesis of 1,2,4-oxadiazoles and pyrimidinones
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A metal-free one-pot approach to the diversity oriented synthesis of N-heterocycles, 1,2,4-oxadiazoles and 2,6 disubstituted pyrimidin-4-ones is described via carboxamidation of amidines with aryl carboxylic acids and aryl propargylic acids. The reactions occur at room temperature forming N-acylamidines which undergo tandem nucleophilic addition-deamination- intramolecular cyclisation to give the corresponding heterocyclic compounds in good to excellent yields. This one pot approach has led to the successful synthesis of the drug lead molecule, ataluren, 3-(5-(2-fluorophenyl)-1,2,4- oxadiazol-3-yl) benzoic acid in two steps. the Partner Organisations 2014.
- Gupta, Puneet K.,Hussain, Mohd. Kamil,Asad, Mohd.,Kant, Ruchir,Mahar, Rohit,Shukla, Sanjeev K.,Hajela, Kanchan
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p. 3062 - 3070
(2014/07/07)
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- Bis-aryloxadiazoles as effective activators of the aryl hydrocarbon receptor
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Bis-aryloxadiazoles are common scaffolds in medicinal chemistry due to their wide range of biological activities. Previously, we identified a 1,2,4-bis-aryloxadiazole that blocks mammary branching morphogenesis through activation of the aryl hydrocarbon receptor (AHR). In addition to defects in mammary differentiation, AHR stimulation induces toxicity in many other tissues. We performed a structure activity relationship (SAR) study of 1,2,4-bis-aryloxadiazole to determine which moieties of the molecule are critical for AHR activation. We validated our results with a functional biological assay, using desmosome formation during mammary morphogenesis to indicate AHR activity. These findings will aid the design of oxadiazole derivative therapeutics with reduced off-target toxicity profiles.
- Basham, Kaitlin J.,Bhonde, Vasudev R.,Kieffer, Collin,Mack, James B.C.,Hess, Matthew,Welm, Bryan E.,Looper, Ryan E.
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p. 2473 - 2476
(2014/05/20)
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- METHODS FOR DOSING AN ORALLY ACTIVE 1,2,4-OXADIAZOLE FOR NONSENSE MUTATION SUPPRESSION THERAPY
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The present invention relates to specific doses of and dosing regimens for using a 1,2,4-oxadiazole benzoic acid compound in treating or preventing diseases associated with nonsense mutations. In particular, the invention relates to specific doses and dosing regimens for the use of 3-[5-(2-fluoro-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid in mammals having diseases associated with nonsense mutations.
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Page/Page column 25-26
(2008/06/13)
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- PROCESSES FOR THE PREPARATION OF 1,2,4-OXADIAZOLE BENZOIC ACIDS
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Provided herein are processes for the preparation of compounds useful for the treatment, prevention or management of diseases associated with a nonsense mutation. More specifically, provided herein are processes for the synthesis of 1,2,4-oxadiazoles. In particular, provided herein are processes useful for the preparation of 3-[5-(2-fluorophenyl)- [1,2,4]oxadiazol-3-yl]-benzoic acid.
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Page/Page column 20-21
(2008/06/13)
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- METHODS FOR THE PRODUCTION OF FUNCTIONAL PROTEIN FROM DNA HAVING A NONSENSE MUTATION AND THE TREATMENT OF DISORDERS ASSOCIATED THEREWITH
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The present invention relates to functional proteins encoded by nucleic acid sequences comprising a nonsense mutation. The present invention also relates to methods for the production of functional proteins encoded by nucleic acid sequences comprising a nonsense mutation and the use of such proteins for prevention, management and/or treatment of diseases associated with a nonsense mutation(s) in a gene.
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Page/Page column 261
(2008/06/13)
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- COMPOSITIONS OF AN ORALLY ACTIVE 1,2,4-OXADIAZOLE FOR NONSENSE MUTATION SUPPRESSION THERAPY
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The present invention relates to specific doses of and dosing regimens for using a 1,2,4-oxadiazole benzoic acid compound in treating or preventing diseases associated with nonsense mutations. In particular, the invention relates to specific doses and dosing regimens for the use of 3-[5-(2-fluoro-phenyl)-[l,2,4]oxadiazol-3-yl]-benzoic acid in mammals having diseases associated with nonsense mutations.
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- 1,2,4-oxadiazole benzoic acid compounds and their use for nonsense suppression and the treatment of disease
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Novel 1,2,4-oxadiazole benzoic acid compounds, methods of using and pharmaceutical compositions comprising an 1,2,4-oxadiazole benzoic acid derivative are disclosed. The methods include methods of treating or preventing a disease ameliorated by modulation of premature translation termination or nonsense-mediated mRNA decay, or ameliorating one or more symptoms associated therewith.
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