氟雷拉纳合成工艺研究

Study on the Synthesis Process of Fluralaner

为了研究氟雷拉纳适合于工业化生产的合成方法,以2-氟甲苯为起始原料,经乙酰氯酰化,氰化钠氰基取代和硫酸水解得到4-乙酰基-2-甲基苯甲酸,然后在三乙胺的作用下,与3',5'-二氯-2,2,2-三氟苯乙酮经缩合,脱水,环化得到中间体4-(5-(3,5-二氯苯基)5-三氟甲基-4,5-二氢异噁唑-3-基)-2-甲基苯甲酸;以甘氨酸为原料,在碱NaOH作用下,与二碳酸二叔丁酯反应生成2-(叔丁氧基羰基氨基)乙酸,然后在N,N-羰基二咪唑和4-二甲胺吡啶的催化下,与三氟乙胺反应,随后通入干燥盐酸气体,得到中间体2-氨基-N-(2,2,2-三氟乙基)乙酰胺盐酸盐;最后两中间体经酰胺化反应合成目标产物氟雷拉纳,产率达86.7%。该合成工艺原料易得,价格便宜,目标产物的产率高,适用于氟雷拉钠工业化合成。

A synthetic method suitable for industrial fluralaner was studied.4-acetyl-2-methylbenzoic acid was prepared by using 2-fluorotoluene as the starting material through these reations of acetylation,cyano substitution and hydrolysis,then under the action of triethylamine,4-acetyl-2-methylbenzoic acid condensed with 3',5'-dichloro-2,2,2-trifluoroaceto-phenone,following being dehydrated,and cyclized to give the intermediate 4-(5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl)-2-methylbenzoic acid.In the present of NaOH,glycine reacted with di-tert-butyl dicarbonate to give the 2-(tert-butoxycarbonylamino)acetic acid,then under the catalysis of N,N-carbonyldiimidazole and 4-dimethyla-minopyridine,2-(tert-butoxycarbonylamino)acetic acid,reacted with trifluoroethylamine and hydrogen chloride to give the 2-amino-N-(2,2,2-trifluoroethyl)acetamide hydrochloride.Finally,fluralaner was prepared by the reaction of 4-(5-(3,5-dichlo-rophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl)-2-methylbenzoic acid with 2-amino-N-(2,2,2-trifluoroethyl)acetamide hydrochloride.The content of products was 86.7%.The process technology was suitable for industrial fluralaner with readily available,inexpensive material and high content of products.