摘要
6-氟-3,4-二氢-2H-1-苯并吡喃-2-甲酸是制备新型抗高血压药奈必洛尔的关键中间体。今以4-氟苯酚为起始原料,经酯化、Fries重排、环化、氢化等6个步骤得到目标产物,总收率27%。4-氟苯酚Ⅰ与乙酸酐酯化得4-氟苯基乙酸酯Ⅱ,Ⅱ在AlCl_3催化下Fries重排得4-氟-2-乙酰基苯酚Ⅲ,比从4-氟苯酚的Friedel-Crafts酰化收率更高,二步总收率58%;Ⅲ与酰化试剂乙二酸二乙酯经酯化、环合及碱性水解得到6-氟-4-氧代-4H-1-苯并吡喃-2-甲酸VI,用一种试剂完成了酰化、环化并引入羧基;Ⅵ在乙酸介质中,以10%Pd/C催化加氢得外消旋6-氟-3,4-二氢-2H-1-苯并吡喃-2-甲酸Ⅶ。以上所述的方法具有条件温和、试剂常见易得、易于工业化的优点,并首次给出了关键中间体及目标产物的光谱图,表明产物结构正确。
6-Fluro-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid is the key intermediate of Nebivolol, a new antihypertensive agent. The process for the synthesis of its racemics was studied, which involves 6 steps including esterification, rearrangment, acylation, cyclization, hydrolyzation and hydrogenation with an overall yield of 27%. 4-Fluorophenol （Ⅰ） is firstly esterified with acetic anhydride to give 4-fluorophenyl acetate （Ⅱ）, which is rearranged in the presence of anhydrous AICI3 to afford 4-fluoro-2-acetyl phenol （Ⅲ） with a higher yield（58%） than that obtained by direct acylation of 4-fiuorophenol. Ⅲis transformed into 6-fiuoro-4-oxo-4H-1-benzopyran-2-car -boxylic acid （Ⅵ） by treatment with diethyloxalate via acylation,cyclization and hydrolyzation, that is to say, the above three reactions finished by using a single agent. The title product, 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid（Ⅶ） was finally obtained from the reduction of VI by hydrogen with 10% Pd/C as catalyst in acetic acid. The process proposed has the potential perspective to be industrialized due to the mild conditions and readily available agents. The spectra of IR and ^1H-NMR of the title compound and its key intermediate were reported to identify the structure of the product.
出处
《高校化学工程学报》
EI
CAS
CSCD
北大核心
2007年第3期442-447,共6页
Journal of Chemical Engineering of Chinese Universities
