Suzuki-Miyaura偶联反应在沙丁胺醇合成中的应用

Synthesis of salbutamol via Suzuki-Miyaura coupling reaction

摘要:

以5-溴水杨醛为起始原料，经还原、苄基保护、Suzuki-Miyaura偶联、双键加成、亲核取代、钯碳还原等反应合成了沙丁胺醇，反应总收率为56.0%（以5-溴水杨醛计）。并对关键的Suzuki-Miyaura偶联反应条件进行了优化，获得最优的反应条件为：n(中间体II)：n(乙烯基三氟硼酸钾)：n(氯化钯)：n(三苯基膦)：n(碳酸铯)=1:1.2:0.02:0.06:2，在四氢呋喃/水（体积比 9:1，0.5 mol/L，以中间体II物质的量计）混合溶剂中回流反应12h。中间体产物的结构经高分辨质谱（HRMS）、1HNMR以及13CNMR进行了确证。该法反应条件温和、操作简单、可控性强、无需柱层析分离，适合沙丁胺醇的放大制备，具有工业化应用价值。

Abstract:

Sulbutamol was synthesized from 5-bromosalicylaldehyde via reduction, benzyl protection, Suzuki-Miyaura coupling reaction, addition of double bond, nucleophilic substitution, Pd/C reduction. The total yield was 56.0% (based on 5-bromosalicylaldehyde). The optimistic condition of Suzuki-Miyaura coupling reaction was established. The optimum reaction conditions were obtained as follows: n(intermediate II) : n(potassium vinyltrifluoroaborate) : n(palladium chloride) : n(triphenylphosphine) : n(cesium carbonate) = 1:1.2:0.02:0.06:2. The reaction was refluxed in tetrahydrofuran / water (volume ratio 9:1, 0.5 mol / L, based on the amount of intermediate II substance) mixed solvent for 12 hours. The structure of salbutamol and the important intermediates were confirmed by HRMS, 1H NMR and 13C NMR. The synthetic route here is suitable for the amplification and preparation of salbutamol and has the value of industrial application because of the mild reaction condition, easy control as well as simple equipment and operation without purification by column chromatography.