抗高血压药物阿利克仑的合成研究

Study on the synthesis of antihypertensive drug aliskiren

目的研究抗高血压药阿利克仑的化学合成方法。方法以光学纯中间体(3S5,S,1'S3,'S)-5-(1'-叠氮基-3'-羟甲基-4'-甲基戊基)-3-异丙基二氢呋喃-2-酮为起始原料,经氧化、亲核加成、氢化、Boc保护、氨解、脱保护等反应得到阿利克仑游离碱。结果与结论以总收率35.7%合成阿利克仑。该合成路线反应步骤少,操作简便,收率高,反应条件温和,适合工业化生产。

Aliskiren was an orally active non-peptide renin inhibitors in renin angiotensin aldosterone system（RAS）.It was the first one with new pharmacological mechanism in the field of hypertension treatment.The synthesis of aliskiren has been accomplished through 5 steps from（3S,5S,1′S,3′S）-5-（1′-azido-3′-hydroxymethyl-4′-methylpentyl）-3-isopropyl-dihydrofuran-2-one,which was efficiently transformed into 3（S）-isopropyl-5（S）-[1（S）-azido-3（S）-isopropyl-4-oxobutyl]-tetrahydrofuran-2-one（2） by NaClO/TEMPO catalyzed oxidation.Nucleophilic addition of aldehyde 2 with 4-methoxy-3-（3-methoxy-propyloxy）-bromobenzene afforded the desired unseparable diastereomers product 3 with the treatment of n-BuLi at-78 ℃ in 70% yield.Compound 3 was then allowed to hydrogenolysis and amino protection to provide the key intermediate lactone 4,which was followed by aminolysis and deprotection.The target compound aliskiren was achieved in 35.7% overall yield.In this improved process,the aldehyde 2 was easily prepared by oxidation of the corresponding alcohol catalyzed by NaClO-TEMPO in 92% yield.While it was obtained from the corresponding acid chloride by DIBAL-H reduction with very low temperature and strict reaction conditions,and low yield.The structure of the intermediates and the target compound were confirmed by 1H-NMR and IR analysis and are in good agreement with those reported.The developed method has some advantages such as simple starting materials,mild reaction conditions,ease operations and high yield.