摘要
目的研究奥美沙坦酯的新合成方法,并对合成中产生的主要杂质进行结构确证和有效控制。方法4-(1-羟基-1-甲基乙基)-2-丙基咪唑-5-羧酸乙酯水解,环合成4,4-二甲基-2-丙基-4,6-二氢呋喃并[3,4-d]咪唑-6-酮,与4-[2-(2-三苯甲基四唑-5-基)苯基]苄基溴缩合,经分离纯化,皂化成钠盐,与4-氯甲基-5-甲基-2-氧代-1,3-二氧杂环戊烯成酯,脱保护基得奥美沙坦酯。对缩合反应的主要杂质应用X-ray单晶衍射谱确证其结构为咪唑位置异构体,并用其合成奥美沙坦酯的咪唑位置异构体。通过优化反应条件抑制异构体的量,从而保证奥美沙坦酯的质量。结果用新路线合成了奥美沙坦酯,总收率60%,纯度大于99·0%;成品中异构体含量小于0·1%。结论本文合成路线是奥美沙坦酯的新合成方法,并首次报道奥美沙坦酯的咪唑位置异构体。
Aim To develop a new synthetic route for olmesartan medoxomil. Methods Olmesartan medoxomil was prepared from ethyl 4-（ 1-hydroxy-l-methylethyl ）-2-propylimidazole-5-carboxylate via hydrolysis and lactonization to afford 4,4- dimethyl-2-propyl-4,6-dihydrofuro [ 3,4-d]-1H-imidazole-6-one which was condensed with 2-（triphenylmethyl） -5-[ 4＇-（bromomethylbiphenyl） -2-yl ] tetrazole, followed by esterification with 4-chloromethyl-5-methyl-1,3-dioxol-2-one, and deprotection. The chemical structure of the major impurity in condensation reaction is the regio-isomer in the imidazole moiety, and confirmed by single crystal X-ray diffraction. The corresponding regio-isomer of olmesartan medoxomil was synthesized from the impurity by similar method. Optimization of the condensation conditions reduced the impurity to a negligible quantity. Results Synthesis of olmesartan medoxomil by the new route gave a product of 60% yield and above 99.0% purity. The content of olmesartan medoxomil regio-isomer was effectively controlled to less than 0. 1%. Conclusion A novel synthetic route for olmesartan medoxomil was developed successfully. The olmesartan medoxomil regio-isomer is reported for the first time.
出处
《药学学报》
CAS
CSCD
北大核心
2006年第6期537-543,共7页
Acta Pharmaceutica Sinica
关键词
奥美沙坦酯
合成
异构体
olmesartan medoxomil
synthesis
regio-isomer
