摘要
设计合成非肽类血管紧张素Ⅱ受体阻滞剂洛沙坦及其活性代谢物5-羧酸洛沙坦的药物标准品———含4个氘原子标记的洛沙坦和5-羧酸洛沙坦。以氘标记对溴甲苯(1)为起始原料,与4',4-二甲基-2-(2'-甲氧基苯基)唑(2)发生格氏反应引入氘原子,再经氧化、取代反应得4个氘原子标记的中间体5,中间体5与2-正丁基-4-氯-5-甲酰基咪唑(6)发生缩合反应得中间体(7),中间体7经叠氮化钠作用得氘标记洛沙坦(10);四丁基溴化铵(8)与高锰酸钾反应可制得氧化剂高锰酸四丁基铵(9),化合物10经氧化剂(9)氧化得到氘标记5-羧酸洛沙坦(11)。目标化合物10和11的总产率分别为15.4%和8.2%,纯度经HPLC测定分别为99.4%和96.4%,通过1H NMR、MS可测得其同位素丰度分别为98.4%和98.3%。
Losartan is a nonpeptide angiotensin II receptor antagonist undergoing substantial first-pass metabolism by cytochrome P450 enzymes,and it is converted,in part,to an active carboxylic acid metabolite-losartan 5-carboxylic acid.The synthesis of four-deuterium-labeled losartan and losartan 5-carboxylic acid were described.Four-deuterium-labeled 4-bromotoluene was chosen as the starting material.After Grignard reaction,oxidation,and substitution,intermediate（5）was obtained.Another key intermediate（7）was synthesized by condensation of intermediate（5）with 2-n-butyl-4-chloro-5-formylimidazole（6）.After compound（7）was reacted with sodium azide in reflux in toluene,the target compound（10）was obtained.Oxidant（9）was synthesized via reaction of tetrabutyl ammonium bromide（8）treated with potassium permanganate.Deuterium labeled losartan was converted to deuterium labeled losartan 5-carboxylic acid using oxidant（9）.The total yield of deuterium labeled losartan was 15.4% with 99.4% chemical purity and 98.4% isotopic enrichment.The total yield of deuterium labeled losartan 5-carboxylic acid was 8.2% with 96.4% chemical purity and 98.3% isotopic enrichment.The structures of the target compounds were confirmed by 1H NMR and high-resolution MS.They are used as excellent internal standards for the pharmaceutical studies of losartan and losartan 5-carboxylic acid.
出处
《中国药科大学学报》
CAS
CSCD
北大核心
2012年第6期497-501,共5页
Journal of China Pharmaceutical University
关键词
氘标记
洛沙坦
5-羧酸洛沙坦
高同位素丰度
合成
deuterium labeled
losartan
losartan 5-carboxylic acid
improved isotopic enrichment
synthesis
