氯-IB-MECA合成的研究进展

Research Progress in Synthesis of 2-Cl-IB-MECA

2-氯-N6-(3-碘苄基)腺苷-5'-N-甲基尿嘧啶(氯-IB-MECA)是由Can-Fite公司开发的具有选择性的A_(3)腺苷受体激动剂,可同时治疗非酒精性脂肪性肝病、非酒精性脂肪性肝炎和肝细胞癌,具有广阔的市场前景。根据起始原料的不同对氯-IB-MECA合成方法进行了系统讨论。方法1以1-O-甲基-β-D-呋喃核糖苷为起始原料,经选择性羟基保护、氧化反应、酯化反应、酰胺化、酸化及脱保护得到氯-IB-MECA。方法2以2-乙酰氧基-5-((苯甲酰氧基)甲基)四氢呋喃-3,4-二基二苯甲酸酯为原料,经Vorbruggen糖苷化反应、亲核取代反应、保护基交换、氧化反应、羧酸酰胺化得到氯-IB-MECA。方法3以四乙酰核糖为原料,经亲核取代反应、脱乙酰基、邻二羟基保护、伯醇氧化、羧酸酰胺化和水解反应得到氯-IB-MECA。方法4以β-D-呋喃呋喃糖醛酸甲酯三乙酸酯为原料,经亲核取代、酯基酰胺化和脱乙酰基后得到氯-IB-MECA。经过比较认为,方法4原料易得,合成步骤少,反应和分离条件温和,收率高,更适合氯-IB-MECA的工业化生产。

2-Chloro-N6-(3-iodobenzyl)adenosine-5'-N-methyluracil(2-Cl-IB-MECA)is a selective A3 adenosine receptor agonist developed by Can-Fite company,which can simultaneously treat non-alcoholic fatty liver disease,non-alcoholic steatohepatitis,and hepatocellular carcinoma,and has broad market prospects.The synthesis methods of 2-Cl-IB-MECA are systematically discussed based on different starting materials.Method 1 uses methylβ-D-ribofuranoside as a starting material to obtain 2-Cl-IB-MECA by selective hydroxyl protection,oxidation,esterification,amidation,acidification,nucleophilic substitution and deprotection.Method 2 uses 2-acetoxy-5-((benzoyloxy)methyl)tetrahydrofuran-3,4-diyldibenzoate as a starting material to form 2-Cl-IB-MECA through Vorbruggen glycosylation reaction,nucleophilic substitution,protective group exchange,oxidation reaction,and amidation of carboxylic acid.Method 3 employs tetraacetylribose as a starting material,through nucleophilic substitution,deacetylation,1,2-dihydroxy protection,oxidation of primary alcohol,amidation of carboxylic acid,and hydrolysis to produce 2-Cl-IB-MECA.Method 4 employsβ-D-ribofuranuronic acid methyl ester triacetate as a starting material,through nucleophilic substitution,amidation of ester,and deacetylation to generate 2-Cl-IB-MECA.After comparison,method 4 is considered to be more suitable for industrial production of 2-Cl-IB-MECA due to the easy availability of starting materials,fewer synthetic steps,mild reaction and separation conditions and high yield.