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【结 构 式】 
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【药物名称】 【化学名称】5-(3',5'-Di-tert-butyl-2'-propoxybiphenyl-2-yl)-3-methyl-2,4-pentadienoic acid sodium salt 【CA登记号】331248-51-2 (free acid) 【 分 子 式 】C29H37NaO3 【 分 子 量 】456.60624 |
【开发单位】Ligand (Originator), Lilly (Originator) 【药理作用】Antidiabetic Drugs, ENDOCRINE DRUGS, Type 2 Diabetes Mellitus, Agents for, ABCA1 Expression Enhancers, Retinoid RXRalpha Ligands |
合成路线1
Alkylation of 2,4-di-tert-butyl-6-iodophenol (I) with bromopropane by means of NaH (1) or CsF (2) provides the corresponding propyl ether (II). Subsequent Suzuki coupling of aryl iodide (II) with 2-formylbenzeneboronic acid (III) leads to the biphenyl aldehyde (IV). This is then condensed with phosphonate (V) producing the dienoate ester (VI). Finally, the ethyl ester group of (VI) is hydrolyzed with LiOH to the target carboxylic acid (1,2).
| 【1】 Chen, J-H.; Michellys, P-Y.; Ardecky, R.J.; Tyhonas, J.S.; Leibowitz, M.D.; Liu, S.; Rungta, D.; D'Arrigo, J.; Mais, D.E.; Miller, A.; Grese, T.A.; Mapes, C.M.; Thompson, A.W.; Boehm, M.F.; Ogilvie, K.M.; Karanewsky, D.S.; RXR modulators. Design and synthesis of new RXR-selective phenyl- and pyridine-locked dienoic acids for the treatment of type 2 diabetes. 225th ACS Natl Meet (March 23 2003, New Orleans) 2003, Abst MEDI 262. |
| 【2】 Jones, T.K.; Ardecky, R.J.; Boehm, M.F.; Hamann, L.G.; Thompson, A.J.; Michellys, P.-Y.; Tyhonas, J.S.; Faulkner, A.L.; Mapes, C.M.; Chen, J.-H. (Ligand Pharmaceuticals, Inc.); RXR modulators with improved pharmacologic profile. EP 1216221; WO 0119770 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 63974 | 2,4-di(tert-butyl)-6-iodophenol | C14H21IO | 详情 | 详情 | |
| (II) | 63975 | 1,5-di(tert-butyl)-3-iodo-2-propoxybenzene; 2,4-di(tert-butyl)-6-iodophenyl propyl ether | C17H27IO | 详情 | 详情 | |
| (III) | 45993 | 2-formylphenylboronic acid | 40138-16-7 | C7H7BO3 | 详情 | 详情 |
| (IV) | 63976 | 3',5'-di(tert-butyl)-2'-propoxy[1,1'-biphenyl]-2-carbaldehyde | C24H32O2 | 详情 | 详情 | |
| (V) | 44704 | ethyl (E)-4-(diethoxyphosphoryl)-3-methyl-2-butenoate | 41891-54-7 | C11H21O5P | 详情 | 详情 |
| (VI) | 63977 | ethyl (2E,4E)-5-[3',5'-di(tert-butyl)-2'-propoxy[1,1'-biphenyl]-2-yl]-3-methyl-2,4-pentadienoate | C31H42O3 | 详情 | 详情 |