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【结 构 式】 
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【药物名称】LGD-1550, ALRT-550, ALRT-1550, LG-1550 【化学名称】(2E,4E,6E)-7-(3,5-Di-tert-butylphenyl)-3-methylocta-2,4,6-trienoic acid 【CA登记号】178600-20-9, 178600-19-6 (stereoisomer) 【 分 子 式 】C23H32O2 【 分 子 量 】340.51029 |
【开发单位】Ligand (Originator) 【药理作用】Acne Therapy, Antipsoriatics, Cervical Cancer Therapy, DERMATOLOGIC DRUGS, Head and Neck Cancer Therapy, Oncolytic Drugs, Retinoid RAR Agonists, Retinoids |
合成路线1
Addition of methyllithium to 3,5-di-tert-butylbenzoic acid (I) at -78 C gave acetophenone (II). The Horner-Emmons condensation of acetophenone (II) with diethyl (cyanomethyl)phosphonate (III) resulted in a mixture of isomeric alpha,beta-unsaturated nitriles (IV). After isolation of the major E-isomer by preparative TLC, cyano group reduction employing DIBAL in CH2Cl2 at -78 C provided aldehyde (V). This was subjected to a new Horner-Emmons condensation with phosphonate (VI) to provide the octatrienoate ester (VII). The target carboxylic acid was then prepared by saponification of ester (VII) with methanolic KOH.
| 【1】 Zhang, L.; et al.; Discovery of novel retinoic acid receptor agonists having potent antiproliferative activity in cervical cancer cells. J Med Chem 1996, 39, 14, 2659. |
| 【2】 Boehm, M.F.; Zhang, L.; Bennani, Y.L.; Nadzan, A.M. (Ligand Pharmaceuticals, Inc.); Novel trienoic retinoid cpds. and methods. JP 1998511948; US 5721103; US 6083977; WO 9620913 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IVa) | 56192 | (E)-3-[3,5-di(tert-butyl)phenyl]-2-butenenitrile | C18H25N | 详情 | 详情 | |
| (IVb) | 56193 | (Z)-3-[3,5-di(tert-butyl)phenyl]-2-butenenitrile | C18H25N | 详情 | 详情 | |
| (I) | 56190 | 3,5-Di-tert-butylbenzoic acid | 16225-26-6 | C15H22O2 | 详情 | 详情 |
| (II) | 56191 | 1-[3,5-di(tert-butyl)phenyl]-1-ethanone | C16H24O | 详情 | 详情 | |
| (III) | 10045 | Diethyl cyanomethylphosphonate | 2537-48-6 | C6H12NO3P | 详情 | 详情 |
| (V) | 56194 | (E)-3-[3,5-di(tert-butyl)phenyl]-2-butenal | C18H26O | 详情 | 详情 | |
| (VI) | 44704 | ethyl (E)-4-(diethoxyphosphoryl)-3-methyl-2-butenoate | 41891-54-7 | C11H21O5P | 详情 | 详情 |
| (VII) | 56195 | ethyl (2E,4E,6E)-7-[3,5-di(tert-butyl)phenyl]-3-methyl-2,4,6-octatrienoate | C25H36O2 | 详情 | 详情 |