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【结 构 式】 
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【药物名称】Terprenin 【化学名称】3',6'-Dimethoxy-4-(3-methyl-2-butenyloxy)-p-terphenyl-2',3,4''-triol 【CA登记号】197899-11-9 【 分 子 式 】C25H26O6 【 分 子 量 】422.48237 |
【开发单位】Shionogi (Originator) 【药理作用】IMMUNOMODULATING AGENTS, Immunosuppressants |
合成路线1
1. The Suzuki coupling of arylboronic acid (I) with 3-bromo-2,5-dimethoxybenzaldehyde (II) with concomitant desilylation provided biphenyl aldehyde (III). After protection of the phenolic hydroxyl as the mesylate (IV), selective bromination of (IV) in the presence of NaOAc in AcOH provided bromoaldehyde (V). A Baeyer-Villiger oxidation of the aldehyde group of (V) with m-chloroperbenzoic acid, followed by acid hydrolysis of the intermediate formate ester, produced phenol (VI). which was coupled with protected boronic acid (VII) in the presence of Pd(PPh3)4 to yield terphenyl (VIII). Mesylation of the hydroxyl groups of (VIII) and further hydrogenolytic cleavage of the benzyl ether gave phenol (X). Then, alkylationof (X) with prenyl bromide (XI) provided prenyl ether (XII). The mesylate groups of (XII) were finally removed by hydrolysis with KOH to furnish the title compound.
| 【1】 Yonezawa, S.; et al.; Total synthesis of terprenin, a novel immunosuppressive p-terphenyl derivative. J Org Chem 1998, 63, 17, 5831. |
| 【2】 Nagashima, K.; Kamigauchi, T.; Sakazaki, R.; et al.; Terprenins, novel immunosuppressants produced by Aspergillus candidus. J Antibiot 1998, 51, 4, 445. |
| 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) | 25602 | 4-[[tert-butyl(dimethyl)silyl]oxy]phenylboronic acid | C12H21BO3Si | 详情 | 详情 | |
| (II) | 25603 | 3-bromo-2,5-dimethoxybenzaldehyde | C9H9BrO3 | 详情 | 详情 | |
| (III) | 25604 | 4'-hydroxy-2,5-dimethoxy[1,1'-biphenyl]-3-carbaldehyde | C15H14O4 | 详情 | 详情 | |
| (IV) | 25605 | 3'-formyl-2',5'-dimethoxy[1,1'-biphenyl]-4-yl methanesulfonate | C16H16O6S | 详情 | 详情 | |
| (V) | 25606 | 4'-bromo-3'-formyl-2',5'-dimethoxy[1,1'-biphenyl]-4-yl methanesulfonate | C16H15BrO6S | 详情 | 详情 | |
| (VI) | 25607 | 4'-bromo-3'-hydroxy-2',5'-dimethoxy[1,1'-biphenyl]-4-yl methanesulfonate | C15H15BrO6S | 详情 | 详情 | |
| (VII) | 25608 | 4-(benzyloxy)-3-[[tert-butyl(dimethyl)silyl]oxy]phenylboronic acid | C19H27BO4Si | 详情 | 详情 | |
| (VIII) | 25609 | Methanesulfonic acid 4''-benzyloxy-3',3''-dihydroxy-2',5'-dimethoxy-p-terphenyl-4-yl ester | C28H26O8S | 详情 | 详情 | |
| (IX) | 25610 | 4-Benzyloxy-3',6'-dimethoxy-p-terphenyl-3,2',4''-triol tris methanesuolfonyl ester | C30H30O12S3 | 详情 | 详情 | |
| (X) | 25611 | 3',6'-Dimethoxy-p-terphenyl-2',3,4,4''-tetrol 2'-O,3-O,4''-O-tris methanesulfonate | C23H24O12S3 | 详情 | 详情 | |
| (XII) | 25612 | 3',6'-Dimethoxy-4-(3-methyl-2-butenyloxy)-p-terphenyl-2',3,4''-triol tris methanesulfonate | C28H32O12S3 | 详情 | 详情 |
合成路线2
2. In an alternative synthesis, 5-bromosalicylaldehyde (XIII) was alkylated with bromoacetaldehyde dimethyl acetal (XIV) to afford ether (XV). Further Baeyer-Villiger reaction with (XV) produced phenol (XVI), which was cyclized to the benzodioxine (XVII) with p-TsOH. Lithiation of (XVII), followed by reaction with triisopropyl borate and hydrolytic work-up, gave boronic acid (XVIII). Aldehyde (II) was treated with MCPBA yielding phenol (XIII), which was iodinated in the presence of tert-butylamine to give the bromo iodo derivative (XIV). Sequential Suzuki coupling of bromo iodo compound (XIV) with boronic acid (XVIII) yielding (XIX), and then with boronic acid (I) provided terphenyl (XX). Hydrolysis of the methyl acetal of (XX) using p-TsOH gave cyclic hemiacetal (XXI). Finally, Wittig reaction of (XXI) with the phosphorane prepared from isopropyl triphenylphosphonium iodide and n-BuLi provided the title compound.
| 【1】 Yonezawa, S.; et al.; Total synthesis of terprenin, a novel immunosuppressive p-terphenyl derivative. J Org Chem 1998, 63, 17, 5831. |
| 【2】 Nagashima, K.; Kamigauchi, T.; Sakazaki, R.; et al.; Terprenins, novel immunosuppressants produced by Aspergillus candidus. J Antibiot 1998, 51, 4, 445. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIIIa) | 25618 | 3-bromo-2,5-dimethoxyphenol | C8H9BrO3 | 详情 | 详情 | |
| (XIVb) | 25619 | 3-bromo-6-iodo-2,5-dimethoxyphenol | C8H8BrIO3 | 详情 | 详情 | |
| (I) | 25602 | 4-[[tert-butyl(dimethyl)silyl]oxy]phenylboronic acid | C12H21BO3Si | 详情 | 详情 | |
| (II) | 25603 | 3-bromo-2,5-dimethoxybenzaldehyde | C9H9BrO3 | 详情 | 详情 | |
| (XIII) | 25613 | 5-bromo-2-hydroxybenzaldehyde; 5-Bromosalicylaldehyde | 1761-61-1 | C7H5BrO2 | 详情 | 详情 |
| (XIV) | 13183 | 2-Bromo-1,1-dimethoxyethane; 2-Bromo-1-methoxyethyl methyl ether; Bromoacetaldehyde dimethyl acetal | 7252-83-7 | C4H9BrO2 | 详情 | 详情 |
| (XV) | 25614 | 5-bromo-2-(2,2-dimethoxyethoxy)benzaldehyde | C11H13BrO4 | 详情 | 详情 | |
| (XVI) | 25615 | 5-bromo-2-(2,2-dimethoxyethoxy)phenol | C10H13BrO4 | 详情 | 详情 | |
| (XVII) | 25616 | 7-bromo-2,3-dihydro-1,4-benzodioxin-2-yl methyl ether | C9H9BrO3 | 详情 | 详情 | |
| (XVIII) | 25617 | 3-methoxy-2,3-dihydro-1,4-benzodioxin-6-ylboronic acid | C9H11BO5 | 详情 | 详情 | |
| (XIX) | 25620 | 3-bromo-2,5-dimethoxy-6-(3-methoxy-2,3-dihydro-1,4-benzodioxin-6-yl)phenol | C17H17BrO6 | 详情 | 详情 | |
| (XX) | 25621 | 2,5-dimethoxy-4-(3-methoxy-2,3-dihydro-1,4-benzodioxin-6-yl)[1,1'-biphenyl]-3,4'-diol | C23H22O7 | 详情 | 详情 | |
| (XXI) | 25622 | 4-(3-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-2,5-dimethoxy[1,1'-biphenyl]-3,4'-diol | C22H20O7 | 详情 | 详情 |