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【结 构 式】 
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【药物名称】 【化学名称】4-[5-[1-(3-Chlorobenzyl)-2-oxopyrrolidin-3(S)-ylaminomethyl]-1H-imidazol-1-ylmethyl]benzonitrile 【CA登记号】330185-25-6, 330182-86-0 (diHCl), 330185-24-5 (enantiomer) 【 分 子 式 】C23H22ClN5O 【 分 子 量 】419.91769 |
【开发单位】Merck & Co. (Originator) 【药理作用】ONCOLYTIC DRUGS, Farnesyl Transferase Inhibitors, Inhibitors of Signal Transduction Pathways |
合成路线1
4-(Hydroxymethyl)imidazole (I) was protected as the 1-trityl derivative (II) by treatment with triphenylmethyl chloride. The hydroxyl group of (II) was then esterified with Ac2O in pyridine to yield acetate (III). After N-alkylation of (III) with 4-cyanobenzyl bromide (IV), the intermediate imidazolium bromide was deprotected by refluxing in MeOH to give (V). Subsequent hydrolysis of the acetate ester with LiOH provided alcohol (VI), which was oxidized to aldehyde (VII) under Swern conditions employing DMSO in the presence of SO3-pyridine complex.
| 【1】 Beshore, D.C.; Bell, I.M.; Gallicchio, S.N.; Sisko, J.T.; Zartman, C.B.; Lumma, W.C. Jr. (Merck & Co., Inc.); Inhibitors of prenyl-protein transferase. WO 0117992 . |
| 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) | 42116 | 1H-imidazol-5-ylmethanol | C4H6N2O | 详情 | 详情 | |
| (II) | 38392 | (1-trityl-1H-imidazol-4-yl)methanol | C23H20N2O | 详情 | 详情 | |
| (III) | 38391 | (1-trityl-1H-imidazol-4-yl)methyl acetate | C25H22N2O2 | 详情 | 详情 | |
| (IV) | 14200 | 4-(Bromomethyl)benzonitrile; alpha-Bromo-p-tolunitrile | 17201-43-3 | C8H6BrN | 详情 | 详情 |
| (V) | 38390 | [1-(4-cyanobenzyl)-1H-imidazol-5-yl]methyl acetate | C14H13N3O2 | 详情 | 详情 | |
| (VI) | 38389 | 4-[[5-(hydroxymethyl)-1H-imidazol-1-yl]methyl]benzonitrile | C12H11N3O | 详情 | 详情 | |
| (VII) | 38388 | 4-[(5-formyl-1H-imidazol-1-yl)methyl]benzonitrile | C12H9N3O | 详情 | 详情 |
合成路线2
Coupling of N-Boc-L-methionine (VIII) with 3-chlorobenzylamine (IX) using PyBOP provided amide (X). Methylation of the sulfide group of (X) with iodomethane gave rise to the sulfonium salt (XI), which was further cyclized to pyrrolidinone (XII) by treatment with lithium bis(trimethylsilyl)amide in cold THF. Acid deprotection of the Boc group of (XII) furnished amine (XIII). This was finally subjected to reductive alkylation with aldehyde (VII) in the presence of sodium cyanoborohydride to provide the corresponding (imidazolylmethyl)amine.
| 【1】 Bell, I.M.; et al.; Design and biological activity of (S)-4-(5-{[1-(3-chlorobenzyl)-2-oxopyrrolidin-3-ylamino]methyl}imidazol-1-ylmethyl)benzonitrile, a 3-aminopyrrolidinone farnesyltransferase inhibitor with excellent cell potency. J Med Chem 2001, 44, 18, 2933. |
| 【2】 Beshore, D.C.; Bell, I.M.; Gallicchio, S.N.; Sisko, J.T.; Zartman, C.B.; Lumma, W.C. Jr. (Merck & Co., Inc.); Inhibitors of prenyl-protein transferase. WO 0117992 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VII) | 38388 | 4-[(5-formyl-1H-imidazol-1-yl)methyl]benzonitrile | C12H9N3O | 详情 | 详情 | |
| (VIII) | 34459 | (3-chlorophenyl)methanamine; 3-chlorobenzylamine | 4152-90-3 | C7H8ClN | 详情 | 详情 |
| (IX) | 17634 | (2S)-2-[(tert-butoxycarbonyl)amino]-4-(methylsulfanyl)butyric acid; N-alpha-t-BOC-L-methionine | 2488-15-5 | C10H19NO4S | 详情 | 详情 |
| (X) | 49995 | tert-butyl (1S)-1-[[(3-chlorobenzyl)amino]carbonyl]-3-(methylsulfanyl)propylcarbamate | C17H25ClN2O3S | 详情 | 详情 | |
| (XI) | 49996 | [(3S)-3-[(tert-butoxycarbonyl)amino]-4-[(3-chlorobenzyl)amino]-4-oxobutyl](dimethyl)sulfonium iodide | C18H28ClIN2O3S | 详情 | 详情 | |
| (XII) | 49997 | tert-butyl (3S)-1-(3-chlorobenzyl)-2-oxopyrrolidinylcarbamate | C16H21ClN2O3 | 详情 | 详情 | |
| (XIII) | 49998 | (3S)-3-amino-1-(3-chlorobenzyl)-2-pyrrolidinone | C11H13ClN2O | 详情 | 详情 |