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【结 构 式】 
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【药物名称】 【化学名称】2-[4-[2(S)-[N-[1-(4-Methoxybenzyl)-4-methyl-2-oxo-1,2-dihydropyridin-3-yl]carbamoyl]-2-[2-methyl-2-(2-naphthyl)propionamido]ethyl]phenyl]-2-methylpropionic acid 【CA登记号】228408-75-1, 228409-88-9 (undefined isomer) 【 分 子 式 】C41H43N3O6 【 分 子 量 】673.81636 |
【开发单位】Boehringer Ingelheim (Originator) 【药理作用】Oncolytic Drugs, IL-2 Production Inhibitors, Src Kinase Inhibitors |
合成路线1
The precursor 2,2-dimethyl-(2-naphthyl)acetic acid (IV) was prepared as follows. 2-Naphthylacetic acid (I) was converted to the benzyl ester (II) by treatment with benzyl bromide and DBU. Dimethylation of the sodium enolate of (II) with iodomethane furnished (III). Removal of the benzyl ester group of (III) was then achieved by hydrogenolysis in the presence of Pd/C.
| 【1】 Betageri, R.; Llinas-Brunet, M.; Moss, N.; Patel, U.; Cardozo, M.; Beaulieu, P.L.; Ferland, J.-M.; Proudfoot, J.R. (Boehringer Ingelheim Pharmaceuticals Inc.); Pyridones as Src family SH2 domain inhibitors. EP 1045836; US 6054470; US 6156784; WO 9931066 . |
| 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) | 50657 | 2-Naphthylacetic acid; beta-Naphthylacetic acid | 581-96-4 | C12H10O2 | 详情 | 详情 |
| (II) | 50658 | benzyl 2-(2-naphthyl)acetate | C19H16O2 | 详情 | 详情 | |
| (III) | 50659 | benzyl 2-methyl-2-(2-naphthyl)propanoate | C21H20O2 | 详情 | 详情 | |
| (IV) | 50660 | 2-methyl-2-(2-naphthyl)propionic acid | C14H14O2 | 详情 | 详情 |
合成路线2
Ethyl phenylacetate (V) was dimethylated upon treatment with iodomethane and sodium bis(trimethylsilyl)amide, yielding (VI). Iodination of (VI) was carried out by means of iodine and sodium iodate in acidic medium, and the resulting iodo ester (VII) was subsequently hydrolyzed with KOH to the carboxylic acid (VIII). This was converted to the tert-butyl ester (X) via conversion to the corresponding acid chloride (IX) with oxalyl chloride, followed by treatment with potassium tert-butoxide. Palladium-catalyzed Heck coupling of aryl iodide (X) with N-Boc-dehydroalanine benzyl ester (XI) furnished the aminocinnamic acid derivative (XII). Then, catalytic hydrogenation of the olefin double bond of (XII) with simultaneous benzyl ester cleavage provided the protected racemic amino acid intermediate (XIII).
| 【1】 Proudfoot, J.R.; et al.; Nonpeptidic, monocharged, cell permeable ligands of the p56lck SH2 domain. J Med Chem 2001, 44, 15, 2421. |
| 【2】 Betageri, R.; Llinas-Brunet, M.; Moss, N.; Patel, U.; Cardozo, M.; Beaulieu, P.L.; Ferland, J.-M.; Proudfoot, J.R. (Boehringer Ingelheim Pharmaceuticals Inc.); Pyridones as Src family SH2 domain inhibitors. EP 1045836; US 6054470; US 6156784; WO 9931066 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (V) | 21045 | ethyl 2-phenylacetate | 101-97-3 | C10H12O2 | 详情 | 详情 |
| (VI) | 17609 | ethyl 2-methyl-2-phenylpropanoate | C12H16O2 | 详情 | 详情 | |
| (VII) | 50661 | ethyl 2-(4-iodophenyl)-2-methylpropanoate | C12H15IO2 | 详情 | 详情 | |
| (VIII) | 50662 | 2-(4-iodophenyl)-2-methylpropionic acid | C10H11IO2 | 详情 | 详情 | |
| (IX) | 50663 | 2-(4-iodophenyl)-2-methylpropanoyl chloride | C10H10ClIO | 详情 | 详情 | |
| (X) | 50664 | tert-butyl 2-(4-iodophenyl)-2-methylpropanoate | C14H19IO2 | 详情 | 详情 | |
| (XI) | 50665 | benzyl 2-[(tert-butoxycarbonyl)amino]acrylate | C15H19NO4 | 详情 | 详情 | |
| (XII) | 50666 | benzyl (E)-2-[(tert-butoxycarbonyl)amino]-3-[4-[2-(tert-butoxy)-1,1-dimethyl-2-oxoethyl]phenyl]-2-propenoate | C29H37NO6 | 详情 | 详情 | |
| (XIII) | 50667 | N-(tert-butoxycarbonyl)-4-[2-(tert-butoxy)-1,1-dimethyl-2-oxoethyl]phenylalanine | C22H33NO6 | 详情 | 详情 |
合成路线3
Alkylation of 4-methyl-3-nitro-2-pyridone (XIV) with p-methoxybenzyl chloride (XV) gave the N-benzylpyridone (XVI). The nitro group of (XVI) was then reduced to amine (XVII) by catalytic hydrogenation over Pd/C. Coupling of the intermediate amino acid derivative (XIII) with the aminopyridone (XVII) provided amide (XVIII). Selective cleavage of the N-Boc group of (XVIII) in the presence of the tert-butyl ester was achieved by treatment with HCl in dioxan. The resultant amine (XIX) was then coupled with 2,2-dimethyl-(2-naphthyl)acetic acid (IV) to furnish amide (XX). Finally, the title (S)-carboxylic acid was obtained by tert-butyl ester cleavage with trifluoroacetic acid followed by separation of the racemic mixture by means of chiral HPLC.
| 【1】 Proudfoot, J.R.; et al.; Nonpeptidic, monocharged, cell permeable ligands of the p56lck SH2 domain. J Med Chem 2001, 44, 15, 2421. |
| 【2】 Betageri, R.; Llinas-Brunet, M.; Moss, N.; Patel, U.; Cardozo, M.; Beaulieu, P.L.; Ferland, J.-M.; Proudfoot, J.R. (Boehringer Ingelheim Pharmaceuticals Inc.); Pyridones as Src family SH2 domain inhibitors. EP 1045836; US 6054470; US 6156784; WO 9931066 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IV) | 50660 | 2-methyl-2-(2-naphthyl)propionic acid | C14H14O2 | 详情 | 详情 | |
| (XIII) | 50667 | N-(tert-butoxycarbonyl)-4-[2-(tert-butoxy)-1,1-dimethyl-2-oxoethyl]phenylalanine | C22H33NO6 | 详情 | 详情 | |
| (XIV) | 50668 | 4-Methyl-3-nitro-2-pyridone | C6H6N2O3 | 详情 | 详情 | |
| (XV) | 11910 | 4-Methoxybenzyl chloride; 1-(Chloromethyl)-4-methoxybenzene; alpha-Chloro-4-methoxytoluene; 4-(Chloromethyl)phenyl methyl ether | 824-94-2 | C8H9ClO | 详情 | 详情 |
| (XVI) | 50669 | 1-(4-methoxybenzyl)-4-methyl-3-nitro-2(1H)-pyridinone | C14H14N2O4 | 详情 | 详情 | |
| (XVII) | 50670 | 3-amino-1-(4-methoxybenzyl)-4-methyl-2(1H)-pyridinone | C14H16N2O2 | 详情 | 详情 | |
| (XVIII) | 50671 | tert-butyl 2-[4-(2-[(tert-butoxycarbonyl)amino]-3-[[1-(4-methoxybenzyl)-4-methyl-2-oxo-1,2-dihydro-3-pyridinyl]amino]-3-oxopropyl)phenyl]-2-methylpropanoate | C36H47N3O7 | 详情 | 详情 | |
| (XIX) | 50672 | tert-butyl 2-[4-(2-amino-3-[[1-(4-methoxybenzyl)-4-methyl-2-oxo-1,2-dihydro-3-pyridinyl]amino]-3-oxopropyl)phenyl]-2-methylpropanoate | C31H39N3O5 | 详情 | 详情 | |
| (XX) | 50673 | tert-butyl 2-[4-(3-[[1-(4-methoxybenzyl)-4-methyl-2-oxo-1,2-dihydro-3-pyridinyl]amino]-2-[[2-methyl-2-(2-naphthyl)propanoyl]amino]-3-oxopropyl)phenyl]-2-methylpropanoate | C45H51N3O6 | 详情 | 详情 |