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【结 构 式】 
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【药物名称】Plevitrexed, BGC-9331, ZD-9331, Vamidex 【化学名称】2(S)-[4-[N-(2,7-Dimethyl-4-oxo-3,4-dihydroquinazolin-6-ylmethyl)-N-(2-propynyl)amino]-2-fluorobenzamido]-4-(1H-tetrazol-5-yl)butyric acid 【CA登记号】153537-73-6, 153537-74-7 ((R)-isomer) 【 分 子 式 】C26H25FN8O4 【 分 子 量 】532.53875 |
【开发单位】AstraZeneca (Originator), BTG (Originator), Institute of Cancer Research (Originator) 【药理作用】Gastric Cancer Therapy, Oncolytic Drugs, Solid Tumors Therapy, Antimetabolites, Thymidylate Synthase Inhibitors |
合成路线1
Cyclization of N-acetyl dimethylanthranilic acid (I) with acetic anhydride produced benzoxazinone (II) which, upon treatment with aqueous ammonia, furnished trimethylquinazolinone (III). Incorporation of the N-(pivaloyloxy)methyl (POM) protecting group of (III) gave (IV), and subsequent regioselective bromination with N-bromosuccinimide in the presence of AIBN yielded the 6-bromomethyl compound (V). Condensation of (V) with p-aminobenzoate derivative (VI) afforded tertiary amine (VII). After trifluoroacetic acid-promoted cleavage of the tert-butyl ester of (VII), coupling with pentafluorophenol in the presence of DCC provided pentafluorophenyl ester (VIII). The title compound was then obtained by condensation of (VIII) with the tetrazolyl aminoester (IX) in the presence of 1-hydroxybenzotriazole, followed by basic hydrolysis of both methyl ester and POM protecting group.
| 【1】 Marsham, P.R.; et al.; Quinazoline antifolate thymidylate synthase inhibitors: replacement of glutamic acid in the C2-methyl series. J Med Chem 1995, 38, 6, 994-1004. |
| 【2】 Jackman, A.L.; Kimbell, R.; Marsham, P.R.; Boyle, F.T.; Wardleworth, M.; Brown, M.; Hennequin, L.F.; Design and synthesis of potent non-polyglutamatable quinazoline antifolate thymidylate synthase inhibitors. J Med Chem 1999, 42, 19, 3809. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 16166 | chloromethyl pivalate | 18997-19-8 | C6H11ClO2 | 详情 | 详情 | |
| (I) | 27958 | 2-(acetamido)-4,5-dimethylbenzoic acid | C11H13NO3 | 详情 | 详情 | |
| (II) | 27959 | 2,6,7-trimethyl-4H-3,1-benzoxazin-4-one | C11H11NO2 | 详情 | 详情 | |
| (III) | 27960 | 2,6,7-trimethyl-4(3H)-quinazolinone | C11H12N2O | 详情 | 详情 | |
| (IV) | 27961 | [2,6,7-trimethyl-4-oxo-3(4H)-quinazolinyl]methyl pivalate | C17H22N2O3 | 详情 | 详情 | |
| (V) | 27962 | [6-(bromomethyl)-2,7-dimethyl-4-oxo-3(4H)-quinazolinyl]methyl pivalate | C17H21BrN2O3 | 详情 | 详情 | |
| (VI) | 27963 | tert-butyl 2-fluoro-4-(2-propynylamino)benzoate | C14H16FNO2 | 详情 | 详情 | |
| (VII) | 27964 | tert-butyl 4-[[(3-[[(2,2-dimethylpropanoyl)oxy]methyl]-2,7-dimethyl-4-oxo-3,4-dihydro-6-quinazolinyl)methyl](2-propynyl)amino]-2-fluorobenzoate | C31H36FN3O5 | 详情 | 详情 | |
| (VIII) | 27965 | 2,3,4,5,6-pentafluorophenyl 4-[[(3-[[(2,2-dimethylpropanoyl)oxy]methyl]-2,7-dimethyl-4-oxo-3,4-dihydro-6-quinazolinyl)methyl](2-propynyl)amino]-2-fluorobenzoate | C33H27F6N3O5 | 详情 | 详情 | |
| (IX) | 27966 | methyl (2S)-2-amino-4-(1H-1,2,3,4-tetraazol-5-yl)butanoate | C6H11N5O2 | 详情 | 详情 |