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【结 构 式】 
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【药物名称】Raltitrexed, NSC-639186, ZN-D1694, ZD-1694, ICI-D-1694, D-1694, Tomudex 【化学名称】N-[5-[N-Methyl-N-(2-methyl-4-oxo-3,4-dihydroquinazolin-6-ylmethyl)amino]-2-thenoyl]-L-glutamic acid 【CA登记号】112887-68-0 【 分 子 式 】C21H22N4O6S 【 分 子 量 】458.49669 |
【开发单位】BTG (Originator), National Cancer Institute (Not Determined), AstraZeneca (Licensee), Ben Venue (Licensee) 【药理作用】Colorectal Cancer Therapy, Leukemia Therapy, Oncolytic Drugs, Solid Tumors Therapy, Pyrimidine Antagonists, Thymidylate Synthase Inhibitors |
合成路线1
The acylation of diethyl L-glutamate (I) with 5-nitro-2-thienylcarbonyl chloride (II) in toluene gives N-(5-nitrothien-2-ylcarbonyl)-L-glutamic acid diethyl ester (III), which is reduced with sodium dithionite in ethanol/water to the corresponding amino compound (IV). The methylation of (IV) with methyl iodide and 2,6-lutidine yields the corresponding methylamine (V), which is condensed with 6-(bromomethyl)-2-methylquinazolin-4(3H)-one (VI) by means of 2,6-lutidine in hot DMF affording the diethyl ester (VIII) of D-1694. Finally, this compound is hydrolyzed with NaOH in ethanol/water. The bromomethyl quinazoline (VI) was obtained by selective radical bromination of 2,6-dimethylquinazolin-4(3H)-one (VII) with N-bromosuccinimide (NBS) and benzoyl peroxide in hot chloroform.
| 【1】 Lohmeyer, M.; Castaner, J.; Tomudex (TM). Drugs Fut 1995, 20, 4, 371. |
| 【2】 Hughes, L.R. (AstraZeneca plc; National Research Development Corp.); Anti-tumor quinazolines. EP 0239362; GB 2188319; JP 1989125373; US 4992550; US 5081124; US 5187167 . |
| 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) | 11013 | diethyl (2S)-2-aminopentanedioate | C9H17NO4 | 详情 | 详情 | |
| (II) | 12467 | 5-Nitro-2-thiophenecarbonyl chloride | C5H2ClNO3S | 详情 | 详情 | |
| (III) | 12468 | diethyl (2S)-2-[[(5-nitro-2-thienyl)carbonyl]amino]pentanedioate | C14H18N2O7S | 详情 | 详情 | |
| (IV) | 12469 | diethyl (2S)-2-[[(5-amino-2-thienyl)carbonyl]amino]pentanedioate | C14H20N2O5S | 详情 | 详情 | |
| (V) | 12470 | diethyl (2S)-2-([[5-(methylamino)-2-thienyl]carbonyl]amino)pentanedioate | 112889-02-8 | C15H22N2O5S | 详情 | 详情 |
| (VI) | 12471 | 6-(Bromomethyl)-2-methyl-4(3H)-quinazolinone | C10H9BrN2O | 详情 | 详情 | |
| (VII) | 12472 | 2,6-Dimethyl-4(3H)-quinazolinone | C10H10N2O | 详情 | 详情 | |
| (VIII) | 12473 | diethyl (2S)-2-[[(5-[methyl[(2-methyl-4-oxo-3,4-dihydro-6-quinazolinyl)methyl]amino]-2-thienyl)carbonyl]amino]pentanedioate | C25H30N4O6S | 详情 | 详情 |