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【结 构 式】 
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【分子编号】11010 【品名】methyl 4-[1-[(2,4-diamino-5,6,7,8-tetrahydro-6-pteridinyl)methyl]propyl]benzoate 【CA登记号】 |
【 分 子 式 】C18H24N6O2 【 分 子 量 】356.4278 【元素组成】C 60.66% H 6.79% N 23.58% O 8.98% |
合成路线1
该中间体在本合成路线中的序号：(VI)A new synthesis for edatrexate has been described: The reaction of 2,4-diamino-6-(bromomethyl)pteridine (I) with tributylphosphine (II) in DMSO gives the corresponding phosphonium salt (III), which is condensed wtih 4-propionylbenzoic acid methyl ester (IV) by means of NaH in DMSO, affording 4-[1-(2,4-diaminopteridin-6-yl)-1-ethylvinyl]benzoic acid methyl ester (V). The hydrogenation of (V) with H2 and PtO2 in acetic acid gives 4-[1-(2,4-diamino-6,7-dihydropteridin-6-ylmethyl)propyl]benzoic acid methyl ester (VI), which, without isolation, is dehydrogenated with H2O2 in the same solvent yielding 4-[1-(2,4-diaminopteridin-6-ylmethyl)propyl]benzoic acid methyl ester (VII). The hydrolysis of (VII) with NaOH in DMSO - water affords the corresponding free acid (VIII), which is condensed with L-glutamic acid diethyl ester (IX) by means of isobutoxycarbonylchloride and triethylamine in DMF, giving edatrexate diethyl ester (X). Finally, this compound is hydrolyzed with NaOH in methanol.
| 【1】 Johnson, C.A.; Sirotnak, F.M.; Piper, J.R.; Otter, G.M.; Synthesis and antifolate evaluation of 10-ethyl-5-methyl-5,10-dideazaaminopterin and an alternative synthesis of 10-ethyl-10-deazaaminopterin (edatrexate). J Med Chem 1992, 35, 16, 3002. |
| 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) | 11006 | 2-Amino-6-(bromomethyl)-4-pteridinylamine; 6-(Bromomethyl)-2,4-pteridinediamine | 52853-40-4 | C7H7BrN6 | 详情 | 详情 |
| (III) | 11007 | Tributyl[(2,4-diamino-6-pteridinyl)methyl]phosphonium bromide | C19H34BrN6P | 详情 | 详情 | |
| (IV) | 11008 | methyl 4-propionylbenzoate | C11H12O3 | 详情 | 详情 | |
| (V) | 11009 | methyl 4-[(E)-2-(2,4-diamino-6-pteridinyl)-1-ethylethenyl]benzoate | C18H18N6O2 | 详情 | 详情 | |
| (VI) | 11010 | methyl 4-[1-[(2,4-diamino-5,6,7,8-tetrahydro-6-pteridinyl)methyl]propyl]benzoate | C18H24N6O2 | 详情 | 详情 | |
| (VII) | 11011 | methyl 4-[1-[(2,4-diamino-6-pteridinyl)methyl]propyl]benzoate | C18H20N6O2 | 详情 | 详情 | |
| (VIII) | 11012 | 4-[1-[(2,4-Diamino-6-pteridinyl)methyl]propyl]benzoic acid | C17H18N6O2 | 详情 | 详情 | |
| (IX) | 11013 | diethyl (2S)-2-aminopentanedioate | C9H17NO4 | 详情 | 详情 | |
| (X) | 11014 | diethyl (2S)-2-[(4-[1-[(2,4-diamino-6-pteridinyl)methyl]propyl]benzoyl)amino]pentanedioate | C26H33N7O5 | 详情 | 详情 |