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【结 构 式】 
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【药物名称】 【化学名称】N5-(2-Carboxybenzoyl)-N2-[4-[2-(2,4-diaminoquinazolin-6-yl)ethyl]benzoyl]-L-ornithine 【CA登记号】 【 分 子 式 】C30H30N6O6 【 分 子 量 】570.6102 |
【开发单位】Dana-Farber Cancer Institute (Originator), Harvard Medical School (Originator) 【药理作用】ONCOLYTIC DRUGS, Dihydrofolate Reductase (DHFR) Inhibitors |
合成路线1
Palladium-catalyzed coupling of 2,4-diamino-6-iodoquinazoline (I) with trimethylsilyl acetylene (II) affords the silylethynyl quinazoline (III). Subsequent treatment of (III) with tetrabutylammonium fluoride leads to the desilylated acetylene compound (IV).
| 【1】 Vaidya, C.M.; Wright, J.E.; Rosowsky, A.; Synthesis and in vitro antitumor activity of new deaza analogues of the nonpolyglutamatable antifolate Nalpha-(4-amino-4-deoxypteroyl)-Nalpha-hemiphtaloyl-L-ornithine (PT523). J Med Chem 2002, 45, 8, 1690. |
| 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) | 65105 | 2-amino-6-iodo-4-quinazolinylamine; 6-iodo-2,4-quinazolinediamine | C8H7IN4 | 详情 | 详情 | |
| (II) | 51602 | 1-Propyne | C3H4 | 详情 | 详情 | |
| (III) | 65103 | 2-amino-6-[2-(trimethylsilyl)ethynyl]-4-quinazolinylamine; 6-[2-(trimethylsilyl)ethynyl]-2,4-quinazolinediamine | C13H16N4Si | 详情 | 详情 | |
| (IV) | 65104 | 2-amino-6-ethynyl-4-quinazolinylamine; 6-ethynyl-2,4-quinazolinediamine | C10H8N4 | 详情 | 详情 |
合成路线2
Condensation between phthaloyl ornithine methyl ester (V) and 4-iodobenzoic acid (VI), via activation with isobutyl chloroformate, furnishes the iodobenzamide (VII). Subsequent coupling of iodo amide (VII) with the ethynyl quinazoline (IV) employing Pd(PPh3)4 and CuI leads to the disubstituted acetylene (VIII). Catalytic hydrogenation of the triple bond in the presence of Pd/C affords (IX). Then, basic hydrolysis of phthalimido ester (IX) by means of Ba(OH)2 produces the target compound.
| 【1】 Vaidya, C.M.; Wright, J.E.; Rosowsky, A.; Synthesis and in vitro antitumor activity of new deaza analogues of the nonpolyglutamatable antifolate Nalpha-(4-amino-4-deoxypteroyl)-Nalpha-hemiphtaloyl-L-ornithine (PT523). J Med Chem 2002, 45, 8, 1690. |
| 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) | 65104 | 2-amino-6-ethynyl-4-quinazolinylamine; 6-ethynyl-2,4-quinazolinediamine | C10H8N4 | 详情 | 详情 | |
| (V) | 42875 | methyl (2S)-2-amino-5-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)pentanoate | C14H16N2O4 | 详情 | 详情 | |
| (VI) | 53872 | 4-iodobenzoic acid | 619-58-9 | C7H5IO2 | 详情 | 详情 |
| (VII) | 65108 | methyl (2S)-5-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-2-[(4-iodobenzoyl)amino]pentanoate | C21H19IN2O5 | 详情 | 详情 | |
| (VIII) | 65107 | methyl (2S)-2-({4-[2-(2,4-diamino-6-quinazolinyl)ethynyl]benzoyl}amino)-5-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)pentanoate | C31H26N6O5 | 详情 | 详情 | |
| (IX) | 65106 | methyl (2S)-2-({4-[2-(2,4-diamino-6-quinazolinyl)ethyl]benzoyl}amino)-5-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)pentanoate | C31H30N6O5 | 详情 | 详情 |