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【结 构 式】 
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【药物名称】GS-1101;CAL-101 【化学名称】5-Fluoro-3-phenyl-2-[1(S)-(9H-purin-6-ylamino)propyl]quinazolin-4(3H)-one 【CA登记号】 【 分 子 式 】C22H18FN7O 【 分 子 量 】415.423 |
【开发单位】Gilead Sciences, Inc. (US) 【药理作用】Phosphatidylinositol 3-Kinase p110δ Inhibitor;Oncolytic |
合成路线1
Chlorination of 2-fluoro-6-nitrobenzoic acid (I) with (COCl)2 by means of DMF in CH2Cl2 gives 2-fluoro-6-nitrobenzoyl chloride (II), which is then coupled with aniline (III) in the presence of NaHCO3 in dioxane/H2O to yield 2-fluoro-6-nitro-N-phenylbenzamide (IV). Activation of amide (IV) as the corresponding imidoyl chloride (V) by means of SOCl2 and DMF at 85 °C, and subsequent coupling with NBoc-2(S)-aminobutyric acid (VI) by means of Et3N in CH2Cl2 affords imide (VII). Reductive cyclization of compound (VII) in the presence of Zn in AcOH affords quinazolinone (VIII), which is N-deprotected with TFA in CH2Cl2 to obtain amine (IX). Finally, amine (IX) is condensed with 6-bromopurine (X) by means of DIEA in t-BuOH at 80 °C .
| 【1】 Kesicki, E.A., Zhichkin, P. (Icos Corp.). Method of preparing 3-phenyl-2-[(9H-purin-6-ylamino)-methyl]-3H-quinazolin-4-one and substituted and related compounds. WO 2005113554. |
| 【2】 Fowler, K.W., Huang, D., Kesicki, E.A., Ooi, H.C., Oliver, A.R., Ruan, F., Treiberg, J. (Icos. Corp.). Quinazolinones as inhibitors of human phosphatidylinositol 3-kinase delta. CA 2566609, CN 102229609, EP 1761540, JP 2007537291, US 2008275067, US 7932260, US 2012015964, WO 2005113556. |
| 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) | 68438 | 2-fluoro-6-nitrobenzoic acid;6-Fluoro-2-nitrobenzoic acid | 385-02-4 | C7H4FNO4 | 详情 | 详情 |
| (II) | 68461 | 2-methyl-6-nitrobenzoyl chloride | 66232-57-3 | C8H6ClNO3 | 详情 | 详情 |
| (III) | 12294 | Aniline; Phenylamine | 62-53-3 | C6H7N | 详情 | 详情 |
| (IV) | 68462 | 2-fluoro-6-nitro-N-phenylbenzamide | C13H9FN2O3 | 详情 | 详情 | |
| (V) | 68464 | (Z)-2-fluoro-6-nitro-N-phenylbenzimidoyl chloride | C13H8ClFN2O2 | 详情 | 详情 | |
| (VI) | 68463 | (S)-2-((tert-butoxycarbonyl)amino)butanoic acid | 34306-42-8 | C9H17NO4 | 详情 | 详情 |
| (VII) | 68465 | (S)-tert-butyl (1-(2-fluoro-6-nitro-N-phenylbenzamido)-1-oxobutan-2-yl)carbamate | C22H24FN3O6 | 详情 | 详情 | |
| (VIII) | 68466 | (S)-tert-butyl (1-(5-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)propyl)carbamate | C22H24FN3O3 | 详情 | 详情 | |
| (IX) | 68467 | (S)-2-(1-aminopropyl)-5-fluoro-3-phenylquinazolin-4(3H)-one | C17H16FN3O | 详情 | 详情 | |
| (X) | 68468 | 6-bromopurine;6-Bromo-1H-purine | 767-69-1 | C5H3BrN4 | 详情 | 详情 |