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【结 构 式】

【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
Extended Information