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【结 构 式】 
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【分子编号】68478 【品名】3-chloro-N-(3,4-dimethoxybenzyl)-4-fluoroaniline 【CA登记号】 |
【 分 子 式 】C15NClFO2 【 分 子 量 】280.622 【元素组成】C 64.20% H 4.99% Cl 12.63% F 6.77% O 11.40% |
合成路线1
该中间体在本合成路线中的序号：(XXII)Compound (XIII) can be obtained by reductocondensation of 3-chloro-4-fluoroaniline (XIX) with 3,4-dimethoxybenzaldehyde (XXI) using NaCNBH3 or NaBH(OAc)3 in AcOH/i-PrOH to yield the benzylaniline derivative (XXII), which by condensation with 4-chloro-7-fluoro-6-nitroquinazoline (XVIII) in i-PrOH gives the tertiary amine (XXIII) . Substitution of fluoroquinazoline (XXIII) with NaOMe in refluxing MeOH affords the 7-methoxyquinazoline derivative (XXIV), which is reduced to the quinazoline-4,6-diamine (XXV) by means of H2 over Raney Ni in THF. Finally, compound (XXV) is coupled with 4-(piperidin-1-yl)-2-butenoyl chloride (IV) in DMA .
4-(Piperidin-1-yl)-2-butenoyl chloride (IV) can be prepared by condensation of methyl 4-bromocrotonate (XI) with piperidine (X) to yield methyl 4-(piperidin-1-yl)-2-butenoate (XXVI), which is then hydrolyzed with HCl to give 4-(piperidin-1-yl)-2-butenoic acid (XXVII). Finally, acid (XXVII) is reacted with (COCl)2 in the presence of DMF in CH2Cl2 .
| 【1】 Fakhoury, S.A., Lee, H.T., Reed, J.E., Schlosser, K.M., Sexton, K.E., Tecle, H., Winters, R.T. (Pfizer, Inc.). 4-Phenylamino-quinazolin-6-yl-amides. EP 1746999, JP 200753668, JP 2009007363, US 2005250761, US 7772243, WO 2005107758. |
| 【2】 Bridges, A.J., Horne, N.M., Jacks, T.E. et al. (Pfizer, Inc.). Preparation of substituted quinazolines. JP 2006517959, US 2004158065, WO 2004069791. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| （XXVI) | 68482 | (E)-methyl 4-(piperidin-1-yl)but-2-enoate | C10H17NO2 | 详情 | 详情 | |
| (IV) | 68473 | 4-(piperidin-1-yl)-2-butenoyl chloride；(E)-4-(piperidin-1-yl)but-2-enoyl chloride | C9H14ClNO | 详情 | 详情 | |
| (X) | 10158 | Piperidine | 110-89-4 | C5H11N | 详情 | 详情 |
| (XI) | 26358 | methyl (E)-4-bromo-2-butenoate | 1117-71-1 | C5H7BrO2 | 详情 | 详情 |
| (XIII) | 68477 | (E)-N-(4-((3-chloro-4-fluorophenyl)(3,4-dimethoxybenzyl)amino)-7-methoxyquinazolin-6-yl)-4-(piperidin-1-yl)but-2-enamide | C33H35ClFN5O4 | 详情 | 详情 | |
| (XVIII) | 19142 | 4-chloro-7-fluoro-6-nitroquinazoline | C8H3ClFN3O2 | 详情 | 详情 | |
| (XIX) | 18688 | 3-Chloro-4-fluorophenylamine; 3-Chloro-4-fluoroaniline | 367-21-5 | C6H5ClFN | 详情 | 详情 |
| (XXI) | 18304 | 3,4-Dimethoxybenzaldehyde; Veratraldehyde | 120-14-9 | C9H10O3 | 详情 | 详情 |
| (XXII) | 68478 | 3-chloro-N-(3,4-dimethoxybenzyl)-4-fluoroaniline | C15NClFO2 | 详情 | 详情 | |
| (XXIII) | 68479 | N-(3-chloro-4-fluorophenyl)-N-(3,4-dimethoxybenzyl)-6-fluoro-7-nitroquinazolin-4-amine | C23H17ClF2N4O4 | 详情 | 详情 | |
| (XXIV) | 68480 | N-(3-chloro-4-fluorophenyl)-N-(3,4-dimethoxybenzyl)-6-methoxy-7-nitroquinazolin-4-amine | C24H20ClFN4O5 | 详情 | 详情 | |
| (XXV) | 68481 | N4-(3-chloro-4-fluorophenyl)-N4-(3,4-dimethoxybenzyl)-6-methoxyquinazoline-4,7-diamine | C24H22ClFN4O3 | 详情 | 详情 | |
| (XXVII) | 26709 | (E)-4-(1-piperidinyl)-2-butenoic acid；(E)-4-(piperidin-1-yl)but-2-enoic acid | C9H15NO2 | 详情 | 详情 |