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【结 构 式】 
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【分子编号】68469 【品名】N-(3-chloro-4-fluorophenyl)-7-methoxy-6-nitroquinazolin-4-amine 【CA登记号】 |
【 分 子 式 】C15H10ClFN4O3 【 分 子 量 】348.721 【元素组成】C 51.66% H 2.89% Cl 10.17% F 5.45% N 16.07% O 13.76% |
合成路线1
该中间体在本合成路线中的序号：(I)Acetylation of the diarylamine (I) with Ac2O yields acetamide (II), which is reduced at the nitro group by means of H2 over Raney Ni in THF to give 6-aminoquinazoline derivative (III). Condensation of amine (III) with 4-(piperidin-1-yl)-2-butenoyl chloride (IV) in DMA affords the butenamide derivative (V), which is then deacetylated with NaOH, yielding anhydrous dacomitinib (VI). Finally, crude dacomitinib (VI) is recrystallized in dichloroethane/water .
Anhydrous dacomitinib (VI) can also be obtained as follows: Reduction of the 6-nitroquinazoline derivative (I) with H2 over Raney Ni in THF yields the 6-aminoquinazoline derivative (VII), which is then condensed with 4-bromo-2-butenoyl chloride (VIII) in the presence of Et3N in THF to give the 4-bromo-2-butenamide derivative (IX). Finally, 4-bromoamide (IX) is condensed with piperidine (X) using Et3N in DMA .
4-Bromo-2-butenoyl chloride (VIII) is obtained by hydrolysis of methyl 4-bromocrotonate (XI) with Ba(OH)2 in EtOH/H2O to produce acid (XII), which is finally treated with (COCl)2 in the presence of DMF in CH2Cl2 .
Anhydrous dacomitinib (VI) is also obtained by N-deprotection of its 3,4-dimethoxybenzyl derivative (XIII) with TFA in THF .
| 【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. |
| 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) | 68469 | N-(3-chloro-4-fluorophenyl)-7-methoxy-6-nitroquinazolin-4-amine | C15H10ClFN4O3 | 详情 | 详情 | |
| (II) | 68470 | N-(3-chloro-4-fluorophenyl)-N-(7-methoxy-6-nitroquinazolin-4-yl)acetamide | C17H12ClFN4O4 | 详情 | 详情 | |
| (III) | 68471 | N-(6-amino-7-methoxyquinazolin-4-yl)-N-(3-chloro-4-fluorophenyl)acetamide | C17H14ClFN4O2 | 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 | |
| (V) | 68472 | (E)-N-(4-(N-(3-chloro-4-fluorophenyl)acetamido)-7-methoxyquinazolin-6-yl)-4-(piperidin-1-yl)but-2-enamide | C26H27ClFN5O3 | 详情 | 详情 | |
| (VI) | 68474 | (E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-(piperidin-1-yl)but-2-enamide | 1110813-31-4 | C24H25ClFN5O2 | 详情 | 详情 |
| (VII) | 68475 | N4 -(3-chloro-4-fluorophenyl)-7-methoxyquinazoline-4,6-diamine | C15H12ClFN4O | 详情 | 详情 | |
| (VIII) | 50564 | (E)-4-bromo-2-butenoyl chloride | C4H4BrClO | 详情 | 详情 | |
| (IX) | 68476 | (E)-N6-(5-bromopenta-1,3-dien-2-yl)-N4-(3-chloro-4-fluorophenyl)-7-methoxyquinazoline-4,6-diamine | C20H17BrClFN4O | 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 |
| (XII) | 50563 | (E)-4-bromo-2-butenoic acid | 13991-36-1 | C4H5BrO2 | 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 |
合成路线2
该中间体在本合成路线中的序号：(I)The 7-methoxy-6-nitroquinazoline derivative (I) can be prepared by cyclization of 2-amino-4-fluorobenzoic acid (XIV) with formamidine acetate (XV) in 2-methoxyethanol to yield 7-fluoroquinazolin-4(3H)-one (XVI), which is then nitrated with HNO3 and H2SO4 to give 7-fluoro-6-nitroquinazolin-4(3H)-one (XVII) (1). Chlorination of quinazolinone (XVII) with SOCl2 at reflux provides 4-chloro-7-fluoro-6-nitroquinazoline (XVIII) , which is then coupled with 3-chloro-4-fluoroaniline (XIX) by means of Et3N or PhNMe2 in i-PrOH to produce the diarylamine (XX). Finally, fluoroquinazoline (XX) is treated with MeOH and NaH in .
| 【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. |
| 【3】 Bridges, A.J., Klohs, W.D., Driscoll, D. (Pfizer, Inc.). N-[4-(3-Chloro-4-fluoro-phenylamino)-7-(3-morpholin-4-yl-propoxy)-quinazolin-6-yl]-acrylamide, an irreversible inhibitor of tyrosine kinases. EP 1131304, JP 2002530386, US 6344455, WO 2000031048. |
| 【4】 Smaill, J.B., Rewcastle, G.W., Loo, J.A. et al. Tyrosine kinase inhibitors. 17. Irreversible inhibitors of the epidermal growth factor receptor: 4-(Phenylamino) quinazoline- and 4-(phenylamino)pyrido[3,2-d]pyrimidine-6-acrylamides bearing additional solublizing functions. J Med Chem 2000, 43(7): 1380-97. |
| 【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 |
|---|---|---|---|---|---|---|
| (I) | 68469 | N-(3-chloro-4-fluorophenyl)-7-methoxy-6-nitroquinazolin-4-amine | C15H10ClFN4O3 | 详情 | 详情 | |
| (XIV) | 10805 | 2-Amino-4-fluorobenzoic acid | 446-32-2 | C7H6FNO2 | 详情 | 详情 |
| (XV) | 67709 | formamidine acetate | 3473-63-0 | CH4N2.C2H4O2 | 详情 | 详情 |
| (XVI) | 19140 | 7-fluoro-4(3H)-quinazolinone | C8H5FN2O | 详情 | 详情 | |
| (XVII) | 19141 | 7-fluoro-6-nitro-4(3H)-quinazolinone | C8H4FN3O3 | 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 |
| (XX) | 54956 | N-(3-chloro-4-fluorophenyl)-7-fluoro-6-nitro-4-quinazolinamine; N-(3-chloro-4-fluorophenyl)-N-(7-fluoro-6-nitro-4-quinazolinyl)amine | 162012-67-1 | C14H7ClF2N4O2 | 详情 | 详情 |