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【结 构 式】

【分子编号】68477

【品名】(E)-N-(4-((3-chloro-4-fluorophenyl)(3,4-dimethoxybenzyl)amino)-7-methoxyquinazolin-6-yl)-4-(piperidin-1-yl)but-2-enamide

【CA登记号】 

【 分 子 式 】C33H35ClFN5O4

【 分 子 量 】620.123

【元素组成】C 63.92% H 5.67% Cl 5.72% F 3.06% N 11.29% O 10.32%

与该中间体有关的原料药合成路线共 2 条

合成路线1

该中间体在本合成路线中的序号:(XIII)

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:(XIII)

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
Extended Information