【结 构 式】 |
【分子编号】19142 【品名】4-chloro-7-fluoro-6-nitroquinazoline 【CA登记号】 |
【 分 子 式 】C8H3ClFN3O2 【 分 子 量 】227.5819432 【元素组成】C 42.22% H 1.33% Cl 15.58% F 8.35% N 18.46% O 14.06% |
合成路线1
该中间体在本合成路线中的序号:(III)Nitration of quinazolinone (I) with fuming HNO3 in H2SO4 at 100 C gave a mixture of 6-nitro and 8-nitroquinazolines, from which the desired 6-isomer was isolated by recrystallization from AcOH. Subsequent treatment with refluxing SOCl2 and a catalytic amount of DMF gave chloride (III), which was condensed with 3-bromoaniline (IV) in isopropanol to afford anilinoquinazoline (V). Reaction with sodium alkoxide (VI) in refluxing THF provided ether (VII). Then, the nitro group was reduced with Fe dust and AcOH in aqueous ethanol to give amine (VIII). Finally, condensation with acrylic acid (X) using 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide.HCl (EDC) in DMF yielded the target acrylamide.
【1】 Rewcastle, G.W.; et al.; Tyrosine kinase inhibitors. 9. Synthesis and evaluation of fused tricyclic quinazoline analogues as ATP site inhibitors of the tyrosine kinase activity of the epidermal growth factor receptor. J Med Chem 1996, 39, 4, 918. |
【2】 Dobrusin, E.M.; Bridges, A.J.; Zhou, H.; Smaill, J.B.; Doherty, A.M.; Denny, W.A.; McNamara, D.J.; Showalter, H.D. (Pfizer Inc.); Irreversible inhibitors of tyrosine kinases. JP 2000508657; WO 9738983 . |
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) | 19140 | 7-fluoro-4(3H)-quinazolinone | C8H5FN2O | 详情 | 详情 | |
(II) | 19141 | 7-fluoro-6-nitro-4(3H)-quinazolinone | C8H4FN3O3 | 详情 | 详情 | |
(III) | 19142 | 4-chloro-7-fluoro-6-nitroquinazoline | C8H3ClFN3O2 | 详情 | 详情 | |
(IV) | 19136 | 3-bromoaniline; 3-bromophenylamine; 3-bromobenzenamine | 591-19-5 | C6H6BrN | 详情 | 详情 |
(V) | 19144 | N-(3-bromophenyl)-N-(7-fluoro-6-nitro-4-quinazolinyl)amine; N-(3-bromophenyl)-7-fluoro-6-nitro-4-quinazolinamine | C14H8BrFN4O2 | 详情 | 详情 | |
(VI) | 19145 | 3-(4-Morpholinyl)-1-propanol sodium salt | C7H14NNaO2 | 详情 | 详情 | |
(VII) | 19146 | N-(3-bromophenyl)-7-[3-(4-morpholinyl)propoxy]-6-nitro-4-quinazolinamine; N-(3-bromophenyl)-N-[7-[3-(4-morpholinyl)propoxy]-6-nitro-4-quinazolinyl]amine | C21H22BrN5O4 | 详情 | 详情 | |
(VIII) | 19147 | N(4)-(3-bromophenyl)-7-[3-(4-morpholinyl)propoxy]-4,6-quinazolinediamine; N-[6-amino-7-[3-(4-morpholinyl)propoxy]-4-quinazolinyl]-N-(3-bromophenyl)amine | C21H24BrN5O2 | 详情 | 详情 | |
(IX) | 19139 | acrylic acid | 79-10-7 | C3H4O2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号:(I)4-Chloro-7-fluoro-6-nitroquinazoline (I) was condensed with 3-chloro-4-fluoroaniline (II) to afford the 4-anilino quinazoline (III). Displacement of the activated fluorine of (III) with the potassium alkoxide of morpholinopropanol (IV) gave the morpholinopropyl ether (V). Subsequent reduction of the nitro group of (V), either using iron dust and acetic acid or catalytic hydrogenation over Raney-Ni, furnished aminoquinazoline (VI). This was finally condensed with acrylic acid (VII), via activation as the mixed anhydride with isobutyl chloroformate or using EDC as the coupling reagent, to provide the title acrylamide.
【1】 Loo, J.A.; Rewcastle, G.W.; Smaill, J.B.; 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 baring additional solubilizing functions. J Med Chem 2000, 43, 7, 1380. |
【2】 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; US 6344455; WO 0031048 . |
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) | 19142 | 4-chloro-7-fluoro-6-nitroquinazoline | C8H3ClFN3O2 | 详情 | 详情 | |
(II) | 18688 | 3-Chloro-4-fluorophenylamine; 3-Chloro-4-fluoroaniline | 367-21-5 | C6H5ClFN | 详情 | 详情 |
(III) | 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 |
(IV) | 54957 | 3-(4-morpholinyl)-1-propanol | C7H15NO2 | 详情 | 详情 | |
(V) | 54958 | N-(3-chloro-4-fluorophenyl)-7-[3-(4-morpholinyl)propoxy]-6-nitro-4-quinazolinamine; N-(3-chloro-4-fluorophenyl)-N-{7-[3-(4-morpholinyl)propoxy]-6-nitro-4-quinazolinyl}amine | C21H21ClFN5O4 | 详情 | 详情 | |
(VI) | 54959 | N-{6-amino-7-[3-(4-morpholinyl)propoxy]-4-quinazolinyl}-N-(3-chloro-4-fluorophenyl)amine; N~4~-(3-chloro-4-fluorophenyl)-7-[3-(4-morpholinyl)propoxy]-4,6-quinazolinediamine | C21H23ClFN5O2 | 详情 | 详情 | |
(VII) | 19139 | acrylic acid | 79-10-7 | C3H4O2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号:(XVIII)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 |
合成路线4
该中间体在本合成路线中的序号:(XVIII)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 |