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【结 构 式】

【分子编号】19140

【品名】7-fluoro-4(3H)-quinazolinone

【CA登记号】

【 分 子 式 】C8H5FN2O

【 分 子 量 】164.1389832

【元素组成】C 58.54% H 3.07% F 11.57% N 17.07% O 9.75%

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:(I)

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:(XVI)

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
Extended Information