7-fluoro-6-nitro-4(3H)-quinazolinone -Drug Synthesis Database

【结构式】

【分子编号】19141

【品名】7-fluoro-6-nitro-4(3H)-quinazolinone

【CA登记号】

【分子式】C₈H₄FN₃O₃

【分子量】209.1365832

【元素组成】C 45.95% H 1.93% F 9.08% N 20.09% O 22.95%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(II)

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.

参考文献中间体

合成目标

【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：(XVII)

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 .

参考文献中间体

合成目标

【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