2-Amino-4-fluorobenzoic acid -Drug Synthesis Database

【结构式】

【分子编号】10805

【品名】2-Amino-4-fluorobenzoic acid

【CA登记号】446-32-2

【分子式】C₇H₆FNO₂

【分子量】155.1285832

【元素组成】C 54.2% H 3.9% F 12.25% N 9.03% O 20.63%

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：(V)

Flosequinan has been synthesized by two new related ways: 1) The reaction of 2-chloro-4-fluorobenzoic acid (I) with refluxing aqueous methylamine Cu powder and CuCl2 gives 4-fluoro-2-(methylamino)benzoic acid (II), which is cyclized with phosgene to yield 7-fluoro-1-methyl-1,2-dihydro-4H-3,1-benzoxazine-2,4-dione (III). The reaction of (III) with dimethyl sulfoxide and NaH in toluene affords 4-fluoro-2-(methylamino)-alpha-(methylsulfinyl)acetophenone (IV), which is finally cyclized with refluxing triethyl orthoformate. 2) The reaction of 2-amino-4-fluorobenzoic acid (V) with phosgene as before gives the corresponding benzoxazine (VI), which is treated with dimethyl sulfoxide and NaH in refluxing toluene to afford 2-amino-4-fluoro-alpha-(methylsulfinyl)acetophenone (VII). The cyclization of (VII) with refluxing trimethyl orthoformate gives 7-fluoro-3-(methylsulfinyl)quinolin-4(1H)-one (VIII), which is finally methylated with dimethyl sulfate and KOH in water.

参考文献中间体

合成目标

【1】 Birch, A.M.; Maclean, L.; Robinson, K.; Davies, R.V.; Syntheses of flosequinan: A novel 4-quinolone shown to be useful in congestive heart failureSyntheses of flosequinan: A novel 4-quinolone shown to be useful in congestive heart failure. J Chem Soc - Perkins Trans I 1994, 4, 387.

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)	10801	2-Chloro-4-fluorobenzoic acid; 4-Fluoro-2-chlorobenzoic acid	2252-51-9	C₇H₄ClFO₂	详情	详情
(II)	10802	4-Fluoro-2-(methylamino)benzoic acid		C₈H₈FNO₂	详情	详情
(III)	10803	7-Fluoro-1-methyl-2H-3,1-benzoxazine-2,4(1H)-dione		C₉H₆FNO₃	详情	详情
(IV)	10804	1-[4-Fluoro-2-(methylamino)phenyl]-2-(methylsulfinyl)-1-ethanone		C₁₀H₁₂FNO₂S	详情	详情
(V)	10805	2-Amino-4-fluorobenzoic acid	446-32-2	C₇H₆FNO₂	详情	详情
(VI)	10806	7-Fluoro-2H-3,1-benzoxazine-2,4(1H)-dione		C₈H₄FNO₃	详情	详情
(VII)	10807	1-(2-Amino-4-fluorophenyl)-2-(methylsulfinyl)-1-ethanone		C₉H₁₀FNO₂S	详情	详情
(VIII)	10808	7-Fluoro-3-(methylsulfinyl)-4(1H)-quinolinone		C₁₀H₈FNO₂S	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XIV)

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