2,3,4-trifluorobenzoic acid -Drug Synthesis Database

【结构式】

【分子编号】34622

【品名】2,3,4-trifluorobenzoic acid

【CA登记号】61079-72-9

【分子式】C₇H₃F₃O₂

【分子量】176.0948296

【元素组成】C 47.75% H 1.72% F 32.37% O 18.17%

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：(I)

The condensation of 2,3,4-trifluorobenzoic acid (I) with 2-chloro-4-iodoaniline (II) in the presence of LDA in THF afforded the aryl anthranilic acid (III), which was then coupled with O-(cyclopropylmethyl)hydroxylamine (IV) using bromo-tris(pyrrolidino)phosphonium hexafluorophosphate (PyBrOP) to furnish the title hydroxamate.

参考文献中间体

合成目标

【1】 Tecle, H.; Dudley, D.T.; Bridges, A.J.; Barrett, S.D.; Saltiel, A.R.; Doherty, A.M. (Pfizer Inc.); 4-Bromo or 4-iodo phenylamino benzhydroxamic acid derivs. and their use as MEK inhibitors. EP 0993439; WO 9901426 .

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)	34622	2,3,4-trifluorobenzoic acid	61079-72-9	C₇H₃F₃O₂	详情	详情
(II)	34623	2-chloro-4-iodophenylamine; 2-chloro-4-iodoaniline	42016-93-3	C₆H₅ClIN	详情	详情
(III)	34624	2-(2-chloro-4-iodoanilino)-3,4-difluorobenzoic acid		C₁₃H₇ClF₂INO₂	详情	详情
(IV)	34625	O-(cyclopropylmethyl)hydroxylamine; 1-[(aminooxy)methyl]cyclopropane		C₄H₉NO	详情	详情

合成路线2

该中间体在本合成路线中的序号：(I)

Nitration of 2,3,4-trifluorobenzoic acid (I) using HNO3 and H2SO4 gives 2,3,4-trifluoro-5-nitrobenzoic acid (II), which by displacement with NH4OH in H2O at 0 °C yields 4-amino-2,3-difluoro-5-nitrobenzoic acid (III). Fisher esterification of acid (III) with Me3SiCHN2 in THF/MeOH at 0 °C affords 4-amino-2,3-difluoro-5-nitrobezoic acid methyl ester (IV), which is condensed with 2-fluoroaniline (V) in xylene at 140 °C to provide methyl 4-amino-3-fluoro-2-(2-fluorophenylamino)-5-nitrobenzoic acid methyl ester (VI). Reduction and cyclization of intermediate (VI) using formic acid and Pd(OH)2/C in EtOH at 95 °C generates methyl 4-fluoro-5-(2-fluorophenylamino)-benzimidazole-6-carboxylate (VII), which by bromination with NBS and p-TsOH in DMF produces the bromo derivative (VIII). N-Methylation of compound (VIII) with methyl iodide by means of K2CO3 in DMF at 75 °C gives compound (IX), which is hydrolyzed with NaOH in THF/H2O to yield the free carboxylic acid (X). Condensation of carboxylic acid (X) with O-[2-(vinyloxy)ethyl]hydroxylamine (XI) using HOBt, Et3N and EDC in DMF affords amide (XII), which is finally treated with HCl in EtOH (1).
Intermediate O-[2-(vinyloxy)ethyl]hydroxylamine (XI) is prepared by Mitsnoubu reaction of 2-(vinyloxy)ethanol (XIII) with N-hydroxy - phthalimide (XIV) using PPh3 and DEAD in THF at 0 °C to give 2-[2-(vinyloxy)ethoxy]-1H-isoindole-1,3(2H)-dione (XV), which is finally treated with MeNHNH2 in CH2Cl2 .

参考文献中间体

合成目标

【1】 Barrett, S.D., Biwersi, C., Warmus, J.S., Tecle, H., Kaufman, M. (Pfizer, Inc.). Oxygenated esters of 4-iodo phenylamino benzhydroxamic acids. WO 2002006213; EP 1301472; CA 2416685; US 2004054172; US 6960614.

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)	34622	2,3,4-trifluorobenzoic acid	61079-72-9	C₇H₃F₃O₂	详情	详情
(II)	67510	2,3,4-trifluoro-5-nitrobenzoic acid		C₇H₂F₃NO₄	详情	详情
(III)	67511	4-amino-2,3-difluoro-5-nitrobenzoic acid		C₇H₄F₂N₂O₄	详情	详情
(IV)	67512	4-amino-2,3-difluoro-5-nitrobezoic acid methyl ester	284030-58-6	C₈H₆F₂N₂O₄	详情	详情
(V)	22296	2-fluorophenylamine; 2-fluoroaniline	348-54-9	C₆H₆FN	详情	详情
(VI)	67513	methyl 4-amino-3-fluoro-2-(2-fluorophenyl-amino)-5-nitrobenzoic acid methyl ester		C₁₅H₁₃F₂N₃O₄	详情	详情
(VII)	67514	methyl 4-fluoro-5-(2-fluorophenylamino)-benzimidazole-6-carboxylate		C₁₅H₁₁F₂N₃O₂	详情	详情
(VIII)	67515	methyl 5-((4-bromo-2-fluorophenyl)amino)-4-fluoro-1H-benzo[d]imidazole-6-carboxylate		C₁₅H₁₀BrF₂N₃O₂	详情	详情
(IX)	67516	methyl 5-((4-bromo-2-fluorophenyl)amino)-4-fluoro-1-methyl-1H-benzo[d]imidazole-6-carboxylate		C₁₆H₁₂BrF₂N₃O₂	详情	详情
(X)	67517	5-((4-bromo-2-fluorophenyl)amino)-4-fluoro-1-methyl-1H-benzo[d]imidazole-6-carboxylic acid		C₁₅H₁₀BrF₂N₃O₂	详情	详情
(XI)	67518	O-[2-(vinyloxy)ethyl]hydroxylamine	391212-29-6	C₄H₉NO₂	详情	详情
(XII)	67519	5-((4-bromo-2-fluorophenyl)amino)-4-fluoro-1-methyl-N-(2-(vinyloxy)ethoxy)-1H-benzo[d]imidazole-6-carboxamide		C₁₉H₁₇BrF₂N₄O₃	详情	详情
(XIII)	67520	2-(vinyloxy)ethanol	764-48-7	C₄H₈O₂	详情	详情
(XIV)	13505	N-Hydroxyphthalimide; 2-Hydroxy-1H-isoindole-1,3(2H)-dione	524-38-9	C₈H₅NO₃	详情	详情
(XV)	67521	2-[2-(vinyloxy)ethoxy]-1H-isoindole-1,3(2H)-dione		C₁₂H₁₁NO₄	详情	详情

Extended Information