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【结 构 式】

【分子编号】67510

【品名】2,3,4-trifluoro-5-nitrobenzoic acid

【CA登记号】 

【 分 子 式 】C7H2F3NO4

【 分 子 量 】221.092

【元素组成】C 38.03% H 0.91% F 25.78% N 6.33% O 28.95%

与该中间体有关的原料药合成路线共 1 条

合成路线1

该中间体在本合成路线中的序号:(II)

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 .

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