Reference of 366-99-4, These common heterocyclic compound, 366-99-4, name is 3-Fluoro-4-methoxyaniline, its traditional synthetic route has been very mature, but the traditional synthetic route has various shortcomings, such as complicated route, low yield, poor purity, etc, below Introduce a new synthetic route.
To cyanuric chloride (0.180 g,1 mmol) in 1,4-dioxane (1 mL) at about- 10 to-20 C was addedN, N-diisopropylethylamine (DIEA) (0.19 mL,lmmol) in CH3CN (1 mL) and3-fluoro-p-anisidine (0.14 g, 1 mmol) inCH3CN(1 mL) and stirred for about1 hour. The reaction mixture was then stirred at room temperature for about I hour. Then a solution of cycloheptylamine (0.13mL,1 mmol) and DIEA (0.19 mL, 1 mmol) inCH3CN (0.5 mL) was added and the reaction mixture was stirred overnightat rt. Then, N-methyl-4 (methylamino) piperidine (0.15 mL,1 mmol) and DIEA (0.19 mL,1 mmol) inCH3CN (0.5 mL) were added and the reaction mixture was refluxed overnight. The reaction mixture was worked-up using saturated sodium bicarbonate, and brine. The organic layer was separated and dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, 90: 9: 1 dichloromethane: methanol:conc. ammonium hydroxide) to give 158 (0.130 g, 28percent) ; TLC (silica gel, 90: 9 : 1,CH2CI2, CH30H, conc.NH40H), Rf 0.26) ;1H NMR (600MHz, CDC13, 55 C)8 7.74 (br s, 1H), 6.94 (br s, 1H), 6.81-6. 84(m, 2H), 4.83 (br resonance, 1H), 4.55 (s,1H), 3.98 (s,1H), 3.82 (s,3H), 2.97 (s, 3H), 2.94 (br d,J=11. 9 Hz, 2H), 2.29 (s, 3H), 2.06-2. 10(m, 2H), 1.93-1. 97(m, 2H), 1.84-1. 90(m, 2H), 1.44-1. 66(m, 12H). Compound 159 was’isolated as a by-product (55 mg) by column chromatography (silica gel, 90: 9: 1 dichloromethane: methanol:conc. ammonium hydroxide); TLC (silica gel, 90: 9: 1,CH2C12, CH30H, conc.NH40H), Rf 0.1) ; HPLC: Inertsil ODS-3V C18, 40: 30: 30 [KH2PO4(0. 01 M, pH 3.2) :CH30H : CH3CN], 264nm, Rt 8.3 min, 93.5percent purity; MS(ESp : m/z 443 (M+H, 100).
Statistics shows that 3-Fluoro-4-methoxyaniline is playing an increasingly important role. we look forward to future research findings about 366-99-4.
Reference:
Patent; REDDY US THERAPEUTICS, INC.; WO2004/26844; (2004); A1;,
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