反应详情

A solution of 4-chloro-5-ethynyl-3′-fluoro-6-[(E)-pyrrolidin-1-yldiazenyl]biphenyl-2-carboxylic acid (830 g, 2.2 mol), N,O-dimethylhydroxylamine hydrochloride (280 g, 2.9 mol), 1-hydroxybenzotriazole hydrate (360 g, 2.4 mol), and N,N-diisopropylethylamine (1.4 L, 7.8 mol) in tetrahydrofuran (5 L) was treated with EDCI HCl (520 g, 2.7 mol) and stirred at room temperature for 36 hours. The reaction mixture was cooled to approximately 5° C. and treated with 2.0 M hydrogen chloride in water (3.4 L, 6.7 mol) in portions while maintaining the internal temperature lower than 10° C. The organic layer was separated and the aqueous layer was extracted with tetrahydrofuran (2 L). The combined organic layers (˜6 L, pH ˜5) were washed with 2.0 M hydrogen chloride in water (2 L), 0.5 M sodium carbonate in water (2 L), and brine, dried over sodium sulfate, filtered, and concentrated to give a crude oil. This material was azeotroped with toluene to give the desired product (theoretical yield 930 g) as a brown oil. This material was used in the next step without further purification. A small sample was purified for spectroscopic analysis. LCMS for C21H21ClFN4O2 (M+H)+: m/z=415.1; Found: 415.0; 1H NMR (400 MHz, DMSO-d6): δ 7.44 (s, 1H), 7.35-7.29 (m, 1H), 7.12-7.06 (m, 1H), 6.93-6.84 (m, 2H), 4.48 (s, 1H), 3.62-3.58 (m, 2H), 3.29 (s, 3H), 3.25-3.17 (m, 2H), 2.93 (s, 15 H), 2.85 (s, 1.5H), 1.89-1.77 (m, 4H).

1. temperatureThe reaction mixture was cooled to approximately 5° C.
2. temperaturewhile maintaining the internal temperature lower than 10° C
3. customThe organic layer was separated
4. extractionthe aqueous layer was extracted with tetrahydrofuran (2 L)
5. washThe combined organic layers (˜6 L, pH ˜5) were washed with 2.0 M hydrogen chloride in water (2 L), 0.5 M sodium carbonate in water (2 L)
6. dry with materialbrine, dried over sodium sulfate
7. filtrationfiltered
8. concentrationconcentrated
9. customto give a crude oil
10. customThis material was azeotroped with toluene