反应详情

温度

2.5 °C

A solution of methyl 6-amino-4-chloro-3′-fluoro-5-[(trimethylsilyl)ethynyl]biphenyl-2-carboxylate (840 g, 2.2 mol) in tetrahydrofuran (12 L) was cooled with an ice-water bath under nitrogen and treated with boron trifluoride etherate (600 mL, 4.7 mol) dropwise [internal temperature changed from 1.4° C. to 4.4° C.] followed by tert-butyl nitrite (800 mL, 6.7 mol) dropwise over 20 minutes [internal temperature rose from 3.1° C. to 8.9° C.]. After the addition was complete a solid formed to give a suspension which was stirred at 0-5° C. for 3 hours. The reaction mixture was treated with pyrrolidine (650 mL, 7.8 mol) in portions over 10 minutes [internal temperature changed from 1° C. to 14° C. gradually] and the reaction mixture was stirred for additional 10 minutes. The reaction mixture was treated with 7.0 M ammonium chloride in water (2.5 L, 17 mol). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (1 L). The tetrahydrofuran layer was stirred with pre-mixed 2.0 M hydrogen chloride in water (1 L, 2.0 mol) and brine (2 L) for 10 minutes. The tetrahydrofuran layer was separated and stirred with 0.5 M sodium carbonate in water (4 L) and brine (1.0 L), and concentrated to give the crude desired product (theoretical yield 1.1 kg) 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 C23H26ClFN3O2Si (M+H)+: m/z=458.1; Found: 458.0; 1H NMR (400 MHz, DMSO-d6): δ 7.64 (s, 1H), 7.36-7.30 (m, 1 H), 7.13-7.10 (m, 1 H), 6.91-6.84 (m, 2 H), 3.70 (br s, 2 H), 3.52 (s, 3 H), 3.18 (br s, 2 H), 1.85 (br s, 4 H), 0.18 (s, 9 H).

1. custom[internal temperature rose from 3.1° C. to 8.9° C.]
2. additionAfter the addition
3. customformed
4. customto give a suspension which
5. customchanged from 1° C. to 14° C.
6. stirringwas stirred for additional 10 minutes
7. customThe organic layer was separated
8. extractionthe aqueous layer was extracted with ethyl acetate (1 L)
9. stirringThe tetrahydrofuran layer was stirred
10. customThe tetrahydrofuran layer was separated
11. stirringstirred with 0.5 M sodium carbonate in water (4 L) and brine (1.0 L)
12. concentrationconcentrated