Acetic Acid → 2-Amino-3-bromo-5-fluoropyridine

To a solution of 5-Fluoro-pyridin-2-ylamine (3.00 g, 26.8 mmol) in acetic acid (30.0 mL, 528 mmol) at 80° C. was added bromine (5.50 mL, 107 mmol) in acetic acid (5.50 mL, 96.7 mmol). The temperature was maintained for one hour. The reaction was poured over ice, neutralized, and extracted with EtOAc. The organic layer was purified with ISCO silica gel chromatography to afford 3-bromo-5-fluoro-pyridine-2-ylamine. 6-Fluoro-8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine was prepared from 3-bromo-5-fluoro-pyridine-2-ylamine in a manner analogous to Steps 2a-b to afford a white solid (80%). MP=243-246° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 8.97 (s, 1H), 7.99 (d, J=8.5 Hz, 1H), 6.28 (bs, 2H). MS=231.0 (MH)+. 105b) 6-Fluoro-8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine prepared from 8-Bromo-6-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine and (4-Methylsulfonylphenyl)boronic acid in a manner analogous to Step 2c to afford a tan solid (45%). MP=226-234° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.00 (s, 1H), 8.43 (d, J=7.8 Hz, 2H), 8.06-8.00 (m, 3H), 6.27 (bs, 2H), 3.28 (s, 3H). MS=307.0 (MH)+. 105c) [6-Fluoro-8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-bis-[3-(4-methyl-piperazin-1-yl)-phenyl]-amine was formed from 6-fluoro-8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine and 1-(3-bromo-phenyl)-4-methyl-piperazine in a manner analogous to Step 2d and was isolated as a yellow solid (14% yield). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.32 (m, 2H), 8.10 (d, J=7.8 Hz, 2H), 7.70 (d, J=9.4 Hz, 1H), 7.55 (s, 1H), 7.49-7.46 (m, 1H), 7.40-7.35 (m, 2H), 7.17-7.13 (m, 2H), 7.01 (s, 1H), 6.71 (d, J=8.0 Hz, 1H), 6.54 (d, J=8.0 Hz, 1H), 3.31 (bm, 4H), 3.18 (bm, 4H), 3.12 (s, 3H), 2.62 (bm, 4H), 2.58 (bm, 4H), 2.40 (s, 3H), 2.38 (s, 3H).

1. temperatureThe temperature was maintained for one hour
2. additionThe reaction was poured over ice
3. extractionneutralized, and extracted with EtOAc
4. customThe organic layer was purified with ISCO silica gel chromatography

ORD record

ord-61077224baf542c2af8925c4d1799706

Source dataset

uspto-grants-2013_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08501936B2