Lithium Hexamethyldisilazide → 5-(2-Fluoro-4-iodophenylamino)-imidazo[1,5-a]pyridine-6-carboxylic acid (2-vinyloxyethoxy)-amide

Temperature

2.5 °C

To a mechanically stirred solution of 5-(2-fluoro-4-iodophenylamino)imidazo[1,5-a]pyridine-6-carboxylic acid methyl ester (82.17 g, 0.2 mol) and O-(2-vinyloxyethyl)hydroxylamine (40.73 g, 0.382 mol) in dry THF (1.27 L) at 5° C. under N2 atmosphere, was added lithium bis(trimethylsilyl)amide as a solution in THF (1 L, 1 M, 1 mol) over 1 hr, maintaining the temperature below 10° C. The reaction mixture was stirred at 0-5° C. for 20 minutes before being quenched with addition water (200 ml) and saturated saline (350 mL). Volatile solvents were removed in vacuo and the residue diluted with water (1.5 L) and extracted 2-methyl tetrahydrofuran (3×1 L). The organic layers were washed water (500 mL), saturated saline (500 mL), dried (Na2CO3) and absorbed onto silica gel (200 g) and purified on silica gel (400 g) using ethyl acetate as eluent. The resultant crude product was triturated with tert-butyl methyl ether (400 mL) to yield the title compound as a brown solid (58.36 g, 60%). LCMS (Method B): RT=2.79 min, [M+H]+=483.

1. temperaturemaintaining the temperature below 10° C
2. custombefore being quenched with addition water (200 ml) and saturated saline (350 mL)
3. customVolatile solvents were removed in vacuo
4. additionthe residue diluted with water (1.5 L)
5. extractionextracted 2-methyl tetrahydrofuran (3×1 L)
6. washThe organic layers were washed water (500 mL), saturated saline (500 mL)
7. dry with materialdried (Na2CO3)
8. customabsorbed onto silica gel (200 g)
9. custompurified on silica gel (400 g)
10. customThe resultant crude product was triturated with tert-butyl methyl ether (400 mL)

ORD record

ord-2b47bcc6cade45faa18c40aa82f0de66

Source dataset

uspto-grants-2015_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09206174B2