2,4-Dichloro-5-fluoropyrimidine → 3-(2-Chloro-5-fluoropyrimidin-4-yl)imidazo[1,2-a]pyridine

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Reaction Steps

To a solution of 3-bromo-imidazo[1,2-a]pyridine (1 g, 5.1 mmol) in dry THF (25 mL) under N2 at −78° C. was added n-BuLi (1.6 M in hexanes, 3.8 mL, 6.12 mmol) and the reaction mixture was stirred at that temperature for 1 hour. Then freshly dried zinc bromide (1.7 g, 7.65 mmol) in dry THF (15 mL) was added slowly and the reaction mixture was slowly warmed up to room temperature and 2,4-dichloro-5-fluoro-pyrimidine (848 mg, 5.1 mmol) and Pd(PPh3)4 (294 mg, 0.26 mmol) was added. After 16 hours at 75° C., the reaction mixture was then concentrated and directly purified by purified by flash chromatography (SiO2, 95:5:0.5/EtOAc:MeOH:TEA) to give 3-(2-chloro-5-fluoro-pyrimidin-4-yl)-imidazo[1,2-a]pyridine (Int-1) MS found for C11H16ClN4F as (M+H)+ 249.51. 1H NMR (400 MHz, CDCl3): δ 10.00 (d, J=6.8 Hz, 1H); 8.62 (s, 1H); 8.48 (d, J=3.2 Hz, 1H); 7.93 (d, J=9.2 Hz, 1H); 7.60 (t, J=7.2 Hz, 1H); 7.21 (t, J=7.2 Hz, 1H) To a solution of Int-1 (71 mg, 0.286 mmol), 4-amino-benzoic acid (47 mg, 0.344 mmol) in dioxane (3 mL), p-TSA (54 mg, 0.286 mmol) was added and heated in pressure vessel at 130° C. for 12 hours. Additional 4-amino-benzoic acid (23 mg, 0.172 mmol) and p-TSA (27 mg, 0.143 mmol) was added and heated at 130° C. After 12 hours, the reaction mixture was cooled to room temperature and diluted with dioxane gave 4-(5-Fluoro-4-imidazo[1,2-a]pyridin-3-yl-pyrimidin-2-ylamino)-benzoic acid (Int-2) as a tan solid which was filtered and dried. MS found for C18H12FN5O2 as (M+H)+ 350.30. To Int-2 (100 mg, 0.29 mmol) in DMF (8 mL), was added HATU (163 mg, 0.43 mmol), O-(tert-butyldimethylsilyl)hydroxylamine (84 mg, 0.57 mmol) and DIPEA (0.15 mL, 0.86 mmol) and stirred at room temperature. After 16 hours, the reaction mixture was diluted with and 1N HCl (3 mL and stirred at room temperature for 12 hours. The reaction mixture was then directly purified by preparative HPLC affording the title compound as tan solid, after lyophilization. MS found for C18H13FN6O2 as (M+H)+ 365.09. 1H NMR (400 MHz, dmso-d6): δ 11.03 (brs, 1H); 10.16 (d, J=7.2 Hz, 1H); 10.05 (s, 1H); 8.64 (d, J=3.6 Hz, 1H); 8.46 (d, J=4.0 Hz, 1H); 7.87-7.74 (m, 5H); 7.62 (t, J=7.6 Hz, 1H); 7.24 (t, J=6.4 Hz, 1H).

Provenance & Evidence