Hydrochloric Acid → HCID 42878560, compound

4-Fluoro-3-methylphenylboric acid (4.62 g; 15 mmol) followed by KF solution (2M in water, 15 ml) and finally Pd(PPh3)4 (520 mg; 0.45 mmol; 3 mol %) were added under a nitrogen atmosphere to a solution of 6-bromoimidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester (4.04 g; 15 mmol) in acetonitrile (30 ml) in a Milestone 100 ml high-pressure vessel. The reaction vessel was rinsed with nitrogen, closed and irradiated in a microwave at 160° C. for 5 min. (DC control: n-hexane-ethyl acetate 1:1). Two batches of the same size were run in parallel and combined prior to processing. The precipitated product was filtered out and washed with diethyl ether. The black crystalline product was taken up in chloroform and filtered over celite. The clear filtrate was concentrated to small volume and crystallized out of diethyl ether. Yield: 4.5 g (50%). Stage 2. The 6-(4-fluoro-3-methylphenyl)-imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester (3.0 g, 10.1 mmol) was dissolved in ethanol (50 ml) and NaOH solution (20% in water, 4 ml) was added. The reaction batch was refluxed for 2 hours. On completion of the reaction the solvent was removed in a rotary evaporator and the residue taken up in as small an amount of water as possible. The solution was carefully adjusted to pH 3-4 with HCl solution (10% in water). The precipitated product was filtered and washed with water. The crude product was used in the next stage without further purification. Yield: 1.69 g (62%). Stage 3. Palladium on activated carbon (350 mg) was added to a solution of 6-(4-fluoro-3-methylphenyl)-imidazo[1,2-a]pyridine-2-carboxylic acid (1.69 g; 6.2 mmol) in a blend of HCl (4% in water, 20 ml) and ethanol (40 ml). The mixture was poured into an autoclave (stainless steel), the autoclave was closed and rinsed a few times with nitrogen. The autoclave was filled with hydrogen (8 bar) and the reaction batch stirred for 20 h at room temperature. The catalyst was filtered out over celite, and the solvent drawn off in a rotary evaporator at room temperature. The product was crystallized out of acetonitrile. As the reaction did not run to completion, the crude product mixture was dissolved again in a blend of HCl (4% in water, 15 ml) and ethanol (30 ml), palladium on activated carbon (260 mg) was added, and the mixture was poured into an autoclave (stainless steel), which was closed and rinsed a few times with nitrogen. The autoclave was filled with hydrogen (8 bar) and the reaction batch stirred for a further 12 hours at room temperature. The catalyst was filtered out over celite and the solvent drawn off in a rotary evaporator at room temperature. The product was crystallized out of acetonitrile. Yield: 609 mg (31%).

1. washThe reaction vessel was rinsed with nitrogen
2. customclosed
3. customirradiated in a microwave at 160° C. for 5 min. (DC control: n-hexane-ethyl acetate 1:1)
4. filtrationThe precipitated product was filtered out
5. washwashed with diethyl ether
6. filtrationfiltered over celite
7. concentrationThe clear filtrate was concentrated to small volume
8. customcrystallized out of diethyl ether
9. temperatureThe reaction batch was refluxed for 2 hours
10. customOn completion of the reaction the solvent
11. customwas removed in a rotary evaporator
12. filtrationThe precipitated product was filtered
13. washwashed with water
14. customThe crude product was used in the next stage without further purification
15. customthe autoclave was closed
16. washrinsed a few times with nitrogen
17. additionThe autoclave was filled with hydrogen (8 bar)
18. filtrationThe catalyst was filtered out over celite
19. customthe solvent drawn off in a rotary evaporator at room temperature
20. customThe product was crystallized out of acetonitrile
21. dissolutionthe crude product mixture was dissolved again in a blend of HCl (4% in water, 15 ml) and ethanol (30 ml), palladium on activated carbon (260 mg)
22. additionwas added
23. additionthe mixture was poured into an autoclave (stainless steel), which
24. customwas closed
25. washrinsed a few times with nitrogen
26. additionThe autoclave was filled with hydrogen (8 bar)
27. stirringthe reaction batch stirred for a further 12 hours at room temperature
28. filtrationThe catalyst was filtered out over celite
29. customthe solvent drawn off in a rotary evaporator at room temperature
30. customThe product was crystallized out of acetonitrile

ORD record

ord-70ac10f4dc974b6a82292c5dccec6378

Source dataset

uspto-grants-2012_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08288424B2