Water → HCID 57732800, compound

Temperature

150 °C

A solution of 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (36 mg, 0.0862 mmol), {5-[(2-methyl-1-pyrrolidinyl)methyl]-2-thienyl}boronic acid (19 mg, 0.0862 mmol) and potassium carbonate (71 mg, 0.517 mmol) was combined in a CEM microwave tube. To this mixture was added water (0.25 mL), dioxane (0.75 mL) and tetrakis(triphenylphosphine)palladium(0) (10 mg, 0.009 mmol). The vial was capped and reacted in a CEM microwave for 20 min at 150° C. To this reaction was added tetrakis(triphenylphosphine)palladium(0) (10 mg, 0.009 mmol) and reacted in a microwave for 20 min at 150° C. Additional tetrakis(triphenylphosphine)palladium(0) (10 mg, 0.009 mmol) was added, and the reaction was heated in the CEM microwave for an additional 20 min at 150° C. The reaction mixture was filtered through a 2 g SCX cartridge (pre-equilibrated with 3 mL H2O), eluting in sequence with water (3 mL), MeOH (9 mL), and a 2 M solution of NH3/MeOH (9 mL). The fraction containing crude product solution was concentrated under a stream of nitrogen, and the residue was taken up in DMSO (3 mL). This DMSO solution of crude product was purified as three separate injections (1 mL each) on the Agilent MDAP (Zorbax Eclipse XDB-C18 column: 21.2×50 mm) eluting at 20 mL per min for 1 min with 10% CH3CN/H2O (0.1% TFA) then a linear gradient of 10% CH3CN/H2O (0.1% TFA) to 95% CH3CN/H2O (0.1% TFA) over 8 min and holding at the final concentration for 30 sec. The two fractions containing product were filtered through a 500 mg Pharmasil CHQAX column (polymer bound ammonium hydroxide; United Chemical Technologies) to remove TFA (2 columns used per fraction) and concentrated under a stream of nitrogen at 40° C. to give 13 mg of the title compound (29.3%).

1. customThe vial was capped
2. customreacted in a CEM microwave for 20 min at 150° C
3. customreacted in a microwave for 20 min at 150° C
4. filtrationThe reaction mixture was filtered through a 2 g SCX cartridge (pre-equilibrated with 3 mL H2O)
5. washeluting in sequence with water (3 mL), MeOH (9 mL)
6. additionThe fraction containing crude product solution
7. concentrationwas concentrated under a stream of nitrogen
8. customThis DMSO solution of crude product was purified as three
9. customseparate injections (1 mL each) on the Agilent MDAP (Zorbax Eclipse XDB-C18 column: 21.2×50 mm)
10. washeluting at 20 mL per min for 1 min with 10% CH3CN/H2O (0.1% TFA)
11. concentrationconcentration for 30 sec
12. additionThe two fractions containing product
13. filtrationwere filtered through a 500 mg Pharmasil CHQAX column (polymer bound ammonium hydroxide; United Chemical Technologies)
14. customto remove TFA (2 columns used per fraction)
15. concentrationconcentrated under a stream of nitrogen at 40° C.

ORD record

ord-3f721b9da01e4de7827c7e74c01acff7

Source dataset

uspto-grants-2013_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08354406B2