Sodium Carbonate → 6-((1R,2S)-2-Aminocyclohexylamino)-7-fluoro-4-(thiophen-2-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one

Temperature

80 °C

In a 30 mL sealed cap glass vial, tert-butyl (1S,2R)-2-(4-chloro-2-(2,4-dimethoxybenzyl)-7-fluoro-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)cyclohexylcarbamate (300 mg, 0.546 mmol), 4,4,5,5-tetramethyl-2-(thiophen-2-yl)-1,3,2-dioxaborolane (172 mg, 0.820 mmol), and trans-dichloro-bis(triphenylphosphine)palladium-II (38.4 mg, 0.055 mmol) were dissolved in dioxane (5 mL). An aqueous solution of 2N Na2CO3 (0.5 mL) was added, the cap was sealed, and the mixture was allowed to react at 85° C. for 3 h. The reaction mixture was subsequently diluted with water (5 mL) and extracted into EtOAc (2×30 mL). The organic layer was dried over sodium sulfate and evaporated. The resulting residue was treated with TFA (4 mL) and heated at 80° C. for 1 h to remove the protecting groups. Next, TFA was evaporated from the reaction mixture. The product was reconstituted in DMSO (8 mL) and was then purified via preparative HPLC eluting with water (0.05% TFA) and ACN (15-45% gradient, 0.035% TFA). The pure fractions were combined and evaporated to a minimal volume. Saturated aq NaHCO3 (10 mL) was added and the mixture was extracted with EtOAc (3×25 mL). The organic layers were combined, dried over sodium sulfate, and evaporated to give the title compound as a pale yellow solid (83 mg, 44%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.16-1.80 (m, 8 H), 3.18 (br s, 1 H), 3.86-4.11 (m, 1 H), 4.39 (s, 2 H), 6.60 (d, J=6.57 Hz, 1 H), 7.13 (dd, J=5.05, 3.79 Hz, 1 H), 7.60 (dd, J=5.18, 1.14 Hz, 1 H), 8.39 (s, 1 H), 9.00 (dd, J=3.79, 1.01 Hz, 1 H). [M+H] calc'd for C17H19FN4OS, 347; found, 347.

1. customIn a 30 mL sealed
2. customthe cap was sealed
3. customto react at 85° C. for 3 h
4. extractionextracted into EtOAc (2×30 mL)
5. dry with materialThe organic layer was dried over sodium sulfate
6. customevaporated
7. additionThe resulting residue was treated with TFA (4 mL)
8. customto remove the protecting groups
9. customNext, TFA was evaporated from the reaction mixture
10. customwas then purified via preparative HPLC
11. washeluting with water (0.05% TFA) and ACN (15-45% gradient, 0.035% TFA)
12. customevaporated to a minimal volume
13. additionSaturated aq NaHCO3 (10 mL) was added
14. extractionthe mixture was extracted with EtOAc (3×25 mL)
15. dry with materialdried over sodium sulfate
16. customevaporated

ORD record

ord-fdbde5880e654fc39e0809bc6ff2e649

Source dataset

uspto-grants-2015_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09108970B2