Hydrochloric Acid → HCID 54674361, compound

A suspension of tert-butyl 5-bromo-3-[(1S)-1-(2-chloro-6-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy}-3-fluorophenyl)ethyl]-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (29.2 mg, 0.0500 mmol), 1,5-dimethyl-1H-pyrazole-4-boronic acid, pinacol ester (20.7 mg, 0.0885 mmol), Pd(PPh3)4 (2.8 mg, 0.0024 mmol), and potassium carbonate (33.2 mg, 0.240 mmol) in a 4:1 mixture of 1,4-dioxane (2 mL) to H2O (0.5 mL) was subjected to microwave heating [Biotage, 95° C.] for 20 min. The reaction was again subjected to microwave heating for an additional 20 minutes, which resulted in protected intermediate, tert-butyl 3-[(1S)-1-(2-chloro-6-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy}-3-fluorophenyl)ethyl]-5-(1,5-dimethyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate. The microwave vial was opened, 4.0 M of HCl in 1,4-dioxane (1 mL, 4 mmol) was added to the stirring suspension, and the reaction was stirred at rt for 1 h, which lead to the BOC-protected intermediate, tert-butyl 3-[(1S)-1-(2-chloro-6-{[(2S)-2,3-dihydroxypropyl]oxy}-3-fluorophenyl)ethyl]-5-(1,5-dimethyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate. 37% HCl (1 mL, 10 mmol) was added and stirred for 1 h at rt. Additional 37% HCl (1 mL, 10 mmol) was added and the reaction was stirred at rt for 15 h. The reaction mixture was concentrated in vacuo. The sample was dissolved in a mixture of CH2Cl2 and MeOH, passed through a syringe filter to remove excess K2CO3, and concentrated in vacuo. The crude was adsorbed onto a pre-filled silica loading cartridge [RediSepRf, 5 gram] and purified using the Teledyne/ISCO purification system [RediSepRf 4 gram silica], eluting with a solvent gradient of 0-20% 7N NH3(MeOH):EtOAc. Fractions containing product were combined and concentrated in vacuo. The sample was dissolved in MeOH, syringe filtered, and purified a second time using MDP, under acidic conditions (TFA). Fractions containing product were combined and concentrated in vacuo. The sample was dissolved in minimal MeOH, syringe filtered, and purified a third time using HPLC, under acidic conditions (formic acid). Fractions containing product were combined and concentrated in vacuo, yielding the title material as a clear and colorless film. 1H NMR (400 MHz, CD3OD): δ=8.10 (br s, 1H), 7.44 (s, 1H), 7.39 (d, J=1.3 Hz, 1H), 7.36 (d, J=1.8 Hz, 1H), 7.08 (dd, J=8.8 Hz, 1H), 6.90 (dd, J=8.7, 4.2 Hz, 1H), 5.12 (br d, J=6.6 Hz, 1H), 3.83-3.90 (m, 1H), 3.81 (s, 3H), 3.76-3.80 (m, 1H), 3.70 (br s, 1H), 3.42-3.51 (m, 1H), 3.34-3.42 (m, 1H), 2.18 (s, 3H), 1.83 (d, J=7.1 Hz, 3H). MS (ES+): m/z 459.08/461.03 (100/74) [MH+]. HPLC: tR=2.93 min (ZQ3, polar—5 min).

1. stirringstirred for 1 h at rt
2. stirringthe reaction was stirred at rt for 15 h
3. concentrationThe reaction mixture was concentrated in vacuo
4. dissolutionThe sample was dissolved in a mixture of CH2Cl2 and MeOH
5. custompassed through a syringe
6. filtrationfilter
7. customto remove excess K2CO3
8. concentrationconcentrated in vacuo
9. custompurified
10. customthe Teledyne/ISCO purification system [RediSepRf 4 gram silica]
11. washeluting with a solvent gradient of 0-20% 7N NH3(MeOH)
12. additionFractions containing product
13. concentrationconcentrated in vacuo
14. dissolutionThe sample was dissolved in MeOH
15. filtrationsyringe filtered
16. custompurified a second time
17. additionFractions containing product
18. concentrationconcentrated in vacuo
19. dissolutionThe sample was dissolved in minimal MeOH
20. filtrationsyringe filtered
21. custompurified a third time
22. additionFractions containing product
23. concentrationconcentrated in vacuo

ORD record

ord-0626a8334ce34c40bb60f1e7a31f1172

Source dataset

uspto-grants-2013_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08445510B2