Methanaminium, N-((1H-benzotriazol-1-yloxy)(dimethylamino)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1) → Methyl 3-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]-5-methylbenzoate

3-Methyl-5-[(methyloxy)carbonyl]benzoic acid (2.91 g, 15.00 mmol) was partially dissolved in dichloromethane (DCM) (500 mL) with stirring under argon at room temperature. HBTU (5.69 g, 15.00 mmol) was added followed by 5-(aminomethyl)-1,6-diethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine hydrochloride (5.10 g, 15 mmol), and then TEA (4.18 mL, 30.0 mmol). The mixture was stirred under argon overnight. The solvent was concentrated and the residue partitioned between EtOAc (300 mL) and water (100 mL). The organic phase was washed with water (3×100 mL), brine, dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product. This was purified by CombiFlash on a 120 g silica column eluted with 35-100% EtOAc in hexane. The purified product was taken up in 300 mL of EtOAc, and washed with 50 mL of 1N NaOH, and then with water (3×100 mL), and 50 mL of brine, dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound as a white solid. LC-MS m/z 480.0 (M+H)+, 0.81 min (ret time); mp 89-93° C.; analytical HPLC shows 95.4% purity, (ret time 12.251 min).

1. stirringThe mixture was stirred under argon overnight
2. concentrationThe solvent was concentrated
3. customthe residue partitioned between EtOAc (300 mL) and water (100 mL)
4. washThe organic phase was washed with water (3×100 mL), brine
5. dry with materialdried over anhydrous sodium sulfate
6. filtrationfiltered
7. concentrationconcentrated
8. customto give the crude product
9. customThis was purified by CombiFlash on a 120 g silica column
10. washeluted with 35-100% EtOAc in hexane
11. washwashed with 50 mL of 1N NaOH
12. dry with materialwith water (3×100 mL), and 50 mL of brine, dried over anhydrous sodium sulfate
13. filtrationfiltered
14. concentrationconcentrated

ORD-Eintrag

ord-19ab3e8468e245a6a7b9cc460056a92a

Quelldatensatz

uspto-grants-2011_11

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US08067408B2