Diisopropylethylamine → Tert-butyl(r)-3-(4-chlorophenyl)-1-(4-(3-((s)-2,3-dihydroxypropoxy)-5-phenyl-1h-pyrazolo[3,4-b]pyridin-4-yl)piperazin-1-yl)-1-oxopropan-2-ylcarbamate

DIEA (0.055 mL, 0.32 mmol) was added to a solution of (S)-3-(5-phenyl-4-(piperazin-1-yl)-1H-pyrazolo[3,4-b]pyridin-3-yloxy)propane-1,2-diol dihydrochloride (0.050 g, 0.079 mmol, see Example 15), (S)-2-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)acetic acid (0.018 g, 0.079 mmol) and TBTU (0.031 g, 0.095 mmol) in DCM (1 mL) and stirred at room temperature for 1 hour. The reaction was then concentrated to dryness, and the residue was dissolved in THF/MeOH (2 mL, 1:1), and an aqueous LiOH solution (1 mL, 2 M) was added. The mixture was stirred for 10 minutes. Ethyl acetate (20 mL) was then added, and the organic layer was separated, washed with brine (10 mL), and dried over sodium sulfate. After removal of the solvent, the residue was purified by column chromatography (ethyl acetate:MeOH, 20:1) to give tert-butyl(R)-3-(4-chlorophenyl)-1-(4-(3-((S)-2,3-dihydroxypropoxy)-5-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazin-1-yl)-1-oxopropan-2-ylcarbamate as a solid. The solid was then dissolved in DCM (1 mL), and TFA (0.4 mL) was added. The mixture was stirred at room temperature for 1 hour and concentrated to dryness. The resulting residue was dissolved in DCM (0.5 mL), and HCl in ether (1 mL, 2 N)) was added. The resulting solid was collected by filtration to give (1-(4-(3-((S)-2,3-dihydroxypropoxy)-5-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazin-1-yl)-2-((S)-pyrrolidin-2-yl)ethanone dihydrochloride (0.019 g, 43%). MS APCI (+) m/z 481.2 detected.

1. concentrationThe reaction was then concentrated to dryness
2. dissolutionthe residue was dissolved in THF/MeOH (2 mL, 1:1)
3. additionan aqueous LiOH solution (1 mL, 2 M) was added
4. stirringThe mixture was stirred for 10 minutes
5. additionEthyl acetate (20 mL) was then added
6. customthe organic layer was separated
7. washwashed with brine (10 mL)
8. dry with materialdried over sodium sulfate
9. customAfter removal of the solvent
10. customthe residue was purified by column chromatography (ethyl acetate:MeOH, 20:1)

ORD-Eintrag

ord-5a00a0f62c2249068f444efca7767eda

Quelldatensatz

uspto-grants-2013_02

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US08372842B2