Diisopropylethylamine → (S)-tert-butyl 2-(4-chlorophenyl)-3-(4-(5-(3-fluorophenoxy)-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazin-1-yl)-3-oxopropyl(isopropyl)carbamate

HRID 387595Notes

Reaction equation

HRID 387595 reaction equation
CCN(C(C)C)C(C)C.Cl.Cl.[F:12][C:13]1[CH:14]=[C:15]([CH:32]=[CH:33][CH:34]=1)[O:16][C:17]1[C:18]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[C:19]2[CH:25]=[N:24][NH:23][C:20]2=[N:21][CH:22]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[C:57]([O:61][C:62]([N:64]([CH:77]([CH3:79])[CH3:78])[CH2:65][C@H:66]([C:70]1[CH:75]=[CH:74][C:73]([Cl:76])=[CH:72][CH:71]=1)[C:67](O)=[O:68])=[O:63])([CH3:60])([CH3:59])[CH3:58]>C(Cl)Cl>[Cl:76][C:73]1[CH:74]=[CH:75][C:70]([C@H:66]([C:67]([N:29]2[CH2:30][CH2:31][N:26]([C:18]3[C:17]([O:16][C:15]4[CH:32]=[CH:33][CH:34]=[C:13]([F:12])[CH:14]=4)=[CH:22][N:21]=[C:20]4[NH:23][N:24]=[CH:25][C:19]=34)[CH2:27][CH2:28]2)=[O:68])[CH2:65][N:64]([CH:77]([CH3:78])[CH3:79])[C:62](=[O:63])[O:61][C:57]([CH3:59])([CH3:58])[CH3:60])=[CH:71][CH:72]=1

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 2733207O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborateHCID 59564929(2S)-3-[tert-butoxycarbonyl(isopropyl)amino]-2-(4-chlorophenyl)propanoic acidHCID 687580405-(3-fluorophenoxy)-4-(piperazin-1-yl)-1H-pyrazolo[3,4-b]pyridine dihydrochloride

Product 1

HCID 68763803(S)-tert-butyl 2-(4-chlorophenyl)-3-(4-(5-(3-fluorophenoxy)-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazin-1-yl)-3-oxopropyl(isopropyl)carbamate

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

DIEA (0.0271 mL, 0.155 mmol) was added to 5-(3-fluorophenoxy)-4-(piperazin-1-yl)-1H-pyrazolo[3,4-b]pyridine dihydrochloride (0.015 g, 0.0388 mmol), 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (0.0150 g, 0.0466 mmol) and (S)-3-(tert-butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)propanoic acid (0.0133 g, 0.0388 mmol, see Example B) in DCM (1 mL) and stirred at room temperature for 30 minutes. The reaction was then concentrated to dryness. The resulting residue was dissolved in THF/MeOH (2 mL, 1:1), and an aqueous LiOH solution (1 mL, 2M) was added. The reaction was stirred for 30 minutes, and then ether (20 mL) was added. The organic layer was separated, washed with brine (10 mL), and dried over sodium sulfate. After removal of the solvent, the resulting residue was purified by column chromatography (hexane:ethyl acetate, 1:1) to give (S)-tert-butyl 2-(4-chlorophenyl)-3-(4-(5-(3-fluorophenoxy)-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazin-1-yl)-3-oxopropyl(isopropyl)carbamate as a solid. The solid was dissolved in DCM (1 mL), and TFA (0.4 mL) was added. The reaction was stirred at room temperature for 30 minutes and concentrated to dryness. The residue was dissolved in DCM (0.5 mL), and HCl in ether (1 mL, 2N) was added. The resulting solid was collected by filtration to give (S)-2-(4-chlorophenyl)-1-(4-(5-(3-fluorophenoxy)-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one (0.006 g, 25%). MS APCI (+) m/z 537.3 detected.

Workup

  1. concentrationThe reaction was then concentrated to dryness
  2. dissolutionThe resulting residue was dissolved in THF/MeOH (2 mL, 1:1)
  3. additionan aqueous LiOH solution (1 mL, 2M) was added
  4. stirringThe reaction was stirred for 30 minutes
  5. additionether (20 mL) was 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 resulting residue was purified by column chromatography (hexane:ethyl acetate, 1:1)

Sources & evidence

ORD record
ord-c3b58f81f4694ece80193a8e74ec852f
Source dataset
uspto-grants-2013_02
Patent number
US08372842B2

Reaction notes

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