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

HRID 387573Notes

Reaction equation

HRID 387573 reaction equation
CCN(C(C)C)C(C)C.Cl.Cl.[N:12]1([C:18]2[CH:23]=[CH:22][N:21]=[C:20]3[NH:24][N:25]=[C:26]([O:27][CH2:28][CH2:29][OH:30])[C:19]=23)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.[C:31]([O:35][C:36]([N:38]([CH:51]([CH3:53])[CH3:52])[CH2:39][C@H:40]([C:44]1[CH:49]=[CH:48][C:47]([Cl:50])=[CH:46][CH:45]=1)[C:41](O)=[O:42])=[O:37])([CH3:34])([CH3:33])[CH3:32].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[Cl:50][C:47]1[CH:48]=[CH:49][C:44]([C@H:40]([C:41]([N:15]2[CH2:16][CH2:17][N:12]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]4[NH:24][N:25]=[C:26]([O:27][CH2:28][CH2:29][OH:30])[C:19]=34)[CH2:13][CH2:14]2)=[O:42])[CH2:39][N:38]([CH:51]([CH3:52])[CH3:53])[C:36](=[O:37])[O:35][C:31]([CH3:33])([CH3:32])[CH3:34])=[CH:45][CH:46]=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 687580382-(4-(piperazin-1-yl)-1H-pyrazolo[3,4-b]pyridin-3-yloxy)ethanol dihydrochloride

Product 1

HCID 68764786(S)-tert-butyl 2-(4-chlorophenyl)-3-(4-(3-(2-hydroxyethoxy)-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazin-1-yl)-3-oxopropyl(isopropyl)carbamate

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

DIEA (0.0815 mL, 0.468 mmol) was added to 2-(4-(piperazin-1-yl)-1H-pyrazolo[3,4-b]pyridin-3-yloxy)ethanol dihydrochloride (0.0472 g, 0.140 mmol), (S)-3-(tert-butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)propanoic acid (0.234 mL, 0.117 mmol, see Example B) and TBTU (0.0451 g, 0.140 mmol) in DCM (1 mL) and stirred at room temperature for 1 hour. The reaction was concentrated to dryness. The resulting residue was dissolved in THF/MeOH (2 mL, 1:1). A LiOH solution (1 mL, 2M) was added and stirred for 10 minutes. Ether (20 mL) was added. The organic layer was separated, washed with brine (5 mL), and dried over sodium sulfate. After removal of the solvent, the resulting residue was purified by chromatography (ethyl acetate) to give (S)-tert-butyl 2-(4-chlorophenyl)-3-(4-(3-(2-hydroxyethoxy)-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazin-1-yl)-3-oxopropyl(isopropyl)carbamate 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 then concentrated to dryness. The resulting residue was dissolved in DCM (0.5 mL), and HCl in ether (1 mL, 2N) was added. The solvent was removed, and the resulting solid was dissolved in MeOH (2 mL). A LiOH solution (2 mL, 2M) was added and stirred for 10 minutes. DCM (20 mL) and water (10 mL) were added. The organic layer was separated, dried over sodium sulfate and concentrated to give (S)-2-(4-chlorophenyl)-1-(4-(3-(2-hydroxyethoxy)-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one (0.018 g, 32%) as a solid. MS APCI (+) m/z 487.3 detected.

Workup

  1. concentrationThe reaction was concentrated to dryness
  2. dissolutionThe resulting residue was dissolved in THF/MeOH (2 mL, 1:1)
  3. additionA LiOH solution (1 mL, 2M) was added
  4. stirringstirred for 10 minutes
  5. additionEther (20 mL) was added
  6. customThe organic layer was separated
  7. washwashed with brine (5 mL)
  8. dry with materialdried over sodium sulfate
  9. customAfter removal of the solvent
  10. customthe resulting residue was purified by chromatography (ethyl acetate)

Sources & evidence

ORD record
ord-b9fe95ff6a6443c7b77bd52c4c41f432
Source dataset
uspto-grants-2013_02
Patent number
US08372842B2

Reaction notes

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