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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

HRID 387599
Notes
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Reaction equation

HRID 387599 reaction equation
CCN([CH:7]([CH3:9])C)C(C)C.[ClH:10].Cl.[C:12]1([C:18]2[C:19]([N:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)=[C:20]3[C:26]([O:27][CH2:28][C@@H:29]([OH:32])[CH2:30][OH:31])=[N:25][NH:24][C:21]3=[N:22][CH:23]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[C:39]([O:43][C:44]([N:46]1[CH2:50][CH2:49][CH2:48][C@H:47]1[CH2:51][C:52](O)=O)=[O:45])([CH3:42])([CH3:41])[CH3:40].CN([C:58]([O:62]N1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[Cl:10][C:52]1[CH:51]=[CH:47][C:48]([CH2:49][C@@H:50]([NH:46][C:44](=[O:45])[O:43][C:39]([CH3:40])([CH3:41])[CH3:42])[C:58]([N:36]2[CH2:35][CH2:34][N:33]([C:19]3[C:18]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)=[CH:23][N:22]=[C:21]4[NH:24][N:25]=[C:26]([O:27][CH2:28][C@@H:29]([OH:32])[CH2:30][OH:31])[C:20]=34)[CH2:38][CH2:37]2)=[O:62])=[CH:9][CH:7]=1
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 688605(S)-2-(1-BOC-2-pyrrolidinyl)acetic acidHCID 2733207O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborateHCID 68756592(S)-3-(5-phenyl-4-(piperazin-1-yl)-1H-pyrazolo[3,4-b]pyridin-3-yloxy)propane-1,2-diol dihydrochloride

Product 1

HCID 131730207
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

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

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.

Workup

  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)

Sources & evidence

ORD record
ord-5a00a0f62c2249068f444efca7767eda
Source dataset
uspto-grants-2013_02
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US08372842B2

Reaction notes

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