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Citric Acid → (2S)-3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-(1-(3-cyano-2-methylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-N-(5-cyanopyridin-2-yl)propanamide

HRID 1098239
Notes
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Reaction equation

HRID 1098239 reaction equation
[H-].[Na+].[Si:3]([O:20][CH2:21][CH2:22][O:23][CH2:24][C@H:25]([OH:37])[C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]#[N:36])=[CH:31][N:30]=1)=[O:27])([C:16]([CH3:19])([CH3:18])[CH3:17])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:39]1[N:44]=[CH:43][N:42]=[C:41]2[N:45]([C:48]3[C:49]([CH3:56])=[C:50]([CH:53]=[CH:54][CH:55]=3)[C:51]#[N:52])[N:46]=[CH:47][C:40]=12.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.O.CCOC(C)=O>[Si:3]([O:20][CH2:21][CH2:22][O:23][CH2:24][C@H:25]([O:37][C:39]1[N:44]=[CH:43][N:42]=[C:41]2[N:45]([C:48]3[CH:55]=[CH:54][CH:53]=[C:50]([C:51]#[N:52])[C:49]=3[CH3:56])[N:46]=[CH:47][C:40]=12)[C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]#[N:36])=[CH:31][N:30]=1)=[O:27])([C:16]([CH3:17])([CH3:18])[CH3:19])([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
ParticipantsConditionsProcedureWorkupSources & evidenceReaction notes

Participants

8

Reactant 4

HCID 311Citric AcidHCID 24758Sodium hydrideHCID 57504676(S)-3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-N-(5-cyanopyridin-2-yl)-2-hydroxypropanamideHCID 575046943-(4-chloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2-methylbenzonitrile

Product 1

HCID 57504555
(2S)-3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-(1-(3-cyano-2-methylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-N-(5-cyanopyridin-2-yl)propanamide
Yield 35.1%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
0 °C

Procedure

Sodium hydride (60% in oil) (87 mg, 2.17 mmol) was added to (S)-3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-N-(5-cyanopyridin-2-yl)-2-hydroxypropanamide (Intermediate AU1) (484 mg, 0.99 mmol) in anhydrous THF (25 ml) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes and then 3-(4-chloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2-methylbenzonitrile (Intermediate AT2) (267 mg, 0.99 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 4 hours. The reaction mixture was neutralised with 1M citric acid and diluted with water and EtOAc. The organic layer was separated and the aqueous layer re-extracted with EtOAc. The combined organics were washed with saturated brine, dried (MgSO4) and evaporated. The crude product was purified by flash silica chromatography, eluting with 0 to 50% EtOAc in isohexane to afford the product (251 mg, 35.1%). m/z (ES+) (M+H)+=723.67; HPLC tR=3.75 min.

Workup

  1. temperatureto warm to room temperature
  2. stirringstirred for 4 hours
  3. customThe organic layer was separated
  4. extractionthe aqueous layer re-extracted with EtOAc
  5. washThe combined organics were washed with saturated brine
  6. dry with materialdried (MgSO4)
  7. customevaporated
  8. customThe crude product was purified by flash silica chromatography
  9. washeluting with 0 to 50% EtOAc in isohexane

Sources & evidence

ORD record
ord-d49388b84871490bb2fb0eb5b2e3953e
Source dataset
uspto-grants-2012_03
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US08143263B2

Reaction notes

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On this pageParticipantsConditionsProcedureWorkupSources & evidenceReaction notes