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Citric Acid → (2S)-N-(5-Chloro-2-pyridinyl)-3-ethoxy-2-[[1-(3-methyl-4-pyridinyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]oxy]propanamide

HRID 1097998
Notes
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Reaction equation

HRID 1097998 reaction equation
[H-].[Na+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11](=[O:18])[C@@H:12]([OH:17])[CH2:13][O:14][CH2:15][CH3:16])=[N:8][CH:9]=1.Cl[C:20]1[N:25]=[CH:24][N:23]=[C:22]2[N:26]([C:29]3[CH:34]=[CH:33][N:32]=[CH:31][C:30]=3[CH3:35])[N:27]=[CH:28][C:21]=12.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11](=[O:18])[C@@H:12]([O:17][C:20]2[C:21]3[CH:28]=[N:27][N:26]([C:29]4[CH:34]=[CH:33][N:32]=[CH:31][C:30]=4[CH3:35])[C:22]=3[N:23]=[CH:24][N:25]=2)[CH2:13][O:14][CH2:15][CH3:16])=[N:8][CH:9]=1
ParticipantsConditionsProcedureWorkupSources & evidenceReaction notes

Participants

6

Reactant 4

HCID 311Citric AcidHCID 24758Sodium hydrideHCID 57438646HCID 57438646, compoundHCID 57504490HCID 57504490, compound

Product 1

HCID 57504364(2S)-N-(5-Chloro-2-pyridinyl)-3-ethoxy-2-[[1-(3-methyl-4-pyridinyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]oxy]propanamideYield 100.6%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
0 °C

Procedure

60% Sodium hydride in mineral oil (48.8 mg, 1.22 mmol) was added in one portion to (S)—N-(5-chloropyridin-2-yl)-3-ethoxy-2-hydroxypropanamide (Intermediate H3) (199 mg, 0.81 mmol) in anhydrous THF (5 mL) cooled to 0° C. under nitrogen. The resulting suspension was stirred at 0° C. for 10 minutes and then 4-chloro-1-(3-methylpyridin-4-yl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate M1) (200 mg, 0.81 mmol) added portionwise over 1 minute. The mixture was stirred at 0° C. for 15 mins, allowed to warm slowly to ambient temperature and stirred for 2 hours. 1M citric acid (2 mL) was added and the mixture extracted with ethyl acetate (2×20 mL). The organic extracts were washed with water (15 mL) and brine (15 mL), dried (MgSO4) and evaporated. The residue was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in EtOAc to afford (2S)—N-(5-chloropyridin-2-yl)-3-ethoxy-2-[1-(3-methylpyridin-4-yl)pyrazolo[4,5-e]pyrimidin-4-yl]oxypropanamide (370 mg, 100%). 1H NMR (400 MHz, CDCl3) δ 1.23 (3H, t), 2.34 (3H, s), 3.61-3.69 (2H, m), 4.06-4.14 (2H, m), 6.05 (1H, t), 7.49 (1H, d), 7.68 (1H, dd), 8.22 (1H, dd), 8.23-8.25 (1H, m), 8.44 (1H, s), 8.61 (1H, s), 8.63 (1H, dd), 8.69 (1H, s), 8.76 (1H, s); m/z (ESI+) (M+H)+=454; HPLC tR=1.93 min.

Workup

  1. stirringThe mixture was stirred at 0° C. for 15 mins
  2. temperatureto warm slowly to ambient temperature
  3. stirringstirred for 2 hours
  4. extractionthe mixture extracted with ethyl acetate (2×20 mL)
  5. washThe organic extracts were washed with water (15 mL) and brine (15 mL)
  6. dry with materialdried (MgSO4)
  7. customevaporated
  8. customThe residue was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in EtOAc

Sources & evidence

ORD record
ord-71514b3fd44f4b42afb5265da0239c67
Source dataset
uspto-grants-2012_03
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US08143263B2

Reaction notes

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