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Citric Acid → (2S)-N-(5-methylpyridin-2-yl)-2-[1-(3-methylpyridin-4-yl)pyrazolo[4,5-e]pyrimidin-4-yl]oxy-3-propan-2-yloxypropanamide

HRID 1098004
Notes
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Reaction equation

HRID 1098004 reaction equation
[H-].[Na+].[OH:3][C@@H:4]([CH2:15][O:16][CH:17]([CH3:19])[CH3:18])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][N:9]=1)=[O:6].Cl[C:21]1[N:26]=[CH:25][N:24]=[C:23]2[N:27]([C:30]3[CH:35]=[CH:34][N:33]=[CH:32][C:31]=3[CH3:36])[N:28]=[CH:29][C:22]=12.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[CH3:14][C:11]1[CH:12]=[CH:13][C:8]([NH:7][C:5](=[O:6])[C@@H:4]([O:3][C:21]2[C:22]3[CH:29]=[N:28][N:27]([C:30]4[CH:35]=[CH:34][N:33]=[CH:32][C:31]=4[CH3:36])[C:23]=3[N:24]=[CH:25][N:26]=2)[CH2:15][O:16][CH:17]([CH3:19])[CH3:18])=[N:9][CH:10]=1
ParticipantsConditionsProcedureWorkupSources & evidenceReaction notes

Participants

6

Reactant 4

HCID 311Citric AcidHCID 24758Sodium hydrideHCID 57438646HCID 57438646, compoundHCID 57504492HCID 57504492, compound2×

Product 1

HCID 57504371(2S)-N-(5-methylpyridin-2-yl)-2-[1-(3-methylpyridin-4-yl)pyrazolo[4,5-e]pyrimidin-4-yl]oxy-3-propan-2-yloxypropanamideYield 82.8%

Reagents, catalysts & solvents

1
HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
0 °C

Procedure

60% Sodium hydride in mineral oil (48.8 mg, 1.22 mmol) was added in one portion to (S)-2-hydroxy-3-isopropoxy-N-(5-methylpyridin-2-yl)propanamide (Intermediate C7) (194 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) as suspension in dry THF (4 mL) added dropwise 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 combined organic extracts were washed with water (15 mL) and brine (15 mL), dried (MgSO4) and evaporated. The residue was purified by flash silica chromatography with ethyl acetate to give the product (300 mg, 82%). 1H NMR (400 MHz, CDCl3) δ 1.17 (3H, d), 1.19 (3H, d), 2.29 (3H, s), 2.34 (3H, s), 3.69-3.76 (1H, m), 4.09 (2H, d), 6.01 (1H, t), 7.51 (1H, d), 7.53 (1H, dd), 8.09-8.10 (1H, m), 8.13 (1H, d), 8.43 (1H, s), 8.60 (1H, s), 8.62 (1H, dd), 8.67 (1H, s), 8.68 (1H, s); m/z (ESI+) (M+H)+=448; HPLC tR=1.78 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 combined 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 with ethyl acetate

Sources & evidence

ORD record
ord-b62458677b8d444a83ff7e089695dbbf
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