Citric Acid → HCID 46938169, compound

HRID 655726Notes

Reaction equation

HRID 655726 reaction equation
[H-].[Na+].[OH:3][C@@H:4]([CH2:15][O:16][C@H:17]([CH3:30])[CH2:18][O:19][Si:20]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])[C:5]([NH:7][C:8]1[CH:13]=[N:12][C:11]([CH3:14])=[CH:10][N:9]=1)=[O:6].[Cl:31][C:32]1[C:33]([N:40]2[C:44]3=[N:45][CH:46]=[N:47][C:48](Cl)=[C:43]3[CH:42]=[N:41]2)=[C:34]([CH:37]=[CH:38][CH:39]=1)[C:35]#[N:36].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[Cl:31][C:32]1[CH:39]=[CH:38][CH:37]=[C:34]([C:35]#[N:36])[C:33]=1[N:40]1[C:44]2=[N:45][CH:46]=[N:47][C:48]([O:3][C@@H:4]([CH2:15][O:16][C@H:17]([CH3:30])[CH2:18][O:19][Si:20]([CH:27]([CH3:29])[CH3:28])([CH:21]([CH3:23])[CH3:22])[CH:24]([CH3:26])[CH3:25])[C:5]([NH:7][C:8]3[CH:13]=[N:12][C:11]([CH3:14])=[CH:10][N:9]=3)=[O:6])=[C:43]2[CH:42]=[N:41]1

Participants

6

Reactant 4

HCID 311Citric AcidHCID 24758Sodium hydrideHCID 575045663-chloro-2-(4-chloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)benzonitrileHCID 57504703(S)-2-hydroxy-N-(5-methylpyrazin-2-yl)-3-((R)-1-(triisopropylsilyloxy)propan-2-yloxy)propanamide

Product 1

HCID 46938169HCID 46938169, compoundYield 67.7%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
0 °C

Procedure

Sodium hydride (60% dispersion in mineral oil) (0.116 g, 2.89 mmol) was added to (S)-2-hydroxy-N-(5-methylpyrazin-2-yl)-3-((R)-1-(triisopropylsilyloxy)propan-2-yloxy)propanamide (Intermediate AZ2) (0.595 g, 1.45 mmol) in anhydrous THF (20 mL) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes and then 3-chloro-2-(4-chloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)benzonitrile (Intermediate AH6) (0.438 g, 1.31 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction mixture was adjusted to pH 7 by addition of 1M citric acid and the majority of the THF removed in vacuo. The reaction mixture was diluted with water (20 mL) and EtOAc (50 mL). The organic layer was separated and the aqueous layer re-extracted with EtOAc (2×100 mL). The combined organics were washed with saturated brine (75 mL), dried (MgSO4) and evaporated. The crude product was purified by flash silica chromatography, eluting with 50 to 100% EtOAc in isohexane to afford the product (0.590 g, 67.5%). 1H NMR (400 MHz, CDCl3) δ 0.98-1.08 (21H, m), 1.12-1.17 (3H, m), 2.54 (3H, s), 3.59-3.78 (3H, m), 4.21-4.26 (1H, m), 4.29-4.36 (1H, m), 6.02-6.06 (1H, m), 7.60-7.65 (1H, m), 7.78-7.81 (1H, m), 7.85-7.87 (1H, m), 8.11-8.13 (1H, m), 8.50 (1H, d), 8.61 (1H, d), 8.71 (1H, d), 9.44 (1H, t); m/z (ES+) M+=665.26; HPLC tR=4.02 min.

Workup

  1. temperatureto warm to room temperature
  2. stirringstirred for 1 hour
  3. customthe majority of the THF removed in vacuo
  4. additionThe reaction mixture was diluted with water (20 mL) and EtOAc (50 mL)
  5. customThe organic layer was separated
  6. extractionthe aqueous layer re-extracted with EtOAc (2×100 mL)
  7. washThe combined organics were washed with saturated brine (75 mL)
  8. dry with materialdried (MgSO4)
  9. customevaporated
  10. customThe crude product was purified by flash silica chromatography
  11. washeluting with 50 to 100% EtOAc in isohexane

Sources & evidence

ORD record
ord-b6598993866d4a26aeb89aceb185240d
Source dataset
uspto-grants-2011_12
Patent number
US08071608B2

Reaction notes

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