Citric Acid → (S)-3-(3-(tert-butyldimethylsilyloxy)azetidin-1-yl)-2-(1-(2,6-dichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-N-(5-methylpyrazin-2-yl)propanamide

HRID 1098267Notes

Reaction equation

HRID 1098267 reaction equation
[H-].[Na+].[Si:3]([O:10][CH:11]1[CH2:14][N:13]([CH2:15][C@H:16]([OH:27])[C:17]([NH:19][C:20]2[CH:25]=[N:24][C:23]([CH3:26])=[CH:22][N:21]=2)=[O:18])[CH2:12]1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].Cl[C:29]1[N:34]=[CH:33][N:32]=[C:31]2[N:35]([C:38]3[C:43]([Cl:44])=[CH:42][CH:41]=[CH:40][C:39]=3[Cl:45])[N:36]=[CH:37][C:30]=12.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.O.C(OCC)(=O)C>[Si:3]([O:10][CH:11]1[CH2:12][N:13]([CH2:15][C@H:16]([O:27][C:29]2[N:34]=[CH:33][N:32]=[C:31]3[N:35]([C:38]4[C:43]([Cl:44])=[CH:42][CH:41]=[CH:40][C:39]=4[Cl:45])[N:36]=[CH:37][C:30]=23)[C:17]([NH:19][C:20]2[CH:25]=[N:24][C:23]([CH3:26])=[CH:22][N:21]=2)=[O:18])[CH2:14]1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:4])[CH3:5]

Participants

8

Reactant 4

HCID 311Citric AcidHCID 24758Sodium hydrideHCID 574386694-chloro-1-(2,6-dichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidineHCID 57504705(S)-3-(3-(tert-butyldimethylsilyl-oxy)azetidin-1-yl)-2-hydroxy-N-(5-methylpyrazin-2-yl)propanamide

Product 1

HCID 46940071(S)-3-(3-(tert-butyldimethylsilyloxy)azetidin-1-yl)-2-(1-(2,6-dichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-N-(5-methylpyrazin-2-yl)propanamideYield 57.6%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
0 °C

Procedure

Sodium hydride (87 mg, 2.18 mmol) was added to (S)-3-(3-(tert-butyldimethylsilyloxy)azetidin-1-yl)-2-hydroxy-N-(5-methylpyrazin-2-yl)propanamide (Intermediate BB2) (400 mg, 1.09 mmol) in anhydrous tetrahydrofuran (15 mL) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes and then 4-chloro-1-(2,6-dichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate BA3) (360 mg, 1.20 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 2 hours. The reaction mixture was neutralised with 1M citric acid and then diluted with water (30 mL) and ethyl acetate (50 mL). The organic layer was separated and the aqueous layer re-extracted with ethyl acetate (50 mL). The combined organics were washed with saturated brine (75 mL), dried (MgSO4), filtered and evaporated. The crude product was purified by flash silica chromatography, eluting with 40 to 80% ethyl acetate in isohexane, to afford the product (395 mg, 57.5%). 1H NMR (400 MHz, CDCl3) δ 0.04 (6H, s), 0.88 (9H, s), 2.54 (3H, s), 3.09-3.13 (2H, m), 3.16-3.21 (1H, m), 3.29-3.34 (1H, m), 3.87-3.92 (2H, m), 4.51 (1H, qn), 5.92-5.95 (1H, m), 7.43-7.47 (1H, m), 7.52-7.55 (2H, m), 8.14 (1H, d), 8.41 (1H, s), 8.59 (1H, s), 9.42 (1H, d), 9.96 (1H, s); m/z (ES+) (M+H)+=631; HPLC tR=2.94 min.

Workup

  1. temperatureto warm to room temperature
  2. stirringstirred for 2 hours
  3. customThe organic layer was separated
  4. extractionthe aqueous layer re-extracted with ethyl acetate (50 mL)
  5. washThe combined organics were washed with saturated brine (75 mL)
  6. dry with materialdried (MgSO4)
  7. filtrationfiltered
  8. customevaporated
  9. customThe crude product was purified by flash silica chromatography
  10. washeluting with 40 to 80% ethyl acetate in isohexane

Sources & evidence

ORD record
ord-7e1641868333426db5425e277a9bd127
Source dataset
uspto-grants-2012_03
Patent number
US08143263B2

Reaction notes

Loading…