Citric Acid → HCID 57504499, compound

HRID 1098007Notes

Reaction equation

HRID 1098007 reaction equation
[H-].[Na+].[CH:3]1([O:7][CH2:8][C@H:9]([OH:20])[C:10]([NH:12][C:13]2[CH:18]=[N:17][C:16]([CH3:19])=[CH:15][N:14]=2)=[O:11])[CH2:6][CH2:5][CH2:4]1.Cl[C:22]1[N:27]=[CH:26][N:25]=[C:24]2[N:28]([C:31]3[C:36]([C:37]([F:40])([F:39])[F:38])=[CH:35][C:34]([Cl:41])=[CH:33][N:32]=3)[N:29]=[CH:30][C:23]=12.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[Cl:41][C:34]1[CH:35]=[C:36]([C:37]([F:40])([F:38])[F:39])[C:31]([N:28]2[C:24]3[N:25]=[CH:26][N:27]=[C:22]([O:20][C@@H:9]([CH2:8][O:7][CH:3]4[CH2:6][CH2:5][CH2:4]4)[C:10]([NH:12][C:13]4[CH:18]=[N:17][C:16]([CH3:19])=[CH:15][N:14]=4)=[O:11])[C:23]=3[CH:30]=[N:29]2)=[N:32][CH:33]=1

Participants

6

Reactant 4

HCID 311Citric AcidHCID 24758Sodium hydrideHCID 575045004-chloro-1-(5-chloro-3-(trifluoromethyl)pyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidineHCID 57504623HCID 57504623, compound

Product 1

HCID 57504499HCID 57504499, compoundYield 100.2%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
0 °C

Procedure

60% Sodium hydride in mineral oil (60 mg, 1.50 mmol) was added in one portion to (S)-3-cyclobutoxy-2-hydroxy-N-(5-methylpyrazin-2-yl)propanamide (Intermediate R1) (251 mg, 1.00 mmol) in anhydrous THF (5 mL) at 0° C. under nitrogen. The resulting suspension was stirred at 0° C. for 10 minutes and then 4-chloro-1-(5-chloro-3-(trifluoromethyl)pyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate K3) (334 mg, 1.00 mmol) as suspension in dry THF (2.5 mL) added dropwise over 1 minute. The mixture was stirred at 0° C. for 15 mins, allowed to warm to ambient temperature and stirred for 6 hours. 1M Citric acid (10 mL) was added and the mixture extracted with ethyl acetate (2×25 mL). The combined organic extracts were washed with water (25 mL) and brine (25 mL), dried (MgSO4) and evaporated. The residue was purified by flash silica chromatography, eluting with 50 to 100% ethyl acetate in isohexane to give the product (550 mg, 100%). 1H NMR (400 MHz, CDCl3) δ 1.46-1.54 (1H, m), 1.66-1.74 (1H, m), 1.89-2.01 (2H, m), 2.18-2.25 (2H, m), 2.54 (3H, s), 3.98-4.08 (3H, m), 6.04 (1H, t), 8.12 (1H, d), 8.25 (1H, d), 8.43 (1H, s), 8.62 (1H, s), 8.63-8.65 (1H, m), 8.82 (1H, d), 9.44 (1H, d); m/z (ESI+) (M+H)+=549; HPLC tR=2.56 min.

Workup

  1. stirringThe mixture was stirred at 0° C. for 15 mins
  2. temperatureto warm to ambient temperature
  3. stirringstirred for 6 hours
  4. extractionthe mixture extracted with ethyl acetate (2×25 mL)
  5. washThe combined organic extracts were washed with water (25 mL) and brine (25 mL)
  6. dry with materialdried (MgSO4)
  7. customevaporated
  8. customThe residue was purified by flash silica chromatography
  9. washeluting with 50 to 100% ethyl acetate in isohexane

Sources & evidence

ORD record
ord-49b59b65ad0941bba0b5b63f507a27ec
Source dataset
uspto-grants-2012_03
Patent number
US08143263B2

Reaction notes

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