Citric Acid → (2S)-2-[1-(3-chloro-2-pyridyl)pyrazolo[4,5-e]pyrimidin-4-yl]oxy-4-hydroxy-N-(5-methyl-2-pyridyl)butanamide

HRID 1098009Notes

Reaction equation

HRID 1098009 reaction equation
C[Al](C)C.[CH3:5][C:6]1[CH:7]=[CH:8][C:9]([NH2:12])=[N:10][CH:11]=1.[Cl:13][C:14]1[C:15]([N:20]2[C:24]3=[N:25][CH:26]=[N:27][C:28]([O:29][C@H:30]4[CH2:34][CH2:33][O:32][C:31]4=[O:35])=[C:23]3[CH:22]=[N:21]2)=[N:16][CH:17]=[CH:18][CH:19]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1(C)C=CC=CC=1.O.C(OCC)(=O)C>[Cl:13][C:14]1[C:15]([N:20]2[C:24]3[N:25]=[CH:26][N:27]=[C:28]([O:29][C@@H:30]([CH2:34][CH2:33][OH:32])[C:31]([NH:12][C:9]4[CH:8]=[CH:7][C:6]([CH3:5])=[CH:11][N:10]=4)=[O:35])[C:23]=3[CH:22]=[N:21]2)=[N:16][CH:17]=[CH:18][CH:19]=1

Participants

8

Reactant 4

HCID 311Citric AcidHCID 153482-Amino-5-methylpyridineHCID 16682925TrimethylaluminumHCID 57504502(3S)-3-(1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)dihydrofuran-2(3H)-one

Product 1

HCID 57504373(2S)-2-[1-(3-chloro-2-pyridyl)pyrazolo[4,5-e]pyrimidin-4-yl]oxy-4-hydroxy-N-(5-methyl-2-pyridyl)butanamideYield 70.1%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 1140TolueneSolvent2×HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
0 °C

Procedure

Trimethylaluminium (0.347 mL, 0.69 mmol) was added to 5-methylpyridin-2-amine (71.7 mg, 0.66 mmol) in toluene (8 mL) cooled to 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 20 minutes. (3S)-3-(1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)dihydrofuran-2(3H)-one (Intermediate T1) (200 mg, 0.60 mmol) in toluene (2 mL) and the reaction was allowed to warm to room temperature and stirred for 1 hour. The reaction was then heated at 50° C. for 2 hours. The reaction mixture was allowed to cool and was neutralised with citric acid (1M, aq.) and then diluted with water (50 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 dried (MgSO4), filtered and evaporated. The crude product was purified by flash silica chromatography, eluting with 0 to 10% MeOH in DCM to afford the product (185 mg, 69.8%). 1H NMR (400 MHz, CDCl3) 2.30 (3H, s) 2.33-2.40 (1H, m), 2.44-2.52 (1H, m), 2.55 (1h, s), 3.83-3.92 (2H, m), 6.07-6.10 (1H, m), 7.46-7.49 (1H, m), 7.52-7.55 (1H, m), 8.00-8.02 (1H, m), 8.09-8.10 (1H, m), 8.13 (1H, d), 8.47 (1H, s), 8.61-8.62 (1H, m), 8.64 (1H, s), 8.68 (1H, s); m/z (ESI+) (M+H)+=440; HPLC tR=1.68 min.

Workup

  1. temperatureto warm to room temperature
  2. stirringstirred for 1 hour
  3. temperatureThe reaction was then heated at 50° C. for 2 hours
  4. temperatureto cool
  5. customThe organic layer was separated
  6. extractionthe aqueous layer re-extracted with ethyl acetate (50 mL)
  7. dry with materialThe combined organics were dried (MgSO4)
  8. filtrationfiltered
  9. customevaporated
  10. customThe crude product was purified by flash silica chromatography
  11. washeluting with 0 to 10% MeOH in DCM

Sources & evidence

ORD record
ord-1f3f919ed00144508fff159a1a8e0c76
Source dataset
uspto-grants-2012_03
Patent number
US08143263B2

Reaction notes

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