Cesium carbonate → HCID 86677891, compound

HRID 1499966Notes

Reaction equation

HRID 1499966 reaction equation
[Cl:1][C:2]1[C:3]([F:20])=[C:4]([CH:14]2[CH2:18][O:17][C:16](=[O:19])[NH:15]2)[C:5]([O:11][CH2:12][CH3:13])=[C:6]([CH2:8][CH2:9]Cl)[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:27][C:28]1[C:36]2[C:31](=[N:32][CH:33]=[N:34][C:35]=2[NH2:37])[NH:30][N:29]=1>CN(C)C=O.O>[NH2:37][C:35]1[N:34]=[CH:33][N:32]=[C:31]2[N:30]([CH:8]([C:6]3[C:5]([O:11][CH2:12][CH3:13])=[C:4]([CH:14]4[CH2:18][O:17][C:16](=[O:19])[NH:15]4)[C:3]([F:20])=[C:2]([Cl:1])[CH:7]=3)[CH3:9])[N:29]=[C:28]([CH3:27])[C:36]=12

Participants

6

Reactant 3

HCID 10796Cesium carbonateHCID 86677890HCID 86677890, compoundHCID 178434474HCID 178434474, compound

Product 1

HCID 86677891HCID 86677891, compound

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
80 °C

Procedure

4-[3-chloro-5-(chloroethyl)-6-ethoxy-2-fluorophenyl]-1,3-oxazolidin-2-one (160 mg, 0.50 mmol) (from Step 11) was stirred in N,N-dimethylformamide (21 mL) with cesium carbonate (324 mg, 0.99 mmol) and 3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (89 mg, 0.60 mmol) was added. The mixture was heated to 80° C. for 1.5 hours and cooled to rt. The mixture was diluted with water and extracted with ethyl acetate. The extracts were washed with brine, dried over sodium sulfate, filtered and evaporated. Purification by preparative LCMS (pH 10) using RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) separated the two diastereomers (peak 1 [compound 353] Rt=4.9 min. and peak 2 [compound 354] Rt=5.6 min.); providing compound 354 as the desired single enantiomer, 28 mg, 13%. peak 2: LCMS calculated for C19H21ClFN6O3 (M+H)+: m/z=435.1; found: 435.1. 1H NMR (300 MHz, CD3OD): δ 8.15 (s, 1 H), 7.62 (m, 1 H), 6.31 (m, 1 H), 5.39 (m, 1 H), 4.79 (m, 1 H), 4.40 (m, 1 H), 3.95 (m, 1 H), 3.80 (m, 1 H), 2.60 (s, 3 H), 1.80 (m, 3 H), 1.40 (m, 3 H).

Workup

  1. additionwas added
  2. temperaturecooled to rt
  3. extractionextracted with ethyl acetate
  4. washThe extracts were washed with brine
  5. dry with materialdried over sodium sulfate
  6. filtrationfiltered
  7. customevaporated
  8. customPurification by preparative LCMS (pH 10)
  9. washeluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min)
  10. customseparated the two diastereomers (peak 1 [compound 353] Rt=4.9 min. and peak 2 [compound 354] Rt=5.6 min.)

Sources & evidence

ORD record
ord-24581beb06e842c2b0dcc39726ef61bf
Source dataset
uspto-grants-2015_12
Patent number
US09199982B2

Reaction notes

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