Cesium carbonate → Methyl 4-(3-amino-6-cyclopropylpyrazin-2-yl)-2-fluorobenzoate

HRID 596073Notes

Reaction equation

[NH2:1][C:2]1[C:3]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([F:19])[CH:10]=2)=[N:4][C:5](Br)=[CH:6][N:7]=1.[C:20]12(P(C34CC5CC(CC(C5)C3)C4)CCCC)[CH2:29]C3CC(CC(C3)[CH2:21]1)C2.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:1][C:2]1[C:3]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([F:19])[CH:10]=2)=[N:4][C:5]([CH:29]2[CH2:20][CH2:21]2)=[CH:6][N:7]=1

Participants

Conditions

Temperature: 100 °C

Procedure

To methyl 4-(3-amino-6-bromopyrazin-2-yl)-2-fluorobenzoate (for synthesis see Example 34, Step 2) (300 mg, 0.920 mmol) in toluene (10 mL) and water (1 mL) was added potassium cyclopropyl trifluoroborate (408 mg, 2.76 mmol), di(1-adamantyl)-n-butylphosphine (66.0 mg, 0.184 mmol), cesium carbonate (1499 mg, 4.60 mmol), and palladium(II) acetate (20.65 mg, 0.092 mmol). The reaction mixture was heated in heating block at 100° C. overnight. The reaction mixture was quenched with sat. NH4Cl and extracted with ethyl acetate. The organic extracts were combined, washed with brine, dried over sodium sulfate, filtered and evaporated. The crude was purified by flash chromatography (0 to 80% EtOAc in heptane) yielding methyl 4-(3-amino-6-cyclopropylpyrazin-2-yl)-2-fluorobenzoate (250 mg, 90%). LCMS (m/z): 288.2 (MH+), 0.756 min.

Workup

temperatureThe reaction mixture was heated
customThe reaction mixture was quenched with sat. NH4Cl
extractionextracted with ethyl acetate
washwashed with brine
dry with materialdried over sodium sulfate
filtrationfiltered
customevaporated
customThe crude was purified by flash chromatography (0 to 80% EtOAc in heptane)

Sources & evidence

ORD record: ord-a6a7ff7247ed47848c5d8f9180cadea7
Source dataset: uspto-grants-2016_01
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09242996B2

Reaction notes

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