1,2-Dimethoxyethane → tert-Butyl 4-(3-aminopyrazin-2-yl)-2-fluorobenzoate

HRID 595953Notes

Reaction equation

HRID 595953 reaction equation
[F:1][C:2]1[CH:14]=[C:13](B2OC(C)(C)C(C)(C)O2)[CH:12]=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[NH2:24][C:25]1[C:30](Cl)=[N:29][CH:28]=[CH:27][N:26]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.O>[NH2:24][C:25]1[C:30]([C:13]2[CH:12]=[CH:11][C:3]([C:4]([O:6][C:7]([CH3:8])([CH3:9])[CH3:10])=[O:5])=[C:2]([F:1])[CH:14]=2)=[N:29][CH:28]=[CH:27][N:26]=1

Participants

7

Reactant 4

HCID 80711,2-DimethoxyethaneHCID 10340Sodium CarbonateHCID 2762242-Amino-3-chloropyrazineHCID 75486460tert-Butyl 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate

Product 1

HCID 118046338tert-Butyl 4-(3-aminopyrazin-2-yl)-2-fluorobenzoateYield 86.3%

Reagents, catalysts & solvents 2

HCID 178418807HCID 178418807, compoundCatalystHCID 962WaterSolvent

Conditions

Temperature
100 °C

Procedure

A 2 L round-bottomed flask was charged with tert-butyl 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (54 g, 151 mmol), 2-amino-3-chloropyrazine (19.54 g, 151 mmol), 2 N sodium carbonate (158 mL, 317 mmol) and DME (600 mL). The reaction mixture was degassed for 10 min using argon, and then PdCl2(dppf)-CH2Cl2 (6.16 g, 7.54 mmol) was added. The reaction mixture was heated to 100° C. and maintained at this temperature for 4 h. After cooling down, the reaction mixture was poured into water (400 mL) and extracted with EtOAc (3×200 mL). The combined organics were washed with brine (3×200 mL), dried over magnesium sulfate, filtered and concentrated. The crude material was purified using flash chromatography on silica gel (0 to 70% EtOAc in heptane over 50 min), giving tert-butyl 4-(3-aminopyrazin-2-yl)-2-fluorobenzoate (37.7 g, 86%) as a solid. LCMS (m/z): 290 (MH+), 0.80 min; 1H NMR (400 MHz, DMSO-d6) δ ppm 7.98 (d, 1H) 7.91-7.81 (m, 2H) 7.65-7.46 (m, 2H) 6.35 (br. s., 2H) 1.54 (s, 9H).

Workup

  1. customThe reaction mixture was degassed for 10 min
  2. temperaturemaintained at this temperature for 4 h
  3. temperatureAfter cooling down
  4. extractionextracted with EtOAc (3×200 mL)
  5. washThe combined organics were washed with brine (3×200 mL)
  6. dry with materialdried over magnesium sulfate
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customThe crude material was purified
  10. customon silica gel (0 to 70% EtOAc in heptane over 50 min)

Sources & evidence

ORD record
ord-a9ef7ed06aad452f96052664971b133f
Source dataset
uspto-grants-2016_01
Patent number
US09242996B2

Reaction notes

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