Lithium Chloride → 2-Amino-5-pyrazin-2-yl-4-trifluoromethyl-benzoic acid methyl ester

HRID 1441646

Reaction equation

HRID 1441646 reaction equation
[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8](I)[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[NH2:15].C([Sn](CCCC)(CCCC)[C:22]1[CH:27]=[N:26][CH:25]=[CH:24][N:23]=1)CCC.[Li+].[Cl-].C(C1C(C)=CC=C(O)C=1C(C)(C)C)(C)(C)C>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([C:22]2[CH:27]=[N:26][CH:25]=[CH:24][N:23]=2)[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[NH2:15]

Participants

7

Reactant 4

HCID 433294Lithium ChlorideHCID 27373162-(Tributylstannyl)pyrazineHCID 3034427Phenol, bis(1,1-dimethylethyl)-4-methyl-HCID 53436880Methyl 2-amino-5-iodo-4-(trifluoromethyl)benzoate

Product 1

HCID 119657822-Amino-5-pyrazin-2-yl-4-trifluoromethyl-benzoic acid methyl esterYield 38.4%

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalyst2×HCID 312751,4-DioxaneSolvent

Conditions

Temperature
120 °C

Procedure

A solution containing 2-amino-5-iodo-4-trifluoromethyl-benzoic acid methyl ester (750 mg, 2.17 mmol), 2-tributylstannylpyrazine (1.0 g, 2.7 mmol) and (Ph3P)4Pd (125.6 mg, 0.109 mmol) in dioxane (40 mL) was heated at 120° C. for 17 h. LiCl (276.4 mg, 6.5 mmol) was added and the reaction mixture was refluxed for 1.5 h prior to the addition of di-t-butyl-p-cresol (188 mg, 0.85 mmol) and another portion of (Ph3P)4Pd (251.2 mg, 0.22 mmol). Heating was continued for 16 h, for a total reaction time of 36 h. After cooling to r.t., the solvent was removed in vacuo and the residue was purified by flash chromatography (200 g silica gel, hexanes→EtOAc:hexanes (3:7 to 1:1)). The fractions containing the product were combined and concentrated in vacuo. The resultant oil was further purified by partitioning between CH3CN and hexanes. The acetonitrile layer was concentrated in vacuo to furnish the title compound (248 mg, 38%) as a solid. API-ES: m/z 298 [M+H]+, rt 4.18 min.

Workup

  1. temperaturethe reaction mixture was refluxed for 1.5 h
  2. temperatureHeating
  3. temperatureAfter cooling to r.t.
  4. customthe solvent was removed in vacuo
  5. customthe residue was purified by flash chromatography (200 g silica gel, hexanes→EtOAc:hexanes (3:7 to 1:1))
  6. additionThe fractions containing the product
  7. concentrationconcentrated in vacuo
  8. customThe resultant oil was further purified
  9. customby partitioning between CH3CN and hexanes
  10. concentrationThe acetonitrile layer was concentrated in vacuo

Sources & evidence

ORD record
ord-ddf1725357c042f9bab24c11b03981ce
Source dataset
uspto-grants-2010_02
Patent number
US07655666B2

Linked notes

Loading…