Water → 2-(4-(6-Cyanopyrazin-2-yl)phenyl)-2-methylpropanoic acid

HRID 1175582Notes

Reaction equation

HRID 1175582 reaction equation
Cl[C:2]1[N:7]=[C:6]([C:8]#[N:9])[CH:5]=[N:4][CH:3]=1.O.[CH3:11][C:12]([C:17]1[CH:22]=[CH:21][C:20](B2OC(C)(C)C(C)(C)O2)=[CH:19][CH:18]=1)([CH3:16])[C:13]([OH:15])=[O:14].C([O-])([O-])=O.[K+].[K+]>COCCOC.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>[C:8]([C:6]1[N:7]=[C:2]([C:20]2[CH:21]=[CH:22][C:17]([C:12]([CH3:16])([CH3:11])[C:13]([OH:15])=[O:14])=[CH:18][CH:19]=2)[CH:3]=[N:4][CH:5]=1)#[N:9]

Participants

7

Reactant 4

HCID 962WaterHCID 11430Potassium CarbonateHCID 813036-Chloropyrazine-2-carbonitrileHCID 684558452-Methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoic acid

Product 1

HCID 687764432-(4-(6-Cyanopyrazin-2-yl)phenyl)-2-methylpropanoic acidYield 70.2%

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalystHCID 80711,2-DimethoxyethaneSolvent

Conditions

Temperature
80 °C

Procedure

6-Chloropyrazine-2-carbonitrile (example 20b) (890 mg, 6.4 mmol) was dissolved in DME (24 mL) and water (6 mL) followed by 2-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoic acid (example 20d) (1.86 g, 6.4 mmol) and K2CO3 (1.76 g, 12.7 mmol). The mixture was degassed using an argon stream, Pd(PPh3)4 (369 mg, 0.32 mmol) was added and the mixture was heated (80° C.) overnight. The solvents were removed under reduced pressure and a residue was suspended in 1M aq. NaOH (10 mL) and washed with EtOAc. The aqueous phase was then acidified to pH 4-5 using 6N aq. HCl and extracted with EtOAc (3×60 mL). The organic extracts were combined, washed with water and brine, dried over MgSO4, filtered and evaporated. The residue was purified on silica gel (5% MeOH in DCM) to give 1.2 g (70%) of the pure intermediate 2-(4-(6-cyanopyrazin-2-yl)phenyl)-2-methylpropanoic acid. 1H NMR (400 MHz, dMSO): δ 1.50 (s, 6H), 1.69 (m, 1H), 7.54-7.56 (d, 2H), 8.13-8.15 (d, 2H), 9.17 (s, 1H), 9.56 (s, 1H), 12.50 (s, 1H).

Workup

  1. customThe mixture was degassed
  2. additionwas added
  3. customThe solvents were removed under reduced pressure
  4. washwashed with EtOAc
  5. extractionextracted with EtOAc (3×60 mL)
  6. washwashed with water and brine
  7. dry with materialdried over MgSO4
  8. filtrationfiltered
  9. customevaporated
  10. customThe residue was purified on silica gel (5% MeOH in DCM)

Sources & evidence

ORD record
ord-dcf27e05734e44b8bf95442214948cd4
Source dataset
uspto-grants-2010_11
Patent number
US07842324B2

Reaction notes

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