Potassium Carbonate → Methyl 6-(2-((tert-butyldimethylsilyloxy)methyl)imidazo[1,2-a]pyridin-6-yl)-5-ethyl-2-methoxynicotinate

HRID 1481703Notes

Reaction equation

HRID 1481703 reaction equation
Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[N:10]=2)[CH:7]=1.[CH3:20]C([O-])=O.[K+].C([O-])([O-])=O.[K+].[K+].Cl[C:32]1[C:40]([CH2:41][CH3:42])=[CH:39][C:35]([C:36]([O-:38])=[O:37])=[C:34]([O:43][CH3:44])[N:33]=1>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].O>[Si:13]([O:12][CH2:11][C:9]1[N:10]=[C:5]2[CH:4]=[CH:3][C:2]([C:32]3[C:40]([CH2:41][CH3:42])=[CH:39][C:35]([C:36]([O:38][CH3:20])=[O:37])=[C:34]([O:43][CH3:44])[N:33]=3)=[CH:7][N:6]2[CH:8]=1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]

Participants

7

Reactant 4

HCID 11430Potassium CarbonateHCID 517044Potassium AcetateHCID 712847896-Bromo-2-((tert-butyldimethylsilyloxy)methyl)imidazo[1,2-a]pyridineHCID 1317366566-Chloro-5-ethyl-2-methoxynicotinate

Product 1

HCID 71284421Methyl 6-(2-((tert-butyldimethylsilyloxy)methyl)imidazo[1,2-a]pyridin-6-yl)-5-ethyl-2-methoxynicotinate

Reagents, catalysts & solvents 2

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)Catalyst2×HCID 962WaterSolvent2×

Conditions

Temperature
130 °C

Procedure

6-bromo-2-((tert-butyldimethylsilyloxy)methyl)imidazo[1,2-a]pyridine (1.00 g, 2.93 mmol), bis(pinacolato) diborate (0.892 g, 3.51 mmol), Pd(dppf)Cl2 (86 mg, 0.12 mmol, 4 mol %), and KOAc (0.860 g, 8.76 mmol) were mixed together in a heat-gun dried flask. The flask was vacuumed and backfilled with argon before dioxane (9 mL) was added. Mixture was heated at 130° C. for ˜3 h until complete consumption of the starting bromide was observed. Reaction mixture was cooled to room temperature before H2O (0.90 mL), K2CO3 (1.20 g, 8.68 mmol), 6-chloro-5-ethyl-2-methoxynicotinate (0.673 g, 2.93 mmol) and fresh Pd(dppf)Cl2 (60 mg, 0.08 mmol, 3 mol %) were added. Reaction flask was resealed under argon and mixture was heated at 120° C. overnight and then cooled to room temperature. Water (10 mL) was added to the reaction mixture and product was extracted with DCM (3×20 mL). Combined organics were washed with NaCl (aqueous saturated, 20 mL) and dried over Na2SO4. Upon concentration of the solvent residue was purified by column chromatography (EtOAc/hexanes, 0-60% gradient). After concentration of the desired fractions, residue was treated with H2O (10-15 mL) and stirred vigorously for 30 min, solid was then filtered and washed with H2O. Upon drying methyl 6-(2-((tert-butyldimethylsilyloxy)methyl)imidazo[1,2-a]pyridin-6-yl)-5-ethyl-2-methoxynicotinate (1.00 g, 75%) was obtained as solid.

Workup

  1. customdried flask
  2. additionwas added
  3. customReaction mixture
  4. additionwere added
  5. customReaction flask
  6. temperaturemixture was heated at 120° C. overnight
  7. temperaturecooled to room temperature
  8. extractionwas extracted with DCM (3×20 mL)
  9. washCombined organics were washed with NaCl (aqueous saturated, 20 mL)
  10. dry with materialdried over Na2SO4
  11. customUpon concentration of the solvent residue was purified by column chromatography (EtOAc/hexanes, 0-60% gradient)
  12. additionAfter concentration of the desired fractions, residue was treated with H2O (10-15 mL)
  13. filtrationsolid was then filtered
  14. washwashed with H2O
  15. dry with materialUpon drying methyl 6-(2-((tert-butyldimethylsilyloxy)methyl)imidazo[1,2-a]pyridin-6-yl)-5-ethyl-2-methoxynicotinate (1.00 g, 75%)
  16. customwas obtained as solid

Sources & evidence

ORD record
ord-f270d69be09243f280e4e6271ab5e4df
Source dataset
uspto-grants-2016_08
Patent number
US09409905B2

Reaction notes

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