Bromide ion → (R)-Methyl 6-(2-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1-methyl-1H-indol-5-yl)-5-ethyl-2-methoxynicotinate

HRID 1481718Notes

Reaction equation

HRID 1481718 reaction equation
Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([C@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:5]2.[CH3:24]C([O-])=O.[K+].[Br-].C([O-])([O-])=O.[K+].[K+].Cl[C:37]1[C:45]([CH2:46][CH3:47])=[CH:44][C:40]([C:41]([O-:43])=[O:42])=[C:39]([O:48][CH3:49])[N:38]=1>CC([O-])=O.CC([O-])=O.[Pd+2].O.O1CCOCC1>[C:20]([O:19][C:17]([N:13]1[CH2:14][CH2:15][CH2:16][C@@H:12]1[C:6]1[N:7]([CH3:11])[C:8]2[C:4]([CH:5]=1)=[CH:3][C:2]([C:37]1[C:45]([CH2:46][CH3:47])=[CH:44][C:40]([C:41]([O:43][CH3:24])=[O:42])=[C:39]([O:48][CH3:49])[N:38]=1)=[CH:10][CH:9]=2)=[O:18])([CH3:23])([CH3:22])[CH3:21]

Participants

9

Reactant 5

HCID 259Bromide ionHCID 11430Potassium CarbonateHCID 517044Potassium AcetateHCID 71284656(R)-tert-Butyl 2-(5-bromo-1-methyl-1H-indol-2-yl)pyrrolidine-1-carboxylateHCID 1317366566-Chloro-5-ethyl-2-methoxynicotinate

Product 1

HCID 71291891(R)-Methyl 6-(2-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1-methyl-1H-indol-5-yl)-5-ethyl-2-methoxynicotinateYield 49.2%

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 962WaterSolvent2×HCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

(R)-tert-Butyl 2-(5-bromo-1-methyl-1H-indol-2-yl)pyrrolidine-1-carboxylate (0.300 g, 0.79 mmol), bis(pinacolato) diborate (0.240 g, 0.95 mmol), Pd(OAc)2 (6.0 mg, 0.03 mmol, 3.5 mol %), Ru-Phos ligand (26.0 mg, 0.06 mmol, 7 mol %) and KOAc (0.240 g, 2.44 mmol) were mixed together in a vial. The vial was vacuumed and backfilled with argon before dioxane (2 mL) was added. Mixture was heated at 100° 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 (0.330 g, 2.39 mmol) and 6-chloro-5-ethyl-2-methoxynicotinate (0.182 g, 0.79 mmol) were added. Reaction vial was resealed under argon and mixture was heated at 100° C. overnight and then cooled to room temperature. Water (7 mL) was added to the reaction mixture and product was extracted with DCM (2×10 mL). Combined organics were washed with NaCl (aqueous saturated, 10 mL) and dried over Na2SO4. Upon concentration of the solvent residue was purified by column chromatography (EtOAc/hexanes, 0-50% gradient) to afford product as solid (0.192 g) in 49% overall yield.

Workup

  1. additionwas added
  2. customReaction mixture
  3. additionwere added
  4. customReaction vial
  5. temperaturecooled to room temperature
  6. extractionwas extracted with DCM (2×10 mL)
  7. washCombined organics were washed with NaCl (aqueous saturated, 10 mL)
  8. dry with materialdried over Na2SO4
  9. customUpon concentration of the solvent residue was purified by column chromatography (EtOAc/hexanes, 0-50% gradient)

Sources & evidence

ORD record
ord-b1f2689501574df48288fec0f168431a
Source dataset
uspto-grants-2016_08
Patent number
US09409905B2

Reaction notes

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