Potassium Carbonate → 2-(1-Acetyl-6-fluoro-1H-indol-3-ylmethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester

HRID 70480Notes

Reaction equation

HRID 70480 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH:13]=[CH:14][CH2:15][N:16]([C:25](=[O:27])[CH3:26])[C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1Br)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.[N+](CCCC)(CCCC)(CCCC)CCCC.[Cl-].C(OCC)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][C:14]1[C:18]2[C:17](=[CH:22][C:21]([F:23])=[CH:20][CH:19]=2)[N:16]([C:25](=[O:27])[CH3:26])[CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]

Participants

7

Reactant 2

HCID 11430Potassium CarbonateHCID 674141342-{3-[Acetyl-(2-bromo-5-fluoro-phenyl)-amino]-propenyl}-pyrrolidine-1-carboxylic acid tert-butyl ester

Product 1

HCID 674128552-(1-Acetyl-6-fluoro-1H-indol-3-ylmethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester

Reagents, catalysts & solvents 4

HCID 70681Tetrabutylammonium ChlorideCatalystHCID 167845palladium(II) acetateCatalystHCID 3283Diethyl EtherSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
85 °C

Procedure

Under a nitrogen atmosphere, a solution of 18 (66 g, 0.15 mol) in anhydrous DMF (350 mL) was charged with (n-Bu)4NCl (41.5 g, 0.15 mol), K2CO3 (20.6 g, 0.15 mol), NaHCO2 (10.2 g, 0.15 mol), and Pd(OAc)2 (3.35 g, 0.015 mol) at ambient temperature. The heterogeneous mixture was immersed in a pre-heated (85° C.) oil bath. After 1 h, TLC analysis revealed some 18 remained therefore more catalyst (1 g) was added. After 1.5 h, another charge of catalyst (0.6 g) was added. After an additional 1.5 h of heating, 18 had been completely consumed by TLC analysis [TLC analysis, 2% MeOH/DCM, Rf(18)=0.7; Rf(19)=0.8]. The warm reaction mixture was transferred to an ice water bath to cool then diluted with diethyl ether and filtered through a pad of celite. The solids were washed with diethyl ether and the filtrate was washed several times with water to remove DMF then once with brine, dried over anhydrous Na2SO4, filtered, and concentrated to afford 52.5 g of crude 19, which was used without further purification. 1H NMR (CDCl3, 300 MHz) δ8.18 (m, 1H), 7.60 (m, 1H), 7.18 (m, 1H), 7.05 (dt, J=2.4, 8.7 Hz, 1H), 4.13 (m, 1H), 3.41 (m, 1H), 3.33 (m, 2H), 3.17 (app dd, J=14.1, 38.1 Hz, 1H), 2.61 (s, 3H), 1.83 (m, 3H), 1.69 (m, 1H), 1.49 (s, 9H) ppm.

Workup

  1. waitAfter 1.5 h
  2. additionwas added
  3. temperatureAfter an additional 1.5 h of heating
  4. custom18 had been completely consumed by TLC analysis [TLC analysis, 2% MeOH/DCM, Rf(18)=0.7; Rf(19)=0.8]
  5. customThe warm reaction mixture
  6. customwas transferred to an ice water bath
  7. temperatureto cool
  8. filtrationfiltered through a pad of celite
  9. washThe solids were washed with diethyl ether
  10. washthe filtrate was washed several times with water
  11. customto remove DMF
  12. dry with materialonce with brine, dried over anhydrous Na2SO4
  13. filtrationfiltered
  14. concentrationconcentrated
  15. customto afford 52.5 g of crude 19, which
  16. customwas used without further purification

Sources & evidence

ORD record
ord-bf6c1e5da2f74b51802536d56ec9eb45
Source dataset
uspto-grants-2014_09
Patent number
US08822525B2

Reaction notes

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