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

HRID 716104ノート

反応式

HRID 716104 の反応式
[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]

参加物

7

反応物 2

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

生成物 1

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

試薬・触媒・溶媒 4

HCID 70681Tetrabutylammonium Chloride触媒HCID 167845palladium(II) acetate触媒HCID 3283Diethyl Ether溶媒HCID 6228Dimethylformamide溶媒

反応条件

温度
85 °C

実験手順

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.

後処理

  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

出典と根拠

ORDレコード
ord-8563badc17534500ab017dfcaedab31c
出典データセット
uspto-grants-2015_11
特許番号
US09187490B2

反応ノート

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