Aniline → (S)-2-(4-chloro-5-fluoroindolin-1-yl)-4-hydroxy-N-phenylbutanamide

HRID 1696157Notes

Reaction equation

HRID 1696157 reaction equation
[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Al](C)C.CCCCCC.[Cl:18][C:19]1[C:27]([F:28])=[CH:26][CH:25]=[C:24]2[C:20]=1[CH2:21][CH2:22][N:23]2[C@H:29]1[CH2:33][CH2:32][O:31][C:30]1=[O:34]>C(Cl)Cl>[Cl:18][C:19]1[C:27]([F:28])=[CH:26][CH:25]=[C:24]2[C:20]=1[CH2:21][CH2:22][N:23]2[C@@H:29]([CH2:33][CH2:32][OH:31])[C:30]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:34]

Participants

6

Reactant 4

HCID 6115AnilineHCID 8058HexaneHCID 16682925TrimethylaluminumHCID 59465668(S)-3-(4-chloro-5-fluoroindolin-1-yl)dihydrofuran-2(3H)-one

Product 1

HCID 59465662(S)-2-(4-chloro-5-fluoroindolin-1-yl)-4-hydroxy-N-phenylbutanamideYield 100%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

Prepared using general procedure 60: To a solution of aniline (1.4 mL, 15.6 mmol) in CH2Cl2 (37 mL) under nitrogen at RT was added a solution of trimethylaluminum in hexane (2.0 M, 7.8 mL, 15.6 mmol) over 5 min. After stirring at RT for 20 min, a solution of (S)-3-(4-chloro-5-fluoroindolin-1-yl)-dihydrofuran-2(3H)-one (4.0 g, 15.6 mmol) in CH2Cl2 (37 mL) was added over 10 min. Heated to reflux for 12 h, then the reaction mixture was cooled to 0° C. and quenched by careful addition of aqueous 1M HCl (70 mL). Phases were separated, and the aqueous phase was extracted with CH2Cl2 (2×75 L). The combined organic extracts were dried over MgSO4 and concentrated. Purification via silica gel chromatography using 2-7.5% MeOH in CH2Cl2 gave (S)-2-(4-chloro-5-fluoroindolin-1-yl)-4-hydroxy-N-phenylbutanamide as a white solid (5.44 g, 100%). 1H NMR (400 MHz, DMSO-d6) δ 10.15 (s, 1H), 7.59 (d, J=7.6 Hz, 2H), 7.31-7.27 (m, 2H), 7.07-6.99 (m, 2H), 6.53 (dd, J=3.6, 8.6 Hz, 1H), 4.70 (t, J=4.9 Hz, 1H), 4.35 (t, J=7.4 Hz, 1H), 3.92-3.80 (m, 1H), 3.68-3.62 (m, 1H), 3.55-3.47 (m, 2H), 3.05-2.89 (m, 2H), 2.12-2.01 (m, 1H), 1.98-1.88 (m, 1H). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=349.1; tR=1.69 min.

Workup

  1. customPrepared
  2. temperatureHeated
  3. temperatureto reflux for 12 h
  4. temperaturethe reaction mixture was cooled to 0° C.
  5. customquenched by careful addition of aqueous 1M HCl (70 mL)
  6. customPhases were separated
  7. extractionthe aqueous phase was extracted with CH2Cl2 (2×75 L)
  8. dry with materialThe combined organic extracts were dried over MgSO4
  9. concentrationconcentrated
  10. customPurification via silica gel chromatography

Sources & evidence

ORD record
ord-180a428317774d60ae61e0a622c05012
Source dataset
uspto-grants-2012_04
Patent number
US08163720B2

Reaction notes

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