Hydrochloric Acid → (S)-2-(4-Chloroindolin-1-yl)-4-hydroxy-N-(4-(N-thiazol-2-ylsulfamoyl)phenyl)butanamide

HRID 1696152Notes

Reaction equation

HRID 1696152 reaction equation
C[Al](C)C.[CH:5]1[C:10]([NH2:11])=[CH:9][CH:8]=[C:7]([S:12]([NH:15][C:16]2[S:20][CH:19]=[CH:18][N:17]=2)(=[O:14])=[O:13])[CH:6]=1.[Cl:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH2:24][CH2:25][N:26]2[C@H:31]1[CH2:35][CH2:34][O:33][C:32]1=[O:36].Cl>CCCCCC.ClCCl.C(OC(=O)C)C>[Cl:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH2:24][CH2:25][N:26]2[C@@H:31]([CH2:35][CH2:34][OH:33])[C:32]([NH:11][C:10]1[CH:5]=[CH:6][C:7]([S:12](=[O:14])(=[O:13])[NH:15][C:16]2[S:20][CH:19]=[CH:18][N:17]=2)=[CH:8][CH:9]=1)=[O:36]

Participants

8

Reactant 4

HCID 313Hydrochloric AcidHCID 5340SulfathiazoleHCID 16682925TrimethylaluminumHCID 59465791HCID 59465791, compound

Product 1

HCID 59465758(S)-2-(4-Chloroindolin-1-yl)-4-hydroxy-N-(4-(N-thiazol-2-ylsulfamoyl)phenyl)butanamideYield 80%

Reagents, catalysts & solvents 3

HCID 6344DichloromethaneSolvent2×HCID 8058HexaneSolventHCID 8857Ethyl AcetateSolvent

Procedure

Prepared using general procedure 58. Under an N2 atmosphere at RT, 2M-trimethyl aluminium in hexane (9.13 mL) was added dropwise to a stirring solution of sulfathiazole (4.6 g, 18.27 mmol) in dichloromethane (100 mL) in 30 minutes. Upon completion of addition, the mixture was stirred at RT for an hour. Added (S)-3-(4-chloroindolin-1-yl)dihydrofuran-2(3H)-one (3.56 g, 14.97 mmol) in dichloromethane (20 mL) to above solution over 30 minutes. The mixture was stirred for 16 hrs at RT. The reaction mixture was diluted with 500 mL of ethylacetate were added. The aqueous phase was acidified to pH 2 with an (1N) aqueous HCl solution. The ethyl acetate layer was washed with (1N) aqueous HCl (3×200 mL) till LCMS showed disappearance of sulfathiazole. The organic layer was dried over MgSO4, filtered, concentrated. Purification via silica gel chromatography using 2-10% methanol in dichloromethane gave the amide as a white solid (5.9 g, 80% yield). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=493.2; tR=1.46 min. 1H NMR (400 MHz, DMSO) δ 12.69 (s, 1H), 7.74 (s, 4H), 7.24 (d, J=4.6 Hz, 1H), 6.98 (t, J=8.0 Hz, 1H), 6.81 (d, J=4.5 Hz, 1H), 6.56-6.54 (m, 2H), 4.71 (t, J=4.8 Hz, 1H), 4.43-4.39 (m, 1H), 3.79 (q, J=9.3 Hz, 1H), 3.64-3.58 (m, 2H), 3.51-3.48 (m, 1H), 3.17 (d, J=5.2 Hz, 1H), 3.00-2.89 (m, 1H), 1.93 (dd, J=6.0, 13.5 Hz, 1H), 1.88 (s, 1H).

Workup

  1. customPrepared
  2. additionUpon completion of addition
  3. stirringThe mixture was stirred for 16 hrs at RT
  4. additionwere added
  5. washThe ethyl acetate layer was washed with (1N) aqueous HCl (3×200 mL) till LCMS
  6. dry with materialThe organic layer was dried over MgSO4
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customPurification via silica gel chromatography

Sources & evidence

ORD record
ord-2d5f1b061c424988b5ea98c4137efeed
Source dataset
uspto-grants-2012_04
Patent number
US08163720B2

Reaction notes

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