Sodium Bicarbonate → (2S,3S,4S)-1-[2-(3-acetyl-indol-1-yl)-acetyl]-3,4-difluoro-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro-benzylamide

HRID 1527609Notes

Reaction equation

HRID 1527609 reaction equation
[F:1][C@@H:2]1[C@@H:6]([F:7])[CH:5]=[N:4][CH2:3]1.[C:8]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([CH2:20][C:21]([OH:23])=O)[CH:12]=1)(=[O:10])[CH3:9].[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31][N+:32]#[C-:33])[C:26]=1[F:34].C([O-])(O)=[O:36].[Na+]>CO>[Cl:24][C:25]1[C:26]([F:34])=[C:27]([CH:28]=[CH:29][CH:30]=1)[CH2:31][NH:32][C:33]([C@H:5]1[C@H:6]([F:7])[C@@H:2]([F:1])[CH2:3][N:4]1[C:21](=[O:23])[CH2:20][N:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]([C:8](=[O:10])[CH3:9])=[CH:12]1)=[O:36]

Participants

6

Reactant 4

HCID 516892Sodium BicarbonateHCID 1088616(3-Acetyl-indol-1-yl)-acetic acidHCID 552654211-Chloro-2-fluoro-3-(isocyanomethyl)benzeneHCID 68283174(3S,4S)-3,4-difluoro-3,4-dihydro-2H-pyrrole

Product 1

HCID 68283089(2S,3S,4S)-1-[2-(3-acetyl-indol-1-yl)-acetyl]-3,4-difluoro-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro-benzylamide

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent2×

Procedure

To the crude solution of (3S,4S)-3,4-difluoro-3,4-dihydro-2H-pyrrole (0.52 mmol) in MeOH under argon were successively added (3-acetyl-indol-1-yl)-acetic acid (57 mg, 0.26 mmol) and 1-chloro-2-fluoro-3-(isocyanomethyl)benzene (44 mg, 0.26 mmol) in MeOH (0.2 mL). The reaction mixture was stirred at RT for 60 h and poured into a saturated aqueous solution of NaHCO3 and extracted with CH2Cl2 (×2). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (Gold RediSep column, 24 g, CH2Cl2 to CH2Cl2/MeOH 95-5), the fractions containing the desired material as a mixture of 2 diastereosiomers were concentrated and the residue was purified again by preparative HPLC (Waters Sunfire C18-OBD, 5 μm, 30×100 mm, eluent: 5% to 100% CH3CN in H2O in 25 min, CH3CN and H2O containing 0.1% TFA, flow: 40 mL/min) to give (2S,3S,4S)-1-[2-(3-acetyl-indol-1-yl)-acetyl]-3,4-difluoro-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro-benzylamide: Rf (EtOAc): 0.60; MS (UPLC): 492.2/494.2 [M+H]+, 536.2/538.2 [M+HCOO]− and (2R,3S,4S)-1-[2-(3-acetyl-indol-1-yl)-acetyl]-3,4-difluoro-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro-benzylamide; Rf (EtOAc): 0.50; MS (UPLC): 492.2/494.2 [M+H]+, 536.2/538.2 [M+HCOO]−; tR (HPLC conditions a): 3.37 min. The absolute stereochemistry has been assigned tentatively based on comparison of 1H-NMR spectra and test results in the biological assay measured for both diastereosiomers.

Workup

  1. extractionextracted with CH2Cl2 (×2)
  2. dry with materialThe combined organic extracts were dried (Na2SO4)
  3. filtrationfiltered
  4. concentrationconcentrated
  5. customThe crude residue was purified by flash column chromatography on silica gel (Gold RediSep column, 24 g, CH2Cl2 to CH2Cl2/MeOH 95-5)
  6. additionthe fractions containing the desired material
  7. additionas a mixture of 2 diastereosiomers
  8. concentrationwere concentrated
  9. customthe residue was purified again by preparative HPLC (Waters Sunfire C18-OBD, 5 μm, 30×100 mm, eluent: 5% to 100% CH3CN in H2O in 25 min, CH3CN and H2O containing 0.1% TFA, flow: 40 mL/min)

Sources & evidence

ORD record
ord-5ae5b134e5254b3893545c7eff5e4c3f
Source dataset
uspto-grants-2015_07
Patent number
US09085555B2

Reaction notes

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