Dichloromethane → N-[(3-chloro-5-fluoro-1-methylindole-2-carbonyl) valinyl]-3-amino-4-oxo-5-fluoropentanoic acid, t-butyl ester

HRID 1859608Notes

Reaction equation

HRID 1859608 reaction equation
[CH2:1]([Cl:3])Cl.C(Cl)(=O)C(Cl)=O.[F:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH3:20])[C:15]([C:21]([NH:23][C@H:24]([C:28]([NH:30][CH:31]([CH:40]([OH:43])[CH2:41][F:42])[CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[O:29])[CH:25]([CH3:27])[CH3:26])=[O:22])=C2>CS(C)=O>[Cl:3][C:1]1[C:18]2[C:17](=[CH:13][CH:12]=[C:11]([F:10])[CH:19]=2)[N:16]([CH3:20])[C:15]=1[C:21]([NH:23][C@H:24]([C:28]([NH:30][CH:31]([C:40](=[O:43])[CH2:41][F:42])[CH2:32][C:33]([O:35][C:36]([CH3:37])([CH3:38])[CH3:39])=[O:34])=[O:29])[CH:25]([CH3:27])[CH3:26])=[O:22]

Participants

5

Reactant 3

HCID 6344Dichloromethane2×HCID 65578Oxalyl chlorideHCID 86585790N-[(5-fluoro-1-methylindole-2-carbonyl)valinyl]-3-amino-4-hydroxy-5-fluoropentanoic acid, t-butyl ester

Product 1

HCID 86584006N-[(3-chloro-5-fluoro-1-methylindole-2-carbonyl) valinyl]-3-amino-4-oxo-5-fluoropentanoic acid, t-butyl ester

Reagents, catalysts & solvents 1

HCID 679Dimethyl SulfoxideSolvent2×

Conditions

Temperature
-78 °C

Procedure

DMSO (0.60 mL, 8.5 mmol) was added to a methylene chloride solution of oxalyl chloride (2.1 mL, 2.0 M, 4.2 mmol, in 15 mL of methylene chloride), and the resultant reaction mixture was stirred for 10 minutes under a nitrogen atmosphere at −78° C. A methylene chloride solution of N-[(5-fluoro-1-methylindole-2-carbonyl)valinyl]-3-amino-4-hydroxy-5-fluoropentanoic acid, t-butyl ester (820 mg, 1.7 mmol, in 8 mL of dry methylene chloride), and DMSO (0.4 mL) were added dropwise to the reaction mixture and stirred for 15 minutes at −78° C. TEA (1.4 mL, 10.2 mmol) was added to the mixture dropwise and the mixture was stirred for 10 minutes at −78° C., then was allowed to warm to room temperature. The reaction mixture was partitioned between ethyl acetate and 5% KHSO4 solution and the aqueous layer was back-extracted with ethyl acetate. The combined ethyl acetate solutions were washed with 5% KHSO4 solution and brine, dried over sodium sulfate, and concentrated to give the title product as a slightly yellow solid. Trituration with ether afforded the title product as a white powder (705 mg, 85%). TLC: (methanol/methylene chloride, 1:9): Rf=0.63. MS for C24H30ClF2N3O5: MH+=514/516; (M−H)−=512/514.

Workup

  1. customthe resultant reaction mixture
  2. stirringstirred for 15 minutes at −78° C
  3. stirringthe mixture was stirred for 10 minutes at −78° C.
  4. temperatureto warm to room temperature
  5. customThe reaction mixture was partitioned between ethyl acetate and 5% KHSO4 solution
  6. extractionthe aqueous layer was back-extracted with ethyl acetate
  7. washThe combined ethyl acetate solutions were washed with 5% KHSO4 solution and brine
  8. dry with materialdried over sodium sulfate
  9. concentrationconcentrated

Sources & evidence

ORD record
ord-a19afe1a46c24caaa106a22ff4affba4
Source dataset
uspto-grants-2003_03
Patent number
US06528506B2

Reaction notes

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