Dimethylformamide → N-[(1,3-Dimethlindole-2-carbonyl)valinyl]-3-amino-4-hydroxy-5-fluoropentanoic acid, t-butyl ester

HRID 634923Notes

Reaction equation

HRID 634923 reaction equation
Cl.CN(C)CCCN=C=NCC.CN(C=O)C.[CH3:18][N:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([CH3:28])=[C:20]1[C:29]([OH:31])=O.[NH2:32][C@H:33]([C:37]([NH:39][CH:40]([CH:49]([OH:52])[CH2:50][F:51])[CH2:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])=[O:38])[CH:34]([CH3:36])[CH3:35]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:18][N:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([CH3:28])=[C:20]1[C:29]([NH:32][C@H:33]([C:37]([NH:39][CH:40]([CH:49]([OH:52])[CH2:50][F:51])[CH2:41][C:42]([O:44][C:45]([CH3:46])([CH3:47])[CH3:48])=[O:43])=[O:38])[CH:34]([CH3:35])[CH3:36])=[O:31]

Participants

7

Reactant 4

HCID 6228DimethylformamideHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 124966631,3-dimethyl-1H-indole-2-carboxylic acidHCID 86584005N-(valinyl)-3-amino-4-hydroxy-5-fluoropentanoic acid, t-butyl ester

Product 1

HCID 86584004N-[(1,3-Dimethlindole-2-carbonyl)valinyl]-3-amino-4-hydroxy-5-fluoropentanoic acid, t-butyl esterYield 56.1%

Reagents, catalysts & solvents 2

HCID 142844-(Dimethylamino)pyridineCatalystHCID 6344DichloromethaneSolvent

Conditions

Temperature
0 °C

Procedure

4-Dimethylaminopyridine (DMAP) (67 mg, 0.55 mmol) and 1-(3′-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDAC) (125 mg, 0.65 mmol) were added as solids to a DMF solution of 1,3-dimethylindole-2-carboxylic acid (95 mg, 0.5 mmol in 1 mL of DMF), and the resultant reaction mixture was stirred for 10 minutes under a nitrogen atmosphere at 0° C. A methylene chloride solution of N-(valinyl)-3-amino-4-hydroxy-5-fluoropentanoic acid, t-butyl ester (153 mg, 0.5 mmol in 1 mL of methylene chloride) was added and the resultant reaction mixture was first stirred for 1 hour at 0° C. and then for 4 hours at room temperature. The reaction mixture was partitioned between ethyl acetate and 5% KHSO4 solution and the aqueous solution was back-extracted with ethyl acetate. The combined ethyl acetate solutions were washed with 5% KHSO4 solution, saturated sodium bicarbonate solution (2×), and brine, dried over sodium sulfate, and concentrated to give a solid. The solid was triturated with ether/hexane to yield the title product as a white solid (134 mg, 56%). TLC (ethyl acetate/hexanes, 2:1): Rf=0.42. 1H-NMR (CDCl3): δ 7.59 (d, J=8.8, 1 H), 7.37 (d, J=7.7, 1 H), 7.29-7.24 (m, 1 H), 7.12-7.07 (m, 1 H), 4.49-4.26 (m, 5 H), 3.81-3.79 (m, 3 H), 2.66-2.47 (m, 5 H), 2.22-2.10 (m, 1 H), 1.45-1.41 (m, 9 H, 1.09-1.03 (m, 6 H).

Workup

  1. customthe resultant reaction mixture
  2. customthe resultant reaction mixture
  3. stirringwas first stirred for 1 hour at 0° C.
  4. waitfor 4 hours at room temperature
  5. customThe reaction mixture was partitioned between ethyl acetate and 5% KHSO4 solution
  6. extractionthe aqueous solution was back-extracted with ethyl acetate
  7. washThe combined ethyl acetate solutions were washed with 5% KHSO4 solution, saturated sodium bicarbonate solution (2×), and brine
  8. dry with materialdried over sodium sulfate
  9. concentrationconcentrated
  10. customto give a solid
  11. customThe solid was triturated with ether/hexane

Sources & evidence

ORD record
ord-80589e6b0ba04e7bb4843a1226b03769
Source dataset
uspto-grants-2001_02
Patent number
US06184244B2

Reaction notes

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