Potassium Hydroxide → 1-{2-[(2S,4R)-2-(3-Chloro-2-fluoro-benzylcarbamoyl)-4-fluoro-pyrrolidin-1-yl]-2-oxo-ethyl}-6-(2-methoxy-ethoxy)-1H-indole-3-carboxylic acid amide

HRID 1527572Notes

Reaction equation

HRID 1527572 reaction equation
[Cl:1][C:2]1[C:3]([F:34])=[C:4]([CH:31]=[CH:32][CH:33]=1)[CH2:5][NH:6][C:7]([C@@H:9]1[CH2:13][C@@H:12]([F:14])[CH2:11][N:10]1[C:15](=[O:30])[CH2:16][N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([OH:26])[CH:24]=2)[C:19]([C:27]([NH2:29])=[O:28])=[CH:18]1)=[O:8].[OH-].[K+].Br[CH2:38][CH2:39][O:40][CH3:41]>CS(C)=O>[Cl:1][C:2]1[C:3]([F:34])=[C:4]([CH:31]=[CH:32][CH:33]=1)[CH2:5][NH:6][C:7]([C@@H:9]1[CH2:13][C@@H:12]([F:14])[CH2:11][N:10]1[C:15](=[O:30])[CH2:16][N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH2:38][CH2:39][O:40][CH3:41])[CH:24]=2)[C:19]([C:27]([NH2:29])=[O:28])=[CH:18]1)=[O:8]

Participants

5

Reactant 3

HCID 14797Potassium HydroxideHCID 809722-Bromoethyl methyl etherHCID 68283145HCID 68283145, compound

Product 1

HCID 682837801-{2-[(2S,4R)-2-(3-Chloro-2-fluoro-benzylcarbamoyl)-4-fluoro-pyrrolidin-1-yl]-2-oxo-ethyl}-6-(2-methoxy-ethoxy)-1H-indole-3-carboxylic acid amide

Reagents, catalysts & solvents 1

HCID 679Dimethyl SulfoxideSolvent

Procedure

A solution of 1-{2-[(2S,4R)-2-(3-chloro-2-fluoro-benzylcarbamoyl)-4-fluoro-pyrrolidin-1-yl]-2-oxo-ethyl}-6-hydroxy-1H-indole-3-carboxylic acid amide Example 578 (50 mg, 0.102 mmol) in DMSO (1 mL) was treated with KOH (26.0 mg, 0.458 mmol). The mixture was stirred at RT for 5 min, followed by addition of (2-bromoethyl)methyl ether (0.015 mL, 0.158 mmol) and stirring at RT for 2 h. The mixture was partitioned between water and CH2Cl2, and the aqueous phase was extracted twice with CH2Cl2. The combined organics were washed with brine (3×), dried (phase separator) and concentrated under reduced pressure. Purification by preparative HPLC (SunFire C18-ODB, 5 μm, 30×100 mm, eluent: 20-100% CH3CN/H2O/20 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA, flow: 40 mL/min) afforded after lyophilization of the purified fractions the title compound as a white solid. MS: 549 [M+H]+; tR (HPLC conditions c): 4.17 min.

Workup

  1. stirringstirring at RT for 2 h
  2. customThe mixture was partitioned between water and CH2Cl2
  3. extractionthe aqueous phase was extracted twice with CH2Cl2
  4. washThe combined organics were washed with brine (3×)
  5. customdried (phase separator)
  6. concentrationconcentrated under reduced pressure
  7. customPurification by preparative HPLC (SunFire C18-ODB, 5 μm, 30×100 mm, eluent: 20-100% CH3CN/H2O/20 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA, flow: 40 mL/min)

Sources & evidence

ORD record
ord-2a92dc39640147b682263c0373234a3f
Source dataset
uspto-grants-2015_07
Patent number
US09085555B2

Reaction notes

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