Pyridine → tert-butyl (S)-1-((S)-1-((S)-2-(2-fluoro-6-(trifluoromethyl)phenylcarbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)-3-methyl-1-oxobutan-2-ylamino)-1-oxopropan-2-yl(methyl)carbamate

HRID 627043Notes

Reaction equation

HRID 627043 reaction equation
CN(C=O)C.C(Cl)(=O)C(Cl)=O.N1C=CC=CC=1.[C:18]([O:22][C:23]([N:25]([CH3:49])[C@@H:26]([CH3:48])[C:27]([NH:29][C@@H:30]([CH:45]([CH3:47])[CH3:46])[C:31]([N:33]1[C:37]2=[N:38][CH:39]=[CH:40][CH:41]=[C:36]2[CH2:35][C@H:34]1[C:42]([OH:44])=O)=[O:32])=[O:28])=[O:24])([CH3:21])([CH3:20])[CH3:19].[F:50][C:51]1[CH:57]=[CH:56][CH:55]=[C:54]([C:58]([F:61])([F:60])[F:59])[C:52]=1[NH2:53].CN1CCOCC1>C(Cl)Cl>[F:50][C:51]1[CH:57]=[CH:56][CH:55]=[C:54]([C:58]([F:61])([F:60])[F:59])[C:52]=1[NH:53][C:42]([C@H:34]1[N:33]([C:31](=[O:32])[C@@H:30]([NH:29][C:27](=[O:28])[C@@H:26]([N:25]([CH3:49])[C:23](=[O:24])[O:22][C:18]([CH3:19])([CH3:20])[CH3:21])[CH3:48])[CH:45]([CH3:46])[CH3:47])[C:37]2=[N:38][CH:39]=[CH:40][CH:41]=[C:36]2[CH2:35]1)=[O:44]

Participants

8

Reactant 6

HCID 1049PyridineHCID 6228DimethylformamideHCID 79724-MethylmorpholineHCID 65578Oxalyl chlorideHCID 5189592-Fluoro-6-(trifluoromethyl)anilineHCID 118353994(S)-1-((S)-2((S)-2-(tert-butoxycarbonyl(methyl)amino)propanamido)-3-methylbutanoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid2×

Product 1

HCID 131735264tert-butyl (S)-1-((S)-1-((S)-2-(2-fluoro-6-(trifluoromethyl)phenylcarbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)-3-methyl-1-oxobutan-2-ylamino)-1-oxopropan-2-yl(methyl)carbamateYield 29.6%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

In a 50 mL round-bottomed flask, DMF (12.2 mg, 12.9 μL, 167 μmol Eq: 1.5) was combined with DCM (1 mL) to give a colorless solution. The reaction mixture was cooled in an ice bath and oxalyl chloride (21.2 mg, 14.6 μL, 167 μmol, Eq: 1.5) was added. Pyridine (13.2 mg, 13.5 μL, 167 μmol, Eq: 1.5) was then added followed by (S)-1-((S)-2-((S)-2-(tert-butoxycarbonyl(methyl)amino)propanamido)-3-methylbutanoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (Intermediate 8) (50 mg, 111 μmol Eq: 1.00) and the reaction was stirred at rt for 1 h. 2-Fluoro-6-(trifluoromethyl)aniline (30.0 mg, 167 μmol, Eq: 1.5) and N-methylmorpholine (18 μL, 167 μmol, Eq: 1.5) were added and the reaction mixture was stirred at rt over the weekend. The reaction mixture was diluted with DCM and washed with water and brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 4 g, 0% to 40% EtOAc in hexanes) to give tert-butyl (S)-1-((S)-1-((S)-2-(2-fluoro-6-(trifluoromethyl)phenylcarbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)-3-methyl-1-oxobutan-2-ylamino)-1-oxopropan-2-yl(methyl)carbamate as a colorless oil (20 mg).

Workup

  1. customto give a colorless solution
  2. temperatureThe reaction mixture was cooled in an ice bath
  3. stirringthe reaction mixture was stirred at rt over the weekend
  4. washwashed with water and brine
  5. dry with materialThe organic layer was dried over Na2SO4
  6. concentrationconcentrated in vacuo
  7. customThe crude material was purified by flash chromatography (silica gel, 4 g, 0% to 40% EtOAc in hexanes)

Sources & evidence

ORD record
ord-a5416f78b5cd4eb1ac6354360a9a2bac
Source dataset
uspto-grants-2016_04
Patent number
US09309248B2

Reaction notes

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