Diphenylphosphinic chloride → tert-butyl (S)-1-((S)-1-((S)-2-(2-fluoro-5-methylphenylcarbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)-3-methyl-1-oxobutan-2-ylamino)-1-oxopropan-2-yl(methyl)carbamate

HRID 627041Notes

Reaction equation

HRID 627041 reaction equation
[C:1]([O:5][C:6]([N:8]([CH3:32])[C@@H:9]([CH3:31])[C:10]([NH:12][C@@H:13]([CH:28]([CH3:30])[CH3:29])[C:14]([N:16]1[C:20]2=[N:21][CH:22]=[CH:23][CH:24]=[C:19]2[CH2:18][C@H:17]1[C:25]([OH:27])=O)=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[F:57][C:58]1[CH:64]=[CH:63][C:62]([CH3:65])=[CH:61][C:59]=1[NH2:60].OS([O-])(=O)=O.[K+]>C(Cl)Cl>[F:57][C:58]1[CH:64]=[CH:63][C:62]([CH3:65])=[CH:61][C:59]=1[NH:60][C:25]([C@H:17]1[N:16]([C:14](=[O:15])[C@@H:13]([NH:12][C:10](=[O:11])[C@@H:9]([N:8]([CH3:32])[C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:4])[CH3:3])[CH3:31])[CH:28]([CH3:30])[CH3:29])[C:20]2=[N:21][CH:22]=[CH:23][CH:24]=[C:19]2[CH2:18]1)=[O:27]

Participants

7

Reactant 5

HCID 73910Diphenylphosphinic chlorideHCID 81531DiisopropylethylamineHCID 2629702-Fluoro-5-methylanilineHCID 516920Potassium bisulfateHCID 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 131735263tert-butyl (S)-1-((S)-1-((S)-2-(2-fluoro-5-methylphenylcarbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)-3-methyl-1-oxobutan-2-ylamino)-1-oxopropan-2-yl(methyl)carbamateYield 79.4%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a solution of (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 diisopropylethylamine (58.4 μL, 334 μmol, Eq: 3) in DCM (1.5 mL) was added diphenylphosphinic chloride (58.0 mg, 46.7 μL, 245 μmol, Eq: 2.2). After stirring for 5 min, 2-fluoro-5-methylaniline (21 mg, 167 μmol, Eq: 1.5) was added and the resulting solution was stirred at rt for 2 days. The reaction mixture was poured into 0.1 M aqueous KHSO4 (20 mL) and extracted with EtOAc. The crude material was purified by flash chromatography (silica gel, 12 g, 0% to 40% EtOAc in hexanes) to give tert-butyl (S)-1-((S)-1-((S)-2-(2-fluoro-5-methylphenylcarbamoyl)-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 (49 mg), m/z=556 (M+H).

Workup

  1. stirringthe resulting solution was stirred at rt for 2 days
  2. extractionextracted with EtOAc
  3. customThe crude material was purified by flash chromatography (silica gel, 12 g, 0% to 40% EtOAc in hexanes)

Sources & evidence

ORD record
ord-addeddafded04755b1653c836ee2b50a
Source dataset
uspto-grants-2016_04
Patent number
US09309248B2

Reaction notes

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