Diisopropylethylamine → (S)-ethyl 1-((S)-2((S)-2-(tert-butoxycarbonyl(methyl)amino)propanamido)-3-methylbutanoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxylate

HRID 525293Notes

Reaction equation

HRID 525293 reaction equation
Cl.[NH2:2][C@@H:3]([CH:20]([CH3:22])[CH3:21])[C:4]([N:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[CH2:8][C@H:7]1[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:5].[C:23]([O:27][C:28]([N:30]([CH3:36])[C@@H:31]([CH3:35])[C:32](O)=[O:33])=[O:29])([CH3:26])([CH3:25])[CH3:24].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C.CCOC(C)=O>[C:23]([O:27][C:28]([N:30]([CH3:36])[C@@H:31]([CH3:35])[C:32]([NH:2][C@@H:3]([CH:20]([CH3:21])[CH3:22])[C:4]([N:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[CH2:8][C@H:7]1[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:5])=[O:33])=[O:29])([CH3:26])([CH3:25])[CH3:24]

Participants

7

Reactant 4

HCID 81531DiisopropylethylamineHCID 7009590(2S)-2-(((tert-butoxy)carbonyl)(methyl)amino)propanoic acidHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 131735254(S)-ethyl 1-((S)-2-amino-3-methylbutanoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxylate hydrochloride

Product 1

HCID 131735253(S)-ethyl 1-((S)-2((S)-2-(tert-butoxycarbonyl(methyl)amino)propanamido)-3-methylbutanoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxylateYield 81.7%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a solution of (S)-ethyl 1-((S)-2-amino-3-methylbutanoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxylate hydrochloride (1.6 g, 4.88 mmol, Eq: 1.00) in DMF (20 mL) was added (S)-2-(tert-butoxycarbonyl(methyl)amino)propanoic acid (1.2 g, 5.9 mmol, Eq: 1.21) and HATU (2.2 g, 5.79 mmol, Eq: 1.19). Diisopropylethylamine (1.63 g, 2.2 mL, 12.6 mmol, Eq: 2.58) was then added and the resulting yellow solution was stirred at rt for 1 h. The reaction mixture was diluted with EtOAc (100 mL) and hexanes (50 mL) and washed with 0.1 M aqueous KHSO4, 0.1 M aqueous NaOH, and brine and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 80 g, 0% to 20% EtOAc/(DCM:hexanes 1:1) then 20% to 40% EtOAc/(DCM:hexanes 1:1) after first spot has eluted) to give (S)-ethyl 1-((S)-2-((S)-2-(tert-butoxycarbonyl(methyl)amino)propanamido)-3-methylbutanoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (1.9 g), m/z=477 (M+H).

Workup

  1. washwashed with 0.1 M aqueous KHSO4, 0.1 M aqueous NaOH, and brine
  2. concentrationconcentrated in vacuo
  3. customThe crude material was purified by flash chromatography (silica gel, 80 g, 0% to 20% EtOAc/(DCM:hexanes 1:1)
  4. wash20% to 40% EtOAc/(DCM:hexanes 1:1) after first spot has eluted)

Sources & evidence

ORD record
ord-93484825a69d482db6250319184ad290
Source dataset
uspto-grants-2016_05
Patent number
US09340573B2

Reaction notes

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