Diisopropylethylamine → tert-butyl (2S)-2-[(2S)-2-amino-3-methylbutanamido]propanoate

HRID 594192Notes

Reaction equation

HRID 594192 reaction equation
Cl.[C:2]([O:6][C:7](=[O:11])[C@H:8]([CH3:10])[NH2:9])([CH3:5])([CH3:4])[CH3:3].[CH3:12][CH:13]([C@H:15]([NH:26]C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C:16](ON1C(=O)CCC1=O)=[O:17])[CH3:14].CCN(C(C)C)C(C)C>ClCCl>[NH2:26][C@@H:15]([CH:13]([CH3:14])[CH3:12])[C:16]([NH:9][C@@H:8]([CH3:10])[C:7]([O:6][C:2]([CH3:5])([CH3:4])[CH3:3])=[O:11])=[O:17]

Participants

5

Reactant 3

HCID 81531DiisopropylethylamineHCID 11275390tert-Butyl alaninate hydrochlorideHCID 11339559Fmoc-val-osu

Product 1

HCID 86676194tert-butyl (2S)-2-[(2S)-2-amino-3-methylbutanamido]propanoate

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

To a mixture of the alanine-O-tert-butyl ester hydrogen chloride salt (98) (500 mg, 2.76 mmol) in dichloromethane (5 mL) was added Fmoc-val-OSu (99) (1.09 g, 2.51 mmol). DIPEA (0.96 ml, 5.5 mmol) was added and the reaction mixture was allowed to stir at an ambient temperature for 16 h. The mixture was poured into dichloromethane (100 mL) and washed with 1N HCl (50 mL) and water (50 mL) before being dried over magnesium sulfate. The material was chromatographed on a 2 mm radial chromatotron plate eluting with 1 to 5% methanol/dichloromethane gradient and product containing fractions were combined and concentrated. The resulting residue was dissolved in dichloromethane (16 mL) and piperidine (4 mL) was added. The mixture was stirred for 10 min before being concentrated under reduced pressure. The resulting residue was chromatographed on a 2 mm plate eluting first with ammonia-saturated dichloromethane followed by 5% methanol in ammonia-saturated dichloromethane to give 494 mg (2.02 mmol, 81% for two steps) of 97: 1H-NMR (400 MHz, CDCl3) δ 7.78 (bs, 1H), 4.47 (m, 1H), 3.30 (d, 1H), 2.30 (m, 1H), 1.38 (d, 3H), 1.47 (s, 9H), 1.00 (d, J=7.0 Hz, 3H), 0.84 (d, J=6.9 Hz, 3H).

Workup

  1. washwashed with 1N HCl (50 mL) and water (50 mL)
  2. dry with materialbefore being dried over magnesium sulfate
  3. customThe material was chromatographed on a 2 mm radial chromatotron plate
  4. washeluting with 1 to 5% methanol/dichloromethane gradient and product
  5. additioncontaining fractions
  6. concentrationconcentrated
  7. dissolutionThe resulting residue was dissolved in dichloromethane (16 mL)
  8. additionpiperidine (4 mL) was added
  9. stirringThe mixture was stirred for 10 min
  10. concentrationbefore being concentrated under reduced pressure
  11. customThe resulting residue was chromatographed on a 2 mm plate
  12. washeluting first with ammonia-saturated dichloromethane

Sources & evidence

ORD record
ord-e6fe23faccf14166ae986c9b47f3f616
Source dataset
uspto-grants-2016_01
Patent number
US09242013B2

Reaction notes

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