Diisopropylethylamine → 3-{[2-[2,6-Bis(isopropyl)phenoxycarbonyl]-benzoyl]amino}-propanoic Acid

HRID 1766138Notes

Reaction equation

HRID 1766138 reaction equation
[CH:1]([C:4]1[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]([CH3:24])[CH3:23])[C:5]=1[O:6][C:7]([C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11](O)=[O:12])=[O:8])([CH3:3])[CH3:2].Cl.C([O:30][C:31](=[O:35])[CH2:32][CH2:33][NH2:34])(C)(C)C.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C=O)C.C(OCC)(=O)C>[CH:22]([C:18]1[CH:19]=[CH:20][CH:21]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]=1[O:6][C:7]([C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([NH:34][CH2:33][CH2:32][C:31]([OH:35])=[O:30])=[O:12])=[O:8])([CH3:24])[CH3:23]

Participants

7

Reactant 4

HCID 81531DiisopropylethylamineHCID 2733084Methanaminium, N-((1H-benzotriazol-1-yloxy)(dimethylamino)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 16218890Tert-butyl 3-aminopropanoate hydrochlorideHCID 211100142-[2,6-Bis(isopropyl)phenoxycarbonyl]-benzoic Acid

Product 1

HCID 114180783-{[2-[2,6-Bis(isopropyl)phenoxycarbonyl]-benzoyl]amino}-propanoic AcidYield 38%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a solution containing (102) (2.1 g, 6.4 mmol) and beta-alanine tert-butyl ester hydrochloride (1.16 g, 6.4 mmol) in DMF (20 mL) was added diisopropylethylamine (2.4 mL, 13.7 mmol) followed by O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (2.5 g, 6.5 mmol). The resulting reaction mixture was stirred at room temperature for 14 h, diluted with ethyl acetate (100 mL), washed with 10% aqueous citric acid solution (50 mL), followed by saturated aqueous NaHCO3 solution (50 mL) and brine (2×50 mL). The organic phase was dried over MgSO4 and concentrated in vacuo. The crude residue was dissolved in anhydrous dichloromethane (30 mL) and cooled to 0° C. before a solution of hydrochloric acid (10 mL, 4 N in dioxane) was added. The reaction was stirred for 1 h at 0° C. and 1 h at room temperature. The solvent was removed in vacuo and the crude residue was purified by preparative LC/MS to afford 0.85 g (38% yield over three steps) of the title compound (101). 1H NMR (400 MHz, CD3OD): δ 8.20 (dd, J=7.6, 0.8 Hz, 1H), 7.70–7.68 (m, 1H), 7.63–7.59 (m, 1H), 7.49 (dd, J=7.6, 0.8 Hz, 1H), 7.22–7.17 (m, 3H), 3.54 (t, J=7.2 Hz, 2H), 3.06–3.00 (m, 2H), 2.57 (t, J=6.8 Hz, 2H), 1.19 (d, J=6.8 Hz, 12H). MS (ESI) m/z 398.3 (M+H+).

Workup

  1. customThe resulting reaction mixture
  2. washwashed with 10% aqueous citric acid solution (50 mL)
  3. dry with materialThe organic phase was dried over MgSO4
  4. concentrationconcentrated in vacuo
  5. dissolutionThe crude residue was dissolved in anhydrous dichloromethane (30 mL)
  6. temperaturecooled to 0° C. before a solution of hydrochloric acid (10 mL, 4 N in dioxane)
  7. additionwas added
  8. stirringThe reaction was stirred for 1 h at 0° C. and 1 h at room temperature
  9. customThe solvent was removed in vacuo
  10. customthe crude residue was purified by preparative LC/MS

Sources & evidence

ORD record
ord-0730ea59c6e94b27bd7fff983dfbe4b5
Source dataset
uspto-grants-2007_06
Patent number
US07230003B2

Reaction notes

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