Ammonia → (s,s)-n-{1-[3-Carbamoyl-1-(5-fluoro-2,3-dihydro-indol-1-ylmethyl)-propylcarbamoyl]-3-methyl-butyl}-3-methyl-benzamide

HRID 132139Notes

Reaction equation

HRID 132139 reaction equation
[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C@@H:12]([NH:18][C:19](=[O:35])[C@@H:20]([NH:25][C:26](=[O:34])[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[CH:28]=1)[CH2:21][CH:22]([CH3:24])[CH3:23])[CH2:13][CH2:14][C:15](O)=[O:16])[CH2:6][CH2:5]2.O1CCOCC1.N.C[N:44](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(OCC)(=O)C>[C:15]([CH2:14][CH2:13][C@H:12]([NH:18][C:19]([C@@H:20]([NH:25][C:26](=[O:34])[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[CH:28]=1)[CH2:21][CH:22]([CH3:23])[CH3:24])=[O:35])[CH2:11][N:7]1[C:8]2[C:4](=[CH:3][C:2]([F:1])=[CH:10][CH:9]=2)[CH2:5][CH2:6]1)(=[O:16])[NH2:44]

Participants

6

Reactant 4

HCID 222AmmoniaHCID 312751,4-DioxaneHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)2×HCID 11386148(s,s)-5-(5-Fluoro-2,3-dihydro-indol-1-yl)-4-[4-methyl-2-(3-methyl-benzoylamino)-pentanoylamino]-pentanoic acid

Product 1

HCID 11271627(s,s)-n-{1-[3-Carbamoyl-1-(5-fluoro-2,3-dihydro-indol-1-ylmethyl)-propylcarbamoyl]-3-methyl-butyl}-3-methyl-benzamideYield 84.9%

Reagents, catalysts & solvents 1

HCID 8857Ethyl AcetateSolvent

Procedure

The title compound of Example 43 (30 mg, 61 μmol) was treated with dioxane (2 mL) and concentrated ammonia (0.2 mL). HATU (35 mg, 92 μmol) was added and the reaction was stirred overnight. Another portion of HATU (80 mg, 210 μmol) was added and the reaction was stirred for an additional 3 hours. The reaction was then diluted with ethyl acetate and extracted once with 1 M NaOH solution. The organics were dried over MgSO4 and the solvent was removed. The residue was purified by silica gel column chromatography using DCM and methanol as solvents to afford the title compound (25 mg, 84%); 1H NMR (CDCl3, 400 MHz) δ 0.90 (s, 3H), 0.91 (s, 3H), 0.88-0.99 (m, 1H), 1.58-1.80 (m, 4H), 1.97-2.12 (m, 2H), 2.23-2.30 (m, 2H), 2.37 (s, 3H), 2.82 (s, 2H), 2.85-3.04 (m, 3H), 3.15 (dd, 1H, J1=6.5, J2=13.6), 3.34 (dd, 1H, J1=8.4, J2=16.9), 3.48 (dd, 1H, J1=8.1, J2=16.0), 4.12-4.21 (m, 1H), 4.40-4.72 (m, 1H), 5.86 (s, 1H), 6.32-6.47 (m, 2H), 6.72 (dd, 1H, J1=J2=8.4), 6.79 (d, 1H, J=7.4), 6.94 (d, 1H, J=7.6), 7.06 (d, 1H, J=8.4), 7.23-7.36 (m, 2H), 7.52-7.61 (m, 2H); HPLC-MS calcd. for C27H35FN4O3 (M+H+) 483.3, found 483.5.

Workup

  1. stirringthe reaction was stirred for an additional 3 hours
  2. extractionextracted once with 1 M NaOH solution
  3. dry with materialThe organics were dried over MgSO4
  4. customthe solvent was removed
  5. customThe residue was purified by silica gel column chromatography

Sources & evidence

ORD record
ord-4a59d7e0a5754a18841b7a8283be897f
Source dataset
uspto-grants-2008_06
Patent number
US07384970B2

Reaction notes

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