Diisopropylethylamine → (s)-4-Methyl-2-[4-(2-methyl-benzooxazol-4-yloxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-pentanoic acid [1-(2-hydroxy-2-methyl-propyl)-1h-pyrazol-3-yl]-amide

HRID 19394Notes

Reaction equation

HRID 19394 reaction equation
CO[C:3](=[O:26])[C@@H:4]([N:9]1[CH2:13][C:12]([O:14][C:15]2[C:20]3[N:21]=[C:22]([CH3:24])[O:23][C:19]=3[CH:18]=[CH:17][CH:16]=2)=[CH:11][C:10]1=[O:25])[CH2:5][CH:6]([CH3:8])[CH3:7].O.[OH-].[Li+].Cl.[OH:31][C@@H:32]([CH2:62]O)[CH2:33][N:34]1[CH:38]=[CH:37][C:36]([NH:39]C(=O)[C@@H](N2CC(OC3C=CC=C(Cl)C=3Cl)=CC2=O)CC(C)C)=[N:35]1.[CH:64](N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>O1CCCC1.O.CN(C)C=O>[OH:31][C:32]([CH3:62])([CH3:64])[CH2:33][N:34]1[CH:38]=[CH:37][C:36]([NH:39][C:3](=[O:26])[C@@H:4]([N:9]2[CH2:13][C:12]([O:14][C:15]3[C:20]4[N:21]=[C:22]([CH3:24])[O:23][C:19]=4[CH:18]=[CH:17][CH:16]=3)=[CH:11][C:10]2=[O:25])[CH2:5][CH:6]([CH3:8])[CH3:7])=[N:35]1

Participants

9

Reactant 5

HCID 81531DiisopropylethylamineHCID 151348Benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphateHCID 168937Lithium hydroxide, monohydrateHCID 66894693HCID 66894693, compoundHCID 66899094HMS5552 HCl

Product 1

HCID 57920126(s)-4-Methyl-2-[4-(2-methyl-benzooxazol-4-yloxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-pentanoic acid [1-(2-hydroxy-2-methyl-propyl)-1h-pyrazol-3-yl]-amideYield 52.2%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 8028TetrahydrofuranSolvent

Procedure

A solution of (S)-4-methyl-2-[4-(2-methyl-benzooxazol-4-yloxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-pentanoic acid methyl ester (0.570 g, 1.59 mmol) in tetrahydrofuran (10 mL) and water (10 mL) was treated with lithium hydroxide monohydrate (0.134 g 3.12 mmol) and the resulting mixture stirred at room temperature for 1.5 h. The mixture was concentrated in vacuo and the residue treated with acetonitrile, and concentrated in vacuo (repeated 2 additional times). The resulting solid was treated with N,N-dimethylformamide (10 mL) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in U.S. Pat. Appl. US2008021032 Example 80, 0.371 g, 2.39 mmol), N,N-diisopropylethylamine (0.820 g, 6.34 mmol) and benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (2.811 g, 6.35 mmol) at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 18 h. The mixture was concentrated in vacuo, the residue dissolved in ethyl acetate, and the resulting solution was washed with aqueous saturated ammonium chloride solution, brine and dried over sodium sulfate. The mixture was filtered and concentrated in vacuo and the residue purified by ISCO flash column chromatography (Silicycle 40 g, 5% to 100% ethyl acetate/hexanes) which afforded (S)-4-methyl-2-[4-(2-methyl-benzooxazol-4-yloxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-pentanoic acid [1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-amide (400 mg, 52%) as a light yellow solid: HR-ES-MS m/z calculated for C25H31N5O5 [M+H]+ 482.2398, observed 482.2398; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.90 (d, J=6.0 Hz, 3H), 0.94 (d, J=6.0 Hz, 3H), 1.05 (br. s., 3H), 1.06 (br. s., 3H), 1.37-1.64 (m, 2H), 1.65-1.85 (m, 1H), 2.62 (s, 3H), 3.89 (s, 2H), 4.24 (d, J=18.1 Hz, 1H), 4.62 (d, J=18.1 Hz, 1H), 4.67 (s, 1H), 4.83 (s, 1H), 4.89 (dd, J=11.0, 3.8 Hz, 1H), 6.45 (s, 1H), 7.29 (d, J=7.8 Hz, 1H), 7.42 (t, J=7.8 Hz, 1H), 7.54 (s, 1H), 7.64 (d, J=7.8 Hz, 1H), 10.80 (s, 1H).

Workup

  1. concentrationThe mixture was concentrated in vacuo
  2. additionthe residue treated with acetonitrile
  3. concentrationconcentrated in vacuo (repeated 2 additional times)
  4. temperatureto warm to room temperature
  5. stirringstirred for 18 h
  6. concentrationThe mixture was concentrated in vacuo
  7. dissolutionthe residue dissolved in ethyl acetate
  8. washthe resulting solution was washed with aqueous saturated ammonium chloride solution, brine
  9. dry with materialdried over sodium sulfate
  10. filtrationThe mixture was filtered
  11. concentrationconcentrated in vacuo
  12. customthe residue purified by ISCO flash column chromatography (Silicycle 40 g, 5% to 100% ethyl acetate/hexanes) which

Sources & evidence

ORD record
ord-33e1447743e64485b559e2497b64b0a9
Source dataset
uspto-grants-2010_06
Patent number
US07741327B2

Reaction notes

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