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

A solution of (S)-2-[4-(benzooxazol-4-yloxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid methyl ester (prepared as in Example 241, 0.137 g, 0.40 mmol) in tetrahydrofuran (10 mL) and water (10 mL) was treated with lithium hydroxide monohydrate (0.033 g 0.77 mmol) and the resulting mixture stirred at room temperature for 1.25 h. The mixture was concentrated in vacuo and the residue treated with acetonitrile, and concentrated in vacuo (repeated 2 additional times). The residue was treated with N,N-dimethylformamide and to this mixture was added 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in U.S. Pat. Appl. US2008021032 Example 80, 0.156 g, 1.00 mmol), N,N-diisopropylethylamine (0.180 g, 1.39 mmol) and benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (0.616 g, 1.39 mmol) at 0° C. The mixture was warmed to room temperature and stirred for 18 h. The mixture was concentrated in vacuo and the residue dissolved in ethyl acetate, washed with aqueous saturated ammonium chloride, brine, and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated in vacuo. The residue was purified by reverse phase HPLC (C18, 20×150 mm column, 30% to 100% acetonitrile/water) to afford (S)-2-[4-(benzooxazol-4-yloxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-amide (0.055 g, 31%) as a tan solid: HR-ES-MS m/z calculated for C24H29N5O5 [M+H]+ 468.2242, observed 468.224; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.91 (d, J=6.3 Hz, 3H), 0.94 (d, J=6.3 Hz, 3H), 1.05 (br. s., 3H), 1.06 (br. s., 3H), 1.36-1.64 (m, 2H), 1.68-1.86 (m, 1H), 3.89 (s, 2H), 4.25 (d, J=18.4 Hz, 1H), 4.65 (d, J=18.4 Hz, 1H), 4.68 (s, 1H), 4.86-4.95 (m, 1H), 4.88 (s, 1H), 6.45 (d, J=2.1 Hz, 1H), 7.38 (d, J=8.0 Hz, 1H), 7.53 (t, J=8.0 Hz, 1H), 7.54 (d, J=2.1 Hz, 1H), 7.76 (d, J=8.0 Hz, 1H), 8.81 (s, 1H), 10.80 (s, 1H).

1. concentrationThe mixture was concentrated in vacuo
2. additionthe residue treated with acetonitrile
3. concentrationconcentrated in vacuo (repeated 2 additional times)
4. additionThe residue was treated with N,N-dimethylformamide and to this mixture
5. temperatureThe mixture was warmed to room temperature
6. stirringstirred for 18 h
7. concentrationThe mixture was concentrated in vacuo
8. dissolutionthe residue dissolved in ethyl acetate
9. washwashed with aqueous saturated ammonium chloride, brine
10. dry with materialdried over anhydrous sodium sulfate
11. filtrationThe mixture was filtered
12. concentrationconcentrated in vacuo
13. customThe residue was purified by reverse phase HPLC (C18, 20×150 mm column, 30% to 100% acetonitrile/water)

ORD record

ord-6683f9b3412b4042852c400beb4914a0

Source dataset

uspto-grants-2010_06

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07741327B2