Reaction #47672

Reaction equation

1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol

(S)-2-[4-(2,3-dichloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-amide hydrochloride

N,N-diisopropylethylamine

benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate

(S)-4-methyl-2-[4-(2-methyl-benzooxazol-4-yloxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-pentanoic acid methyl ester

lithium hydroxide monohydrate

→

(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

Yield 52.2%

Solvents

N,N-dimethylformamide

tetrahydrofuran

water

Conditions

Workup

1. 1
   ConcentrationThe mixture was concentrated in vacuo
2. 2
   workup.ADDITIONthe residue treated with acetonitrile
3. 3
   Concentrationconcentrated in vacuo (repeated 2 additional times)
4. 4
   Temperatureto warm to room temperature
5. 5
   workup.STIRRINGstirred for 18 h
6. 6
   ConcentrationThe mixture was concentrated in vacuo
7. 7
   workup.DISSOLUTIONthe residue dissolved in ethyl acetate
8. 8
   Washthe resulting solution was washed with aqueous saturated ammonium chloride solution, brine
9. 9
   Dryingdried over sodium sulfate
10. 10
    FiltrationThe mixture was filtered
11. 11
    Concentrationconcentrated in vacuo
12. 12
    Otherthe residue purified by ISCO flash column chromatography (Silicycle 40 g, 5% to 100% ethyl acetate/hexanes) which

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).

Source