Reacción #47667

Ecuación de reacción

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

lithium hydroxide monohydrate

→

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

Rendimiento 16.0%

Disolventes

N,N-dimethylformamide

tetrahydrofuran

water

Condiciones de reacción

Tratamiento posterior

1. 1
   Otropartitioned between ethyl acetate and water
2. 2
   Extracciónextracted with ethyl acetate
3. 3
   SecadoThe combined organic layers were dried over magnesium sulfate
4. 4
   Filtraciónfiltered
5. 5
   Concentraciónconcentrated in vacuo
6. 6
   workup.ADDITIONThe resulting residue was treated with acetonitrile, dichloromethane/hexanes which
7. 7
   Otroformed a yellow precipitate
8. 8
   OtroThe precipitate was isolated by filtration
9. 9
   TemperaturaThe reaction mixture was then warmed up to room temperature
10. 10
    workup.STIRRINGstirred for 18 h
11. 11
    ConcentraciónThe mixture was concentrated in vacuo
12. 12
    workup.DISSOLUTIONthe resulting residue was dissolved in ethyl acetate
13. 13
    LavadoThe ethyl acetate layer was washed with aqueous saturated ammonium chloride and brine
14. 14
    Secadodried over sodium sulfate
15. 15
    Filtraciónfiltered
16. 16
    Concentraciónconcentrated in vacuo
17. 17
    OtroThe residue was purified by reverse phase HPLC (C18, 20×150 mm column, 40% to 100% acetonitrile/water gradient) which

Procedimiento

To a solution of (S)-2-[4-(benzooxazol-4-yloxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid methyl ester (0.140 g, 0.41 mmol) in tetrahydrofuran (10 mL) and water (10 mL) was added lithium hydroxide monohydrate (0.033 g 0.77 mmol). The mixture was stirred at room temperature for 1.25 h and then partitioned between ethyl acetate and water. The aqueous phase was acidified with 1N aqueous hydrochloric acid (pH<2), and extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting residue was treated with acetonitrile, dichloromethane/hexanes which formed a yellow precipitate. The precipitate was isolated by filtration and dissolved in N,N-dimethylformamide (2 mL). This mixture was treated with 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in U.S. Pat. Appl. US2008021032 Example 80, 0.021 g, 0.14 mmol), N,N-diisopropylethylamine (0.035 g, 0.27 mmol) and benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (0.060 g, 0.14 mmol) at 0° C. The reaction mixture was then warmed up to room temperature and stirred for 18 h. The mixture was concentrated in vacuo and the resulting residue was dissolved in ethyl acetate. The ethyl acetate layer was washed with aqueous saturated ammonium chloride and brine, and dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase HPLC (C18, 20×150 mm column, 40% to 100% acetonitrile/water gradient) which afforded (S)-2-[4-(2-amino-3-hydroxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-amide (0.007 g, 16%) as a yellow solid: HR-ES-MS m/z calculated for C23H31N5O5 [M+H]+ 458.2398, observed 458.2397; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.88 (d, J=6.0 Hz, 3H), 0.92 (d, J=6.0 Hz, 3H), 1.03 (br. s., 3H), 1.04 (br. s., 3H), 1.38-1.60 (m, 2H), 1.62-1.80 (m, 1H), 3.87 (s, 2H), 4.18 (d, J=17.8 Hz, 1H), 4.47-4.60 (m, 3H), 4.62 (s, 1H), 4.66 (s, 1H), 4.87 (dd, J=10.6, 4.5 Hz, 1H), 6.38-6.45 (m, 2H), 6.54 (dd, J=8.2, 1.0 Hz, 1H), 6.59 (dd, J=7.5, 1.0 Hz, 1H), 7.52 (d, J=2.1 Hz, 1H), 9.47 (s, 1H), 10.75 (s, 1H).

Fuente