Reaktion #47667

Reaktionsgleichung

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

Ausbeute 16.0%

Lösungsmittel

N,N-dimethylformamide

tetrahydrofuran

water

Reaktionsbedingungen

Aufarbeitung

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

Vorschrift

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).

Quelle