Reaktion #47335

Reaktionsgleichung

1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-ylamine

(S)-2-[4-(3-chloro-2-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid

1-(3-dimethylaminopropyl)-3-ethylcarbodiimide

1-hydroxybenzotriazole

→

(S)-2-[4-(3-chloro-2-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-amide

Ausbeute 49.0%

Lösungsmittel

dichloromethane

dichloromethane

Reaktionsbedingungen

Aufarbeitung

1. 1
   workup.STIRRINGThe reaction mixture was stirred at 25° C. for 18 h
2. 2
   Waschenwas washed with a saturated aqueous ammonium chloride solution (2×50 mL)
3. 3
   Trocknena saturated aqueous sodium bicarbonate solution (1×100 mL), water (1×100 mL) and a saturated aqueous sodium chloride solution (1×100 mL), dried over magnesium sulfate
4. 4
   Filtrationfiltered
5. 5
   Waschenrinsed with dichloromethane
6. 6
   Einengenconcentrated in vacuo
7. 7
   SonstigePurification by Analogix flash chromatography (40 g, 50-100% ethyl acetate/hexanes)

Vorschrift

A solution of (S)-2-[4-(3-chloro-2-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (0.75 g, 2.20 mmol) in dichloromethane (39 mL) was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.42 mL, 2.40 mmol) and 1-hydroxybenzotriazole (0.31 g, 2.29 mmol). The reaction was stirred at 25° C. for 20 min. At this time, the reaction was treated with 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-ylamine (prepared as in Example 49, 0.53 g, 2.68 mmol). The reaction mixture was stirred at 25° C. for 18 h. At this time, the reaction was diluted with dichloromethane (50 mL) and was washed with a saturated aqueous ammonium chloride solution (2×50 mL), a saturated aqueous sodium bicarbonate solution (1×100 mL), water (1×100 mL) and a saturated aqueous sodium chloride solution (1×100 mL), dried over magnesium sulfate, filtered, rinsed with dichloromethane and concentrated in vacuo. Purification by Analogix flash chromatography (40 g, 50-100% ethyl acetate/hexanes) afforded (S)-2-[4-(3-chloro-2-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-amide (0.56 g, 49%) as a light yellow solid: HR-ES-MS m/z calculated for C25H30N4O5FCl [M+H]+ 521.1962, observed 521.1963; 1H NMR (400 MHz, DMSO-d6) δ ppm 0.91 (d, J=6.4 Hz, 3H), 0.94 (d, J=6.4 Hz, 3H), 1.25 (s, 3H), 1.30 (s, 3H), 1.46 (br. s., 1H), 1.51-1.65 (m, 1H), 1.71-1.82 (m, 1H), 3.74 (dd, J=8.5, 5.8 Hz, 1H), 4.01 (dd, J=8.2, 6.3 Hz, 1H), 4.04-4.18 (m, 2H), 4.25 (d, J=18.5 Hz, 1H), 4.35 (dq, J=6.0, 5.8 Hz, 1H), 4.61 (d, J=18.5 Hz, 1H), 4.89 (dd, J=10.9, 4.7 Hz, 1H), 5.03 (s, 1H), 6.44 (d, J=2.1 Hz, 1H), 7.33 (td, J=8.3, 1.3 Hz, 1H), 7.50-7.60 (m, 2H), 7.60 (d, J=2.1 Hz, 1H), 10.80 (s, 1H).

Quelle