反応 #47581

反応方程式

oxalyl chloride

2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-(trans-3-methyl-cyclobutyl)-propionic acid

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

2,6-lutidine

→

2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-3-(trans-3-methyl-cyclobutyl)-propionamide

収率 36.0%

溶媒

dichloromethane

dichloromethane

dichloromethane

反応条件

後処理

1. 1
   その他In a round bottom flask under argon was placed
2. 2
   その他at 25° C
3. 3
   その他which resulted in gas evolution
4. 4
   濃縮concentrated in vacuo
5. 5
   workup.ADDITIONadded dropwise into another flask
6. 6
   workup.STIRRINGstirred for 1.5 h at 25° C.
7. 7
   その他quenched with methanol
8. 8
   workup.ADDITIONThe mixture was diluted with dichloromethane
9. 9
   洗浄washed with a 1N aqueous hydrochloric acid solution
10. 10
    その他The organic layer was separated
11. 11
    乾燥dried over sodium sulfate
12. 12
    濃縮concentrated in vacuo with silica gel (2 g)
13. 13
    その他Purification by Biotage flash chromatography (40S column, 25% ethyl acetate/hexanes)

実験手順

In a round bottom flask under argon was placed 2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-(trans-3-methyl-cyclobutyl)-propionic acid (100 mg, 0.29 mmol), dichloromethane (5 mL) and N,N-dimethylformamide (3 drops) at 25° C. To this mixture was added a 2.0M solution of oxalyl chloride in dichloromethane (180 μL, 0.36 mmol) dropwise, which resulted in gas evolution. The mixture was stirred for 15 min at 25° C. and then concentrated in vacuo. This residue was taken up in dichloromethane (5 mL) and added dropwise into another flask containing a solution of 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared as in US20080021032, Example 80, 55 mg, 0.35 mmol), dichloromethane (5 mL) and 2,6-lutidine (180 μL, 0.58 mmol) at 25° C. and stirred for 1.5 h at 25° C. and then quenched with methanol. The mixture was diluted with dichloromethane and washed with a 1N aqueous hydrochloric acid solution. The organic layer was separated, dried over sodium sulfate and concentrated in vacuo with silica gel (2 g). Purification by Biotage flash chromatography (40S column, 25% ethyl acetate/hexanes) afforded 2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-3-(trans-3-methyl-cyclobutyl)-propionamide (51 mg, 36%) as a light amber foam: HR-ES-MS m/z calculated for C25H31N4O4Cl [M+H]+ 487.2107, observed 487.2107; 1H NMR (500 MHz, DMSO-d6) δ ppm 1.06 (d, J=6.8 Hz, 9H), 1.48-1.57 (m, 1H), 1.65-1.73 (m, 1H), 1.75-1.83 (m, 1H), 1.88-2.01 (m, 3H), 2.14-2.26 (m, 1H), 2.28-2.37 (m, 1H), 3.90 (s, 2H), 4.20 (d, J=18.6 Hz, 1H), 4.58 (d, J=18.6 Hz, 1H), 4.66 (s, 1H), 4.73 (dd, J=9.3, 6.3 Hz, 1H), 4.78 (s, 1H), 6.44 (d, J=2.4 Hz, 1H), 7.37 (td, J=7.8, 1.5 Hz, 1H), 7.47 (td, J=7.8, 1.5 Hz, 1H), 7.51 (dd, J=7.8, 1.5 Hz, 1H), 7.53 (d, J=2.4 Hz, 1H), 7.65 (dd, J=7.8, 1.5 Hz, 1H), 10.75 (s, 1H).

出典