反応 #47584

反応方程式

oxalyl chloride

2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-(cis-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-(cis-3-methyl-cyclobutyl)-propionamide

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 h at 25° C
7. 7
   その他The mixture was quenched with methanol
8. 8
   workup.ADDITIONdiluted with dichloromethane
9. 9
   洗浄The organic layer was then washed with a 1N aqueous hydrochloric acid solution
10. 10
    乾燥dried over sodium sulfate
11. 11
    濃縮concentrated in vacuo with silica gel (2 g)
12. 12
    その他Purification by Biotage flash chromatography (40S column, 33% 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-(cis-3-methyl-cyclobutyl)-propionic acid (92 mg, 0.26 mmol), dichloromethane (6 mL) and N,N-dimethylformamide (3 drops) at 25° C. To this mixture was added a 2.0M solution of oxalyl chloride in dichloromethane (300 μL, 0.60 mmol) dropwise, which resulted in gas evolution. The mixture was stirred for 15 min at 25° C. and then concentrated in vacuo. The 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, 50 mg, 0.31 mmol), dichloromethane (5 mL) and 2,6-lutidine (150 μL, 0.52 mmol) at 25° C. and stirred for 1 h at 25° C. The mixture was quenched with methanol and then diluted with dichloromethane. The organic layer was then washed with a 1N aqueous hydrochloric acid solution, dried over sodium sulfate and concentrated in vacuo with silica gel (2 g). Purification by Biotage flash chromatography (40S column, 33% ethyl acetate/hexanes) and then reverse phase HPLC 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-(cis-3-methyl-cyclobutyl)-propionamide, as a mixture of enantiomers (17 mg, 13%): HR-ES-MS m/z calculated for C25H31N4O4Cl [M+H]+ 487.2107, observed 487.2105; 1H NMR (400 MHz, DMSO-d6) δ ppm 0.98 (d, J=6.2 Hz, 3H), 1.05 (s, 3H), 1.06 (s, 3H), 1.16-1.29 (m, 2H), 1.29-1.40 (m, 1H), 1.74-2.25 (m, 6H), 3.90 (s, 2H), 4.21 (d, J=18.3 Hz, 1H), 4.57 (d, J=18.3 Hz, 1H), 4.71 (dd, J=9.6, 5.8 Hz, 1H), 4.78 (s, 1H), 6.44 (d, J=2.2 Hz, 1H), 7.37 (td, J=7.9, 1.7 Hz, 1H), 7.47 (td, J=7.9, 1.4 Hz, 1H), 7.50-7.53 (m, 1H), 7.53 (d, J=2.2 Hz, 1H), 7.66 (dd, J=7.9, 1.4 Hz, 1H), 10.75 (s, 1H).

出典