反応 #734090

反応方程式

N,N-dimethylglycine

EDCI

HOBt

DIEA

4-cyano-1H-pyrrole-2-carboxylic acid [2-(4-methyl-piperidin-1-yl)-4-piperidin-4-yl-phenyl]-amide

trifluoroacetic acid

NaOH MeOH

→

title compound

収率 78.0%

4-Cyano-1H-pyrrole-2-carboxylic acid [4-[1-(2-dimethylamino-acetyl)-piperidin-4-yl]-2-(4-methyl-piperidin-1-yl)-phenyl]-amide

収率 78.0%

溶媒

DCM

EtOAc

EtOAc

反応条件

後処理

1. 1
   洗浄the mixture was washed with H2O (3×5 mL)
2. 2
   抽出The aqueous layers were extracted with EtOAc (2×5 mL)
3. 3
   洗浄The combined organic layers were washed with brine (10 mL)
4. 4
   乾燥dried (Na2SO4)
5. 5
   濃縮concentrated in vacuo
6. 6
   その他to give a white solid
7. 7
   workup.STIRRINGThe resulting mixture was stirred at RT for 4 h
8. 8
   洗浄the mixture was washed with H2O (3×5 mL), brine (5 mL)
9. 9
   乾燥dried (Na2SO4)
10. 10
    その他Removal of the solvent under reduced pressure

実験手順

A mixture of 4-cyano-1H-pyrrole-2-carboxylic acid [2-(4-methyl-piperidin-1-yl)-4-piperidin-4-yl-phenyl]-amide bis(trifluoroacetic acid salt) (as prepared in Example 35, 20.0 mg, 0.0320 mmol) in 2 mL of 1:1 1N NaOH/MeOH solution was stirred at RT for 1 h. Treated with 20 mL of EtOAc, the mixture was washed with H2O (3×5 mL). The aqueous layers were extracted with EtOAc (2×5 mL). The combined organic layers were washed with brine (10 mL), dried (Na2SO4) and concentrated in vacuo to give a white solid. The solid was added to a mixture of N,N-dimethylglycine (5.0 mg, 0.048 mmol), EDCI (9.2 mg, 0.048 mmol), HOBt (6.5 mg, 0.048 mmol) and DIEA (16.7 μL, 0.096 mmol) in 0.80 mL of DCM. The resulting mixture was stirred at RT for 4 h. Treated with 30 mL of EtOAc, the mixture was washed with H2O (3×5 mL), brine (5 mL) and dried (Na2SO4). Removal of the solvent under reduced pressure followed by flash chromatography of the residue on silica gel (1-5% MeOH/DCM) gave 12 mg (78%) of the title compound as a white solid: 1H-NMR (CDCl3; 400 MHz): δ 11.0 (s, 1H), 9.17 (s, 1H), 8.31 (d, 1H, J=8.4 Hz), 7.48 (d, 1H, J=1.3 Hz), 7.05 (d, 1H, J=1.8 Hz), 7.01 (dd, 1H, J=8.4, 1.8 Hz), 6.87 (d, 1H, J=1.3 Hz), 4.77 (d, 1H, J=13.3 Hz), 4.24 (d, 1H, J=13.3 Hz), 3.07-3.25 (m, 3H), 2.96 (d, 2H, J=11.8 Hz), 2.61-2.77 (m, 4H), 2.33 (s, 6H), 1.82-1.94 (m, 4H), 1.53-1.70 (m, 3H), 1.32-1.47 (m, 2H), 1.09 (d, 3H, J=6.5 Hz). Mass spectrum (ESI, m/z): Calcd. for C27H36N6O2, 477.3 (M+H), found 477.2.

出典