反応 #49230

反応方程式

(2R,4R)-tert-butyl 2-((1S,2S)-2-amino-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)propyl)-4-propoxypyrrolidine 1-carboxylate

(2R,4R)-tert-butyl 2-((1S,2S)-2-amino-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)propyl)-4-propoxypyrrolidine-1-carboxylate

tert-butyl 2-((1S,2S)-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)-2-(3-(methoxycarbonyl)benzamido)propyl)-4-propoxypyrrolidine-1-carboxylate

3-(methoxycarbonyl)benzoic acid

Hunig's base

HATU

→

title compound

収率 88.0%

N-((1R,2S)-3-(3,5-difluorophenyl)-1-hydroxy-1-((2R,4R)-4-propoxypyrrolidin-2-yl)propan-2-yl)-3-((R)-2-(methoxymethyl)pyrrolidine-1-carbonyl)benzamide

収率 88.0%

溶媒

dichloromethane

DMF

Ethyl acetate

反応条件

後処理

1. 1
   workup.ADDITIONwas then added
2. 2
   workup.STIRRINGthe reaction mixture was stirred at rt overnight
3. 3
   洗浄the mixture was washed with H2O
4. 4
   その他dried
5. 5
   濃縮concentrated
6. 6
   その他The crude mixture was purified by silica gel Flash Chromatography (0% to 20% to 40% to 60% to 80% EtOAc/Hexane step gradient)

実験手順

Step 1 (B): 2R,4R)-tert-butyl 2-((1S,2S)-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)-2-(3-(methoxycarbonyl)benzamido)propyl)-4-propoxypyrrolidine-1-carboxylate. To a solution of 3-(methoxycarbonyl)benzoic acid (450 mg, 2.5 mmol) in dichloromethane (20 mL) and DMF (5 mL) was added Hunig's base (646 mg, 5.01 mmol) to make a clear solution and HATU (1.08 g, 2.84 mmol) was then added. After stirring for 20 min, the reaction mixture was added (2R,4R)-tert-butyl 2-((1S,2S)-2-amino-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)propyl)-4-propoxypyrrolidine 1-carboxylate (Step 1 (A), 900 mg, 1.67 mmol) and the reaction mixture was stirred at rt overnight. Ethyl acetate (200 mL) was added and the mixture was washed with H2O, dried and concentrated. The crude mixture was purified by silica gel Flash Chromatography (0% to 20% to 40% to 60% to 80% EtOAc/Hexane step gradient) to give 1.02 g of the title compound (88% yield for 2 steps): 1H NMR (CDCl3, 500 MHz) δ 0.02 (3H, s), 0.06 (3H, s), 0.84 (9H, s), 0.86-0.89 (3H, m), 1.52 (9H, s), 2.00-2.05 (2H, m), 2.20 (1H, d, J=15 Hz), 2.68 (1H, dd, J=10, 15 Hz), 2.92 (1H, m), 3.27-3.37 (3H, m), 3.76 (1H, dd, J=5, 10 Hz), 3.91 (3H, s), 3.99 (1H, s), 4.07-4.12 (2H, m), 4.64 (1H, m), 6.59 (1H, m), 6.78 (2H, d, J=5 Hz), 7.46-7.49 (1H, m), 8.08 (1H, d, J=10 Hz), 8.12 (1H, d, J=5 Hz), 8.29 (1H, brd s), 8.56 (1H, s). MS (ESI) (M+H)+ 691.33.

出典