Реакция #49240

Уравнение реакции

methylbutylamine

3-(((1S,2S)-1-((2R,4R)-1-(tert-butoxycarbonyl)-4-propoxypyrrolidin-2-yl)-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)propan-2-yl)carbamoyl)-5-methylbenzoic acid

Hunig's base

( A )

(2R,4R)-tert-butyl 2-((1S,2S)-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)-2-(3-((R)-2-(methoxymethyl)pyrrolidine-1-carbonyl)-5-methylbenzamido)propyl)-4-propoxypyrrolidine-1-carboxylate

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

HATU

→

title compound

Выход 85.0%

N1-butyl-N3-((1R,2S)-3-(3,5-difluorophenyl)-1-hydroxy-1-((2R,4R)-4-propoxypyrrolidin-2-yl)propan-2-yl)-N1,5-dimethylisophthalamide

Выход 85.0%

Растворители

dichloromethane

Условия реакции

Обработка

1. 1
   workup.ADDITIONwas then added
2. 2
   workup.STIRRINGthe reaction mixture was stirred at rt for 6 h
3. 3
   ДругоеThe crude mixture was purified by silica gel Flash Chromatography (0% to 10% to 30% EtOAc/Hexane step gradient)

Методика

Step 9 (A): (2R,4R)-tert-butyl 2-((1S,2S)-2-(3-(benzamido)-5-methylbenzamido)-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)propyl)-4-propoxypyrrolidine-1-carboxylate. To a solution of 3-(((1S,2S)-1-((2R,4R)-1-(tert-butoxycarbonyl)-4-propoxypyrrolidin-2-yl)-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)propan-2-yl)carbamoyl)-5-methylbenzoic acid (Preparation G, 26 mg, 0.037 mmol) in dichloromethane (1 mL) was added Hunig's base (15 mg, 0.114 mmol) to make a clear solution and HATU (19 mg, 0.05 mmol) was then added. After stirring for 20 min, the reaction mixture was added methylbutylamine (5 mg, 0.057 mmol) and the reaction mixture was stirred at rt for 6 h. The crude mixture was purified by silica gel Flash Chromatography (0% to 10% to 30% EtOAc/Hexane step gradient) to give 24 mg of the title compound (85% yield): 1H NMR (CDCl3, 500 MHz) δ ppm 0.02 (3H, s), 0.06 (3H, s), 0.72-0.97 (15H, m), 1.12 (1H, m), 1.36-1.53 (11H, m), 1.61 (1H, m), 1.78 (2H, s), 2.05 (1H, m), 2.19 (1H, m), 2.38 (3H, s), 2.62 (1H, m), 2.91-2.95 (3H, m), 3.04 (1H, s), 3.21 (1H, m), 3.27-3.36 (3H, m), 3.50 (1H, m), 3.76 (1H, m), 3.98 (1H, m), 4.03-4.06 (1H, m), 4.10-4.12 (1H, m), 4.56 (1H, m), 6.59 (1H, m), 6.76 (2H, d, J=5 Hz), 7.29 (1H, d, J=10 Hz), 7.64 (1H, s), 7.71 (1H, s), 8.03 (1H, brd s). MS (ESI) (M+H)+ 760.61.

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