Réaction #49243

Équation de réaction

(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)-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)-2-(3-((R)-2-(methoxymethyl)pyrrolidine-1-carbonyl)-5-(oxazol-2-yl)benzamido)propyl)-4-propoxypyrrolidine-1-carboxylate

3-(dipropylcarbamoyl)-5-(oxazol-2-yl)benzoic 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-(oxazol-2-yl)benzamido)propyl)-4-propoxypyrrolidine-1-carboxylate

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

HATU

→

title compound

Rendement 95.0%

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)-5-(oxazol-2-yl)benzamide

Rendement 95.0%

Solvants

dichloromethane

Conditions de réaction

Traitement

1. 1
   workup.ADDITIONwas then added
2. 2
   workup.STIRRINGthe reaction mixture was stirred at rt for 6 h
3. 3
   AutreThe crude mixture was purified by silica gel Flash Chromatography (0% to 10% to 20% to 30% to 40% EtOAc/Hexane step gradient)

Mode opératoire

Step 12 (A): Preparation of (2R,4R)-tert-butyl 2-((1S,2S)-2-(3-(benzamido)-5-(oxazol-2-yl)benzamido)-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)propyl)-4-propoxypyrrolidine-1-carboxylate. To a solution of 3-(dipropylcarbamoyl)-5-(oxazol-2-yl)benzoic acid (WO 2002/02512), 45 mg, 0.14 mmol) in dichloromethane (2 mL) was added Hunig's base (54 mg, 0.42 mmol) to make a clear solution and HATU (65 mg, 0.17 mmol) was then added. After stirring for 30 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), 81 mg, 0.154 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 20% to 30% to 40% EtOAc/Hexane step gradient) to give 110 mg of the title compound (95% yield): 1H NMR (CDCl3, 500 MHz) δ ppm 0.03 (3H, s), 0.06 (3H, s), 0.69 (3H, m), 0.82 (9H, s), 0.87 (3H, m), 0.96 (3H, m), 1.21-1.28 (2H, m), 1.47-1.51 (11H, 1.68 (2H, m), 2.01 (1H, m), 2.18 (1H, d, J=15 Hz), 2.68 (1H, dd, J=10, 15 Hz), 2.88 (1H, dd, J=5, 15 Hz), 3.14 (2H, m), 3.26-3.36 (3H, m), 3.44 (2H, m), 3.74 (1H, dd, J=5, 10 Hz), 3.98 (1H, m), 4.08-4.11 (2H, m), 4.64 (1H, dd, J=10, 15 Hz), 6.59 (1H, m), 6.78 (2H, d, J=5 Hz), 7.22 (1H, s), 7.68 (1H, s), 7.97 (1H, s), 8.14 (1H, s), 8.64 (2H, m).

Source