Reaktion #49248

Reaktionsgleichung

1-(4-fluorophenyl)ethanamine

3-(((1S,2S)-1-((2R,4R)-1-(tert-butoxycarbonyl)-4-propoxypyrrolidin-2-yl)-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)propan-2-yl)carbamoyl)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)-1-(tert-butyldimethylsilyloxy)-2-(3-(carbamoyl)benzamido)-3-(3,5-difluorophenyl) propyl)-4-propoxypyrrolidine-1-carboxylate

HATU

→

title compound

Ausbeute 84.0%

N1-((1R,2S)-3-(3,5-difluorophenyl)-1-hydroxy-1-((2R,4R)-4-propoxypyrrolidin-2-yl)propan-2-yl)-N3-(1-(4-fluorophenyl)ethyl)isophthalamide

Ausbeute 84.0%

Lösungsmittel

dichloromethane

Reaktionsbedingungen

Aufarbeitung

1. 1
   workup.ADDITIONwas then added
2. 2
   workup.STIRRINGthe reaction mixture was stirred at rt overnight
3. 3
   EinengenThe reaction mixture was concentrated under vacuum
4. 4
   Sonstigepurified by silica gel Flash Chromatography (0% to 15% to 30% EtOAc/Hexane step gradient)

Vorschrift

Step 16 (A): (2R,4R)-tert-Butyl 2-((1S,2S)-1-(tert-butyldimethylsilyloxy)-2-(3-(carbamoyl)benzamido)-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)benzoic acid (Step 1 (C), 40 mg, 0.06 mmol) in dichloromethane (1.5 mL) was added Hunig's base (24 mg, 0.18 mmol) to make a clear solution and HATU (28 mg, 0.072 mmol) was then added. After stirring for 20 min, the reaction mixture was added 1-(4-fluorophenyl)ethanamine (17 mg, 0.12 mmol) and the reaction mixture was stirred at rt overnight. The reaction mixture was concentrated under vacuum and purified by silica gel Flash Chromatography (0% to 15% to 30% EtOAc/Hexane step gradient) to give 38 mg of the title compound (84% yield): 1H NMR (CDCl3, 500 MHz) δ 0.02 (3H, s), 0.05 (3H, s), 0.84 (9H, s), 0.89 (3H, m), 1.47 (9H, s), 1.50 (2H, m), 1.58 (3H, d, J=5 Hz), 2.00-2.05 (1H, m), 2.22 (1H, m), 2.64 (1H, m), 2.86-2.92 (1H, m), 3.28-3.37 (3H, m), 3.76 (1H, m), 4.00 (1H, m), 4.07-4.12 (2H, m), 4.61 (1H, m), 5.31 (1H, m), 6.51-6.52 (1H, m), 6.60 (1H, m), 6.77 (2H, d, J=10 Hz), 7.00 (2H, m), 7.34 (2H, dd, J=5, 10 Hz), 7.49 (1H, m), 7.99-8.02 (2H, m), 8.20 (1H, s), 8.33 (1H, m). MS (ESI) (M+H)+ 798.46.

Quelle