Reaktion #49230

Reaktionsgleichung

(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

Ausbeute 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

Ausbeute 88.0%

Lösungsmittel

dichloromethane

DMF

Ethyl acetate

Reaktionsbedingungen

Aufarbeitung

1. 1
   workup.ADDITIONwas then added
2. 2
   workup.STIRRINGthe reaction mixture was stirred at rt overnight
3. 3
   Waschenthe mixture was washed with H2O
4. 4
   Sonstigedried
5. 5
   Einengenconcentrated
6. 6
   SonstigeThe crude mixture was purified by silica gel Flash Chromatography (0% to 20% to 40% to 60% to 80% EtOAc/Hexane step gradient)

Vorschrift

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.

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