Реакция #49239

Уравнение реакции

(R)-2-(methoxymethyl)pyrrolidine

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 )

N1-((1S,2S)-1-((2R,4R)-4-(allyloxy)-1-benzhydrylpyrrolidin-2-yl)-3-(3,5-difluorophenyl)-1-hydroxypropan-2-yl)-N3,N3-dipropylisophthalamide

(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

HATU

→

title compound

Выход 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-methylbenzamide

Выход 95.0%

Растворители

dichloromethane

Ethyl acetate

Условия реакции

Обработка

1. 1
   workup.ADDITIONwas then added
2. 2
   workup.STIRRINGthe reaction mixture was stirred at rt overnight
3. 3
   Промывкаthe mixture was washed with Brine, H2O
4. 4
   Другоеdried
5. 5
   Концентрированиеconcentrated

Методика

Step 8 (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. 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, 28 mg, 0.038 mmol) in dichloromethane (1 mL) was added Hunig's base (14 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 (R)-2-(methoxymethyl)pyrrolidine (65 mg, 0.057 mmol) and the reaction mixture was stirred at rt overnight. Ethyl acetate (100 mL) was added and the mixture was washed with Brine, H2O, dried and concentrated to give 30 mg of the title compound (95% yield): 1H NMR (CDCl3, 500 MHz) δ ppm 0.01 (3H, s), 0.06 (3H, s), 0.85 (9H, s), 0.88 (3H, t, J=5 Hz), 1.48-1.54 (11H, m), 1.73 (1H, m), 1.92-22.09 (5H, m), 2.18 (1H, m), 2.38 (3H, s), 2.62 (1H, m), 2.96 (1H, m), 3.05 (1H, m), 3.26-3.39 (5H, m), 3.47 (1H, m), 3.58 (1H, m), 3.68 (1H, m), 3.76 (1H, dd, J=5, 15 Hz), 3.97 (1H, m), 4.04-4.07 (1H, m), 4.11-4.14 (1H, m), 4.41 (1H, brd s), 4.56 (1H, m), 6.59 (1H, m), 6.76 (1H, s), 6.77 (1H, s), 7.43 (1H, s), 7.72 (1H, s), 7.74 (1H, s), 7.98 (1H, brd s). MS (ESI) (M+H)+ 788.61.

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