Remdesivir synthesis

Yield:1809249-37-3 73%

Reaction Conditions:

Stage #1: (3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrilewith 2,6-dimethylpyridine;C₁₇H₂₁N₃O₂ in dichloromethane at -20 - 20; for 0.333333 h;Molecular sieve;Inert atmosphere;
Stage #2: 2-ethylbutyl (2S)-2-{[chloro(phenoxy)phosphoryl]amino}propanoate in dichloromethane at -20; for 24 h;
Stage #3: with toluene-4-sulfonic acid in methanol at 20; for 24 h;

Steps:

2

In a flame dried round bottom flask, a mixture of acetonide-nucleoside acceptor 7 (1.0 g, 3.02 mmol) and catalyst 29 (180 mg, 0.62 mmol) were co-evaporated with anhydrous toluene (20 mL, 2 times), dried for 2 h on high-vacuum. The mixture was dissolved in dry CH₂Cl₂ (50 mL) and then freshly activated 4? molecular sieves (1.5 g) followed by 2,6-luditine (700 μL, 6.04 mmol) were added. The suspension was then stirred under N₂ atmosphere at room temparature for 10 min, and then cooled to -20 °C. After 10 min, a solution of phosphochloridate 4 (1.57 g, 4.53 mmol) in dry CH₂Cl₂ (5 mL) was added and the reaction mixture was allowed to stir at same temperature for 24 h. TLC analysis indicates the complete conversion of starting materials into the products. Then the CH₂Cl₂ was evaporated by vacuum. Later on, the crude material was treated with 10.0 equiv of p-TSA in MeOH (50 mL). The reaction mixture was allowed to stir for 24 h at room temperature and the TLC analysis indicated the product formation. Then the reaction mixture was filtered through a pad of Celite to remove 4? molecular sieves, quenched by adding Et₃N and concentrated in vacuo. The crude residue was dissolved in EtOAc and washed with Saturated NaHCO₃, the aqueous layer was back extracted with EtOAc (3 x 50 mL) and the combined organic layers were dried over MgSO₄, filtered and concentrated in vacuo. The crude residue was subjected to silica gel column chromatography by using EtOAc in hexane (0→ 100%) as an eluent to afford the products as a foamy solid. The diastereomeric mixture was purified by using C 18 column to give compound 1 as a foamy solid (1.39 g, 73%). ¹H NMR (600 MHz, CD₃OD) δ 7.87 (s, 1H), 7.30 (t, J = 7.8 Hz, 2H), 7.21- 7.14 (m, 3H), 6.91 (d, J= 4.6 Hz, 1H), 6.88 (d, J= 4.6 Hz, 1H), 4.79 (d, J= 5.4 Hz, 1H), 4.42-4.35 (m, 2H), 4.28 (dt, J= 10.5, 5.1 Hz, 1H), 4.17 (t, J= 5.6 Hz, 1H), 4.02 (dd, J= (0148) 10.9, 5.8 Hz, 1H), 3.90 (ddd, J= 23.7, 12.7, 6.4 Hz, 2H), 1.45 (dt, J= 12.3, 6.2 Hz, 1H), 1.34-1.28 (m, TH), 0.85 (t, J= 7.5 Hz, 6H). ¹³C NMR (150 MHz, CD₃OD) δ 175.15, 175.1, 157.4, 152.3, 152.3, 148.4, (0150) 130.9, 126.2, 125.7, 121.51, 121.5, 118.1, 117.7, 112.5, 102.8, 84.44, 81.4, 84.4, 75.9, 71.8, 68.2, 67.3, 67.27, 41.8, 24.4, 24.3, 20.7, 20.6, 11.5, 11.4.

References:

WO2022/76638,2022,A1 Location in patent:Paragraph 0137; 0139-0142