1262523-70-5 synthesis - chemicalbook

L-Glutamine, N2-[(1,1-dimethylethoxy)carbonyl]-4-[[(4-methylphenyl)sulfonyl]oxy]-N-[(2,4,6-trimethoxyphenyl)methyl]-, 1,1-dimethylethyl ester, (4R)-

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Yield:1262523-70-5 77%

Reaction Conditions:

with tris(dimethylamino)sulfonium trimethylsilyldifluoride;triethylamine in tetrahydrofuran;dichloromethane at 50; for 10 h;

Steps:

To a stirred solution of tris(dimethylamino)sulfonium difluorotrimethylsilicate (TASF, 1.38 g, 5.0 mmol) in CH₂C1₂/THF (1.5 mL/1.5 mL) was added Et₃ND(HF)₃ (0.25 mL) dropwise. After that, tosylate 11' (0.391 g, 0.6 mmol), THF (1 mL) and above "neutralized" TASF (2.7 mL, 3.0 mmol) were added one by one to a 25 mL two-neck flask equipped with a reflux condenser. The mixture was heated to 50 ⁰C by oil bath for 1O h, the oil bath was removed, the reaction mixture was diluted with EtOAc and washed with half saturated NaHCO₃, water and brine subsequently. The EtOAc phase was collected, dried by MgSO₄, filtered, concentrated in vacuo. The left residue was purified by FC (EtOAc/Hexanes, 25/75 to 40/60, V/V) to provide a pale white foamy solid 12' (0.232 g, 77%); [α]²⁴_D = + 1.70 (c = 1.14, MeOH); HPLC of 12': [99%, major peak: Rt = 22.8 min; 1%, minor peak: Rt = 25.2 min; column: Chiralcel OD (250 x 4.6 mm), UV detector, 210 nm, 1.5% EtOH in hexanes; flow rate: 1.2 mL/min]. ¹H NMR (200 MHz, CDCl₃) δ 6.69 (br s, 1 H), 6.12 (s, 2 H), 5.32 (d, 1 H, J= 8.6 Hz), 5.13 (dd, 0.5 H, J₁ = 8.8 Hz, J₂ = 3.2 Hz), 4.88 (dd, 0.5 H, J₁ = 8.8 Hz, J₂ = 3.2 Hz), 4.60 (dd, 1 H, J₁ = 13.6 Hz, J₂ = 6.0 Hz), 4.42- 4.34 (m, 2 H), 3.81 (s, 9 H), 2.64-2.06 (m, 2 H), 1.45 (s, 9 H), 1.43 (s, 9 H). ¹³C NMR (50 MHz, CDCl₃) ￡170.9, 168.8, 168.4, 161.3, 159.5, 155.3, 106.2, 91.2, 90.8, 87.5, 82.5, 80.0, 56.0, 55.6, 51.2, 35.7, 35.3, 32.2, 28.5, 28.1. HRMS calcd for C₂₄H₃₈FN₂O₈ (M + H)⁺: 501.2612; found:501.2613.Crystals of 12' suitable for X-ray crystal structure analysis were obtained from a slow solvent evaporation of CH₂C1₂/Hexanes solution of 12'.

References:

WO2011/20018,2011,A1 Location in patent:Page/Page column 29-30

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