Compound 18

Synthetic procedure: See article for the definitive version of this procedure and for full experimental details.

A round-bottomed flask was charged with (1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid [CAS 197142-34-0; Neptune Technotrade, USA] (12.0 g, 52.8 mmol) and 300 mL CH₂Cl₂. To this solution was added HBTU (24.0 g, 63.4 mmol), Hünig’s base (32.3 ml, 185 mmol) and (R)-1-(3-chloro-2-fluorophenyl)ethanamine HCl salt [CAS 1253792-97-0; APAC Pharmaceutical, LLC, USA] (12.2 g, 58.1 mmol). After stirring at room temperature for 18h, the reaction mixture was diluted with CH₂Cl₂ and the organic layer was washed with saturated aqueous NaHCO₃ solution (50 mL) and 1M HCl (50 mL). The organic phase was dried and concentrated under reduced pressure. Purification by flash chromatography on silica gel (25–33% AcOEt in cHex) afforded (1R,3S,5R)-tert-butyl 3-((R)-1-(3-chloro-2-fluorophenyl)ethylcarbamoyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate benzoate (18) (19.0 g, 92% yield) as a colorless oil. TLC (cHex:AcOEt, 1:1 v/v): RF = 0.57; HPLC t_R = 4.71 min (purity = 98% at 215 nm); ¹H NMR (500 MHz, DMSO-d₆) δ 8.34 (d, J = 7.2 Hz, 1H), 7.50–7.15 (m, 2H), 7.18 (m, 1H), 5.13 (br m, 1H), 3.88 (br m, 1H), 3.32 (br m, 1H), 2.24 (br m, 1H), 2.01 (m, 1H), 1.63–1.08 (m, 13H), 0.73 (m, 1H), 0.39 (m, 1H); ¹³C NMR (126 MHz, DMSO-d₆) δ 170.6, 158.3 and 158.0, 154.5 (d, J = 247 Hz), 133.4, 128.8, 126.6, 125.1, 119.6, 78.9, 61.1, 42.4, 37.7, 33.3, 27.9, 21.0, 15.0, 14.1; ¹⁹F NMR (376 MHz, DMSO-d₆) δ –122.11, –122.65 (two rotamers); IR (neat): 3300, 3075, 2978, 1685, 1547, 1455, 1177, 1134 cm^-1; HRMS (m/z): [M+H]⁺ calcd for C₁₉H₂₄ClFN₂O₃, 383.1532; found, 383.1537.

PubChemID:

318123747

MDL Molfile:

41589_2016_BFnchembio2208_MOESM35_ESM.mol

ChemDraw:

41589_2016_BFnchembio2208_MOESM36_ESM.cdx