Synthesis of Azithromycin Chloramphenicol Conjugate

A solution of the compound 3 (0.91 g, 1.00 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 0.30 mL, 2.00 mmol) and 1,2-diaminoethane (0.20 g, 3.00 mmol) in DMF (10 mL) was stirred for 2 h at room temperature. The reaction mixture was diluted with 5% aqueous NaHCO₃ (20 mL), and the product was extracted with ethyl acetate (3 × 15 mL). The combined organic layers were washed with brine (15 mL), and dried over Na₂SO₄. The solvent was evaporated, yielding 2′-O-acetyl-4′′-O-((2-aminoethyl)carbamoyl)-11,12-cyclic carbonate of azithromycin as a white solid, which was used for the next step without purification.
The crude powder of 2′-O-acetyl-4′′-O-((2-aminoethyl)carbamoyl)-11,12-cyclic carbonate of azithromycin was dissolved in DMF (5 mL) and added to the solution of chloramphenicol hemisuccinate [31 (link)] (0.47 g, 1.1 mmol), DIPEA (0.52 mL, 3 mmol), and PyBOP (0.78 g, 1.5 mmol) in DMF (5 mL). The reaction mixture was stirred for 1 h at room temperature, and diluted with 5% aqueous NaHCO₃ solution (10 mL). The product was extracted with ethyl acetate (3 × 15 mL), the combined organic layers were washed with brine (10 mL), dried over Na₂SO₄, and the solvent was evaporated. The crude residue was purified via column chromatography (CHCl₃:MeOH, 15:1) to give 0.26 g (20%) of compound 4a as a white powder; R_f = 0.31 (DCM/MeOH, 7:1). HPLC: t_R = 13.6 min (system A). ¹H and ¹³C NMR spectra are given in Table S1 and Figures S19 and S20, Supplementary Materials. HRMS (ESI) calculated for C₅₉H₉₃Cl₂N₆O₂₂ [M + H]⁺: 1307.5715; found: 1307.5711 (Figure S4, Supplementary Materials).