C([N:3]([CH2:6][CH3:7])[CH2:4][CH3:5])C.ClC([O:11][CH2:12]C)=O.[NH3:14].Cl.[O:16]1[CH2:20][CH2:19][CH2:18]C1>O>[N:3]1[C:4]2[CH2:5][C:12](=[O:11])[NH:14][C:20](=[O:16])[C:19]=2[CH:18]=[CH:7][CH:6]=1
Tetrahydrofuran (9 vol) is charged to the reactor followed by the starting material ester (1 eq) and a rinse of tetrahydrofuran (1 vol). The mixture is cooled to −2.5±7.5° C. under nitrogen atmosphere then treated with triethylamine (1.35 eq) and later ethyl chloroformate (1.25 eq). The reaction is stirred for 1 h at −2.5±7.5° C. then sampled. On receipt of a successful result the reaction is carefully treated with aq. ammonia, stirred, then water is added. Dilute HCl is added at <5° C. to adjust the pH to 6.5-7.5. The mixture is distilled under vacuum at <40° C. to 12-14 volumes and cooled to 7.5±2.5° C. The suspension is stirred ˜1 h at 7.5±2.5° C. then filtered. The solid is washed with water (1 vol) then offloaded and dried under vacuum (NLT 650 mm of Hg) at 52.5±2.5° C. for 12.0 h.
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