benzyl 1-benzylazetidine-2-carboxylate

反应条件: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To 68.3 g of methyl N-benzylazetidine-2-carboxylate (see Example 4 above; purity 89.8 area % ), acetonitrile (127 mL), K2CO3(s) (23.3 g) and benzyl alcohol (75.6 g) were added. The stirred reaction slurry was heated to between 75 and 80° C., and a modest vacuum (p>700 mbar) was applied. Methanol and acetonitrile were distilled off and, as the reaction slurry became highly concentrated, more acetonitrile was added and the distillation was continued. This procedure was repeated until a conversion of 97% was attained. The concentrated reaction mixture was cooled to 20° C. and diluted with acetonitrile (70 mL). The solid salts were filtered off and the filter cake was washed with acetonitrile (3×50 mL). The solvent was evaporated off at 40° C. To the remaining high-boiling liquid, heptane (1.5 L) and 5% (w/w) NaCl(aq.) (700 mL) were added, giving a mixture of three phases. 2 M H2SO4 (5 mL) was added to give a pH of about 8. After two more extractions of the organic phase with 5% (w/w) NaCl (aq), and water at pH 8, almost all of the third phase (benzyl alcohol) was successfully dissolved. Water (550 mL) was added to the organic phase and the pH was adjusted to 2.6 with 2M H2SO4 (38 mL). After separation, the organic phase was extracted with two more portions of acidified water (150 mL H2O at pH 2.2, followed by 50 mL H2O at pH 2.6). The organic phase was discarded. To the combined aqueous phases (pH 2.5), heptane (1.25 L) was added and pH was adjusted to 4.5 with K2CO3(s). The organic phase was separated off and washed with 10% (w/w) NaCl (aq.) and water. The obtained organic phase was evaporated at 40° C., until a bright yellow to brownish liquid remained (65.1 g, according to titration 94.0% (w/w) product, 4.3% (w/w) benzyl alcohol, purity(GC) 99.5 area % ). A second crop of product was isolated as above by extracting the remaining water phase (pH 4.5) with three more portions of heptane (0.25/0.1/0.1 L heptane at pH 5.8/5.2/4.9). Yield 7.8 g of a slightly more coloured product (assay 90% (w/w) according to titr., purity(GC) 97.9 area %), resulting in a total yield of 87% (68.2 g, 0.242 mol). The stirred reaction slurry was heated to between 75 and 80° C. Methanol and acetonitrile were distilled off and, as the reaction slurry became highly concentrated more acetonitrile was added the distillation The concentrated reaction mixture The solid salts were filtered off the filter cake was washed with acetonitrile (3×50 mL) The solvent was evaporated off at 40° C To the remaining high-boiling liquid, heptane (1.5 L) and 5% (w/w) NaCl(aq.) (700 mL) were added giving a mixture of three phases to give a pH of about 8 After two more extractions of the organic phase with 5% (w/w) NaCl (aq), and water at pH 8 almost all of the third phase (benzyl alcohol) was successfully dissolved Water (550 mL) was added to the organic phase After separation the organic phase was extracted with two more portions of acidified water (150 mL H2O at pH 2.2, followed by 50 mL H2O at pH 2.6) To the combined aqueous phases (pH 2.5), heptane (1.25 L) was added The organic phase was separated off washed with 10% (w/w) NaCl (aq.) and water The obtained organic phase was evaporated at 40° C. A second crop of product was isolated as above by extracting the remaining water phase (pH 4.5) with three more portions of heptane (0.25/0.1/0.1 L heptane at pH 5.8/5.2/4.9) Yield 7.8 g of a slightly more coloured product (assay 90% (w/w) according to titr., purity(GC) 97.9 area %), resulting in a total yield of 87% (68.2 g, 0.242 mol)