1-O-tert-butyl 2-O-methyl azetidine-1,2-dicarboxylate

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of azetidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (1 eq.) in dry THF under Argon at −78° C. was added a solution of LiHMDS 1M in hexane (1.3 eq.). The mixture was stirred at −78° C. for 1 h, then benzyl bromide (1.3 eq.) was added. The reaction was stirred at −78° C. for 30 min, then at 0° C. for 2 h, then at 20° C. for 1 h. The crude was diluted with EtOAc, carefully hydrolyzed with a saturated aqueous solution of NH4Cl. The organic layer was washed with water and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude was purified by chromatography on silica gel (elution with heptane/EtOAc: 98/2 to 80/20) to afford 2-benzyl-azetidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester. The reaction was stirred at −78° C. for 30 min at 0° C. for 2 h at 20° C. for 1 h The organic layer was washed with water and brine dried over MgSO4 filtered concentrated under reduced pressure The crude was purified by chromatography on silica gel (elution with heptane/EtOAc: 98/2 to 80/20)

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of azetidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (1 eq.) in dry THF under Argon at −78° C. was added a solution of LiHMDS 1M in hexane (1.3 eq.). The mixture was stirred at −78° C. for 1 h, then benzyl bromide (1.3 eq.) was added. The reaction was stirred at −78° C. for 30 min, then at 0° C. for 2 h, then at 20° C. for 1 h. The crude was diluted with EtOAc, carefully hydrolyzed with a saturated aqueous solution of NH4Cl. The organic layer was washed with water and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude was purified by chromatography on silica gel (elution with heptane/EtOAc: 98/2 to 80/20) to afford 2-benzyl-azetidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester. The reaction was stirred at −78° C. for 30 min at 0° C. for 2 h at 20° C. for 1 h The organic layer was washed with water and brine dried over MgSO4 filtered concentrated under reduced pressure The crude was purified by chromatography on silica gel (elution with heptane/EtOAc: 98/2 to 80/20)

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Azetidine-1,2-dicarboxylic acid 1-t-butyl ester 2-methyl ester (1.0 g) was added to a solution of lithium hydroxide monohydrate (0.586 g) in water (6 ml) and dioxane (12 ml) and the resultant mixture was stirred at room temperature for 2.5 hours. The mixture was evaporated to dryness and ice cold 1M HCl was added to the cooled residue. DCM was added and the organic layer was separated and washed with water, brine, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness to give azetidine-1,2-dicarboxylic acid-1-t-butyl ester (0.925 g) as a colourless oil. The mixture was evaporated to dryness and ice cold 1M HCl was added to the cooled residue DCM was added the organic layer was separated washed with water, brine dried (Na2SO4) filtered The filtrate was evaporated to dryness

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 5-chloro-2,3-difluoropyridine (1.39 g, 9.29 mmol, Eq: 1.00) and 1-tert-butyl 2-methyl azetidine-1,2-dicarboxylate (2 g, 9.29 mmol, Eq: 1.00) in toluene (15 ml) was added dropwise at 0° C. over 15 min a 0.5 M solution of KHMDS (18.6 ml, 9.29 mmol, Eq: 1.00) in toluene. The colorless solution turned into light brown. After stirring at 0° C. for 45 min, the reaction mixture was allowed to warm up to 25° C. The reaction mixture was stirred for 2.5 h. Saturated aqueous NH4Cl solution (100 ml) was added and the aqueous phase was extracted with AcOEt (2×150 ml). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography (silica gel, 40 g, 10% to 60% AcOEt in heptane) to yield a colorless viscous oil as a racemate (1.746 g; 55%). m/z=345.2 [M+H]+. to warm up to 25° C The reaction mixture was stirred for 2.5 h the aqueous phase was extracted with AcOEt (2×150 ml) The combined organic layers were washed with brine dried over Na2SO4 filtered concentrated under reduced pressure The crude material was purified by flash chromatography (silica gel, 40 g, 10% to 60% AcOEt in heptane) to yield a colorless viscous oil as a racemate (1.746 g; 55%)

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of azetidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (1 eq.) in dry THF under Argon at −78° C. was added a solution of LiHMDS 1M in hexane (1.3 eq.). The mixture was stirred at −78° C. for 1 h, then benzyl bromide (1.3 eq.) was added. The reaction was stirred at −78° C. for 30 min, then at 0° C. for 2 h, then at 20° C. for 1 h. The crude was diluted with EtOAc, carefully hydrolyzed with a saturated aqueous solution of NH4Cl. The organic layer was washed with water and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude was purified by chromatography on silica gel (elution with heptane/EtOAc: 98/2 to 80/20) to afford 2-benzyl-azetidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester. The reaction was stirred at −78° C. for 30 min at 0° C. for 2 h at 20° C. for 1 h The organic layer was washed with water and brine dried over MgSO4 filtered concentrated under reduced pressure The crude was purified by chromatography on silica gel (elution with heptane/EtOAc: 98/2 to 80/20)