methyl 2-[(4-chlorophenyl)methylamino]acetate

Conditions: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 1-[2-(3,5-dimethyl-phenyl)-acetyl]-2-methyl-azetidine-2-carboxylic acid, Intermediate 119 (1 eq.) in DCM under nitrogen, was added DMF (0.01 eq.) then oxalyl chloride (2 eq.). The solution was stirred at 20° C. for 30 min, then cooled to 0° C. A solution of (4-Chloro-benzylamino)-acetic acid methyl ester (1.5 eq.) and either TEA or DIPEA (2 to 7 eq.) in DCM was then added to the previous mixture. The solution was stirred at 0° C. for 1 h then at 20° C. until completion (1 h). The reaction was quenched with a saturated aqueous solution of NaHCO3 and extracted three times with DCM. The organic layers were combined, dried over MgSO4, filtered and concentrated under reduced pressure. The crude was purified by chromatography on silica gel (elution with heptane/EtOAc: 1/0 to 1/1) to afford ((4-chloro-benzyl)-{1-[2-(3,5-dimethyl-phenyl)-acetyl]-2-methyl-azetidine-2-carbonyl}-amino)-acetic acid methyl ester. cooled to 0° C The solution was stirred at 0° C. for 1 h at 20° C. until completion (1 h) The reaction was quenched with a saturated aqueous solution of NaHCO3 extracted three times with DCM dried over MgSO4 filtered concentrated under reduced pressure The crude was purified by chromatography on silica gel (elution with heptane/EtOAc: 1/0 to 1/1)

Conditions: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 4-chloro-benzylamine (1 eq.) in MeCN was added bromo-acetic acid methyl ester (1 eq.), K2CO3 (1.5 eq.) and KI (0.1 eq.). The reaction was stirred for 15 h at 20° C. The crude was concentrated under reduced pressure then partitioned between water and EtOAc. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The crude was purified by chromatography on silica gel (elution with heptane/EtOAc: 1/0 to 8/2) to afford (4-chloro-benzylamino)-acetic acid methyl ester. The crude was concentrated under reduced pressure then partitioned between water and EtOAc The organic layer was dried over MgSO4 filtered concentrated under reduced pressure The crude was purified by chromatography on silica gel (elution with heptane/EtOAc: 1/0 to 8/2)

Conditions: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 1-[2-(3,5-dimethyl-phenyl)-acetyl]-2-methyl-azetidine-2-carboxylic acid, Intermediate 119 (1 eq.) in DCM under nitrogen, was added DMF (0.01 eq.) then oxalyl chloride (2 eq.). The solution was stirred at 20° C. for 30 min, then cooled to 0° C. A solution of (4-Chloro-benzylamino)-acetic acid methyl ester (1.5 eq.) and either TEA or DIPEA (2 to 7 eq.) in DCM was then added to the previous mixture. The solution was stirred at 0° C. for 1 h then at 20° C. until completion (1 h). The reaction was quenched with a saturated aqueous solution of NaHCO3 and extracted three times with DCM. The organic layers were combined, dried over MgSO4, filtered and concentrated under reduced pressure. The crude was purified by chromatography on silica gel (elution with heptane/EtOAc: 1/0 to 1/1) to afford ((4-chloro-benzyl)-{1-[2-(3,5-dimethyl-phenyl)-acetyl]-2-methyl-azetidine-2-carbonyl}-amino)-acetic acid methyl ester. cooled to 0° C The solution was stirred at 0° C. for 1 h at 20° C. until completion (1 h) The reaction was quenched with a saturated aqueous solution of NaHCO3 extracted three times with DCM dried over MgSO4 filtered concentrated under reduced pressure The crude was purified by chromatography on silica gel (elution with heptane/EtOAc: 1/0 to 1/1)

Conditions: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 4-chloro-benzylamine (1 eq.) in MeCN was added bromo-acetic acid methyl ester (1 eq.), K2CO3 (1.5 eq.) and KI (0.1 eq.). The reaction was stirred for 15 h at 20° C. The crude was concentrated under reduced pressure then partitioned between water and EtOAc. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The crude was purified by chromatography on silica gel (elution with heptane/EtOAc: 1/0 to 8/2) to afford (4-chloro-benzylamino)-acetic acid methyl ester. The crude was concentrated under reduced pressure then partitioned between water and EtOAc The organic layer was dried over MgSO4 filtered concentrated under reduced pressure The crude was purified by chromatography on silica gel (elution with heptane/EtOAc: 1/0 to 8/2)

Conditions: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 1-[2-(3,5-dimethyl-phenyl)-acetyl]-2-methyl-azetidine-2-carboxylic acid, Intermediate 119 (1 eq.) in DCM under nitrogen, was added DMF (0.01 eq.) then oxalyl chloride (2 eq.). The solution was stirred at 20° C. for 30 min, then cooled to 0° C. A solution of (4-Chloro-benzylamino)-acetic acid methyl ester (1.5 eq.) and either TEA or DIPEA (2 to 7 eq.) in DCM was then added to the previous mixture. The solution was stirred at 0° C. for 1 h then at 20° C. until completion (1 h). The reaction was quenched with a saturated aqueous solution of NaHCO3 and extracted three times with DCM. The organic layers were combined, dried over MgSO4, filtered and concentrated under reduced pressure. The crude was purified by chromatography on silica gel (elution with heptane/EtOAc: 1/0 to 1/1) to afford ((4-chloro-benzyl)-{1-[2-(3,5-dimethyl-phenyl)-acetyl]-2-methyl-azetidine-2-carbonyl}-amino)-acetic acid methyl ester. cooled to 0° C The solution was stirred at 0° C. for 1 h at 20° C. until completion (1 h) The reaction was quenched with a saturated aqueous solution of NaHCO3 extracted three times with DCM dried over MgSO4 filtered concentrated under reduced pressure The crude was purified by chromatography on silica gel (elution with heptane/EtOAc: 1/0 to 1/1)

Conditions: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 4-chloro-benzylamine (1 eq.) in MeCN was added bromo-acetic acid methyl ester (1 eq.), K2CO3 (1.5 eq.) and KI (0.1 eq.). The reaction was stirred for 15 h at 20° C. The crude was concentrated under reduced pressure then partitioned between water and EtOAc. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The crude was purified by chromatography on silica gel (elution with heptane/EtOAc: 1/0 to 8/2) to afford (4-chloro-benzylamino)-acetic acid methyl ester. The crude was concentrated under reduced pressure then partitioned between water and EtOAc The organic layer was dried over MgSO4 filtered concentrated under reduced pressure The crude was purified by chromatography on silica gel (elution with heptane/EtOAc: 1/0 to 8/2)