(S)-N-BOC-AZETIDINE-2-CARBOXYLIC ACID METHYL ESTER

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

Procedure: To a solution of diisopropylamine (1.05 equiv; 5.9 mmol, 0.6 g, 0.83 mL) in anhydrous tetrahydrofuran (15 mL) was added n-butyl lithium (1.05 equiv; 5.9 mmol, 2.36 mL of a 2.5M solution in hexanes) and the resulting light yellow solution was warmed to 0° C. for 10 min. It was then cooled back to −78° C. and N-(tert-butoxycarbonyl)-azetidine-2(S)-carboxylic acid, methyl ester (5.63 mmol, 1.21 g) in dry tetrahydrofuran (3.0 mL) was added dropwise and stirring was continued for 45 min. After this time, hexamethylphosphoramide (2.0 equiv; 11.3 mmol, 2.02 g, 1.96 mL) was added and the reaction mixture was stirred for 0.5 h. At this point, iodomethane (5.0 equiv; 28.2 mmol, 3.99 g, 1.75 mL) was added (−78° C.), the cooling bath was removed, and stirring was continued overnight (16 h) at ambient temperature. Addition of saturated ammonium chloride solution, extraction with ethyl acetate, washing of the combined organic layer with water (2×) and brine, drying (MgSO4), and concentration yielded crude material which was purified by Biotage flash-coloumn chromatography (15% ethyl acetate, 85% hexanes) to provide N-(tert-butyloxycarbonyl)-2(R,S)-methylazetidine-2-carboxylic acid, methyl ester (0.9 g, 70% yield). the reaction mixture was stirred for 0.5 h the cooling bath was removed stirring was continued overnight (16 h) at ambient temperature Addition of saturated ammonium chloride solution, extraction with ethyl acetate washing of the combined organic layer with water (2×) and brine drying (MgSO4), and concentration yielded crude material which was purified by Biotage flash-coloumn chromatography (15% ethyl acetate, 85% hexanes)

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

Procedure: To a solution of diisopropylamine (1.05 equiv; 5.9 mmol, 0.6 g, 0.83 mL) in anhydrous tetrahydrofuran (15 mL) was added n-butyl lithium (1.05 equiv; 5.9 mmol, 2.36 mL of a 2.5M solution in hexanes) and the resulting light yellow solution was warmed to 0° C. for 10 min. It was then cooled back to −78° C. and N-(tert-butoxycarbonyl)-azetidine-2(S)-carboxylic acid, methyl ester (5.63 mmol, 1.21 g) in dry tetrahydrofuran (3.0 mL) was added dropwise and stirring was continued for 45 min. After this time, hexamethylphosphoramide (2.0 equiv; 11.3 mmol, 2.02 g, 1.96 mL) was added and the reaction mixture was stirred for 0.5 h. At this point, iodomethane (5.0 equiv; 28.2 mmol, 3.99 g, 1.75 mL) was added (−78° C.), the cooling bath was removed, and stirring was continued overnight (16 h) at ambient temperature. Addition of saturated ammonium chloride solution, extraction with ethyl acetate, washing of the combined organic layer with water (2×) and brine, drying (MgSO4), and concentration yielded crude material which was purified by Biotage flash-coloumn chromatography (15% ethyl acetate, 85% hexanes) to provide N-(tert-butyloxycarbonyl)-2(R,S)-methylazetidine-2-carboxylic acid, methyl ester (0.9 g, 70% yield). the reaction mixture was stirred for 0.5 h the cooling bath was removed stirring was continued overnight (16 h) at ambient temperature Addition of saturated ammonium chloride solution, extraction with ethyl acetate washing of the combined organic layer with water (2×) and brine drying (MgSO4), and concentration yielded crude material which was purified by Biotage flash-coloumn chromatography (15% ethyl acetate, 85% hexanes)

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

Procedure: To a stirred solution of pyrazin-2-amine (1.626 g, 17.10 mmol) in THF (40 mL) was added isopropylmagnesium chloride (8.44 mL, 16.88 mmol) at 0° C. under N2. The resulting slurry was stirred at RT for 30 min. A solution of (S)-1-tert-butyl 2-methyl azetidine-1,2-dicarboxylate (0.92 g, 4.27 mmol) in THF (5 ml) was added to the reaction slurry. The reaction mixture was stirred at RT for 4 h. and concentrated. The residue was dissolved in EtOAc and washed with 1N HCl, water, and brine. The organic layer was dried over Na2SO4 and filtered. The crude product (1.05 g, 88%) was used in the next step without purification. 1H NMR (400 MHz, MeOD) δ ppm 1.38 (s, 9H) 2.31 (br s, 1H) 2.53 (ddd, J=8.81, 6.17, 2.39 Hz, 1H) 3.89-4.00 (m, 2H) 4.81-4.86 (m, 1H) 8.30-8.37 (m, 2H) 9.41 (s, 1H); LC/MS [M+H]+: 279; Ret time (Method F): 2.27 min. The reaction mixture was stirred at RT for 4 h. concentrated The residue was dissolved in EtOAc washed with 1N HCl, water, and brine The organic layer was dried over Na2SO4 filtered The crude product (1.05 g, 88%) was used in the next step without purification 2.27 min.

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

Procedure: To a solution of diisopropylamine (1.05 equiv; 5.9 mmol, 0.6 g, 0.83 mL) in anhydrous tetrahydrofuran (15 mL) was added n-butyl lithium (1.05 equiv; 5.9 mmol, 2.36 mL of a 2.5M solution in hexanes) and the resulting light yellow solution was warmed to 0° C. for 10 min. It was then cooled back to −78° C. and N-(tert-butoxycarbonyl)-azetidine-2(S)-carboxylic acid, methyl ester (5.63 mmol, 1.21 g) in dry tetrahydrofuran (3.0 mL) was added dropwise and stirring was continued for 45 min. After this time, hexamethylphosphoramide (2.0 equiv; 11.3 mmol, 2.02 g, 1.96 mL) was added and the reaction mixture was stirred for 0.5 h. At this point, iodomethane (5.0 equiv; 28.2 mmol, 3.99 g, 1.75 mL) was added (−78° C.), the cooling bath was removed, and stirring was continued overnight (16 h) at ambient temperature. Addition of saturated ammonium chloride solution, extraction with ethyl acetate, washing of the combined organic layer with water (2×) and brine, drying (MgSO4), and concentration yielded crude material which was purified by Biotage flash-coloumn chromatography (15% ethyl acetate, 85% hexanes) to provide N-(tert-butyloxycarbonyl)-2(R,S)-methylazetidine-2-carboxylic acid, methyl ester (0.9 g, 70% yield). the reaction mixture was stirred for 0.5 h the cooling bath was removed stirring was continued overnight (16 h) at ambient temperature Addition of saturated ammonium chloride solution, extraction with ethyl acetate washing of the combined organic layer with water (2×) and brine drying (MgSO4), and concentration yielded crude material which was purified by Biotage flash-coloumn chromatography (15% ethyl acetate, 85% hexanes)