1-O-tert-butyl 2-O-methyl 4-aminopyrrolidine-1,2-dicarboxylate

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

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

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

Procedure: 4-Azido-pyrrolidine-1,2-dicarboxylic acid 1-t-butyl ester 2-methyl ester (303.10 mg, 1.12 mmol) was taken up in ethyl acetate in a Paar vessel. The solution was flushed with argon and Pd/C (400.00 mg) was added to the vessel. The argon atmosphere was replaced by hydrogen at 50 psi. The vessel was shaken for 12 h. The hydrogen atmosphere was replaced by argon and the solution was filtered through a celite pad. The pad was washed twice with ethyl acetate. The solvent was removed under reduced pressure. The product was used without further purification. Yield 262.66 mg. C11H20N2O4 MS m/e=244.2 (M+). The solution was flushed with argon and Pd/C (400.00 mg) was added to the vessel the solution was filtered through a celite pad The pad was washed twice with ethyl acetate The solvent was removed under reduced pressure The product was used without further purification

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

Procedure: 4-Azido-pyrrolidine-1,2-dicarboxylic acid 1-t-butyl ester 2-methyl ester (303.10 mg, 1.12 mmol) was taken up in ethyl acetate in a Paar vessel. The solution was flushed with argon and Pd/C (400.00 mg) was added to the vessel. The argon atmosphere was replaced by hydrogen at 50 psi. The vessel was shaken for 12 h. The hydrogen atmosphere was replaced by argon and the solution was filtered through a celite pad. The pad was washed twice with ethyl acetate. The solvent was removed under reduced pressure. The product was used without further purification. Yield 262.66 mg. C11H20N2O4 MS m/e=244.2 (M+). The solution was flushed with argon and Pd/C (400.00 mg) was added to the vessel the solution was filtered through a celite pad The pad was washed twice with ethyl acetate The solvent was removed under reduced pressure The product was used without further purification

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

Procedure: The titled compound is prepared as an orange viscous oil following Scheme 1 and in analogy to Example 1 using 3-bromomethyl-6-methoxy-3,4-dihydro-2H-1-thia-9-aza-phenanthrene, 4-amino-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester and 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid as starting material.

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

Procedure: The titled compound is prepared as an orange viscous oil following Scheme 1 and in analogy to Example 1 using 3-bromomethyl-6-methoxy-3,4-dihydro-2H-1-thia-9-aza-phenanthrene, 4-amino-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester and 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid as starting material.

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

Procedure: To a solution of 4-amino-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (2 mmol, 1 equvi) was dissolved in dry DCM (20 ml) cooled to 0 centigrade was added 2,4-difluorobenzaldehyde (1.05 equiv), then NaBH(OAc)3 (2 equiv) and 5 drops of HOAc. The mixture was warmed to room temperature and stirred overnight. The mixture was diluted with DCM, washed with brine, and dried over anhydrous sodium sulfate. After removal of solvent, the crude product was used for the next step without further purification. MS m/e=371.4 [M+H]+. cooled to 0 centigrade washed with brine dried over anhydrous sodium sulfate After removal of solvent the crude product was used for the next step without further purification

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

Procedure: To a solution of 4-amino-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (2 mmol, 1 equvi) was dissolved in dry DCM (20 ml) cooled to 0 centigrade was added 2,4-difluorobenzaldehyde (1.05 equiv), then NaBH(OAc)3 (2 equiv) and 5 drops of HOAc. The mixture was warmed to room temperature and stirred overnight. The mixture was diluted with DCM, washed with brine, and dried over anhydrous sodium sulfate. After removal of solvent, the crude product was used for the next step without further purification. MS m/e=371.4 [M+H]+. cooled to 0 centigrade washed with brine dried over anhydrous sodium sulfate After removal of solvent the crude product was used for the next step without further purification

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

Procedure: To a solution of 4-amino-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester, dissolved in DCM and cooled to 0 centigrade is added a corresponding benzaldehyde, then NaBH(OAc)3 and 5 drops of HOAc. The mixture is warmed to room temperature and stirred overnight. The mixture is diluted with DCM, washed with brine, and dried. After removal of solvent, the crude 4-(benzylamino)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester is obtained (33) and used for the next step without further purification. cooled to 0 centigrade washed with brine dried After removal of solvent

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

Procedure: To a solution of 4-amino-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester, dissolved in DCM and cooled to 0 centigrade is added a corresponding benzaldehyde, then NaBH(OAc)3 and 5 drops of HOAc. The mixture is warmed to room temperature and stirred overnight. The mixture is diluted with DCM, washed with brine, and dried. After removal of solvent, the crude 4-(benzylamino)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester is obtained (33) and used for the next step without further purification. cooled to 0 centigrade washed with brine dried After removal of solvent

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

Procedure: A solution of 4-azido-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester, THF and PPh3 and water is refluxed for about 6 hours and then concentrated. The residue is dissolved in Et2O and treated with HCl. The aqueous layer is extracted, washed, dried and concentrated to afford 4-amino-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (32). concentrated The residue is dissolved in Et2O treated with HCl The aqueous layer is extracted washed dried concentrated

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

Procedure: To a solution of 4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (2.45 g, 10 mmol) in ethyl acetate (20 mL) and methanol (5 mL) was added DIPEA (0.15 g, 1.14 mmol) followed by ethyl trifluoroacetate (1.54 g, 11 mmol). The reaction mixture was stirred at room temperature overnight and partitioned between water and ethyl acetate. The ethyl acetate layer was washed with water, brine, dried over Na2SO4, filtered, and the solvent evaporated in vacuo to yield a crude solid which was used directly to the next step without further purification. partitioned between water and ethyl acetate The ethyl acetate layer was washed with water, brine dried over Na2SO4 filtered the solvent evaporated in vacuo to yield a crude solid which was used directly to the next step without further purification