tert-butyl 1-(aminomethyl)cyclobutane-1-carboxylate

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

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

Procedure: A solution of 1-aminomethyl-cyclobutanecarboxylic acid tert-butyl ester (step 2) (1.47 g, 7.38 mmol) in DCM (40 ml) was treated with TEA (2.57 ml, 18.44 mmol) followed by methyl 3-(chlorosulfonyl)benzoate (1.91 g, 8.11 mmol) and DMAP (0.09 g, 0.74 mmol). The mixture was stirred at RT for 2 h and then partitioned between DCM and water. The aqueous portion was extracted with DCM and the combined organic extracts were washed with 0.1N HCl, brine, dried over MgSO4 and concentrated in vacuo. Purification of the resulting oil by chromatography on silica eluting with 0-40% EtOAc in iso-hexane afforded the title compound as a colourless oil; 1H NMR (400 MHz, CDCl3) δ 8.56 (1H, s), 8.27 (1H, d), 8.08 (1H, d), 7.64 (1H, t), 5.21 (1H, br t), 3.98 (3H, s), 3.20 (2H, d), 2.37 (2H, m), 1.96 (4H, m), 1.46 (9H, s). partitioned between DCM and water The aqueous portion was extracted with DCM the combined organic extracts were washed with 0.1N HCl, brine dried over MgSO4 concentrated in vacuo Purification of the resulting oil by chromatography on silica eluting with 0-40% EtOAc in iso-hexane

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

Procedure: A suspension of Raney Ni (0.6 g, 13.19 mmol) in MeOH (30 ml) in a hydrogenation steel pressure vessel was treated with 1-cyano-cyclobutanecarboxylic acid tert-butyl ester (2.39 g, 13.19 mmol). The reaction mixture was placed under an atmosphere of hydrogen (3 bar) overnight. The mixture was filtered and concentrated in vacuo. The residue was dissolved in MeOH and passed through a 20 g Isolute® SCX-2 cartridge. The cartridge was washed with MeOH followed by product 7M ammonia in MeOH. The ammonia washings were concentrated in vacuo to afford the title product which was used without further purification. 1H NMR (400 MHz, CDCl3) δ 2.45 (2H, m), 2.01-1.67 (6H, m), 0.49 (9H, s). The mixture was filtered concentrated in vacuo The residue was dissolved in MeOH The cartridge was washed with MeOH The ammonia washings were concentrated in vacuo

Conditions: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 7-benzyl-1-cyano-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (25 mg, 0.075 mmol) and 1-aminomethyl-cyclobutanecarboxylic acid tert-butyl ester (55 mg, 0.30 mmol) in EtOH (2 mL) was heated at 140° C. in a microwave reactor for 2 h. Solvent was evaporated in vacuo, and the residue was purified by chromatography (0-30% EtOAc/hexanes+2% AcOH) to give 32 mg of the title compound as a viscous oil. MS: (+) m/z 489.33 (M+1). Solvent was evaporated in vacuo the residue was purified by chromatography (0-30% EtOAc/hexanes+2% AcOH)

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

Procedure: A solution of 1-aminomethyl-cyclobutanecarboxylic acid tert-butyl ester (step 2) (1.47 g, 7.38 mmol) in DCM (40 ml) was treated with TEA (2.57 ml, 18.44 mmol) followed by methyl 3-(chlorosulfonyl)benzoate (1.91 g, 8.11 mmol) and DMAP (0.09 g, 0.74 mmol). The mixture was stirred at RT for 2 h and then partitioned between DCM and water. The aqueous portion was extracted with DCM and the combined organic extracts were washed with 0.1N HCl, brine, dried over MgSO4 and concentrated in vacuo. Purification of the resulting oil by chromatography on silica eluting with 0-40% EtOAc in iso-hexane afforded the title compound as a colourless oil; 1H NMR (400 MHz, CDCl3) δ 8.56 (1H, s), 8.27 (1H, d), 8.08 (1H, d), 7.64 (1H, t), 5.21 (1H, br t), 3.98 (3H, s), 3.20 (2H, d), 2.37 (2H, m), 1.96 (4H, m), 1.46 (9H, s). partitioned between DCM and water The aqueous portion was extracted with DCM the combined organic extracts were washed with 0.1N HCl, brine dried over MgSO4 concentrated in vacuo Purification of the resulting oil by chromatography on silica eluting with 0-40% EtOAc in iso-hexane

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

Procedure: A suspension of Raney Ni (0.6 g, 13.19 mmol) in MeOH (30 ml) in a hydrogenation steel pressure vessel was treated with 1-cyano-cyclobutanecarboxylic acid tert-butyl ester (2.39 g, 13.19 mmol). The reaction mixture was placed under an atmosphere of hydrogen (3 bar) overnight. The mixture was filtered and concentrated in vacuo. The residue was dissolved in MeOH and passed through a 20 g Isolute® SCX-2 cartridge. The cartridge was washed with MeOH followed by product 7M ammonia in MeOH. The ammonia washings were concentrated in vacuo to afford the title product which was used without further purification. 1H NMR (400 MHz, CDCl3) δ 2.45 (2H, m), 2.01-1.67 (6H, m), 0.49 (9H, s). The mixture was filtered concentrated in vacuo The residue was dissolved in MeOH The cartridge was washed with MeOH The ammonia washings were concentrated in vacuo

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

Procedure: A suspension of Raney Ni (0.6 g, 13.19 mmol) in MeOH (30 ml) in a hydrogenation steel pressure vessel was treated with 1-cyano-cyclobutanecarboxylic acid tert-butyl ester (2.39 g, 13.19 mmol). The reaction mixture was placed under an atmosphere of hydrogen (3 bar) overnight. The mixture was filtered and concentrated in vacuo. The residue was dissolved in MeOH and passed through a 20 g Isolute® SCX-2 cartridge. The cartridge was washed with MeOH followed by product 7M ammonia in MeOH. The ammonia washings were concentrated in vacuo to afford the title product which was used without further purification. 1H NMR (400 MHz, CDCl3) δ 2.45 (2H, m), 2.01-1.67 (6H, m), 0.49 (9H, s). The mixture was filtered concentrated in vacuo The residue was dissolved in MeOH The cartridge was washed with MeOH The ammonia washings were concentrated in vacuo

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

Procedure: A solution of 1-aminomethyl-cyclobutanecarboxylic acid tert-butyl ester (step 2) (1.47 g, 7.38 mmol) in DCM (40 ml) was treated with TEA (2.57 ml, 18.44 mmol) followed by methyl 3-(chlorosulfonyl)benzoate (1.91 g, 8.11 mmol) and DMAP (0.09 g, 0.74 mmol). The mixture was stirred at RT for 2 h and then partitioned between DCM and water. The aqueous portion was extracted with DCM and the combined organic extracts were washed with 0.1N HCl, brine, dried over MgSO4 and concentrated in vacuo. Purification of the resulting oil by chromatography on silica eluting with 0-40% EtOAc in iso-hexane afforded the title compound as a colourless oil; 1H NMR (400 MHz, CDCl3) δ 8.56 (1H, s), 8.27 (1H, d), 8.08 (1H, d), 7.64 (1H, t), 5.21 (1H, br t), 3.98 (3H, s), 3.20 (2H, d), 2.37 (2H, m), 1.96 (4H, m), 1.46 (9H, s). partitioned between DCM and water The aqueous portion was extracted with DCM the combined organic extracts were washed with 0.1N HCl, brine dried over MgSO4 concentrated in vacuo Purification of the resulting oil by chromatography on silica eluting with 0-40% EtOAc in iso-hexane

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

Procedure: A suspension of Raney Ni (0.6 g, 13.19 mmol) in MeOH (30 ml) in a hydrogenation steel pressure vessel was treated with 1-cyano-cyclobutanecarboxylic acid tert-butyl ester (2.39 g, 13.19 mmol). The reaction mixture was placed under an atmosphere of hydrogen (3 bar) overnight. The mixture was filtered and concentrated in vacuo. The residue was dissolved in MeOH and passed through a 20 g Isolute® SCX-2 cartridge. The cartridge was washed with MeOH followed by product 7M ammonia in MeOH. The ammonia washings were concentrated in vacuo to afford the title product which was used without further purification. 1H NMR (400 MHz, CDCl3) δ 2.45 (2H, m), 2.01-1.67 (6H, m), 0.49 (9H, s). The mixture was filtered concentrated in vacuo The residue was dissolved in MeOH The cartridge was washed with MeOH The ammonia washings were concentrated in vacuo

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

Procedure: A mixture of 1-cyano-4-hydroxy-7-phenylsulfanyl-isoquinoline-3-carboxylic acid methyl ester (43 mg) and 1-aminomethyl-cyclobutanecarboxylic acid tert-butyl ester (48 mg) in EtOH (0.5 mL) was microwaved at 140° C. for 1 h. The mixture was cooled, concentrated and the residue was column purified to give the desired product (58 mg). LC MS ESI+: 490 (M+1)+. was microwaved at 140° C. for 1 h The mixture was cooled concentrated purified

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

Procedure: A mixture of 1-cyano-cyclobutanecarboxylic acid tert-butyl ester (6.58 g) and Raney Ni (10 mL in water) in MeOH (250 mL) was stirred at rt under H2 atmosphere (balloon) overnight. Then the reaction mixture was filtered over Celite pad, filtrate was concentrated to give the desired product (5.59 g). 1H NMR in CDCl3, δ in ppm: 2.94 (s, 2H), 2.4-2.2 (m, 2H), 2.0-1.8 (m, 4H), 1.46 (s, 9H). Then the reaction mixture was filtered over Celite pad, filtrate was concentrated

Conditions: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 7-benzyl-1-cyano-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (25 mg, 0.075 mmol) and 1-aminomethyl-cyclobutanecarboxylic acid tert-butyl ester (55 mg, 0.30 mmol) in EtOH (2 mL) was heated at 140° C. in a microwave reactor for 2 h. Solvent was evaporated in vacuo, and the residue was purified by chromatography (0-30% EtOAc/hexanes+2% AcOH) to give 32 mg of the title compound as a viscous oil. MS: (+) m/z 489.33 (M+1). Solvent was evaporated in vacuo the residue was purified by chromatography (0-30% EtOAc/hexanes+2% AcOH)