tert-butyl 3-(aminomethyl)azetidine-1-carboxylate

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

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: A mixture of 3,3-dimethylbutanal (3.7 mL, 30 mmol), tert-butyl 3-(aminomethyl)azetidine-1-carboxylate (Astatech, 5 g, 27 mmol), and 8 g of 4 Å molecular sieves (8-12 mesh beads) in acetonitrile (50 mL) was stirred at ambient temperature for 72 h. The material was filtered through Celite with acetonitrile (additional 25 mL) then potassium thiocyanate (3.5 g, 35 mmol) was added and the mixture was warmed to 50° C. Iodine (6.81 g, 26.8 mmol) was added and the mixture stirred at 50° C. for 16 h then was cooled to ambient temperature. The mixture was stirred with 75 mL of 20% aqueous sodium metabisulfite for 1 h then the layers were separated and the aqueous layer was extracted with 3×10 mL CH2Cl2. The combined organics were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude title compound (6.3 g, 19 mmol, 72% yield) which was carried on without further purification. MS (DCI/NH3) m/z 326 (M+H)+. The material was filtered through Celite with acetonitrile (additional 25 mL) the mixture was warmed to 50° C the mixture stirred at 50° C. for 16 h then was cooled to ambient temperature the layers were separated the aqueous layer was extracted with 3×10 mL CH2Cl2 The combined organics were dried over anhydrous Na2SO4 filtered concentrated under reduced pressure

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

Procedure: A mixture of 3,3-dimethylbutanal (3.7 mL, 30 mmol), tert-butyl 3-(aminomethyl)azetidine-1-carboxylate (Astatech, 5 g, 27 mmol), and 8 g of 4 Å molecular sieves (8-12 mesh beads) in acetonitrile (50 mL) was stirred at ambient temperature for 72 h. The material was filtered through Celite with acetonitrile (additional 25 mL) then potassium thiocyanate (3.5 g, 35 mmol) was added and the mixture was warmed to 50° C. Iodine (6.81 g, 26.8 mmol) was added and the mixture stirred at 50° C. for 16 h then was cooled to ambient temperature. The mixture was stirred with 75 mL of 20% aqueous sodium metabisulfite for 1 h then the layers were separated and the aqueous layer was extracted with 3×10 mL CH2Cl2. The combined organics were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude title compound (6.3 g, 19 mmol, 72% yield) which was carried on without further purification. MS (DCI/NH3) m/z 326 (M+H)+. The material was filtered through Celite with acetonitrile (additional 25 mL) the mixture was warmed to 50° C the mixture stirred at 50° C. for 16 h then was cooled to ambient temperature the layers were separated the aqueous layer was extracted with 3×10 mL CH2Cl2 The combined organics were dried over anhydrous Na2SO4 filtered concentrated under reduced pressure

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

Procedure: Using General Procedure B: Reaction of 3-aminomethyl-azetidine-1-carboxylic acid tert-butyl ester (Falgueyret, J.-P. et al. J. Med. Chem. 2001, 44, 94-104) in CH2Cl2 with 3-methyl-pyridine-2-carbaldehyde and NaBH(OAc)3 gave 3-{[(3-methyl-pyridin-2-ylmethyl)-amino]-methyl}-azetidine-1-carboxylic acid tert-butyl ester as a yellow oil. 1H NMR (CDCl3) δ 1.44 (s, 9H), 2.30 (s, 3H), 2.66-2.75 (m, 1H), 2.92 (d, 2H, J=6.0 Hz), 3.61-3.66 (m, 2H), 3.88 (s, 2H), 4.02 (t, 2H, J=9.0 Hz).

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

Procedure: Using General Procedure B: Reaction of 3-aminomethyl-azetidine-1-carboxylic acid tert-butyl ester (Falgueyret, J.-P. et al. J. Med. Chem. 2001, 44, 94-104) in CH2Cl2 with 3-methyl-pyridine-2-carbaldehyde and NaBH(OAc)3 gave 3-{[(3-methyl-pyridin-2-ylmethyl)-amino]-methyl}-azetidine-1-carboxylic acid tert-butyl ester as a yellow oil. 1H NMR (CDCl3) δ 1.44 (s, 9H), 2.30 (s, 3H), 2.66-2.75 (m, 1H), 2.92 (d, 2H, J=6.0 Hz), 3.61-3.66 (m, 2H), 3.88 (s, 2H), 4.02 (t, 2H, J=9.0 Hz).

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

Procedure: A mixture of 5-amino-6-nitro-isoindole-1,3-dione (994 mg, 4.8 mmol), 3-Aminomethyl-azetidine-1-carboxylic acid tert-butyl ester (1.0 g, 5.4 mmol) and imidazole (493 mg, 7.25 mmol) in dioxane (140 mL) was sealed in a ChemGlass heavy wall pressure flask. After it was heated at 140° C. for 61 h, the reaction mixture was evaporated to dryness at 95° C. (the bath temperature) under reduced pressure. The chromatography of the residue with CH2Cl2/MeOH/28% aqueous NH4OH (400:10:1) afforded the title compound (830 mg, 46%). 1H NMR (MeOH-d4) δ 1.44 (s, 9H), 2.94 (m, 1H), 3.78 (m, 2H), 3.88 (d, J=6 Hz, 2H), 4.00 (m, 2H), 7.44 (s, 1H), 8.52 (s, 1H); ESI-MS m/z 377.3 (MH+). was sealed in a ChemGlass heavy wall pressure flask the reaction mixture was evaporated to dryness at 95° C. (the bath temperature) under reduced pressure

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

Procedure: A mixture of 5-amino-6-nitro-isoindole-1,3-dione (994 mg, 4.8 mmol), 3-Aminomethyl-azetidine-1-carboxylic acid tert-butyl ester (1.0 g, 5.4 mmol) and imidazole (493 mg, 7.25 mmol) in dioxane (140 mL) was sealed in a ChemGlass heavy wall pressure flask. After it was heated at 140° C. for 61 h, the reaction mixture was evaporated to dryness at 95° C. (the bath temperature) under reduced pressure. The chromatography of the residue with CH2Cl2/MeOH/28% aqueous NH4OH (400:10:1) afforded the title compound (830 mg, 46%). 1H NMR (MeOH-d4) δ 1.44 (s, 9H), 2.94 (m, 1H), 3.78 (m, 2H), 3.88 (d, J=6 Hz, 2H), 4.00 (m, 2H), 7.44 (s, 1H), 8.52 (s, 1H); ESI-MS m/z 377.3 (MH+). was sealed in a ChemGlass heavy wall pressure flask the reaction mixture was evaporated to dryness at 95° C. (the bath temperature) under reduced pressure

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

Procedure: To a solution of benzhydryl 1-(((Z)-(1-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-(((2R,3S)-2-((4-formyl-2H-1,2,3-triazol-2-yl)methyl)-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)cyclopropanecarboxylate (150 mg, 0.21 mmol) in DCE (4 ml) at 0° C. was added tert-butyl 3-(aminomethyl)azetidine-1-carboxylate (78 mg, 0.420 mmol), sodium triacetoxyborohydride (66.7 mg, 0.315 mmol), and DMF (0.4 mL). After stirring at rt for 3 h, the reaction mixture was quenched with saturated NaHCO3 (aq) and diluted with 10% EtOH/DCM (40 mL). The organic layer was separated, dried with Na2SO4, filtered and concentrated in vacuo. The crude residue was used as such in the following step. LCMS: Rt=0.55 min, m/z=885.5 (M+1). Method 2m_acidic. the reaction mixture was quenched with saturated NaHCO3 (aq) diluted with 10% EtOH/DCM (40 mL) The organic layer was separated dried with Na2SO4 filtered concentrated in vacuo

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

Procedure: To a solution of benzhydryl 1-(((Z)-(1-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-(((2R,3S)-2-((4-formyl-2H-1,2,3-triazol-2-yl)methyl)-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)cyclopropanecarboxylate (150 mg, 0.21 mmol) in DCE (4 ml) at 0° C. was added tert-butyl 3-(aminomethyl)azetidine-1-carboxylate (78 mg, 0.420 mmol), sodium triacetoxyborohydride (66.7 mg, 0.315 mmol), and DMF (0.4 mL). After stirring at rt for 3 h, the reaction mixture was quenched with saturated NaHCO3 (aq) and diluted with 10% EtOH/DCM (40 mL). The organic layer was separated, dried with Na2SO4, filtered and concentrated in vacuo. The crude residue was used as such in the following step. LCMS: Rt=0.55 min, m/z=885.5 (M+1). Method 2m_acidic. the reaction mixture was quenched with saturated NaHCO3 (aq) diluted with 10% EtOH/DCM (40 mL) The organic layer was separated dried with Na2SO4 filtered concentrated in vacuo

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

Procedure: tert-Butyl 3-(aminomethyl)azetidine-1-carboxylate (1.10 g, 5.91 mmol) was dissolved in dichloromethane (50 mL), and thereafter, 4-nitrophenyl chloroformate (1.19 g, 5.91 mmol) and pyridine (0.47 g, 5.91 mmol) were added to the obtained solution. The obtained mixture was stirred for 16 hours. Thereafter, the reaction solution was concentrated in vacuo to obtain tert-butyl 3-((((4-nitrophenoxy)carbonyl)amino)methyl)azetidine-1-carboxylate (2.52 g, quant) in the form of a white solid. Thereafter, the reaction solution was concentrated in vacuo