methyl 1-(aminomethyl)cyclopentane-1-carboxylate

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

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

Procedure: To a solution of (S)-2-hydroxy-3-methyl-butyric acid (300 mg, 2.5 mmol) in CH2Cl2/DMF (5:1, 20 mL) at 0° C. was added HOBT (382 mg, 2.5 mmol) and EDC (477 mg, 2.5 mmol). The mixture was stirred for 10 min then methyl 1-(aminomethyl)cyclopentanecarboxylate (321 mg, 2.25 mmol) and iPr2NEt (0.5 mL, 2.5 mmol) were added and stirring was continued for 3 h. The reaction was diluted with water and extracted with EtOAc. The combined extracts were washed with water, 1N HCl, sat'd NaHCO3, dried over magnesium sulfate, concentrated, and purified using flash chromatography to give a white solid (420 mg, 72%). MS [M+H]+258. stirring was continued for 3 h extracted with EtOAc The combined extracts were washed with water, 1N HCl dried over magnesium sulfate concentrated purified

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

Procedure: To a solution of methyl 1-cyanocyclopentanecarboxylate (15 g, 98 mmol) in MeOH (250 mL) was added RaNi (3 g). The reaction was charged with H2 at 50 psi and shaken in the Parr shaker for 24 h. The RaNi catalyst was removed by filtration through a layer of celite. The solvent was removed under vacuum. The crude product was dissolved in 1N NaHSO4 (100 mL) and then washed with Et2O (2×100 mL). The organic layer was dried over magnesium sulfate and then filtered. The solvents were removed under reduced pressure to provide the amine in 77%; 1H NMR (300 MHz, CD3OD) δ3.75 (s, 3H), 3.12 (s, 2H), 2.14×2.07 (m, 2H), 1.83×1.65 (m, 6H). MS [M+H]+470. The reaction was charged with H2 at 50 psi The RaNi catalyst was removed by filtration through a layer of celite The solvent was removed under vacuum The crude product was dissolved in 1N NaHSO4 (100 mL) washed with Et2O (2×100 mL) The organic layer was dried over magnesium sulfate filtered The solvents were removed under reduced pressure

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

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

Procedure: To a solution of (S)-2-hydroxy-3-methyl-butyric acid (300 mg, 2.5 mmol) in CH2Cl2/DMF (5:1, 20 mL) at 0° C. was added HOBT (382 mg, 2.5 mmol) and EDC (477 mg, 2.5 mmol). The mixture was stirred for 10 min then methyl 1-(aminomethyl)cyclopentanecarboxylate (321 mg, 2.25 mmol) and iPr2NEt (0.5 mL, 2.5 mmol) were added and stirring was continued for 3 h. The reaction was diluted with water and extracted with EtOAc. The combined extracts were washed with water, 1N HCl, sat'd NaHCO3, dried over magnesium sulfate, concentrated, and purified using flash chromatography to give a white solid (420 mg, 72%). MS [M+H]+258. stirring was continued for 3 h extracted with EtOAc The combined extracts were washed with water, 1N HCl dried over magnesium sulfate concentrated purified

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

Procedure: To a solution of methyl 1-cyanocyclopentanecarboxylate (15 g, 98 mmol) in MeOH (250 mL) was added RaNi (3 g). The reaction was charged with H2 at 50 psi and shaken in the Parr shaker for 24 h. The RaNi catalyst was removed by filtration through a layer of celite. The solvent was removed under vacuum. The crude product was dissolved in 1N NaHSO4 (100 mL) and then washed with Et2O (2×100 mL). The organic layer was dried over magnesium sulfate and then filtered. The solvents were removed under reduced pressure to provide the amine in 77%; 1H NMR (300 MHz, CD3OD) δ3.75 (s, 3H), 3.12 (s, 2H), 2.14×2.07 (m, 2H), 1.83×1.65 (m, 6H). MS [M+H]+470. The reaction was charged with H2 at 50 psi The RaNi catalyst was removed by filtration through a layer of celite The solvent was removed under vacuum The crude product was dissolved in 1N NaHSO4 (100 mL) washed with Et2O (2×100 mL) The organic layer was dried over magnesium sulfate filtered The solvents were removed under reduced pressure

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

Procedure: Methyl1-cyanocyclopentane-1-carboxylate (Intermediate 260; 6 g, 39.2 mmol) in acetic acid (70 mL) was hydrogenated using Pt O2 (600 mg) as a catalyst at room temperature under 4 Bar pressure for 4 hours. The reaction mixture was filtered and concentrated. The residue was taken up in methanol and absorbed on to an SCX column (3×50 g), which was then washed with methanol and eluted with ammonia in methanol. Concentration of product containing fractions yielded the title compound as a pale yellow liquid (6.18 g, 100%). at room temperature for 4 hours The reaction mixture was filtered concentrated absorbed on to an SCX column (3×50 g), which was then washed with methanol eluted with ammonia in methanol Concentration of product containing fractions

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

Procedure: Methyl1-(aminomethyl)cyclopentane-1-carboxylate (Intermediate 259; 1.5 g, 9.54 mmol) and cyclopentanone (1.0 mL, 11.45 mmol) were stirred in DCM (40 mL). Sodium acetate (940 mg, 11.45 mmol) and sodium triacetoxyborohydride (3.04 g, 14.31 mmol) were added. The mixture was stirred at room temperature for 48 hours. The reaction mixture was filtered and the filtrate concentrated. The residue was dissolved in methanol and absorbed on to an SCX column, which was then washed with methanol and eluted with ammonia in methanol. Product containing fractions were combined and evaporated to yield the title compound as a colourless oil (1.64 g, 81%). The reaction mixture was filtered the filtrate concentrated The residue was dissolved in methanol absorbed on to an SCX column, which was then washed with methanol eluted with ammonia in methanol Product containing fractions evaporated

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

Procedure: Methyl1-(aminomethyl)cyclopentane-1-carboxylate (Intermediate 259; 1.5 g, 9.54 mmol) and cyclopentanone (1.0 mL, 11.45 mmol) were stirred in DCM (40 mL). Sodium acetate (940 mg, 11.45 mmol) and sodium triacetoxyborohydride (3.04 g, 14.31 mmol) were added. The mixture was stirred at room temperature for 48 hours. The reaction mixture was filtered and the filtrate concentrated. The residue was dissolved in methanol and absorbed on to an SCX column, which was then washed with methanol and eluted with ammonia in methanol. Product containing fractions were combined and evaporated to yield the title compound as a colourless oil (1.64 g, 81%). The reaction mixture was filtered the filtrate concentrated The residue was dissolved in methanol absorbed on to an SCX column, which was then washed with methanol eluted with ammonia in methanol Product containing fractions evaporated

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

Procedure: Methyl1-[(cyclopentylamino)methyl]cyclopentane-1-carboxylate (Intermediate 258; 1.60 g, 7.10 mmol), 2,4-dichloro-5-nitropyrimidine (Aldrich; 1.66 g, 8.52 mmol) and triethylamine (1.2 mL, 8.52 mmol) were stirred in acetonitrile (50 mL) for 4 hours. The reaction mixture was evaporated and the residue dissolved in DCM, washed with water, dried (MgSO4) and evaporated. The residue was purified on a silica column eluting with 1% methanol/DCM to yield the title compound as a yellow oil that crystallised on standing (945 mg, 35%). The reaction mixture was evaporated the residue dissolved in DCM washed with water dried (MgSO4) evaporated The residue was purified on a silica column eluting with 1% methanol/DCM

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

Procedure: Methyl1-[(cyclopentylamino)methyl]cyclopentane-1-carboxylate (Intermediate 258; 1.60 g, 7.10 mmol), 2,4-dichloro-5-nitropyrimidine (Aldrich; 1.66 g, 8.52 mmol) and triethylamine (1.2 mL, 8.52 mmol) were stirred in acetonitrile (50 mL) for 4 hours. The reaction mixture was evaporated and the residue dissolved in DCM, washed with water, dried (MgSO4) and evaporated. The residue was purified on a silica column eluting with 1% methanol/DCM to yield the title compound as a yellow oil that crystallised on standing (945 mg, 35%). The reaction mixture was evaporated the residue dissolved in DCM washed with water dried (MgSO4) evaporated The residue was purified on a silica column eluting with 1% methanol/DCM

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

Procedure: Methyl1-[(cyclopentylamino)methyl]cyclopentane-1-carboxylate (Intermediate 258; 1.60 g, 7.10 mmol), 2,4-dichloro-5-nitropyrimidine (Aldrich; 1.66 g, 8.52 mmol) and triethylamine (1.2 mL, 8.52 mmol) were stirred in acetonitrile (50 mL) for 4 hours. The reaction mixture was evaporated and the residue dissolved in DCM, washed with water, dried (MgSO4) and evaporated. The residue was purified on a silica column eluting with 1% methanol/DCM to yield the title compound as a yellow oil that crystallised on standing (945 mg, 35%). The reaction mixture was evaporated the residue dissolved in DCM washed with water dried (MgSO4) evaporated The residue was purified on a silica column eluting with 1% methanol/DCM