tert-butyl 4-(aminomethyl)-4-hydroxypiperidine-1-carboxylate

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

Procedure: 4-Aminomethyl-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester is prepared from 1-oxa-6-aza-spiro[2.5]octane-6-carboxylic acid tert-butyl ester (Bourrain et al Bioorg. Med. Chem. Lett. 9(23):3369-3374 (1999)). Concentrated aqueous NH4OH (6 mL) is added to a solution of 1-oxa-6-aza-spiro[2.5]octane-6-carboxylic acid tert-butyl ester (0.50 g, 2.3 mmol) in MeOH (4 mL) at 0° C. The reaction mixture is removed from the cooling and allowed to warm to room temperature. After 7 hours, the reaction mixture is concentrated under reduced pressure to afford desired product as a white solid. The reaction mixture is removed from the cooling and the reaction mixture is concentrated under reduced pressure

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

Procedure: 4-Aminomethyl-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester is prepared from 1-oxa-6-aza-spiro[2.5]octane-6-carboxylic acid tert-butyl ester (Bourrain et al Bioorg. Med. Chem. Lett. 9(23):3369-3374 (1999)). Concentrated aqueous NH4OH (6 mL) is added to a solution of 1-oxa-6-aza-spiro[2.5]octane-6-carboxylic acid tert-butyl ester (0.50 g, 2.3 mmol) in MeOH (4 mL) at 0° C. The reaction mixture is removed from the cooling and allowed to warm to room temperature. After 7 hours, the reaction mixture is concentrated under reduced pressure to afford desired product as a white solid. The reaction mixture is removed from the cooling and the reaction mixture is concentrated under reduced pressure

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A stirred mixture of 4-aminomethyl-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (529 mg, 2.3 mmol) in tetrahydrofuran (15 ml) was added slowly with lithium aluminum hydride (0.88 g, 23 mmol) while maintaining the temperature at 0˜5° C. Upon completion of the addition, the mixture was stirred at 80° C. in oil bath overnight. The mixture was added with potassium sodium tartrate tetrahydrate (6.3 g, 22.3 mmol) and stirred for 8 hours at room temperature. The mixture was filtered and washed with tetrahydrofuran (10 ml×3). The combined organic extracts were concentrated under reduced pressure to give 4-aminomethyl-1-methyl-piperidin-4-ol (245 mg, 74%) as a white oil which was used as such. while maintaining the temperature at 0˜5° C Upon completion of the addition stirred for 8 hours at room temperature The mixture was filtered washed with tetrahydrofuran (10 ml×3) The combined organic extracts were concentrated under reduced pressure

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A stirred mixture of 4-aminomethyl-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (529 mg, 2.3 mmol) in tetrahydrofuran (15 ml) was added slowly with lithium aluminum hydride (0.88 g, 23 mmol) while maintaining the temperature at 0˜5° C. Upon completion of the addition, the mixture was stirred at 80° C. in oil bath overnight. The mixture was added with potassium sodium tartrate tetrahydrate (6.3 g, 22.3 mmol) and stirred for 8 hours at room temperature. The mixture was filtered and washed with tetrahydrofuran (10 ml×3). The combined organic extracts were concentrated under reduced pressure to give 4-aminomethyl-1-methyl-piperidin-4-ol (245 mg, 74%) as a white oil which was used as such. while maintaining the temperature at 0˜5° C Upon completion of the addition stirred for 8 hours at room temperature The mixture was filtered washed with tetrahydrofuran (10 ml×3) The combined organic extracts were concentrated under reduced pressure

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

Procedure: A stirred solution of 1-oxa-6-aza-spiro[2.5]octane-6-carboxylic acid tert-butyl ester (9.0 g, 42.2 mmol) in ethanol (60 ml) was added with ammonia (100 ml). The resulting mixture was stirred under a nitrogen atmosphere overnight. The mixture was concentrated under reduced pressure. The residue was added with water (50 ml) and extracted with ethyl acetate (150 ml×3). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with dichloromethane:methanol (20:1) as eluents to give 4-aminomethyl-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (5.87 g, 60.5%) as a white solid. The mixture was concentrated under reduced pressure The residue was added with water (50 ml) extracted with ethyl acetate (150 ml×3) The combined organic extracts were dried over anhydrous sodium sulfate filtered concentrated under reduced pressure The residue was purified by silica gel column chromatography with dichloromethane:methanol (20:1) as eluents

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

Procedure: To a suspension of lithium aluminum hydride (84 mg, 2.2 mmol) in THF (5 mL), a solution of tert-butyl 4-cyano-4-hydroxypiperidine-1-carboxylate (200 mg, 0.88 mmol, step 1 of Example 22) in THF (1 mL) was added dropwise at 0° C. The mixture was stirred for 1 h at that temperature and Na2SO4.10H2O (400 mg) was added slowly, and the mixture was stirred for 5 h at room temperature. The mixture was filtered though a pad of Celite, washed with CH2Cl2 (20 mL×2), the filtrate was concentrated to give clear colorless oil. The residue was chromatographed on a column of silica gel eluting with CH2Cl2/MeOH/NH4OH (14:1:0.1) to give 120 mg (59%) of the title compound as white solid. was added slowly The mixture was filtered though a pad of Celite washed with CH2Cl2 (20 mL×2) the filtrate was concentrated to give clear colorless oil The residue was chromatographed on a column of silica gel eluting with CH2Cl2/MeOH/NH4OH (14:1:0.1)

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

Procedure: To a solution of tert-butyl 4-(aminomethyl)-4-hydroxy-piperidine-1-carboxylate (3.00 g, 13.0 mmol) in N,N-dimethylformamide (30 mL) was added ethyl 2-bromo-2,2-difluoro-acetate (2.65 g, 13.0 mmol) and the reaction mixture stirred for 1 h under nitrogen. The reaction mixture was mixture diluted with ethyl acetate and water (25 mL) and brine (25 mL). The organic layer was dried over Na2SO4, filtered and concentrated to provide tert-butyl 4-[[(2-bromo-2,2-difluoro-acetyl)amino]methyl]-4-hydroxy-piperidine-1-carboxylate (4.98 g, 12.9 mmol, 99%). 1H NMR (400 MHz, DMSO-d6) δ 9.04 (t, J=5.9 Hz, 1H), 4.66 (s, 1H), 3.65 (d, J=12.7 Hz, 2H), 3.16 (d, J=6.1 Hz, 2H), 3.02 (s, 2H), 1.38 (m, 13H). The organic layer was dried over Na2SO4 filtered concentrated

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

Procedure: To a solution of tert-butyl 4-(aminomethyl)-4-hydroxy-piperidine-1-carboxylate (3.00 g, 13.0 mmol) in N,N-dimethylformamide (30 mL) was added ethyl 2-bromo-2,2-difluoro-acetate (2.65 g, 13.0 mmol) and the reaction mixture stirred for 1 h under nitrogen. The reaction mixture was mixture diluted with ethyl acetate and water (25 mL) and brine (25 mL). The organic layer was dried over Na2SO4, filtered and concentrated to provide tert-butyl 4-[[(2-bromo-2,2-difluoro-acetyl)amino]methyl]-4-hydroxy-piperidine-1-carboxylate (4.98 g, 12.9 mmol, 99%). 1H NMR (400 MHz, DMSO-d6) δ 9.04 (t, J=5.9 Hz, 1H), 4.66 (s, 1H), 3.65 (d, J=12.7 Hz, 2H), 3.16 (d, J=6.1 Hz, 2H), 3.02 (s, 2H), 1.38 (m, 13H). The organic layer was dried over Na2SO4 filtered concentrated

Conditions: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of tert-butyl 4-(aminomethyl)-4-hydroxypiperidine-1-carboxylate (1.702 g) in DMF (20 mL) at 20° C. was treated with ethyl 2-bromo-2,2-difluoroacetate (1.5 g) and the mixture stirred for 90 minutes at 20° C. under nitrogen. The mixture was partitioned between ethyl acetate and brine, the organic layer was washed twice with brine, dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure to afford the subtitled compound. Yield 2.5 g. The mixture was partitioned between ethyl acetate and brine the organic layer was washed twice with brine dried over sodium sulphate filtered the solvent evaporated under reduced pressure

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

Procedure: Chloroacetyl chloride (4.88 mL) was added dropwise to a vigorously stirred mixture at 0° C. of potassium carbonate (17.43 g) in water (78 mL) and tert-butyl 4-(aminomethyl)-4-hydroxypiperidine-1-carboxylate (10.4 g) in ethyl acetate (92 mL). After 30 minutes at 0° C. the mixture was extracted with ethyl acetate and the organic layer dried over sodium sulfate, filtered and the solvent evaporated under reduced pressure. The residue was dissolved in THF (200 mL) and added dropwise over 3 hours to a stirred solution under nitrogen and heated at reflux of potassium tert-butoxide (1M in tert-butanol, 75 mL) and THF (250 mL). The mixture was cooled to room temperature and allowed to stir for 18 hours. Most of the solvent was removed under reduced pressure and the residue partitioned between ethyl acetate and brine, the aqueous layer was re-extracted with ethyl acetate and the combined organics were dried over sodium sulfate, filtered and the solvent removed under reduced pressure. The residue was purified by trituration with a mixture of ether (30 mL) and isohexane (20 mL) to afford the subtitled product. Yield 8.20 g. After 30 minutes at 0° C. the mixture was extracted with ethyl acetate the organic layer dried over sodium sulfate filtered the solvent evaporated under reduced pressure The residue was dissolved in THF (200 mL) added dropwise over 3 hours to a stirred solution under nitrogen heated at reflux of potassium tert-butoxide (1M in tert-butanol, 75 mL) and THF (250 mL) Most of the solvent was removed under reduced pressure the residue partitioned between ethyl acetate and brine the aqueous layer was re-extracted with ethyl acetate the combined organics were dried over sodium sulfate filtered the solvent removed under reduced pressure The residue was purified by trituration with a mixture of ether (30 mL) and isohexane (20 mL)

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

Procedure: 4-Aminomethyl-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester is prepared from 1-oxa-6-aza-spiro[2.5]octane-6-carboxylic acid tert-butyl ester (Bourrain et al Bioorg. Med. Chem. Lett. 9(23):3369-3374 (1999)). Concentrated aqueous NH4OH (6 mL) is added to a solution of 1-oxa-6-aza-spiro[2.5]octane-6-carboxylic acid tert-butyl ester (0.50 g, 2.3 mmol) in MeOH (4 mL) at 0° C. The reaction mixture is removed from the cooling and allowed to warm to room temperature. After 7 hours, the reaction mixture is concentrated under reduced pressure to afford desired product as a white solid. The reaction mixture is removed from the cooling and the reaction mixture is concentrated under reduced pressure

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

Procedure: Under a nitrogen atmosphere a solution of tert-butyl 4-(aminomethyl)-4-hydroxypiperidine-1-carboxylate (38.9 g, 169 mmol, prepared according to Parts A and B of Example 4) in dichloromethane (420 mL) was cooled to 0° C. Triethylamine (23.6 mL, 169 mmol) was added followed by the portionwise addition of 4-chloro-3-nitronaphthyridine (30.8 g, 147 mmol). The reaction mixture was stirred at ambient temperature overnight and then diluted with saturated aqueous sodium bicarbonate (200 mL). The layers were separated and the aqueous was extracted with dichloromethane (3×100 mL). The combined organics were concentrated under reduced pressure to provide a dark yellow solid. This material was triturated with saturated aqueous sodium bicarbonate, isolated by filtration, rinsed well with water, and then dried in a vacuum oven at 70° C. overnight to provide 58.85 g of tert-butyl 4-hydroxy-4-{[(3-nitro[1,5]naphthyridin-4-yl)amino]methyl}piperidine-1-carboxylate as a yellow solid. The layers were separated the aqueous was extracted with dichloromethane (3×100 mL) The combined organics were concentrated under reduced pressure to provide a dark yellow solid This material was triturated with saturated aqueous sodium bicarbonate isolated by filtration rinsed well with water dried in a vacuum oven at 70° C. overnight