4-(hydroxymethyl)piperidine-1-carbonitrile

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

Procedure: A solution of 1N ZnCl2 in Et2O (182 mL, 182 mmol) was added to a solution of 4-(hydroxymethyl)-1-piperidinecarbonitrile (21.3 g, 152 mmol) and N-hydroxy-2-methylpropanimidamide (18.6 g, 182 mmol) in EtOAc (50 mL) at ambient temperature. The reaction mixture was left at ambient temperature for 30 min, decanted, and was treated with concentrated HCl (45 mL) and ethanol 20 mL). The mixture was heated at reflux for 2 h. The mixture was evaporated to dryness, and the resulting residue was charged with water and the pH was adjusted to basic with K2CO3. The mixture was extracted with EtOAc and the material obtained was combined with 9 other batches prepared similarly and purified by silica gel chromatography to give 150 g of {1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}methanol. decanted was treated with concentrated HCl (45 mL) and ethanol 20 mL) The mixture was heated at reflux for 2 h The mixture was evaporated to dryness the resulting residue was charged with water The mixture was extracted with EtOAc the material obtained prepared similarly purified by silica gel chromatography

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 4-piperidinemethanol (140 g, 1.22 mol) in CH2Cl2 (1 L) was treated with a slurry of NaHCO3 (205 g, 2.44 mol) in water (1.4 L) at 0° C. The mixture was stirred at 0° C. for 15 min, and then charged with a solution of cyanogen bromide in CH2Cl2, (1.34 mol) at 0° C. The reaction mixture was stirred and allowed to warm to ambient temperature, and stirred overnight. The aqueous layer was separated and extracted with CH2Cl2. The combined organic extracts were dried over Na2SO4, filtered, and the filtrate was concentrated. The crude product was combined with other batches made similarly and purified by chromatography on a silica gel column to give 300 g of 4-(hydroxymethyl)-1-piperidinecarbonitrile. The reaction mixture was stirred to warm to ambient temperature stirred overnight The aqueous layer was separated extracted with CH2Cl2 The combined organic extracts were dried over Na2SO4 filtered the filtrate was concentrated purified by chromatography on a silica gel column

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

Procedure: [1-(3-Methyl-1,2,4-oxadiazol-5-yl)-4-piperidinyl]methanol (143 mg, 13%) was prepared from a solution of 1N ZnCl2 in Et2O (6.8 mL, 6.8 mmol), 4-(hydroxymethyl)-1-piperidinecarbonitrile (prepared as in Example 20, Step 1, 0.79 g, 5.6 mmol) and N-hydroxyacetamidine (0.5 g, 6.8 mmol) in EtOAc (10 mL) followed by concentrated HCl (2 mL) in EtOH (2 mL) in a manner similar to Example 20, Step 3. 1H NMR (400 MHz, CDCl3): δ 4.22-4.10 (m, 2H), 3.54 (d, 2H, J=6.4 Hz), 3.11-3.01 (m, 2 H), 2.21 (s, 3H), 1.89-1.79 (m, 2H), 1.78-1.69 (m, 1H), 1.41-1.20 (m, 2H); LRMS (ESI), m/z 198 (M+H).

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

Procedure: A solution of 1N ZnCl2 in Et2O (60.7 mL, 60.7 mmol) was added dropwise over 15 min to a solution of 4-(hydroxymethyl)-1-piperidinecarbonitrile (7.09 g, 50.6 mmol) and N-hydroxy-2-methylpropanimidamide (6.2 g, 60.7 mmol) in EtOAc (150 mL) at ambient temperature. The reaction mixture was left at ambient temperature for 15 min, decanted, and triturated with Et2O to give a white solid. The solid was heated in a solution of concentrated HCl (15 mL) and ethanol (30 mL) for 1 h. Ethanol was removed in vacuo, and the resulting residue was charged with water (150 mL). The mixture was neutralized with Na2CO3, and extracted with CH2Cl2. The organic extracts were dried over MgSO4, filtered, and the filtrate was concentrated. The crude product was purified by chromatography on a silica gel column using 0 to 100% EtOAc/hexane to give 4.44 g (39%) of {1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}methanol as a clear oil. 1H NMR (400 MHz, CDCl3): δ 4.20-4.10 (m, 2H), 3.51 (d, 2H, J=6.4 Hz), 3.07-2.97 (m, 2H), 2.90-2.75 (m, 1H), 1.85-1.75 (m, 2H), 1.76-1.62 (m, 1H), 1.36-1.19 (m, 8H); LRMS (ESI), m/z 226 (M+H). decanted triturated with Et2O to give a white solid Ethanol was removed in vacuo the resulting residue was charged with water (150 mL) extracted with CH2Cl2 The organic extracts were dried over MgSO4 filtered the filtrate was concentrated The crude product was purified by chromatography on a silica gel column

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 4-piperidinemethanol (10 g, 86.8 mmol) in CH2Cl2 (20 mL) was added dropwise to a slurry of NaHCO3 (14.6 g, 173.6 mmol) in water (10 mL) at 0° C. The mixture was stirred at 0° C. for 30 min, and then charged with cyanogen bromide (3.0M in CH2Cl2, 32 mL, 95.5 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 30 min, then allowed to warm to ambient temperature, and stirred overnight. The aqueous layer was separated and extracted with CH2Cl2. The combined organic extracts were dried over MgSO4, filtered, and the filtrate was concentrated. The crude product was purified by chromatography on a silica gel column using 0 to 100% EtOAc/hexane to give 7.88 g (65%) of 4-(hydroxymethyl)-1-piperidinecarbonitrile as a tan solid. 1H NMR (400 MHz, CDCl3): δ 3.52 (d, 2H, J=6.4 Hz), 3.50-3.40 (m, 2 H), 3.05-2.95 (m, 2H), 1.77 (m, 2H), 1.68-1.54 (m, 1H) 1.44-1.29 (m, 2H); LRMS (ESI), m/z 141 (M+H). The reaction mixture was stirred at 0° C. for 30 min to warm to ambient temperature stirred overnight The aqueous layer was separated extracted with CH2Cl2 The combined organic extracts were dried over MgSO4 filtered the filtrate was concentrated The crude product was purified by chromatography on a silica gel column

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

Procedure: A solution of 1N ZnCl2 in Et2O (182 mL, 182 mmol) was added to a solution of 4-(hydroxymethyl)-1-piperidinecarbonitrile (21.3 g, 152 mmol) and N-hydroxy-2-methylpropanimidamide (18.6 g, 182 mmol) in EtOAc (50 mL) at ambient temperature. The reaction mixture was left at ambient temperature for 30 min, decanted, and was treated with concentrated HCl (45 mL) and ethanol 20 mL). The mixture was heated at reflux for 2 h. The mixture was evaporated to dryness, and the resulting residue was charged with water and the pH was adjusted to basic with K2CO3. The mixture was extracted with EtOAc and the material obtained was combined with 9 other batches prepared similarly and purified by silica gel chromatography to give 150 g of {1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}methanol. decanted was treated with concentrated HCl (45 mL) and ethanol 20 mL) The mixture was heated at reflux for 2 h The mixture was evaporated to dryness the resulting residue was charged with water The mixture was extracted with EtOAc the material obtained prepared similarly purified by silica gel chromatography

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 4-piperidinemethanol (140 g, 1.22 mol) in CH2Cl2 (1 L) was treated with a slurry of NaHCO3 (205 g, 2.44 mol) in water (1.4 L) at 0° C. The mixture was stirred at 0° C. for 15 min, and then charged with a solution of cyanogen bromide in CH2Cl2, (1.34 mol) at 0° C. The reaction mixture was stirred and allowed to warm to ambient temperature, and stirred overnight. The aqueous layer was separated and extracted with CH2Cl2. The combined organic extracts were dried over Na2SO4, filtered, and the filtrate was concentrated. The crude product was combined with other batches made similarly and purified by chromatography on a silica gel column to give 300 g of 4-(hydroxymethyl)-1-piperidinecarbonitrile. The reaction mixture was stirred to warm to ambient temperature stirred overnight The aqueous layer was separated extracted with CH2Cl2 The combined organic extracts were dried over Na2SO4 filtered the filtrate was concentrated purified by chromatography on a silica gel column

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

Procedure: [1-(3-Methyl-1,2,4-oxadiazol-5-yl)-4-piperidinyl]methanol (143 mg, 13%) was prepared from a solution of 1N ZnCl2 in Et2O (6.8 mL, 6.8 mmol), 4-(hydroxymethyl)-1-piperidinecarbonitrile (prepared as in Example 20, Step 1, 0.79 g, 5.6 mmol) and N-hydroxyacetamidine (0.5 g, 6.8 mmol) in EtOAc (10 mL) followed by concentrated HCl (2 mL) in EtOH (2 mL) in a manner similar to Example 20, Step 3. 1H NMR (400 MHz, CDCl3): δ 4.22-4.10 (m, 2H), 3.54 (d, 2H, J=6.4 Hz), 3.11-3.01 (m, 2 H), 2.21 (s, 3H), 1.89-1.79 (m, 2H), 1.78-1.69 (m, 1H), 1.41-1.20 (m, 2H); LRMS (ESI), m/z 198 (M+H).

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

Procedure: A solution of 1N ZnCl2 in Et2O (60.7 mL, 60.7 mmol) was added dropwise over 15 min to a solution of 4-(hydroxymethyl)-1-piperidinecarbonitrile (7.09 g, 50.6 mmol) and N-hydroxy-2-methylpropanimidamide (6.2 g, 60.7 mmol) in EtOAc (150 mL) at ambient temperature. The reaction mixture was left at ambient temperature for 15 min, decanted, and triturated with Et2O to give a white solid. The solid was heated in a solution of concentrated HCl (15 mL) and ethanol (30 mL) for 1 h. Ethanol was removed in vacuo, and the resulting residue was charged with water (150 mL). The mixture was neutralized with Na2CO3, and extracted with CH2Cl2. The organic extracts were dried over MgSO4, filtered, and the filtrate was concentrated. The crude product was purified by chromatography on a silica gel column using 0 to 100% EtOAc/hexane to give 4.44 g (39%) of {1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}methanol as a clear oil. 1H NMR (400 MHz, CDCl3): δ 4.20-4.10 (m, 2H), 3.51 (d, 2H, J=6.4 Hz), 3.07-2.97 (m, 2H), 2.90-2.75 (m, 1H), 1.85-1.75 (m, 2H), 1.76-1.62 (m, 1H), 1.36-1.19 (m, 8H); LRMS (ESI), m/z 226 (M+H). decanted triturated with Et2O to give a white solid Ethanol was removed in vacuo the resulting residue was charged with water (150 mL) extracted with CH2Cl2 The organic extracts were dried over MgSO4 filtered the filtrate was concentrated The crude product was purified by chromatography on a silica gel column

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

Procedure: A solution of 1N ZnCl2 in Et2O (60.7 mL, 60.7 mmol) was added dropwise over 15 min to a solution of 4-(hydroxymethyl)-1-piperidinecarbonitrile (7.09 g, 50.6 mmol) and N-hydroxy-2-methylpropanimidamide (6.2 g, 60.7 mmol) in EtOAc (150 mL) at ambient temperature. The reaction mixture was left at ambient temperature for 15 min, decanted, and triturated with Et2O to give a white solid. The solid was heated in a solution of concentrated HCl (15 mL) and ethanol (30 mL) for 1 h. Ethanol was removed in vacuo, and the resulting residue was charged with water (150 mL). The mixture was neutralized with Na2CO3, and extracted with CH2Cl2. The organic extracts were dried over MgSO4, filtered, and the filtrate was concentrated. The crude product was purified by chromatography on a silica gel column using 0 to 100% EtOAc/hexane to give 4.44 g (39%) of {1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}methanol as a clear oil. 1H NMR (400 MHz, CDCl3): δ 4.20-4.10 (m, 2H), 3.51 (d, 2H, J=6.4 Hz), 3.07-2.97 (m, 2H), 2.90-2.75 (m, 1H), 1.85-1.75 (m, 2H), 1.76-1.62 (m, 1H), 1.36-1.19 (m, 8H); LRMS (ESI), m/z 226 (M+H). decanted triturated with Et2O to give a white solid Ethanol was removed in vacuo the resulting residue was charged with water (150 mL) extracted with CH2Cl2 The organic extracts were dried over MgSO4 filtered the filtrate was concentrated The crude product was purified by chromatography on a silica gel column

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 4-piperidinemethanol (10 g, 86.8 mmol) in CH2Cl2 (20 mL) was added dropwise to a slurry of NaHCO3 (14.6 g, 173.6 mmol) in water (10 mL) at 0° C. The mixture was stirred at 0° C. for 30 min, and then charged with cyanogen bromide (3.0M in CH2Cl2, 32 mL, 95.5 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 30 min, then allowed to warm to ambient temperature, and stirred overnight. The aqueous layer was separated and extracted with CH2Cl2. The combined organic extracts were dried over MgSO4, filtered, and the filtrate was concentrated. The crude product was purified by chromatography on a silica gel column using 0 to 100% EtOAc/hexane to give 7.88 g (65%) of 4-(hydroxymethyl)-1-piperidinecarbonitrile as a tan solid. 1H NMR (400 MHz, CDCl3): δ 3.52 (d, 2H, J=6.4 Hz), 3.50-3.40 (m, 2 H), 3.05-2.95 (m, 2H), 1.77 (m, 2H), 1.68-1.54 (m, 1H) 1.44-1.29 (m, 2H); LRMS (ESI), m/z 141 (M+H). The reaction mixture was stirred at 0° C. for 30 min to warm to ambient temperature stirred overnight The aqueous layer was separated extracted with CH2Cl2 The combined organic extracts were dried over MgSO4 filtered the filtrate was concentrated The crude product was purified by chromatography on a silica gel column

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 4-piperidinemethanol (10 g, 86.8 mmol) in CH2Cl2 (20 mL) was added dropwise to a slurry of NaHCO3 (14.6 g, 173.6 mmol) in water (10 mL) at 0° C. The mixture was stirred at 0° C. for 30 min, and then charged with cyanogen bromide (3.0M in CH2Cl2, 32 mL, 95.5 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 30 min, then allowed to warm to ambient temperature, and stirred overnight. The aqueous layer was separated and extracted with CH2Cl2. The combined organic extracts were dried over MgSO4, filtered, and the filtrate was concentrated. The crude product was purified by chromatography on a silica gel column using 0 to 100% EtOAc/hexane to give 7.88 g (65%) of 4-(hydroxymethyl)-1-piperidinecarbonitrile as a tan solid. 1H NMR (400 MHz, CDCl3): δ 3.52 (d, 2H, J=6.4 Hz), 3.50-3.40 (m, 2 H), 3.05-2.95 (m, 2H), 1.77 (m, 2H), 1.68-1.54 (m, 1H) 1.44-1.29 (m, 2H); LRMS (ESI), m/z 141 (M+H). The reaction mixture was stirred at 0° C. for 30 min to warm to ambient temperature stirred overnight The aqueous layer was separated extracted with CH2Cl2 The combined organic extracts were dried over MgSO4 filtered the filtrate was concentrated The crude product was purified by chromatography on a silica gel column