2-(benzylamino)-2-methylpropan-1-ol

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

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-(Benzylamino)-2-methyl-propan-1-ol hydrochloride (539 mg, 2.50 mmol) was treated with aqueous sodium hydroxide (50 mL of 2 M, 100 mmol), then diethyl ether (50 mL) was added to the solution and stirred for 3 min. The organic layer was separated, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to provide the 2-(benzylamino)-2-methyl-propan-1-ol free base as a white powder. The 2-(benzylamino)-2-methyl-propan-1-ol (2.50 mmol) and tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (500 mg, 2.344 mmol) were dissolved in ethanol (2 mL) and the reaction mixture was heated in a sealed tube at 100° C. for 48 h. The ethanol was evaporated and the crude material purified by silica gel column chromatography (1-100% ethyl acetate/hexanes) to provide tert-butyl 4-((benzyl(1-hydroxy-2-methylpropan-2-yl)amino)methyl)-4-hydroxypiperidine-1-carboxylate as white powder (551 mg, 60%). ESI-MS m/z calc. 392.5. found 373.3 (M+1)+; Retention time: 1.14 minutes (3 min run). 1H NMR (400 MHz, DMSO-d6) δ 7.43 (d, J=7.4 Hz, 2H), 7.24 (t, J=7.6 Hz, 2H), 7.13 (t, J=7.3 Hz, 1H), 4.66 (t, J=5.1 Hz, 1H), 4.43 (s, 1H), 3.91 (s, 2H), 3.62 (s, 2H), 3.22 (d, J=4.8 Hz, 2H), 2.97 (s, 2H), 2.58 (s, 2H), 1.44-1.27 (m, 13H), 0.88 (s, 6H). The ethanol was evaporated the crude material purified by silica gel column chromatography (1-100% ethyl acetate/hexanes)

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

Procedure: 2-(Benzylamino)-2-methyl-propan-1-ol hydrochloride (539 mg, 2.50 mmol) was treated with aqueous sodium hydroxide (50 mL of 2 M, 100 mmol), then diethyl ether (50 mL) was added to the solution and stirred for 3 min. The organic layer was separated, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to provide the 2-(benzylamino)-2-methyl-propan-1-ol free base as a white powder. The 2-(benzylamino)-2-methyl-propan-1-ol (2.50 mmol) and tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (500 mg, 2.344 mmol) were dissolved in ethanol (2 mL) and the reaction mixture was heated in a sealed tube at 100° C. for 48 h. The ethanol was evaporated and the crude material purified by silica gel column chromatography (1-100% ethyl acetate/hexanes) to provide tert-butyl 4-((benzyl(1-hydroxy-2-methylpropan-2-yl)amino)methyl)-4-hydroxypiperidine-1-carboxylate as white powder (551 mg, 60%). ESI-MS m/z calc. 392.5. found 373.3 (M+1)+; Retention time: 1.14 minutes (3 min run). 1H NMR (400 MHz, DMSO-d6) δ 7.43 (d, J=7.4 Hz, 2H), 7.24 (t, J=7.6 Hz, 2H), 7.13 (t, J=7.3 Hz, 1H), 4.66 (t, J=5.1 Hz, 1H), 4.43 (s, 1H), 3.91 (s, 2H), 3.62 (s, 2H), 3.22 (d, J=4.8 Hz, 2H), 2.97 (s, 2H), 2.58 (s, 2H), 1.44-1.27 (m, 13H), 0.88 (s, 6H). The organic layer was separated washed with brine dried over Na2SO4 filtered concentrated in vacuo

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

Procedure: Acetic acid (5.4 ml) was added to a solution of 2-amino-2-methyl-1-propanol (8.4 g) and benzaldehyde (10 g) in 1,2-dichloroethane (140 ml) under ice-cooling. After 30 minutes of stirring at the same temperature, sodium triacetoxyborohydride (26 g) was added by small portions to the solution over 10 minutes. After 2 hours of stirring at room temperature, the mixture was poured into a solution of sodium hydrogen carbonate (48 g) in water (300 ml). The aqueous layer was separated and adjusted to pH 12 with 24% sodium hydroxide aqueous solution. The alkaline solution was extracted with ethyl acetate (2 times). The extract was dried over sodium sulfate and evaporated under reduced pressure to give colorless crystals of 2-benzylamino-2-methyl-1-propanol (13.2 g). cooling was added by small portions to the solution over 10 minutes The aqueous layer was separated The alkaline solution was extracted with ethyl acetate (2 times) The extract was dried over sodium sulfate evaporated 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: Reaction of 47 g of 2-benzylamino-2-methyl-1-propanol, 13.3 g of sodium hydride dispersion and 23.5 g of 6-chloronicotinic acid amide in 300 ml of dimethylformamide analogously to Example 1(a) gives 6-(2-benzylamino-2,2-dimethyl-ethoxy)-nicotinic acid amide of melting point 125°-126° C.

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

Procedure: Reaction of 47 g of 2-benzylamino-2-methyl-1-propanol, 13.3 g of sodium hydride dispersion and 23.5 g of 6-chloronicotinic acid amide in 300 ml of dimethylformamide analogously to Example 1(a) gives 6-(2-benzylamino-2,2-dimethyl-ethoxy)-nicotinic acid amide of melting point 125°-126° C.

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

Procedure: A mixture of 106 g of benzaldehyde, 89 g of 2-amino-2-methyl-1-propanol, 2 ml of glacial acetic acid and 500 ml of benzene is heated for 3 hours under reflux, using a water separator. After completion of the reaction, the mixture is evaporated and the residue is dissolved in 2 liters of ethanol. After adding a total of 76 g of sodium borohydride in portions over the course of 2-3 hours, continuing to stir the mixture overnight at room temperature, and working up in the usual manner, 2-benzylamino-2-methyl-1-propanol is obtained, which melts at 50°-55° C. after crystallisation from ether. is heated for 3 hours under reflux After completion of the reaction the mixture is evaporated the residue is dissolved in 2 liters of ethanol After adding a total of 76 g of sodium borohydride in portions over the course of 2-3 hours

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

Procedure: A mixture of 106 g of benzaldehyde, 89 g of 2-amino-2-methyl-1-propanol, 2 ml of glacial acetic acid and 500 ml of benzene is heated for 3 hours under reflux, using a water separator. After completion of the reaction, the mixture is evaporated and the residue is dissolved in 2 liters of ethanol. After adding a total of 76 g of sodium borohydride in portions over the course of 2-3 hours, continuing to stir the mixture overnight at room temperature, and working up in the usual manner, 2-benzylamino-2-methyl-1-propanol is obtained, which melts at 50°-55° C. after crystallisation from ether. is heated for 3 hours under reflux After completion of the reaction the mixture is evaporated the residue is dissolved in 2 liters of ethanol After adding a total of 76 g of sodium borohydride in portions over the course of 2-3 hours

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-(Benzylamino)-2-methyl-propan-1-ol hydrochloride (539 mg, 2.50 mmol) was treated with aqueous sodium hydroxide (50 mL of 2 M, 100 mmol), then diethyl ether (50 mL) was added to the solution and stirred for 3 min. The organic layer was separated, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to provide the 2-(benzylamino)-2-methyl-propan-1-ol free base as a white powder. The 2-(benzylamino)-2-methyl-propan-1-ol (2.50 mmol) and tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (500 mg, 2.344 mmol) were dissolved in ethanol (2 mL) and the reaction mixture was heated in a sealed tube at 100° C. for 48 h. The ethanol was evaporated and the crude material purified by silica gel column chromatography (1-100% ethyl acetate/hexanes) to provide tert-butyl 4-((benzyl(1-hydroxy-2-methylpropan-2-yl)amino)methyl)-4-hydroxypiperidine-1-carboxylate as white powder (551 mg, 60%). ESI-MS m/z calc. 392.5. Found 373.3 (M+1)+; Retention time: 1.14 minutes (3 min run). 1H NMR (400 MHz, DMSO-d6) δ 7.43 (d, J=7.4 Hz, 2H), 7.24 (t, J=7.6 Hz, 2H), 7.13 (t, J=7.3 Hz, 1H), 4.66 (t, J=5.1 Hz, 1H), 4.43 (s, 1H), 3.91 (s, 2H), 3.62 (s, 2H), 3.22 (d, J=4.8 Hz, 2H), 2.97 (s, 2H), 2.58 (s, 2H), 1.44-1.27 (m, 13H), 0.88 (s, 6H). The ethanol was evaporated the crude material purified by silica gel column chromatography (1-100% ethyl acetate/hexanes)

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

Procedure: 2-(Benzylamino)-2-methyl-propan-1-ol hydrochloride (539 mg, 2.50 mmol) was treated with aqueous sodium hydroxide (50 mL of 2 M, 100 mmol), then diethyl ether (50 mL) was added to the solution and stirred for 3 min. The organic layer was separated, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to provide the 2-(benzylamino)-2-methyl-propan-1-ol free base as a white powder. The 2-(benzylamino)-2-methyl-propan-1-ol (2.50 mmol) and tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (500 mg, 2.344 mmol) were dissolved in ethanol (2 mL) and the reaction mixture was heated in a sealed tube at 100° C. for 48 h. The ethanol was evaporated and the crude material purified by silica gel column chromatography (1-100% ethyl acetate/hexanes) to provide tert-butyl 4-((benzyl(1-hydroxy-2-methylpropan-2-yl)amino)methyl)-4-hydroxypiperidine-1-carboxylate as white powder (551 mg, 60%). ESI-MS m/z calc. 392.5. Found 373.3 (M+1)+; Retention time: 1.14 minutes (3 min run). 1H NMR (400 MHz, DMSO-d6) δ 7.43 (d, J=7.4 Hz, 2H), 7.24 (t, J=7.6 Hz, 2H), 7.13 (t, J=7.3 Hz, 1H), 4.66 (t, J=5.1 Hz, 1H), 4.43 (s, 1H), 3.91 (s, 2H), 3.62 (s, 2H), 3.22 (d, J=4.8 Hz, 2H), 2.97 (s, 2H), 2.58 (s, 2H), 1.44-1.27 (m, 13H), 0.88 (s, 6H). The organic layer was separated washed with brine dried over Na2SO4 filtered concentrated in vacuo

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

Procedure: Reaction of 47 g of 2-benzylamino-2-methyl-1-propanol, 13.3 g of sodium hydride dispersion and 23.5 g of 6-chloronicotinic acid amide in 300 ml of dimethylformamide analogously to Example 1 a) gives 6-(2-benzylamino-2,2-dimethyl-ethoxy)-nicotinic acid amide of melting point 125°-126° C.