tert-butyl 2-methyl-4-oxopiperidine-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:

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

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

Procedure: To a solution of tert-butyl 2-methyl-4-oxopiperidine-1-carboxylate (727 mg, 3.41 mmol, Small Molecules Inc.) in MeOH (6.0 mL) at 0° C. was added sodium borohydride (193 mg, 5.11 mmol, Aldrich) in several portions. The reaction mixture was stirred at 0° C. for 1 hr and warmed up to room temperature and continuously stirred for another 2.5 hrs. The resulting mixture was then quenched with saturated NH4Cl aqueous solution and evaporated under reduced pressure to remove MeOH followed by extraction with CH2Cl2 (3×). The combined extracts were dried (Na2SO4) and concentrated in vacuo to give the title compound (745 mg) as a colorless sticky oil which was used without further purification. warmed up to room temperature continuously stirred for another 2.5 hrs The resulting mixture was then quenched with saturated NH4Cl aqueous solution evaporated under reduced pressure to remove MeOH followed by extraction with CH2Cl2 (3×) The combined extracts were dried (Na2SO4) concentrated in vacuo

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

Procedure: Following the procedure found in Plettenburg, Oliver et. Al (PCT Int. Appl., 2007012421), sodium borohydride (213 mg, 5.6 mmol) was added portion-wise to a solution of tert-butyl 2-methyl-4-oxopiperidine-1-carboxylate (1.0 g, 4.7 mmol) in ethanol (10 mL). The mixture was stirred at room temperature for 2 h. The solution was concentrated in vacuo and then partitioned between water (40 mL) and ethyl acetate (40 mL). The aqueous layer was extracted twice with ethyl acetate (40 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via column chromatography on silica gel (Biotage 50 g column, gradient elution with 40-50% ethyl acetate in hexanes) to afford (rac)-tert-butyl (cis)-4-hydroxy-2-methylpiperidine-1-carboxylate (367 mg, 36%) and (rac)-tert-butyl (trans)-4-hydroxy-2-methylpiperidine-1-carboxylate (205 mg, 20%) as white solids. The solution was concentrated in vacuo partitioned between water (40 mL) and ethyl acetate (40 mL) The aqueous layer was extracted twice with ethyl acetate (40 mL) The combined organic layers were washed with brine (20 mL) dried over anhydrous sodium sulfate filtered concentrated in vacuo The residue was purified via column chromatography on silica gel (Biotage 50 g column, gradient elution with 40-50% ethyl acetate in hexanes)

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

Procedure: 213 mg (5.6 mmol) of NaBH4 were added portionwise at 0° C. to a solution of 1.0 g (4.7 mmol) 1-Boc-2-methyl-piperidin-4-on in 10 mL EtOH. The mixture was stirred at room temperature for another 2 h. The solvent was removed by distillation and the remainder was dissolved in water and ethyl acetate. The aqueous layer was extracted twice with ethyl acetated and the combined organic layers were dried over Na2SO4. After filtration the solvent was removed by distillation and the crude product was purified by column chromatography n-heptane/ethyl acetate (1/1) to yield 367 mg (36%) of the cis-isomer 25 and 205 mg (20%) of the trans-isomer 26 in addition to 97 mg (10%) mixture of both isomers. The solvent was removed by distillation the remainder was dissolved in water The aqueous layer was extracted twice with ethyl the combined organic layers were dried over Na2SO4 After filtration the solvent was removed by distillation the crude product was purified by column chromatography n-heptane/ethyl acetate (1/1) to yield 367 mg (36%) of the cis-isomer 25 and 205 mg (20%) of the trans-isomer 26

Conditions: temp:160.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Bromo-6-(1-methylhydrazinyl)pyridine (1.60 g, 7.98 mmol) and tert-butyl 2-methyl-4-oxopiperidine-1-carboxylate (enantiomer B) (1.70 g, 7.98 mmol) were heated in EtOH (10 mL) at reflux for 16 h and then the mixture was concentrated to provide a white foam. This foam was combined with para-toluenesulphonic acid (3.18 g, 16.7 mmol) and heated to 160° C. for 10 minutes. The mixture was allowed to cool and isopropanol (20 mL), water (8 mL), potassium carbonate (5.00 g, 36.2 mmol), and di-tert-butyl dicarbonate (2.55 g, 11.7 mmol) were added. After stirring for 16 h, the mixture was partitioned between methylene chloride and water, and the organic layer was removed, dried, and concentrated. The residue was purified by column chromatography eluting with ethyl acetate/hexanes (1:4) to provide the title compound (360 mg, 11%) as a white solid: ESI MS m/z 380 [M+H]+. at reflux for 16 h the mixture was concentrated to provide a white foam to cool the mixture was partitioned between methylene chloride and water the organic layer was removed dried concentrated The residue was purified by column chromatography eluting with ethyl acetate/hexanes (1:4)

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

Procedure: Under an argon atmosphere, in a 50-mL pear-shaped evaporating flask was weighed a solution of lanthanum chloride lithium chloride complex in THF (15.6 mL) and cooled to 0° C. To the solution was added dropwise a solution of isobutylmagnesium chloride in THF (3.5 mL) and stirred at 0° C. for 3 hours. A solution of tert-butyl 2-methyl-4-oxopiperidine-1-carboxylate (1 g) in THF (2.0 mL) was further added dropwise. The reaction solution was stirred at 0° C. for 1 hour, heated to 25° C., poured to hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution and dried over anhydrous magnesium sulphate. The filtrate was concentrated and the resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=9:1→3:1) to give the titled compound (450 mg) having the following physical properties. Under an argon atmosphere, in a 50-mL pear-shaped evaporating flask was weighed The reaction solution was stirred at 0° C. for 1 hour heated to 25° C. extracted with ethyl acetate The organic layer was washed with water a saturated sodium chloride solution and dried over anhydrous magnesium sulphate The filtrate was concentrated the resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=9:1→3:1)

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

Procedure: 2-Methyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester. A solution of 1,4-dioxa-8-aza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester (2.97 g) in TMEDA (2.2 mL) was cooled to −78° C. and sec-BuLi (1.8 M in THF, 13 mL) was added dropwise. The resulting yellow solution was aged at −78° C. for 1 h. Methyl iodide (1.5 mL) was added and the mixture was warmed from −78° C. to RT over 16 h. The reaction mixture was poured into water (800 mL) and extracted with EtOAc. The combined organic extracts were washed with H2O, brine, and dried over Na2SO4. Purification on SiO2 (330 g, 5 to 20% EtOAc/hexanes) provided 1.65 g of 7-methyl-1,4-dioxa-8-aza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester. Multiple aliquots of this ester were combined (2.29 g), treated with 5 mL of conc. HCl in 10 mL of dioxane, and heated at 65° C. for 6 h. The solvent was removed and the residue was dissolved in CH2Cl2 and treated with di-tert-butyldicarbonate (1.0 g). After 5 d, the mixture was diluted with satd. aq. NaHCO3 and H2O, and extracted with CH2Cl2. Purification on SiO2 (120 g, 5 to 15% EtOAc/hexanes) provided 1.40 g of the desired product as a white solid. 1H NMR (500 MHz, CDCl3): 4.69-4.59 (m, 1H), 4.21-4.12 (m, 1H), 3.30-3.20 (m, 1H), 2.66-2.57 (m, 1H), 2.47-2.36 (m, 1H), 2.32-2.23 (m, 1H), 2.22-2.15 (m, 1H), 1.42 (s, 9H), 1.11 (d, J=7.1 Hz, 3H). the mixture was warmed from −78° C. to RT over 16 h extracted with EtOAc The combined organic extracts were washed with H2O, brine dried over Na2SO4 Purification on SiO2 (330 g, 5 to 20% EtOAc/hexanes)

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

Procedure: 2-Methyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester. A solution of 1,4-dioxa-8-aza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester (2.97 g) in TMEDA (2.2 mL) was cooled to −78° C. and sec-BuLi (1.8 M in THF, 13 mL) was added dropwise. The resulting yellow solution was aged at −78° C. for 1 h. Methyl iodide (1.5 mL) was added and the mixture was warmed from −78° C. to RT over 16 h. The reaction mixture was poured into water (800 mL) and extracted with EtOAc. The combined organic extracts were washed with H2O, brine, and dried over Na2SO4. Purification on SiO2 (330 g, 5 to 20% EtOAc/hexanes) provided 1.65 g of 7-methyl-1,4-dioxa-8-aza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester. Multiple aliquots of this ester were combined (2.29 g), treated with 5 mL of conc. HCl in 10 mL of dioxane, and heated at 65° C. for 6 h. The solvent was removed and the residue was dissolved in CH2Cl2 and treated with di-tert-butyldicarbonate (1.0 g). After 5 d, the mixture was diluted with satd. aq. NaHCO3 and H2O, and extracted with CH2Cl2. Purification on SiO2 (120 g, 5 to 15% EtOAc/hexanes) provided 1.40 g of the desired product as a white solid. 1H NMR (500 MHz, CDCl3): 4.69-4.59 (m, 1H), 4.21-4.12 (m, 1H), 3.30-3.20 (m, 1H), 2.66-2.57 (m, 1H), 2.47-2.36 (m, 1H), 2.32-2.23 (m, 1H), 2.22-2.15 (m, 1H), 1.42 (s, 9H), 1.11 (d, J=7.1 Hz, 3H). the mixture was warmed from −78° C. to RT over 16 h extracted with EtOAc The combined organic extracts were washed with H2O, brine dried over Na2SO4 Purification on SiO2 (330 g, 5 to 20% EtOAc/hexanes)