4-(aminomethyl)-1-methylpiperidin-4-ol

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:; See reaction.notes.procedure_details.

Procedure: A solution of 2-carboxymethyl-4-methyl-1H-pyrrole-3-carboxylic acid ethyl ester (3.717 g, 17.62 mmol) in dichloromethane (91 ml) in an ice-water bath was added with 4-aminomethyl-1-methyl-piperidin-4-ol (4 g, 19.38 mmol), N,N′-dimethylformamide (9.1 ml), N-ethyl-N′-(dimethylaminopropyl)-carbodiimide hydrochloride (8.751 g, 45.6 mmol) and 1-hydroxybenzotriazol (3,577 g, 26.5 mmol). Upon completion of the addition, the resulting mixture was stirred at room temperature overnight. The mixture was added with ice to quench the reaction, and washed with saturated potassium carbonate solution (10 ml×3) with brine (50 ml×3) The resulting mixture was partitioned and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2-{[(4-hydroxy-1-methyl-piperidin-4-ylmethyl)-carbamoyl]-methyl}-4-methyl-1H-pyrrole-3-carboxylic acid ethyl ester (8.891 g) as a brown oil, which was used as such. Upon completion of the addition The mixture was added with ice to quench the reaction washed with saturated potassium carbonate solution (10 ml×3) with brine (50 ml×3) The resulting mixture was partitioned the organic phase was dried over anhydrous sodium sulfate filtered 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:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 4-aminomethyl-1-methyl-piperidin-4-ol (2.127 g, 14.77 mmol) in dichloromethane (15 ml) was added anhydrous magnesium sulfate (2.9 g). The resulting mixture was cooled to 0° C. and freshly distilled acetaldehyde (835 μl, 14.78 mmol) was added. After 6 h of stirring at room temperature, the mixture was filtered and the solvent was evaporated under reduced pressure to give the title compound (2.16 g) as an almost colorless liquid. 1H NMR (CDCl3, 500 MHz) δ 4.60 (q, J=5.40 Hz, 1H, CHCH3), 3.01 (d, J=12 Hz, 1H, CHHNH), 2.76 (d, J=12 Hz, 1H, CHHNH), 2.55-2.31 (m, 4H, CH2N), 2.28 (s, 3H, NCH3), 1.77-1.58 (m, 4H, CH2CO), 1.36 (d, J=5.40 Hz, 3H, CH3CH) ppm; 13C NMR (CDCl3, 300 MHz) δ 87.57 (CH), 57.19 (CH2), 53.14 (C), 52.96 (CH2), 46.15 (CH3), 37.28 (CH2), 35.73 (CH2), 20.32 (CH3) ppm. the mixture was filtered the solvent was evaporated under reduced pressure

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

Procedure: To a solution of 4-aminomethyl-1-methyl-piperidin-4-ol (2.127 g, 14.77 mmol) in dichloromethane (15 ml) was added anhydrous magnesium sulfate (2.9 g). The resulting mixture was cooled to 0° C. and freshly distilled acetaldehyde (835 μl, 14.78 mmol) was added. After 6 h of stirring at room temperature, the mixture was filtered and the solvent was evaporated under reduced pressure to give the title compound (2.16 g) as an almost colorless liquid. 1H NMR (CDCl3, 500 MHz) δ 4.60 (q, J=5.40 Hz, 1H, CHCH3), 3.01 (d, J=12 Hz, 1H, CHHNH), 2.76 (d, J=12 Hz, 1H, CHHNH), 2.55-2.31 (m, 4H, CH2N), 2.28 (s, 3H, NCH3), 1.77-1.58 (m, 4H, CH2CO), 1.36 (d, J=5.40 Hz, 3H, CH3CH) ppm; 13C NMR (CDCl3, 300 MHz) δ 87.57 (CH), 57.19 (CH2), 53.14 (C), 52.96 (CH2), 46.15 (CH3), 37.28 (CH2), 35.73 (CH2), 20.32 (CH3) ppm. the mixture was filtered the solvent was evaporated under reduced pressure

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

Procedure: The precursor amine compounds may in turn be prepared as described in greater detail below. Thus, for example, 2,8-Dimethyl-1-oxa-3,8-diaza-spiro[4.5]decane may be obtained by reaction of 4-aminomethyl-1-methyl-piperidin-4-ol with acetaldehyde in dry dichloromethane. 2,8-Dimethyl-1-oxa-4,8-diazaspiro[4.5]decane may be obtained by reaction of 1-amino-2-propanol with 1-methyl-4-piperidone under reflux. 1′,4-Dimethylspiro[3-oxa-6-azabicyclo[3.1.0]hexane-2,4′-piperidine] may be obtained by first preparing 2,8-dimethyl-1-oxa-8-azaspiro[4.5]decan-3-one oxime from 1-methyl-4-piperidone via 2,8-dimethyl-1-oxa-8-azaspiro[4.5]decan-3-one per the procedure of Tsukamoto et. al., Chem. Pharm. Bull. 1995, 43, 842-852, followed by reduction of the oxime with Red-A1 (sodium bis(2-methoxyethoxy)aluminumhydride) and then basic workup to yield 1′,4-Dimethylspiro[3-oxa-6-azabicyclo[3.1.0]hexane-2,4′-piperidine]. 2,8-Dimethyl-1-oxa-8-aza-spiro[4.5]dec-3-yl amine may be obtained by first preparing 2,8-dimethyl-1-oxa-8-azaspiro[4.5]decan-3-one oxime from 1-methyl-4-piperidone via 2,8-dimethyl-1-oxa-8-azaspiro[4.5]decan-3-one per the procedure of Tsukamoto et. al., Chem. Pharm. Bull. 1995, 43, 842-852, followed by reduction of the oxime with lithium aluminum hydride/aluminum chloride. Compounds of formula I may then be prepared from these amines by an appropriate coupling reaction.

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

Procedure: Palladium hydroxide (2.3 g of 20% on carbon) was added to a solution of 1-methyl-4-nitromethylpiperidin-4-ol (11.57 g) in ethanol (120 mL). The mixture was placed under hydrogen pressure (50 psi, 3.4×105 Pa) on a Parr apparatus for 55 hours. The reaction mixture was filtered through a layer of CELITE filter aid and the filter cake was rinsed with methanol (100 mL). The filtrate was concentrated under reduced pressure to provide 10.18 g of 4-aminomethyl-1-methylpiperidin-4-ol as a thick oil. for 55 hours The reaction mixture was filtered through a layer of CELITE filter aid the filter cake was rinsed with methanol (100 mL) The filtrate was concentrated under reduced pressure

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