1-methylpiperidine-2-carboxylic acid

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: N-Methyl-piperidine-2-carboxylic acid ethyl ester (5.1 g) was dissolved in a mixture of 100 ml methanol and 10 ml water. NaOH (8 g) was added and the reaction mixture was stirred at room temperature overnight. The solution was then neutralized with hydrochloric acid, evaporated to dryness, and evaporated four times with toluene. The resulting powdery residue was used directly in the next step. evaporated to dryness evaporated four times with toluene

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

Procedure: N-Methyl-piperidine-2-carboxylic acid ethyl ester (5.1 g) was dissolved in a mixture of 100 ml methanol and 10 ml water. NaOH (8 g) was added and the reaction mixture was stirred at room temperature overnight. The solution was then neutralized with hydrochloric acid, evaporated to dryness, and evaporated four times with toluene. The resulting powdery residue was used directly in the next step. evaporated to dryness evaporated four times with toluene

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

Procedure: Example 90 was prepared as a light yellow solid from Example 26 and N-methyl-pipecolic acid as described for Example 62.

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

Procedure: Into a 25 ml 3-necked round bottom flask, was placed piperidine-2-carboxylic acid (975 mg, 7.56 mmol), HCHO (2.0 ml) and HCOOH (2.6 ml). The resulting solution was allowed to react, with stirring, for 5 hours while the temperature was maintained at reflux. The reaction progress was monitored by LCMS. The mixture was then concentrated by evaporation under vacuum using a rotary evaporator. The residue was triturated with 30 ml of Et2O to provide 1-methylpiperidine-2-carboxylic acid of as a white solid (0.5 g, 41%). Into a 25 ml 3-necked round bottom flask, was placed to react was maintained at reflux The mixture was then concentrated by evaporation under vacuum a rotary evaporator The residue was triturated with 30 ml of Et2O

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

Procedure: Into a 25 ml 3-necked round bottom flask, was placed piperidine-2-carboxylic acid (975 mg, 7.56 mmol), HCHO (2.0 ml) and HCOOH (2.6 ml). The resulting solution was allowed to react, with stirring, for 5 hours while the temperature was maintained at reflux. The reaction progress was monitored by LCMS. The mixture was then concentrated by evaporation under vacuum using a rotary evaporator. The residue was triturated with 30 ml of Et2O to provide 1-methylpiperidine-2-carboxylic acid of as a white solid (0.5 g, 41%). Into a 25 ml 3-necked round bottom flask, was placed to react was maintained at reflux The mixture was then concentrated by evaporation under vacuum a rotary evaporator The residue was triturated with 30 ml of Et2O

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

Procedure: N-Methyl-piperidine-2-carboxylic acid ethyl ester (5.1 g) was dissolved in a mixture of 100 ml methanol and 10 ml water. NaOH (8 g) was added and the reaction mixture was stirred at room temperature overnight. The solution was then neutralized with hydrochloric acid, evaporated to dryness, and evaporated four times with toluene. The resulting powdery residue was used directly in the next step. evaporated to dryness evaporated four times with toluene

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

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

Procedure: N-Methyl-piperidine-2-carboxylic acid ethyl ester (5.1 g) was dissolved in a mixture of 100 ml methanol and 10 ml water. NaOH (8 g) was added and the reaction mixture was stirred at room temperature overnight. The solution was then neutralized with hydrochloric acid, evaporated to dryness, and evaporated four times with toluene. The resulting powdery residue was used directly in the next step. evaporated to dryness evaporated four times with toluene

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

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

Procedure: To a suspension of N-methyl pipecolinic acid (0.15 mmole, 21 mg) in dichlbromethane (5 mL) were subsequently added, in the order, HOAt (0.11 mmole, 15 mg), HATU (0.11 mmole, 42 mg) and Et3N (0.21 mmole, 29 μL). After stirring for 5 minutes, a solution in dichloromethane (1 mL) of the compound obtained in example 15.3 (0.1 mmole, 46 mg) was added. The reaction mixture was stirred for 4 hours, At the end dichloromethane was removed under vacuum. The crude product was dissolved in ethyl acetate (10 mL) and washed, in the order, with a NaHCO3 saturated aqueous solution (1×10 mL) and with brine (1×10 mL). The organic phase were dried over Na2SO4, filtered and concentrated under vacuum. The product was purified by flash chromatography (eluent chloroform:methanol 97:3 volume/volume). 58 mg (99% yield) of pure 2-((1R,3R)-3-((2S,3S)-2-azido-N-(2-methoxyethyl)-3-methylpentanamido)-1-hydroxy-4-methylpentyl)-N-methylthiazole-4-carboxamide were isolated. Rf=0.37 (chloroform/methanol 97:3 volume/volume). 1HNMR (400 MHz, CDCl3) δ: 8.07 (s, 1H), 7.62 (m, 1H), 7.57 (m, 1H), 5.75 (dd, 1H), 4.61 (dd, 1H), 4.11 (m, 1H), 3.70-3.48 (m, 4H), 3.22 (s, 3H), 3, 20-3.08 (m, 1H), 2.92 (m, 3H), 2.88-2.78 (m, 1H), 2.40 (m, 1H), 2.2-2.09 (m, 6H), 2.09-1.81 (m, 5H), 1.69-1.48 (m, 5H), 1.39-1.30 (m, 1H), 1.26-1.09 (m, 1H), 1.08-0.86 (m, 12H). was removed under vacuum The crude product was dissolved in ethyl acetate (10 mL) washed, in the order, with a NaHCO3 saturated aqueous solution (1×10 mL) and with brine (1×10 mL) The organic phase were dried over Na2SO4 filtered concentrated under vacuum The product was purified by flash chromatography (eluent chloroform:methanol 97:3 volume/volume)