3-AMINOPHENYL N,N-DIMETHYLCARBAMATE, 97

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: N-Boc-amino-(4-N-Boc-piperidinyl)carboxylic acid (0.114 g, 0.33 mmol), HATU (0.151 g, 0.40 mmol) and N,N-diisopropylethylamine (128 mg, 1.0 mmol) were combined in isopropyl acetate (2.3 mL) and stirred at room temperature for 15 minutes. 3-aminophenyl dimethylcarbamate (0.072 g, 0.40 mmol) was added, and the mixture heated at 80° C. for 1.5 hours. The reaction mixture was allowed to cool, diluted with EtOAc, washed with 2 N Na2CO3, 1 N HCl, and brine, and then dried over MgSO4 and concentrated. Purification by silica gel chromatography (60% EtOAc/hexanes) gave the title compound (0.075 g, 45%) as a white solid. MS (ES+) [M+NH4]+=524. the mixture heated at 80° C. for 1.5 hours to cool washed with 2 N Na2CO3, 1 N HCl, and brine dried over MgSO4 concentrated Purification by silica gel chromatography (60% EtOAc/hexanes)

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

Procedure: To a solution of carboxylic acids from step B, pyridine (0.2 mL, 2.48 mmol), and DMF (catalytic, 2 drops) in CH2Cl2 (3.1 mL) was added dropwise oxalyl chloride (60 μL, 0.68 mmol, caution: exothermic). After gas evolution subsided, the reaction was stirred at ambient temperature for 30 minutes. 3-Aminophenyl dimethylcarbamate (112 mg, 0.62 mmol) was added in one portion to this solution, which was stirred for another 30 minutes. The reaction was quenched with saturated aq. NH4Cl, and the aqueous layer was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine, dried with MgSO4, filtered, and concentrated under vacuum. Silica gel chromatography (80% ethyl acetate:hexanes) afforded the title compound as an off-white solid (150 mg). MS (ES+) [M+CH3CN]+=529.3. was stirred for another 30 minutes The reaction was quenched with saturated aq. NH4Cl the aqueous layer was extracted with ethyl acetate (3×50 mL) The combined organic layers were washed with brine dried with MgSO4 filtered concentrated under vacuum

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 1-(tert-butoxycarbonyl)-4-((1-trityl-1H-imidazol-4-yl)methyl)piperidine-4-carboxylic acid from step B (270 mg, 0.6 mmol) in isopropyl acetate (5 mL) were added HATU (273 mg, 0.73 mmol) and N,N-diisopropylethylamine (205 μL, 1.2 mmol). The mixture was stirred for 5 min, and 3-aminophenyl dimethylcarbamate (108 mg, 0.6 mmol) was added. The resulting mixture was heated at 90° C. for 2 hours. The reaction mixture was diluted with EtOAc (10 mL), washed with aqueous NaHCO3 and brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (10-70% EtOAc:Hexanes) to afford the title compound (185 mg, 43%). MS (ES+) [M+H]+=714.2. washed with aqueous NaHCO3 and brine dried over Na2SO4 filtered concentrated under vacuum The residue was purified by silica gel chromatography (10-70% EtOAc:Hexanes)

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1-(tert-Butoxycarbonyl)-4-(2-(dimethylamino)ethyl)piperidine-4-carboxylic acid from step B (100 mg, 0.33 mmol), HATU (175 mg, 0.46 mmol), and N,N-diisopropylethylamine (0.116 mL, 0.67 mmol) were stirred in isopropyl acetate for 10 minutes. 3-aminophenyl dimethylcarbamate (90 mg, 0.5 mmol) was added, and the reaction was stirred at 85° C. for 2 hours, cooled to room temperature, stirred overnight, and then diluted with EtOAc, washed with sat. aq. Na2CO3 and brine (with back extraction), dried over MgSO4, filtered, and concentrated under vacuum, to give the title compound as a viscous oil. MS (ES+) [M+H]+=463. cooled to room temperature stirred overnight washed with sat. aq. Na2CO3 and brine (with back extraction) dried over MgSO4 filtered concentrated under vacuum

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

Procedure: To a solution of 1-(tert-butoxycarbonyl)-4-(2-methoxyethoxy)piperidine-4-carboxylic acid from step B (1.6 g, 5.1 mmol) in dichloroethane was added pyridine (1.6 g, 20 mmol) and DMF (0.05 mL), followed by oxalyl chloride (0.65 g, 5.1 mmol). The mixture was stirred for 30 minutes, and then 3-aminophenyl dimethylcarbamate (0.91 g, 5.04 mmol) was added. The mixture was stirred for 18 hours, then diluted with dichloromethane, washed twice with 1 N aq. HCl and once with brine, dried over MgSO4, and concentrated. Silica gel chromatography (0-5% MeOH:CH2Cl2) gave the title compound in 88% yield. MS (ES+) [M+H]+=480. The mixture was stirred for 18 hours washed twice with 1 N aq. HCl and once with brine dried over MgSO4 concentrated

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

Procedure: To a solution of 1-(tert-butoxycarbonyl)-4-(methoxymethyl)-piperidine-4-carboxylic acid from step B (718 mg, 2.63 mmol), pyridine (0.84 mL, 10.52 mmol), and DMF (catalytic, 3 drops) in CH2Cl2 (13 mL) was added dropwise oxalyl chloride (0.25 mL, 2.89 mmol, caution: exothermic). After gas evolution subsided, the reaction was stirred at ambient temperature for 30 minutes. 3-Aminophenyl dimethylcarbamate (475 mg, 2.63 mmol) was added in one portion to this solution and stirred for another 30 minutes. The reaction was quenched with saturated aqueous NH4Cl, and the aqueous layer was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under vacuum. Silica gel chromatography (50% ethyl acetate:hexanes) afforded the title compound (1.03 g, 90% yield for two steps). MS (ES+) [M+NH4]+=453.3 stirred for another 30 minutes The reaction was quenched with saturated aqueous NH4Cl the aqueous layer was extracted with ethyl acetate (3×50 mL) The combined organic layers were washed with brine dried over MgSO4 filtered concentrated under vacuum

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1-(tert-Butoxycarbonyl)-4-methylpiperidine-4-carboxylic acid (67 mg, 0.28 mmol), EDC (64 mg, 0.33 mmol), HOBT (45 mg, 0.33 mmol) and dichloroethane (2.0 mL) were combined in a pressure rated sealed tube and stirred for 45 min. 3-Aminophenyl dimethylcarbamate (50 mg, 0.28 mmol) was added, and the mixture was heated at 85° C. for 18 hours. The mixture was concentrated and chromatographed (SiO2, 0-2% MeOH:CH2Cl2) to give the title compound in 50% yield. MS (ES+) [M+H]+=406. rated sealed tube The mixture was concentrated chromatographed (SiO2, 0-2% MeOH:CH2Cl2)

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

Procedure: N-Boc-amino-(4-N-Boc-piperidinyl)carboxylic acid (0.114 g, 0.33 mmol), HATU (0.151 g, 0.40 mmol) and N,N-diisopropylethylamine (128 mg, 1.0 mmol) were combined in isopropyl acetate (2.3 mL) and stirred at room temperature for 15 minutes. 3-aminophenyl dimethylcarbamate (0.072 g, 0.40 mmol) was added, and the mixture heated at 80° C. for 1.5 hours. The reaction mixture was allowed to cool, diluted with EtOAc, washed with 2 N Na2CO3, 1 N HCl, and brine, and then dried over MgSO4 and concentrated. Purification by silica gel chromatography (60% EtOAc/hexanes) gave the title compound (0.075 g, 45%) as a white solid. MS (ES+) [M+NH4]+=524. the mixture heated at 80° C. for 1.5 hours to cool washed with 2 N Na2CO3, 1 N HCl, and brine dried over MgSO4 concentrated Purification by silica gel chromatography (60% EtOAc/hexanes)