1,2-dichloro-1-ethoxyethane

Conditions: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a sealed tube, a mixture of 2-amino-3-chloro-5-(2,4-dichloro-phenyl)-isonicotinonitrile (285 mg, 0.96 mmol) and 1,2-dichloro-1-ethoxy-ethane (0.64 mL, 5.25 mmol) was heated at 150° C. for 17 min under microwave irradiation. The reaction mixture was cooled to RT, poured into AcOEt (75 mL) and washed with a 2.0 M Na2CO3 solution in water (2×25 mL). The organic layer was dried over Na2SO4, filtered and evaporated. The residue was purified by Combi-Flash Companion™ (Isco Inc.) column chromatography (SiO2; gradient elution, [hexane/DCM 1:1]/TBME 95:5→3:7) to yield the title compound (185 mg, 0.57 mmol, 60%) as a brownish solid. MS: 322 [M+1]+; HPLC: AtRet=2.17; TLC: RF 0.13 (hexane/DCM/TBME 1:1:2). The reaction mixture was cooled to RT washed with a 2.0 M Na2CO3 solution in water (2×25 mL) The organic layer was dried over Na2SO4 filtered evaporated The residue was purified by Combi-Flash Companion™ (Isco Inc.) column chromatography (SiO2; gradient elution, [hexane/DCM 1:1]/TBME 95:5→3:7)

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

Procedure: An ice-chilled solution of sodium hydroxide (1.9 g) in water (25 ml) was added, during 40 minutes, to a stirred solution of 4-methyl-3-oxo-pentanoic acid ethyl ester (3 g, 18.96 mmoles) and 1,2-dichloro-1-ethoxy-ethane (3.3 g, 35.19 mmole) in diethyl ether (15 ml) with ice bath cooling. When the addition was complete the mixture was stirred rapidly for 1 hour, then the ethereal layer was separated, washed with water and dried. Evaporation of the solvent gave a yellow oil, which was purified by flash chromatography using a gradient elution from neat pentane to pentane/diethyl ether 9:1 v/v as eluent, to afford compound 82 as an oil (2.4 g). cooling When the addition the ethereal layer was separated washed with water dried Evaporation of the solvent gave a yellow oil, which was purified by flash chromatography a gradient elution from neat pentane to pentane/diethyl ether 9:1 v/v as eluent

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

Procedure: An ice-chilled solution of sodium hydroxide (1.9 g) in water (25 ml) was added, during 40 minutes, to a stirred solution of 4-methyl-3-oxo-pentanoic acid ethyl ester (3 g, 18.96 mmoles) and 1,2-dichloro-1-ethoxy-ethane (3.3 g, 35.19 mmole) in diethyl ether (15 ml) with ice bath cooling. When the addition was complete the mixture was stirred rapidly for 1 hour, then the ethereal layer was separated, washed with water and dried. Evaporation of the solvent gave a yellow oil, which was purified by flash chromatography using a gradient elution from neat pentane to pentane/diethyl ether 9:1 v/v as eluent, to afford compound 82 as an oil (2.4 g). cooling When the addition the ethereal layer was separated washed with water dried Evaporation of the solvent gave a yellow oil, which was purified by flash chromatography a gradient elution from neat pentane to pentane/diethyl ether 9:1 v/v as eluent

Conditions: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of N,N-diisopropyl-3-carbamoyl-3-phenylpropanamine, prepared in Example 34.2 (4.05 g, 15.4 mmol), 1,2-dichloroethyl ethyl ether (2,32 g, 16.2 mmol), water (0.300 g, 16.6 mmol) and formic acid (50 mL) was stirred at 75° C. for 3 hours. The formic acid was evaporated and the residue was dissolved in water/diethyl ether. The aqueous phase was made alkaline (11 M NaOH) and extracted twice with diethyl ether. The combined organic phases were dried (Na2SO4) and the solvent evaporated. The crude product was chromatographed on silica (petroleum ether-triethylamine 97:3). The pure amine was precipitated as hydrochloride salt with HCl-saturated diethyl ether, affording the title compound as white crystals, 0.61 g (12%): mp 157-158° C.; 1H NMR (DMSO(d6)) δ1.11 (m, 12H), 2.35 (m, 1H), 2.63 (m, 1H), 3.03 (m, 2H), 3.56 (m, 2H), 4.45 (m, 1H), 7.21-7.40 (m, 6H) 8.06 (d, 1H), 10.20 (br, 1H). The formic acid was evaporated the residue was dissolved in water/diethyl ether extracted twice with diethyl ether The combined organic phases were dried (Na2SO4) the solvent evaporated The crude product was chromatographed on silica (petroleum ether-triethylamine 97:3) The pure amine was precipitated as hydrochloride salt with HCl-saturated diethyl ether

Conditions: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a sealed tube, a mixture of 2-amino-3-chloro-5-(2,4-dichloro-phenyl)-isonicotinonitrile (285 mg, 0.96 mmol) and 1,2-dichloro-1-ethoxy-ethane (0.64 mL, 5.25 mmol) was heated at 150° C. for 17 min under microwave irradiation. The reaction mixture was cooled to RT, poured into AcOEt (75 mL) and washed with a 2.0 M Na2CO3 solution in water (2×25 mL). The organic layer was dried over Na2SO4, filtered and evaporated. The residue was purified by Combi-Flash Companion™ (Isco Inc.) column chromatography (SiO2; gradient elution, [hexane/DCM 1:1]/TBME 95:5→3:7) to yield the title compound (185 mg, 0.57 mmol, 60%) as a brownish solid. MS: 322 [M+1]+; HPLC: AtRet=2.17; TLC: RF 0.13 (hexane/DCM/TBME 1:1:2). The reaction mixture was cooled to RT washed with a 2.0 M Na2CO3 solution in water (2×25 mL) The organic layer was dried over Na2SO4 filtered evaporated The residue was purified by Combi-Flash Companion™ (Isco Inc.) column chromatography (SiO2; gradient elution, [hexane/DCM 1:1]/TBME 95:5→3:7)

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

Procedure: An ice-chilled solution of sodium hydroxide (1.9 g) in water (25 ml) was added, during 40 minutes, to a stirred solution of 4-methyl-3-oxo-pentanoic acid ethyl ester (3 g, 18.96 mmoles) and 1,2-dichloro-1-ethoxy-ethane (3.3 g, 35.19 mmole) in diethyl ether (15 ml) with ice bath cooling. When the addition was complete the mixture was stirred rapidly for 1 hour, then the ethereal layer was separated, washed with water and dried. Evaporation of the solvent gave a yellow oil, which was purified by flash chromatography using a gradient elution from neat pentane to pentane/diethyl ether 9:1 v/v as eluent, to afford compound 82 as an oil (2.4 g). cooling When the addition the ethereal layer was separated washed with water dried Evaporation of the solvent gave a yellow oil, which was purified by flash chromatography a gradient elution from neat pentane to pentane/diethyl ether 9:1 v/v as eluent

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

Procedure: An ice-chilled solution of sodium hydroxide (1.9 g) in water (25 ml) was added, during 40 minutes, to a stirred solution of 4-methyl-3-oxo-pentanoic acid ethyl ester (3 g, 18.96 mmoles) and 1,2-dichloro-1-ethoxy-ethane (3.3 g, 35.19 mmole) in diethyl ether (15 ml) with ice bath cooling. When the addition was complete the mixture was stirred rapidly for 1 hour, then the ethereal layer was separated, washed with water and dried. Evaporation of the solvent gave a yellow oil, which was purified by flash chromatography using a gradient elution from neat pentane to pentane/diethyl ether 9:1 v/v as eluent, to afford compound 82 as an oil (2.4 g) cooling When the addition the ethereal layer was separated washed with water dried Evaporation of the solvent gave a yellow oil, which was purified by flash chromatography a gradient elution from neat pentane to pentane/diethyl ether 9:1 v/v as eluent

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

Procedure: An ice-chilled solution of sodium hydroxide (1.9 g) in water (25 ml) was added, during 40 minutes, to a stirred solution of 4-methyl-3-oxo-pentanoic acid ethyl ester (3 g, 18.96 mmoles) and 1,2-dichloro-1-ethoxy-ethane (3.3 g, 35.19 mmole) in diethyl ether (15 ml) with ice bath cooling. When the addition was complete the mixture was stirred rapidly for 1 hour, then the ethereal layer was separated, washed with water and dried. Evaporation of the solvent gave a yellow oil, which was purified by flash chromatography using a gradient elution from neat pentane to pentane/diethyl ether 9:1 v/v as eluent, to afford compound 82 as an oil (2.4 g). cooling When the addition the ethereal layer was separated washed with water dried Evaporation of the solvent gave a yellow oil, which was purified by flash chromatography a gradient elution from neat pentane to pentane/diethyl ether 9:1 v/v as eluent

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

Procedure: An ice-chilled solution of sodium hydroxide (1.9 g) in water (25 ml) was added, during 40 minutes, to a stirred solution of 4-methyl-3-oxo-pentanoic acid ethyl ester (3 g, 18.96 mmoles) and 1,2-dichloro-1-ethoxy-ethane (3.3 g, 35.19 mmole) in diethyl ether (15 ml) with ice bath cooling. When the addition was complete the mixture was stirred rapidly for 1 hour, then the ethereal layer was separated, washed with water and dried. Evaporation of the solvent gave a yellow oil, which was purified by flash chromatography using a gradient elution from neat pentane to pentane/diethyl ether 9:1 v/v as eluent, to afford compound 82 as an oil (2.4 g). cooling When the addition the ethereal layer was separated washed with water dried Evaporation of the solvent gave a yellow oil, which was purified by flash chromatography a gradient elution from neat pentane to pentane/diethyl ether 9:1 v/v as eluent

Conditions: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of N,N-diisopropyl-3-carbamoyl-3-phenylpropanamine, prepared in Example 34.2 (4.05 g, 15.4 mmol), 1,2-dichloroethyl ethyl ether (2,32 g, 16.2 mmol), water (0.300 g, 16.6 mmol) and formic acid (50 mL) was stirred at 75° C. for 3 hours. The formic acid was evaporated and the residue was dissolved in water/diethyl ether. The aqueous phase was made alkaline (11 M NaOH) and extracted twice with diethyl ether. The combined organic phases were dried (Na2SO4) and the solvent evaporated. The crude product was chromatographed on silica (petroleum ether-triethylamine 97:3). The pure amine was precipitated as hydrochloride salt with HCl-saturated diethyl ether, affording the title compound as white crystals, 0.61 g (12%): mp 157-158° C.; 1H NMR (DMSO(d6)) δ1.11 (m, 12H), 2.35 (m, 1H), 2.63 (m, 1H), 3.03 (m, 2H), 3.56 (m, 2H), 4.45 (m, 1H), 7.21-7.40 (m, 6H) 8.06 (d, 1H), 10.20 (br, 1H). The formic acid was evaporated the residue was dissolved in water/diethyl ether extracted twice with diethyl ether The combined organic phases were dried (Na2SO4) the solvent evaporated The crude product was chromatographed on silica (petroleum ether-triethylamine 97:3) The pure amine was precipitated as hydrochloride salt with HCl-saturated diethyl ether

Conditions: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a sealed tube, a mixture of 2-amino-3-chloro-5-(2,4-dichloro-phenyl)-isonicotinonitrile (285 mg, 0.96 mmol) and 1,2-dichloro-1-ethoxy-ethane (0.64 mL, 5.25 mmol) was heated at 150° C. for 17 min under microwave irradiation. The reaction mixture was cooled to RT, poured into AcOEt (75 mL) and washed with a 2.0 M Na2CO3 solution in water (2×25 mL). The organic layer was dried over Na2SO4, filtered and evaporated. The residue was purified by Combi-Flash Companion™ (Isco Inc.) column chromatography (SiO2; gradient elution, [hexane/DCM 1:1]/TBME 95:5→3:7) to yield the title compound (185 mg, 0.57 mmol, 60%) as a brownish solid. MS: 322 [M+1]+; HPLC: AtRet=2.17; TLC: RF 0.13 (hexane/DCM/TBME 1:1:2). The reaction mixture was cooled to RT washed with a 2.0 M Na2CO3 solution in water (2×25 mL) The organic layer was dried over Na2SO4 filtered evaporated The residue was purified by Combi-Flash Companion™ (Isco Inc.) column chromatography (SiO2; gradient elution, [hexane/DCM 1:1]/TBME 95:5→3:7)