tert-butyl (3S)-3-(hydroxymethyl)-3,4-dihydro-1H-isoquinoline-2-carboxylate

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of oxalyl chloride (0.798 mL, 9.15 mmol) in CH2Cl2 (11 mL) at −78° C. is added DMSO (1.08 mL, 15.25 mmol) dropwise (evolution of gas observed) and the mixture stirred at −78° C. for 1.5 h. To this is added a solution of (S)-3-hydroxymethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (0.803 g, 3.05 mmol) in CH2Cl2 (9 mL) and the mixture is stirred at −78° C. for 1.5 h. Triethylamine (3.4 mL, 24.41 mmol) is added and the mixture is stirred for 10 min at −78° C. and then warmed to room temperature for 1.5 h. The mixture is extracted with EtOAc (2×30 mL), washed with 1N HCl (1×35 mL) and extracted again with EtOAc (1×30 mL). The combined organic layers are washed with 1N HCl (2×30 mL) and brine (2×30 mL), dried over Na2SO4 and concentrated to afford the title compound. the mixture is stirred at −78° C. for 1.5 h the mixture is stirred for 10 min at −78° C. warmed to room temperature for 1.5 h The mixture is extracted with EtOAc (2×30 mL) washed with 1N HCl (1×35 mL) extracted again with EtOAc (1×30 mL) The combined organic layers are washed with 1N HCl (2×30 mL) and brine (2×30 mL) dried over Na2SO4 concentrated

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of oxalyl chloride (0.798 mL, 9.15 mmol) in CH2Cl2 (11 mL) at −78° C. is added DMSO (1.08 mL, 15.25 mmol) dropwise (evolution of gas observed) and the mixture stirred at −78° C. for 1.5 h. To this is added a solution of (S)-3-hydroxymethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (0.803 g, 3.05 mmol) in CH2Cl2 (9 mL) and the mixture is stirred at −78° C. for 1.5 h. Triethylamine (3.4 mL, 24.41 mmol) is added and the mixture is stirred for 10 min at −78° C. and then warmed to room temperature for 1.5 h. The mixture is extracted with EtOAc (2×30 mL), washed with 1N HCl (1×35 mL) and extracted again with EtOAc (1×30 mL). The combined organic layers are washed with 1N HCl (2×30 mL) and brine (2×30 mL), dried over Na2SO4 and concentrated to afford the title compound. the mixture is stirred at −78° C. for 1.5 h the mixture is stirred for 10 min at −78° C. warmed to room temperature for 1.5 h The mixture is extracted with EtOAc (2×30 mL) washed with 1N HCl (1×35 mL) extracted again with EtOAc (1×30 mL) The combined organic layers are washed with 1N HCl (2×30 mL) and brine (2×30 mL) dried over Na2SO4 concentrated

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

Procedure: A solution of (S)-3,4-dihydro-1H-isoquinoline-2,3-dicarboxylic acid 2-tert-butyl ester (1.0 g, 3.61 mmol) in THF (20 mL) is stirred at RT for 10 min. HATU (1.51 g, 3.97 mmol) is added and the suspension is allowed to stir at RT for 30 min. To the solution is added iPr2NEt (1.57 mL, 9.02 mmol) and the mixture is allowed to stir at RT for 18 h. NaBH4 is added (0.164 g, 4.33 mmol) then the mixture is quenched with MeOH (1 mL), extracted with EtOAc (2×30 mL), washed with 1N HCl (4×50 mL), saturated NaHCO3 (2×50 mL) and brine (2×50 mL). The organic layer is dried over Na2SO4 and concentrated. The residue is purified by column chromatography, eluting with a gradient of 20-50% EtOAc/hexane as eluent to afford the title compound. to stir at RT for 18 h the mixture is quenched with MeOH (1 mL) extracted with EtOAc (2×30 mL) washed with 1N HCl (4×50 mL), saturated NaHCO3 (2×50 mL) and brine (2×50 mL) The organic layer is dried over Na2SO4 concentrated The residue is purified by column chromatography eluting with a gradient of 20-50% EtOAc/hexane as eluent

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

Procedure: To 50 mL dichloromethane solution containing (S)-3-hydroxymethy-1,2,3,4-tetrahydroisoquinoline (4.53 g, 27.75 mmol) was added di-tert-butyl dicarbonate (5.45 g, 25.0 mmol, 0.9 eq) and the reaction mixture was stirred for 2 hours until no gas bubbling was observed. The reaction mixture was washed with 0.5 N HCl (50 mL) followed by brine (50 mL) to remove the residual starting material. After drying wth MgSO4 and filtration the, dichloromethane mixture was evaporated to yield crude (S)-N-tert-Butyloxycarbonyl-3-hydroxymethyl-1,2,3,4-tetrahydroisoquinoline. The crude N-tert-Butyloxycarbonyl-3-hydroxymethyl-1,2,3,4-tetrahydroisoquinoline was redissolved in 100 mL tetrahydrofuran. NaH (60%, 1.22 g) was added portion by portion to the solution at 0° C. and after 30 min stirring at room temperature, MeNCS (2.23 g) was added and the mixture was stirred for 2 h at rt. Brine (50 mL) was added to the mixture to quench the reaction and after evaporation of volatile component in vacuo, it was extracted with dichloromethane (50 mL×2) and combined layer was dried (MgSO4), filtered, evaporated. The resulting material was chromatographed with hexane-EtOAc (4:1) mixture over SiO2 to provide 7.07 g (81.8%) of (S)-N-tert-butyloxycarbonyl-3-(-Methyl-thiocarbamoyloxymethyl)-1,2,3,4tetrahydroisoquinoline. This material was dissolved in THF(30 mL) and 10 mL conc. HCl was added to the solution. One hour later, 5 mL of conc. HCl was added and stirred another 1 h until the reaction was finished. The reaction mixture was diluted with 30 mL of water and volatile components were evaporated. During the evaporation, desired product was precipitated as white solid. The solid was filtered and dried to yield the product as the hydrochloride salt (4.8 g). the mixture was stirred for 2 h at rt to quench the reaction after evaporation of volatile component in vacuo, it was extracted with dichloromethane (50 mL×2) was dried (MgSO4) filtered evaporated The resulting material was chromatographed with hexane-EtOAc (4:1) mixture over SiO2

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

Procedure: To 50 mL dichloromethane solution containing (S)-3-hydroxymethy-1,2,3,4-tetrahydroisoquinoline (4.53 g, 27.75 mmol) was added di-tert-butyl dicarbonate (5.45 g, 25.0 mmol, 0.9 eq) and the reaction mixture was stirred for 2 hours until no gas bubbling was observed. The reaction mixture was washed with 0.5 N HCl (50 mL) followed by brine (50 mL) to remove the residual starting material. After drying wth MgSO4 and filtration the, dichloromethane mixture was evaporated to yield crude (S)-N-tert-Butyloxycarbonyl-3-hydroxymethyl-1,2,3,4-tetrahydroisoquinoline. The crude N-tert-Butyloxycarbonyl-3-hydroxymethyl-1,2,3,4-tetrahydroisoquinoline was redissolved in 100 mL tetrahydrofuran. NaH (60%, 1.22 g) was added portion by portion to the solution at 0° C. and after 30 min stirring at room temperature, MeNCS (2.23 g) was added and the mixture was stirred for 2 h at rt. Brine (50 mL) was added to the mixture to quench the reaction and after evaporation of volatile component in vacuo, it was extracted with dichloromethane (50 mL×2) and combined layer was dried (MgSO4), filtered, evaporated. The resulting material was chromatographed with hexane-EtOAc (4:1) mixture over SiO2 to provide 7.07 g (81.8%) of (S)-N-tert-butyloxycarbonyl-3-(-Methyl-thiocarbamoyloxymethyl)-1,2,3,4tetrahydroisoquinoline. This material was dissolved in THF(30 mL) and 10 mL conc. HCl was added to the solution. One hour later, 5 mL of conc. HCl was added and stirred another 1 h until the reaction was finished. The reaction mixture was diluted with 30 mL of water and volatile components were evaporated. During the evaporation, desired product was precipitated as white solid. The solid was filtered and dried to yield the product as the hydrochloride salt (4.8 g). the mixture was stirred for 2 h at rt to quench the reaction after evaporation of volatile component in vacuo, it was extracted with dichloromethane (50 mL×2) was dried (MgSO4) filtered evaporated The resulting material was chromatographed with hexane-EtOAc (4:1) mixture over SiO2

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of oxalyl chloride (0.798 mL, 9.15 mmol) in CH2Cl2 (11 mL) at −78° C. is added DMSO (1.08 mL, 15.25 mmol) dropwise (evolution of gas observed) and the mixture stirred at −78° C. for 1.5 h. To this is added a solution of (S)-3-hydroxymethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (0.803 g, 3.05 mmol) in CH2Cl2 (9 mL) and the mixture is stirred at −78° C. for 1.5 h. Triethylamine (3.4 mL, 24.41 mmol) is added and the mixture is stirred for 10 min at −78° C. and then warmed to room temperature for 1.5 h. The mixture is extracted with EtOAc (2×30 mL), washed with 1N HCl (1×35 mL) and extracted again with EtOAc (1×30 mL). The combined organic layers are washed with 1N HCl (2×30 mL) and brine (2×30 mL), dried over Na2SO4 and concentrated to afford the title compound. the mixture is stirred at −78° C. for 1.5 h the mixture is stirred for 10 min at −78° C. warmed to room temperature for 1.5 h The mixture is extracted with EtOAc (2×30 mL) washed with 1N HCl (1×35 mL) extracted again with EtOAc (1×30 mL) The combined organic layers are washed with 1N HCl (2×30 mL) and brine (2×30 mL) dried over Na2SO4 concentrated

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

Procedure: A solution of (S)-3,4-dihydro-1H-isoquinoline-2,3-dicarboxylic acid 2-tert-butyl ester (1.0 g, 3.61 mmol) in THF (20 mL) is stirred at RT for 10 min. HATU (1.51 g, 3.97 mmol) is added and the suspension is allowed to stir at RT for 30 min. To the solution is added iPr2NEt (1.57 mL, 9.02 mmol) and the mixture is allowed to stir at RT for 18 h. NaBH4 is added (0.164 g, 4.33 mmol) then the mixture is quenched with MeOH (1 mL), extracted with EtOAc (2×30 mL), washed with 1N HCl (4×50 mL), saturated NaHCO3 (2×50 mL) and brine (2×50 mL). The organic layer is dried over Na2SO4 and concentrated. The residue is purified by column chromatography, eluting with a gradient of 20-50% EtOAc/hexane as eluent to afford the title compound. to stir at RT for 18 h the mixture is quenched with MeOH (1 mL) extracted with EtOAc (2×30 mL) washed with 1N HCl (4×50 mL), saturated NaHCO3 (2×50 mL) and brine (2×50 mL) The organic layer is dried over Na2SO4 concentrated The residue is purified by column chromatography eluting with a gradient of 20-50% EtOAc/hexane as eluent

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

Procedure: To 50 mL dichloromethane solution containing (S)-3-hydroxymethy-1,2,3,4-tetrahydroisoquinoline (4.53 g, 27.75 mmol) was added di-tert-butyl dicarbonate (5.45 g, 25.0 mmol, 0.9 eq) and the reaction mixture was stirred for 2 hours until no gas bubbling was observed. The reaction mixture was washed with 0.5 N HCl (50 mL) followed by brine (50 mL) to remove the residual starting material. After drying wth MgSO4 and filtration the, dichloromethane mixture was evaporated to yield crude (S)-N-tert-Butyloxycarbonyl-3-hydroxymethyl-1,2,3,4-tetrahydroisoquinoline. The crude N-tert-Butyloxycarbonyl-3-hydroxymethyl-1,2,3,4-tetrahydroisoquinoline was redissolved in 100 mL tetrahydrofuran. NaH (60%, 1.22 g) was added portion by portion to the solution at 0° C. and after 30 min stirring at room temperature, MeNCS (2.23 g) was added and the mixture was stirred for 2 h at rt. Brine (50 mL) was added to the mixture to quench the reaction and after evaporation of volatile component in vacuo, it was extracted with dichloromethane (50 mL×2) and combined layer was dried (MgSO4), filtered, evaporated. The resulting material was chromatographed with hexane-EtOAc (4:1) mixture over SiO2 to provide 7.07 g (81.8%) of (S)-N-tert-butyloxycarbonyl-3-(-Methyl-thiocarbamoyloxymethyl)-1,2,3,4tetrahydroisoquinoline. This material was dissolved in THF(30 mL) and 10 mL conc. HCl was added to the solution. One hour later, 5 mL of conc. HCl was added and stirred another 1 h until the reaction was finished. The reaction mixture was diluted with 30 mL of water and volatile components were evaporated. During the evaporation, desired product was precipitated as white solid. The solid was filtered and dried to yield the product as the hydrochloride salt (4.8 g). the mixture was stirred for 2 h at rt to quench the reaction after evaporation of volatile component in vacuo, it was extracted with dichloromethane (50 mL×2) was dried (MgSO4) filtered evaporated The resulting material was chromatographed with hexane-EtOAc (4:1) mixture over SiO2