4-[1-hydroxy-2-(methylamino)ethyl]phenol

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 N-(4-chlorobenzyl)-6-(chloromethyl)-1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide (0.09 gm) from Preparation No. 35 in dry DMF (2 mL) containing diisopropylethylamine (0.07 mL) is treated with synephrine (0.05 gm). The reaction mixture is stirred overnight. The reaction mixture is diluted with dichloromethane (50 mL) and washed with water (2×10 mL), brine (10 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue is purified by flash column chromatography eluting with 3% to 6% methanol in dichloromethane and then by recrystallization from toluene to afford 0.09 gm of the title compound as a tan solid. washed with water (2×10 mL), brine (10 mL) dried (Na2SO4) concentrated under reduced pressure The residue is purified by flash column chromatography eluting with 3% to 6% methanol in dichloromethane by recrystallization from toluene

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of N-(4-chlorobenzyl)-2-(chloromethyl)-3,4-dimethyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide (48 mg, 0.12 mmol), synephrine (Aldrich, 30 mg, 0.18 mmol) and diisopropylethylamine (31 μL, 0.18 mmol) in dry DMF (2.0 mL) was heated to 60° C., becoming a solution. The reaction was stirred for 3 hours at that temperature. After cooling to room temperature, the solution was diluted with water (5 mL). The resulting milky suspension was stirred vigorously for 30 minutes, and then left standing overnight at room temp. The mixture was filtered, and the collected solid was washed with water and dried in vacuo, leaving a white solid. Recrystallization from acetonitrile (10 mL, dissolved with warming and then cooled to 0° C. overnight) gave the title compound (49 mg) as a white solid. After cooling to room temperature The resulting milky suspension was stirred vigorously for 30 minutes left standing overnight at room temp The mixture was filtered the collected solid was washed with water dried in vacuo leaving a white solid Recrystallization from acetonitrile (10 mL dissolved with warming cooled to 0° C. overnight)

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

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

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of N-(4-chlorobenzyl)-2-(chloromethyl)-3,4-dimethyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide (48 mg, 0.12 mmol), synephrine (Aldrich, 30 mg, 0.18 mmol) and diisopropylethylamine (31 μL, 0.18 mmol) in dry DMF (2.0 mL) was heated to 60° C., becoming a solution. The reaction was stirred for 3 hours at that temperature. After cooling to room temperature, the solution was diluted with water (5 mL). The resulting milky suspension was stirred vigorously for 30 minutes, and then left standing overnight at room temp. The mixture was filtered, and the collected solid was washed with water and dried in vacuo, leaving a white solid. Recrystallization from acetonitrile (10 mL, dissolved with warming and then cooled to 0° C. overnight) gave the title compound (49 mg) as a white solid. After cooling to room temperature The resulting milky suspension was stirred vigorously for 30 minutes left standing overnight at room temp The mixture was filtered the collected solid was washed with water dried in vacuo leaving a white solid Recrystallization from acetonitrile (10 mL dissolved with warming cooled to 0° C. overnight)

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

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

Procedure: To a solution of N-(4-chlorobenzyl)-2-(hydroxymethyl)-7-methyl-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxamide (0.300 g) from Example No. 35 in DMF (17 mL) are added DMAP (16 mg), 2,4,6-collidine (0.27 mL), and methanesulfonyl chloride (0.16 mL). The reaction mixture is stirred at room temperature for 1 h and then synephrine (1.39 g) is added. The mixture is stirred at room temperature for 18 h and is then poured into water (50 mL). The resulting off-white solid is filtered off. Additional material precipitates out of the filtrate. The two lots of material are combined and purified by column chromatography (CH2Cl2, CH2Cl2/methanol, 99/1; 98/2; 96/4) to yield 0.253 g (60%) of the title compound as a white solid. The mixture is stirred at room temperature for 18 h The resulting off-white solid is filtered off Additional material precipitates out of the filtrate purified by column chromatography (CH2Cl2, CH2Cl2/methanol, 99/1; 98/2; 96/4)

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

Procedure: N,N-Diisopropylethylamine (0.14 mL) and N-(4-chlorobenzyl)-2-(chloromethyl)-7-methyl-4-oxo-4,7-dihydrofuro[2,3-b]pyridine-5-carboxamide (Example 2, 0.150 g) were added to a solution of synephrine (0.137 g) in DMF (10 mL). The reaction mixture was heated to 90° C. for 1 h. The mixture was allowed to cool to room temperature, poured into water (25 mL), and extracted with CH2Cl2 (4×25 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated in vacuo. The resulting oil was purified by column chromatography (CH2Cl2/methanol; 98/2, 97/3) followed by recrystallization from ethyl acetate/methanol to yield 0.120 g of the title compound as a white solid. Physical characteristics. M.p. 117-122° C.; 1H NMR (400 MHz, DMSO-d6) δ 10.65, 9.21, 8.54, 7.41-7.33, 7.09, 6.85, 6.65, 4.88, 4.614.57, 4.55, 3.89, 3.71, 2.58-2.45, 2.30; 13C NMR (100 MHz, CDCl3) δ 173.7, 164.8, 156.1, 153.2, 150.9, 141.2, 137.1, 132.9, 132.8, 128.9, 128.7, 127.4, 116.6, 115.3, 114.8, 106.6, 69.5, 64.0, 54.0, 42.6, 42.2, 37.8; MS (ESI+) m/z 496 (M+H)+ to cool to room temperature extracted with CH2Cl2 (4×25 mL) The combined organic layers were dried (MgSO4) filtered concentrated in vacuo The resulting oil was purified by column chromatography (CH2Cl2/methanol; 98/2, 97/3) followed by recrystallization from ethyl acetate/methanol