1,2,3,4-Tetrahydroisoquinoline-3-methanol

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

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

Procedure: 34 N Sulphuric acid (d=1.83; 36.8 cc) is added, over a period of a few minutes, to a suspension of (RS)-3-hydroxymethyl-1,2,3,4-tetrahydroisoquinoline (106 g) in water (226 cc). The temperature rises to 60° C. and the solid goes into solution. The mixture is heated at 100°-110° C. whilst water is distilled off, and then at 160° C. whilst concentrating under reduced pressure (20 mm Hg). The concentration process is concluded under a pressure of 1mm Hg. The residue crystallises on cooling. Crude (RS)-3-hydroxysulphonyloxymethyl-1,2,3,4-tetrahydroisoquinoline (151 g) is thus obtained in the form of pale yellow crystals. rises to 60° C. is distilled off at 160° C. whilst concentrating under reduced pressure (20 mm Hg) The residue crystallises on cooling

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

Procedure: 34 N Sulphuric acid (d=1.83; 36.8 cc) is added, over a period of a few minutes, to a suspension of (RS)-3-hydroxymethyl-1,2,3,4-tetrahydroisoquinoline (106 g) in water (226 cc). The temperature rises to 60° C. and the solid goes into solution. The mixture is heated at 100°-110° C. whilst water is distilled off, and then at 160° C. whilst concentrating under reduced pressure (20 mm Hg). The concentration process is concluded under a pressure of 1mm Hg. The residue crystallises on cooling. Crude (RS)-3-hydroxysulphonyloxymethyl-1,2,3,4-tetrahydroisoquinoline (151 g) is thus obtained in the form of pale yellow crystals. rises to 60° C. is distilled off at 160° C. whilst concentrating under reduced pressure (20 mm Hg) The residue crystallises on cooling

Conditions: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a sealed tube, a mixture of 1.80 g of 1,2,3,4-tetrahydro-3-isoquinolinemethanol, 1.69 g of 90% formic acid and 1.04 g of 35% formalin was heated at 140° C. for 16 hours. The reaction solution was cooled and then made alkaline by addition of 10% aqueous sodium solution. Subsequently, potassium carbonate was added to the solution and a precipitated oil was extracted with chloroform. The extract was dried over anhydrous sodium sulfate and placed under reduced pressure to remove the solvent. There was obtained 1.95 g of 2-methyl-1,2,3,4-tetrahydro-3-isoquinolinemethanol. The reaction solution was cooled a precipitated oil was extracted with chloroform The extract was dried over anhydrous sodium sulfate to remove the solvent

Conditions: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a sealed tube, a mixture of 1.80 g of 1,2,3,4-tetrahydro-3-isoquinolinemethanol, 1.69 g of 90% formic acid and 1.04 g of 35% formalin was heated at 140° C. for 16 hours. The reaction solution was cooled and then made alkaline by addition of 10% aqueous sodium solution. Subsequently, potassium carbonate was added to the solution and a precipitated oil was extracted with chloroform. The extract was dried over anhydrous sodium sulfate and placed under reduced pressure to remove the solvent. There was obtained 1.95 g of 2-methyl-1,2,3,4-tetrahydro-3-isoquinolinemethanol. The reaction solution was cooled a precipitated oil was extracted with chloroform The extract was dried over anhydrous sodium sulfate to remove the solvent

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 272 mg (1.0 mmol) of 3,5-diethyl-1-(2,4,6-trimethylphenyl)pyrazole-4-methanol in 5 mL of methylene chloride cooled to 0° C. under dry nitrogen in a 25 mL 3-neck flask, was added to 0.2 mL (2.5 mmol) of triethylamine and 0.092 mL (2.0 mmol) of methanesulfonyl chloride. This mixture was stirred for 15 minutes at 0° C. and then 0.648 g (4.0 mmol) of (+)-3-hydroxymethyl-1,2,3,4-tetrahydroisoquinoline in 1 mL of 50:50 dimethylformamide acetonitrile was added. The reaction mixture was heated at reflux overnight whereupon no starting material was seen by TLC. The cooled reaction mixture was diluted with water and the product was extracted with ethyl acetate. After drying (brine wash, magnesium sulfate) and evaporation, the crude product was chromatographed on silica gel, eluting with 10:1 and 5:1 hexane/ethyl acetate to give 184 mg (44%) of the desired product. 1H-NMR (CDCl3):0.80 (3H, t, J=7), 1.18 (3H, t, J=7), 1.92 (6H, s), 2.21 (2H, q, J=7), 2.28 (3H, s), 2.55 (2H, q, J=7), 2.97 (2H, d of d, J=7), 3.25 (1H, m), 3.50-3.66 (5H, m), 3.80 (2H, d, J=12), 6.82-7.16 (6H, m). The reaction mixture was heated at reflux overnight whereupon no starting material The cooled reaction mixture the product was extracted with ethyl acetate After drying (brine wash, magnesium sulfate) and evaporation the crude product was chromatographed on silica gel eluting with 10:1 and 5:1 hexane/ethyl acetate

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 272 mg (1.0 mmol) of 3,5-diethyl-1-(2,4,6-trimethylphenyl)pyrazole-4-methanol in 5 mL of methylene chloride cooled to 0° C. under dry nitrogen in a 25 mL 3-neck flask, was added to 0.2 mL (2.5 mmol) of triethylamine and 0.092 mL (2.0 mmol) of methanesulfonyl chloride. This mixture was stirred for 15 minutes at 0° C. and then 0.648 g (4.0 mmol) of (+)-3-hydroxymethyl-1,2,3,4-tetrahydroisoquinoline in 1 mL of 50:50 dimethylformamide acetonitrile was added. The reaction mixture was heated at reflux overnight whereupon no starting material was seen by TLC. The cooled reaction mixture was diluted with water and the product was extracted with ethyl acetate. After drying (brine wash, magnesium sulfate) and evaporation, the crude product was chromatographed on silica gel, eluting with 10:1 and 5:1 hexane/ethyl acetate to give 184 mg (44%) of the desired product. 1H-NMR (CDCl3):0.80 (3H, t, J=7), 1.18 (3H, t, J=7), 1.92 (6H, s), 2.21 (2H, q, J=7), 2.28 (3H, s), 2.55 (2H, q, J=7), 2.97 (2H, d of d, J=7), 3.25 (1H, m), 3.50-3.66 (5H, m), 3.80 (2H, d, J=12), 6.82-7.16 (6H, m). The reaction mixture was heated at reflux overnight whereupon no starting material The cooled reaction mixture the product was extracted with ethyl acetate After drying (brine wash, magnesium sulfate) and evaporation the crude product was chromatographed on silica gel eluting with 10:1 and 5:1 hexane/ethyl acetate

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

Procedure: 34 N Sulphuric acid (d=1.83; 36.8 cc) is added, over a period of a few minutes, to a suspension of (RS)-3-hydroxymethyl-1,2,3,4-tetrahydroisoquinoline (106 g) in water (226 cc). The temperature rises to 60° C. and the solid goes into solution. The mixture is heated at 100°-110° C. whilst water is distilled off, and then at 160° C. whilst concentrating under reduced pressure (20 mm Hg). The concentration process is concluded under a pressure of 1mm Hg. The residue crystallises on cooling. Crude (RS)-3-hydroxysulphonyloxymethyl-1,2,3,4-tetrahydroisoquinoline (151 g) is thus obtained in the form of pale yellow crystals. rises to 60° C. is distilled off at 160° C. whilst concentrating under reduced pressure (20 mm Hg) The residue crystallises on cooling

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

Conditions: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a sealed tube, a mixture of 1.80 g of 1,2,3,4-tetrahydro-3-isoquinolinemethanol, 1.69 g of 90% formic acid and 1.04 g of 35% formalin was heated at 140° C. for 16 hours. The reaction solution was cooled and then made alkaline by addition of 10% aqueous sodium solution. Subsequently, potassium carbonate was added to the solution and a precipitated oil was extracted with chloroform. The extract was dried over anhydrous sodium sulfate and placed under reduced pressure to remove the solvent. There was obtained 1.95 g of 2-methyl-1,2,3,4-tetrahydro-3-isoquinolinemethanol. The reaction solution was cooled a precipitated oil was extracted with chloroform The extract was dried over anhydrous sodium sulfate to remove the solvent

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

Procedure: To a solution of 500 mg (3.06 mmol) of (+)-3-hydroxymethyl-1,2,3,4-tetrahydroisoquinoline in 10 mL of DMSO was added 122 mg (3.06 mmol) of NaH (60% in oil) and the mixture was stirred for 45 minutes at room temperature. Then 0.403 mL (3.06 mmol) of diethylsulfate was added via syringe. Foaming occurred and subsided in approximately 15 minutes. The reaction mixture was then stirred at room temperature overnight and poured into water. The product was extracted into ethyl acetate and dried and evaporated to an oil. This was chromatographed on silica gel to give the desired product as an oil, 190 mg. 1H-NMR (CDCl3) δ 1.22 (3H, t, J=7), 2.29 (1H, broad s), 2.55-2.70 (2H, m), 3.09-3.18 (1H, m), 3.41 (1H, t, J=7), 3.50-3.59 (3H, m), 4.06 (2H, ABq, J=5, 21), 7.00-7.13 (4H, m). subsided in approximately 15 minutes The reaction mixture was then stirred at room temperature overnight The product was extracted into ethyl acetate dried evaporated to an oil This was chromatographed on silica gel

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To an ice bath-chilled solution of [1-(4-bromo-2,6-dimethylphenyl)-3,5-diethyl-1H-pyrazol-4-yl-methanol (770 mg, 2.3 mmol) and triethylamine (0.382 ml, 2.7 mmol) in methylene chloride (10 ml) methane sulfonyl chloride (0.1 94 ml, 2.5 mmol) was added dropwise. After stirring the reaction at 0-5° C. for 30 minutes, (+)-3-hydroxymethyl-1,2,3,4-tetrahydroisoquinoline (1.49 g, 9.1 mmol) and anhydrous N,N-dimethylformamide (2.2 ml) were added, and the resulting reaction mixture was heated (50° C. oil bath) for 21 hours. The solvent was removed in vacuo, and the residue was extracted with ethyl acetate/water (10 ml of each). The aqueous phase was then extracted twice with equal-volume portions of fresh ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to afford a yellow oil (1.5 g). Flash chromatography (silica gel, 40 micron mesh; elution with ethyl acetate/hexane=1:5 in volume) afforded the title compound (0.45 g) as a light yellow oil. the reaction at 0-5° C. for 30 minutes the resulting reaction mixture The solvent was removed in vacuo the residue was extracted with ethyl acetate/water (10 ml of each) The aqueous phase was then extracted twice with equal-volume portions of fresh ethyl acetate The combined organic layers were dried over anhydrous sodium sulfate concentrated in vacuo