1-(3,4-dihydro-1H-isochromen-1-yl)propan-2-one

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

Procedure: A mixture of (-)-(isochroman-1-yl)acetone (LXXXIV, 0.73 g), ammonium acetate (1.48 g), methanol (2.5 ml), and THF (2.5 ml) is stirred for 25 min and then acetic acid (1.5 ml) and sodium cyanoborohydride (0.48 g) are added. After stirring for 2 hr, the mixture is concentrated and the residue is stirred with dichloromethane and sodium hydroxide (4N). The mixture is extracted with dichloromethane and washed with saline/sodium hydroxide (1N). The organic phase is separated and dried over sodium sulfate to give 2-[(-)-isochroman-1-yl]-(±)-1-methylethylamine. After stirring for 2 hr the mixture is concentrated the residue is stirred with dichloromethane and sodium hydroxide (4N) The mixture is extracted with dichloromethane washed with saline/sodium hydroxide (1N) The organic phase is separated dried over sodium sulfate

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

Procedure: An oily product was obtained in the same manner as in Example 1, using (isochroman-1-yl)acetone and 2-amino-1-(4-hydroxyphenyl)-1-propanol [J. Med. Chem., 14, 148 (1971)]. The product was dissolved in anhydrous methanol, and concentrated hydrochloric acid was added thereto. The solvent was evaporated off to give a hydrochloride. The hydrochloride was then washed with ether to give Compound 24 as crystals in a yield of 72%. An oily product was obtained in the same manner as in Example 1 The solvent was evaporated off

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

Procedure: An oily product was obtained in the same manner as in Example 1, using (isochroman-1-yl)acetone and 2-amino-1-(4-hydroxyphenyl)-1-propanol [J. Med. Chem., 14, 148 (1971)]. The product was dissolved in anhydrous methanol, and concentrated hydrochloric acid was added thereto. The solvent was evaporated off to give a hydrochloride. The hydrochloride was then washed with ether to give Compound 24 as crystals in a yield of 72%. An oily product was obtained in the same manner as in Example 1 The solvent was evaporated off

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

Procedure: In 15 ml of anhydrous methanol were dissolved 2.93 g (15.5 mmol) of (isochroman-1-yl)acetone [Chem. Pharm. Bull., 36, 1758 (1988)] and 1.57 g (10.3 mmol) of 2-amino-1-(4-hydroxyphenyl)ethanol [U.S. Pat. No. 2,585,988 (1952)], and the resulting solution was stirred for 3 hours at room temperature. Methanol was evaporated, and anhydrous benzene was added to the mixture, and water formed was removed off by azeotropic distillation. To the resulting mixture was added 15 ml of anhydrous methanol. Subsequently, 567 mg (15 mmol) of sodium borohydride was gradually added under ice cooling, and the resulting mixture was stirred for 3 hours at room temperature. The methanol was evaporated off, and then 10% sulfuric acid aqueous solution was added to the residue, and the mixture was washed with ether. The resulting mixture was rendered basic with the addition of saturated aqueous potassium hydrogencarbonate and then extracted with ethyl acetate. The ethyl acetate layer was washed with water and then dried over anhydrous magnesium sulfate. The solvent was evaporated off, and the residue was subjected to silica gel column chromatography (ethyl acetate :triethylamine=20:1) to give 2.8 g (83%) of crystals of Compound 1. Methanol was evaporated anhydrous benzene was added to the mixture, and water formed was removed off by azeotropic distillation To the resulting mixture was added 15 ml of anhydrous methanol the resulting mixture was stirred for 3 hours at room temperature The methanol was evaporated off 10% sulfuric acid aqueous solution was added to the residue the mixture was washed with ether The resulting mixture was rendered basic with the addition of saturated aqueous potassium hydrogencarbonate extracted with ethyl acetate The ethyl acetate layer was washed with water dried over anhydrous magnesium sulfate The solvent was evaporated off

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

Procedure: A mixture of (-)-(isochroman-1-yl)acetone (LXXXIV, 0.73 g), ammonium acetate (1.48 g), methanol (2.5 ml), and THF (2.5 ml) is stirred for 25 min and then acetic acid (1.5 ml) and sodium cyanoborohydride (0.48 g) are added. After stirring for 2 hr, the mixture is concentrated and the residue is stirred with dichloromethane and sodium hydroxide (4N). The mixture is extracted with dichloromethane and washed with saline/sodium hydroxide (1N). The organic phase is separated and dried over sodium sulfate to give 2-[(-)-isochroman-1-yl]-(±)-1-methylethylamine. After stirring for 2 hr the mixture is concentrated the residue is stirred with dichloromethane and sodium hydroxide (4N) The mixture is extracted with dichloromethane washed with saline/sodium hydroxide (1N) The organic phase is separated dried over sodium sulfate

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

Procedure: A mixture of (-)-(isochroman-1-yl)acetone (LXXXIV, 0.73 g), ammonium acetate (1.48 g), methanol (2.5 ml), and THF (2.5 ml) is stirred for 25 min and then acetic acid (1.5 ml) and sodium cyanoborohydride (0.48 g) are added. After stirring for 2 hr, the mixture is concentrated and the residue is stirred with dichloromethane and sodium hydroxide (4N). The mixture is extracted with dichloromethane and washed with saline/sodium hydroxide (1N). The organic phase is separated and dried over sodium sulfate to give 2-[(-)-isochroman-1-yl]-(±)-1-methylethylamine. After stirring for 2 hr the mixture is concentrated the residue is stirred with dichloromethane and sodium hydroxide (4N) The mixture is extracted with dichloromethane washed with saline/sodium hydroxide (1N) The organic phase is separated dried over sodium sulfate

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

Procedure: A mixture of (-)-(isochroman-1-yl)acetone (LXXXIV, 0.73 g), ammonium acetate (1.48 g), methanol (2.5 ml), and THF (2.5 ml) is stirred for 25 min and then acetic acid (1.5 ml) and sodium cyanoborohydride (0.48 g) are added. After stirring for 2 hr, the mixture is concentrated and the residue is stirred with dichloromethane and sodium hydroxide (4N). The mixture is extracted with dichloromethane and washed with saline/sodium hydroxide (1N). The organic phase is separated and dried over sodium sulfate to give 2-[(-)-isochroman-1-yl]-(±)-1-methylethylamine. After stirring for 2 hr the mixture is concentrated the residue is stirred with dichloromethane and sodium hydroxide (4N) The mixture is extracted with dichloromethane washed with saline/sodium hydroxide (1N) The organic phase is separated dried over sodium sulfate

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

Procedure: An oily product was obtained in the same manner as in Example 1, using (isochroman-1-yl)acetone and 2-amino-1-(4-hydroxyphenyl)-1-propanol [J. Med. Chem., 14, 148 (1971)]. The product was dissolved in anhydrous methanol, and concentrated hydrochloric acid was added thereto. The solvent was evaporated off to give a hydrochloride. The hydrochloride was then washed with ether to give Compound 24 as crystals in a yield of 72%. An oily product was obtained in the same manner as in Example 1 The solvent was evaporated off

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

Procedure: In 15 ml of anhydrous methanol were dissolved 2.93 g (15.5 mmol) of (isochroman-1-yl)acetone [Chem. Pharm. Bull., 36, 1758 (1988)] and 1.57 g (10.3 mmol) of 2-amino-1-(4-hydroxyphenyl)ethanol [U.S. Pat. No. 2,585,988 (1952)], and the resulting solution was stirred for 3 hours at room temperature. Methanol was evaporated, and anhydrous benzene was added to the mixture, and water formed was removed off by azeotropic distillation. To the resulting mixture was added 15 ml of anhydrous methanol. Subsequently, 567 mg (15 mmol) of sodium borohydride was gradually added under ice cooling, and the resulting mixture was stirred for 3 hours at room temperature. The methanol was evaporated off, and then 10% sulfuric acid aqueous solution was added to the residue, and the mixture was washed with ether. The resulting mixture was rendered basic with the addition of saturated aqueous potassium hydrogencarbonate and then extracted with ethyl acetate. The ethyl acetate layer was washed with water and then dried over anhydrous magnesium sulfate. The solvent was evaporated off, and the residue was subjected to silica gel column chromatography (ethyl acetate :triethylamine=20:1) to give 2.8 g (83%) of crystals of Compound 1. Methanol was evaporated anhydrous benzene was added to the mixture, and water formed was removed off by azeotropic distillation To the resulting mixture was added 15 ml of anhydrous methanol the resulting mixture was stirred for 3 hours at room temperature The methanol was evaporated off 10% sulfuric acid aqueous solution was added to the residue the mixture was washed with ether The resulting mixture was rendered basic with the addition of saturated aqueous potassium hydrogencarbonate extracted with ethyl acetate The ethyl acetate layer was washed with water dried over anhydrous magnesium sulfate The solvent was evaporated off

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

Procedure: A mixture of (-)-(isochroman-1-yl)acetone (LXXXIV, 0.73 g), ammonium acetate (1.48 g), methanol (2.5 ml), and THF (2.5 ml) is stirred for 25 min and then acetic acid (1.5 ml) and sodium cyanoborohydride (0.48 g) are added. After stirring for 2 hr, the mixture is concentrated and the residue is stirred with dichloromethane and sodium hydroxide (4N). The mixture is extracted with dichloromethane and washed with saline/sodium hydroxide (1N). The organic phase is separated and dried over sodium sulfate to give 2-[(-)-isochroman-1-yl]-(±)-1-methylethylamine. After stirring for 2 hr the mixture is concentrated the residue is stirred with dichloromethane and sodium hydroxide (4N) The mixture is extracted with dichloromethane washed with saline/sodium hydroxide (1N) The organic phase is separated dried over sodium sulfate