| 86% |
Stage #1: 1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-2-(naphthalen-1-yl)-1-phenylbutan-2-ol With (R)-5,5',6,6',7,7',8,8'-octahydro-1,1'-binaphthyl-2,2' diyl hydrogen phosphate In methanol; N,N-dimethyl-formamide at 80℃; for 1h;
Stage #2: With potassium carbonate In water; toluene for 0.166667h;
Stage #3: (2E)-but-2-enedioic acid for 1h; Reflux; |
2-3 A. Preparation of salts of splitting agents and (1R,2S)-1-(6-Bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-butan-2-ol
The powder (2.8g; 5.04mmol) obtained in Example 1 was added to the reaction unit, and methanol (56mL) and dimethylformamide (5.6mL) were added thereto, followed by stirring. (11bR)-8,9,10,11,12,13,14,15-octahydro-4-hydroxy-4-oxide-dinaphtho[2,1-d:1',2'-f][1,3,2]dioxaphospepine After adding It heated up to 80°C and stirred for 1 hour. Thereafter, after cooling to room temperature, the mixture was cooled to 0-5° C. and stirred for 90 minutes. The solid was filtered and washed with methanol (14 mL). The washed solid was suspended in methanol (21 mL) and dimethylformamide (2.1 mL), and the temperature was raised to 80° C. and stirred for 30 minutes. The mixture was cooled to room temperature and then cooled to 0-5° C. and stirred for 90 minutes. The solid was filtered and washed with methanol (10 mL).The washed solid was dried under vacuum at 30 ° C. (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-butan-2-ol and ( 11bR)-8,9,10,11,12,13,14,15-octahydro-4-hydroxy-4-oxide-dinaphtho[2,1-d:1',2'-f][1 ,3,2] 1.96 g of a salt of dioxaphospepine was obtained. Yield: 43%, purity: 93.3%, optical purity: 99.9%.B.(1R,2S)-1-(6-Bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-butan-2-ol and from salts of splitting agentsLiberation of (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-butan-2-ol The solid obtained in step A (1.9 g; 2.08 mmol) was added to the reaction unit, and toluene (38 mL) was added thereto, followed by stirring. Potassium carbonate (0.86 g; 6.25 mmol) was dissolved in water (38 mL) and added to the reaction unit, followed by stirring for 10 minutes. The layers were separated to remove the aqueous layer, and the organic layer was washed with water (38 mL) and brine (38 mL) in that order. After dehydration and filtration over anhydrous sodium sulfate, the mixture was concentrated under reduced pressure at 55°C. Ethyl acetate (1 mL) and methanol (10 mL) were added to the concentrate, followed by stirring at 50° C. for 1 hour. After cooling to room temperature, the mixture was cooled to 0-5° C. and stirred for 90 minutes. The solid was filtered and washed with methanol (5 mL). Drying under vacuum at 30°C (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-butane 0.78 g of -2-ol was obtained. Yield: 67%, purity: 97.6%. Preparation of (1R,2S)-1-(6-Bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-butan-2-ol fumarate The solid (0.75 g; 1.35 mmol) obtained in step B of Example 2 was added to the reaction unit, and isopropyl alcohol (15 mL) was added thereto, followed by stirring. After adding fumaric acid (0.17 g; 1.43 mmol), the mixture was stirred under reflux for 1 hour. The mixture was filtered and washed with isopropyl alcohol (3.8 mL). The mixture was cooled to 0-5° C. and stirred for 2 hours. The solid was filtered and washed with isopropyl alcohol (3.8 mL). Drying under vacuum at 30°C (1R,2S)-1-(6-Bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-butan-2-ol fumarate 0.78 g was obtained. Yield: 86%, purity: 99.9%, optical purity: 100%. |
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