ethyl 2-[(3R)-piperidin-3-yl]acetate

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 290 mg (1.07 mmol) of ethyl (R)-(1-tert-butoxycarbonylpiperidin-3-yl)acetate (Example 17A) are stirred with 2 ml of dichloromethane and 2 ml of trifluoroacetic acid at RT for 1 h. The volatile components are removed on a rotary evaporator and the residue is dried under high vacuum. The resulting oil (301 mg, 99% of theory) is reacted further as it is. The volatile components are removed on a rotary evaporator the residue is dried under high vacuum The resulting oil (301 mg, 99% of theory) is reacted further as it

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a mixture of (S)-4-(2-bromo-1-(tert-butyldimethylsilyloxy)ethyl)benzonitrile (7 g, 20.57 mmol) and sodium bicarbonate (2.073 g, 24.68 mmol) in THF (100 mL) was added (R)-ethyl 2-(piperidin-3-yl)acetate (3.52 g, 20.57 mmol). The reaction was heated at reflux for 5 days and then cooled, filtered, and concentrated in vacuo. The crude product was purified on a silica gel cartridge eluting with methanol/dichloromethane gradient (0% for 5 minutes then 0-100% over 20 minutes) to afford 5.5 g of ethyl 2-((R)-1-((S)-2-(tert-butyldimethylsilyloxy)-2-(4-cyanophenyl)ethyl)piperidin-3-yl)acetate. MS (M+1)=431; HPLC RT=1.90 minutes. 1H NMR (400 MHz, CDCl3) δ ppm 7.61 (2H, d), 7.45 (2H, d), 4.76 (1H, m), 4.12 (2H, q), 2.75 (1H, m), 2.69 (1H, m), 2.52 (1H, dd), 2.33 (1H, dd), 2.18 (2H, m), 2.10 (1H, dt), 2.00 (1H, m), 1.88 (1H, tt), 1.72 (1H, m), 1.59 (2H, m), 1.25 (3H, t), 1.0 (1H, m), 0.89 (9H, s), 0.08 (3H, s), −0.07 (3H, s). The reaction was heated at reflux for 5 days cooled filtered concentrated in vacuo The crude product was purified on a silica gel cartridge eluting with methanol/dichloromethane gradient (0% for 5 minutes

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a mixture of 4-(2-bromoacetyl)benzonitrile (5.5g, 24.55 mmol) in toluene was added (R)-ethyl 2-(piperidin-3-yl)acetate (4 g, 23.36 mmol). The reaction mixture was stirred for 4 days at room temperature and then stirred from one day at 50° C. Solvents were removed in vacuo. The resulting solids were triturated with EtOAc. The solid material was filtered and washed with EtOAc. The solid material was collected and dried to yield 5 g of (R)-ethyl 2-(1-(2-(4-cyanophenyl)-2-oxoethyl)piperidin-3-yl)acetate. MS (M+1)=314. HPLC Peak RT=0.77 minutes. stirred from one day at 50° C Solvents were removed in vacuo The resulting solids were triturated with EtOAc The solid material was filtered washed with EtOAc The solid material was collected dried

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a mixture of (R)-2-(1-(tert-butoxycarbonyl)piperidin-3-yl)acetic acid (6 g, 24.66 mmol) in ethanol (20 mL) was bubbled HCl (g) for 10 minutes. The reaction mixture was stirred for 1 hr and then HCl was bubbled through the mixture for 5 minutes. After 1 hour, solvents were removed from the mixture in vacuo. The reaction mixture was diluted with ethyl acetate and washed with saturated NaHCO3. The aqueous layer was backextracted 2 times with 10% IPA/chloroform. The organic layers were combined, dried, and concentrated in vacuo to yield 4.05 g of (R)-ethyl 2-(piperidin-3-yl)acetate. MS (M+1)=172. HPLC Peak RT=0.96 minutes. was bubbled HCl (g) for 10 minutes HCl was bubbled through the mixture for 5 minutes After 1 hour solvents were removed from the mixture in vacuo The reaction mixture was diluted with ethyl acetate washed with saturated NaHCO3 dried concentrated in vacuo

反応条件: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 7-(oxiran-2-yl)-3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazole (Preparation 13A, 150 mg, 0.353 mmol) and (R)-ethyl 2-(piperidin-3-yl)acetate (90 mg, 0.526 mmol) in 2-propanol (5 mL) was stirred at 85° C. under a nitrogen atmosphere for 5 hr. The reaction mixture was concentrated and purified by silica gel column chromatography using ethyl acetate/heptane followed by 10% methanol in ethyl acetate to afford ethyl 2-((3R)-1-(2-hydroxy-2-(3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)ethyl)piperidin-3-yl)acetate (125 mg, 0.210 mmol, 59.4% yield) as a yellow solid. LC/MS M+1=596.3. The reaction mixture was concentrated purified by silica gel column chromatography

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 290 mg (1.07 mmol) of ethyl (R)-(1-tert-butoxycarbonylpiperidin-3-yl)acetate (Example 17A) are stirred with 2 ml of dichloromethane and 2 ml of trifluoroacetic acid at RT for 1 h. The volatile components are removed on a rotary evaporator and the residue is dried under high vacuum. The resulting oil (301 mg, 99% of theory) is reacted further as it is. The volatile components are removed on a rotary evaporator the residue is dried under high vacuum The resulting oil (301 mg, 99% of theory) is reacted further as it