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With tetrabutyl ammonium fluoride; In tetrahydrofuran; at 20℃; for 12h;Inert atmosphere;
Step 1: To a solution of N-Boc-3-pyrrolidone (2.8 g, 15 mmol) in tetrahydrofuran (30 mL), (trifluoromethyl)trimethylsilane (2.6 mL)Tetrabutylammonium fluoride (528 mg, 1.7 mmol). The system was stirred to room temperature under nitrogen for 12 hours. Aqueous saturated ammonium chloride (24 mL) was added and stirred for 15 min. The organic phases were combined and washed with brine.Dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure.The residue was flash chromatographed (petroleum ether / ethyl acetate = 4/1)Purification afforded Nu-Boc-3-hydroxy-3-(trifluoromethyl)pyrrolidine (3.1 g, yield: 82%) as a white solid.
tert-Butyl 3-oxopyrrolidine-1-carboxylate (926 mg, 5.0 mmol) was dissolved in THF (10 mL) and the solution was cooled to 0C, trimethyl (trifluoromethyl) silane (0.872 mL) and tetrabutylammonium fluoride (TBAF) (176 mg, 0.557 mmol) were added. The ice-bath was removed and the reaction mixture was stirred at room temperature overnight. Saturated aqueous NH4CI solution (8 mL) was added and stirring was continued. After 15 min TBAF (2.36 g TBAF in 7.5 mL THF) was added and the reaction mixture was stirred at room temperature for 1h. The reaction mixture was extracted with ethyl acetate, washed with H2O, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel flash chromatography (0-40% ethyl acetate in petroleum spirit) to give the subtitled compound (800 mg). 1H-NMR (CDCl3, 400 MHz): delta 3.78-3.38 (m, 4H); 2.25 (m, 1H) ; 2.00 (m, 1H) ; 1.40 (s, 9H).
With tetrabutyl ammonium fluoride; ammonium chloride; In tetrahydrofuran; at 20℃; for 1.5h;
A) Production of 3-(trifluoromethyl)pyrrolidin-3-ol A mixture of tert-butyl 3-oxopyrrolidine-1-carboxylate (600 mg), trimethyl(trifluoromethyl)silane (0.57 mL), 1M N,N,N-tributylbutane-1-aminium fluoride/tetrahydrofuran solution (0.50 mL) and tetrahydrofuran (6 mL) was stirred at room temperature for 30 min. Saturated aqueous ammonium chloride solution (2 mL) and 1M N,N,N-tributylbutane-1-aminium fluoride/tetrahydrofuran solution (1 mL) were added, and the reaction mixture was stirred at room temperature for 1 hr. The mixture was extracted with ethyl acetate, washed successively with water and brine, and dried over anhydrous sodium sulfate. Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give a pale-brown solid. The obtained solid was dissolved in methanol (1 mL), and 4M hydrochloric acid/ethyl acetate solution (2 mL) was added at room temperature. The reaction mixture was stirred at room temperature for 4 hr, and the reaction system was concentrated under reduced pressure. Saturated aqueous sodium hydrogen carbonate (1 mL) was added to the residue, and the mixture was extracted with ethyl acetate/tetrahydrofuran and dried over anhydrous sodium sulfate. Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (260 mg) as a brown solid. 1H-NMR(CDCl3) delta 1.80-1.91(1H,m), 2.14-2.25(1H,m), 2.93-3.10(2H,m), 3.12-3.29(2H,m).
With trifluoroacetic acid; In dichloromethane; at 20℃; for 4h;
tert-Butyl 3-hydroxy-3-(trifluoromethyl)pyrrolidine-1-carboxylate (310 mg, 1.21 mmol) was treated with 20% CF3CO2H in CH2Cl2 for 4h at room temperature. The volatiles were removed in vacuo to give the subtitled compound (330 mg). 1H-NMR (CD3OD, 400 MHz): delta 3.72-3.59 (m, 4H); 2.38 (m, 1H) ; 2.22 (m, 1H). APCI-MS: m/z 156 (MH+).
To a solution of tert-butyl3-hydroxy-3-(trifluoromethyl)pyrrolidine-1-carboxylate (468 mg, 1.83 mmol) in pyridine (10 mL) was added SOCl2 (1.71 mL) and the reaction mixture was stirred at reflux temperature under nitrogen for 25 min, cooled to room temperature, H2O (20 mL) was added, extracted with ethyl acetate. The combined organic layer was washed with dilute aqueous HCI, saturated aqueous NaHCO3 and H2O successively. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was dissolved in ethanol (10 mL), Pd/C (10%) (300 mg) was added and it was hydrogeneted at room temperature over the weekend. The catalyst was removed by filtration. The filtrate was concentrated in vacuo to give the subtitled compound (100 mg). APCI-MS: m/z 140 (MH+-Boc).
With hydrogenchloride; In methanol; at 20℃; for 4h;
Step 2:To step 1 product (57 mg, 0.22 mmol) in methanol (1 mL)A solution of methanolic hydrochloric acid (2 mL) was added to the solution.The reaction system was stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure.A saturated aqueous solution of sodium hydrogencarbonate (1 mL) was added to the residue.The aqueous phase was extracted with ethyl acetate (3 mL x 2).The organic phase was combined, washed with brine, dried over anhydrous sodium sulfate and filtered.The filtrate was concentrated under reduced pressure to give Intermediate 98 (20 mg, yield: 59%) it is a brown solid.
With hydrogenchloride; In methanol; ethyl acetate; at 20℃; for 4h;
A) Production of 3-(trifluoromethyl)pyrrolidin-3-ol A mixture of tert-butyl 3-oxopyrrolidine-1-carboxylate (600 mg), trimethyl(trifluoromethyl)silane (0.57 mL), 1M N,N,N-tributylbutane-1-aminium fluoride/tetrahydrofuran solution (0.50 mL) and tetrahydrofuran (6 mL) was stirred at room temperature for 30 min. Saturated aqueous ammonium chloride solution (2 mL) and 1M N,N,N-tributylbutane-1-aminium fluoride/tetrahydrofuran solution (1 mL) were added, and the reaction mixture was stirred at room temperature for 1 hr. The mixture was extracted with ethyl acetate, washed successively with water and brine, and dried over anhydrous sodium sulfate. Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give a pale-brown solid. The obtained solid was dissolved in methanol (1 mL), and 4M hydrochloric acid/ethyl acetate solution (2 mL) was added at room temperature. The reaction mixture was stirred at room temperature for 4 hr, and the reaction system was concentrated under reduced pressure. Saturated aqueous sodium hydrogen carbonate (1 mL) was added to the residue, and the mixture was extracted with ethyl acetate/tetrahydrofuran and dried over anhydrous sodium sulfate. Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (260 mg) as a brown solid. 1H-NMR(CDCl3) delta 1.80-1.91(1H,m), 2.14-2.25(1H,m), 2.93-3.10(2H,m), 3.12-3.29(2H,m).
tBuOK (136 mg; 1.2 mmol; 1.5 eq.) was added at 10C to a solution of 3-hydroxy-3- trifluoromethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (247 mg; 0.97 mmol; 1.2 eq.) in 1 ,4-dioxane (10 mL) and the reaction mixture was stirred at room temperature for 15 minutes whereupon 2-fluoro-benzaldehyde (100 mg; 0.81 mmol; 1 eq.) was added. The reaction mixture was stirred at 100C for 3 hours then diluted with sat. aq. NH4CI and extracted with EA (2x). The combined organics were washed with brine, dried over magnesium sulfate and concentrated in vacuo. Purification by column chromatography (DCM) afforded the title compound (95 mg, 33%) as a colourless oil. HPLC (max plot) 98.2%, Rt .87 min.
With tetrabutyl ammonium fluoride; In tetrahydrofuran; at 20℃;Cooling with ice;
Dissolve 1-tert-butoxycarbonyl-3-pyrrolidone (926mg, 5mmol) in 10mL tetrahydrofuran,Stir in an ice bath,Add 0.872mL trifluoromethylchlorosilane and tetrabutylammonium fluoride (176mg, 0.67mmol),React overnight at room temperature,Add 8mL saturated ammonium chloride solution to the reaction solution,Stir for 15min and add tetrabutylammonium fluoride (1.49g, 5.7mmol) in tetrahydrofuran solution (7.5mL),After stirring at room temperature for 1 hour,Extract with ethyl acetate (50mL×3), wash with water (100mL),After drying, it is concentrated and directly put into the next step.
3-[(2S)-3-(5-chloro-1'H,3H-spiro[1-benzofuran-2,4'-piperidin]-1'-yl)-2-hydroxypropyl]oxy}-4-[3-(trifluoromethyl)pyrrolidin-1-yl]carbonyl} phenol[ No CAS ]
1-(2-[(2S)-3-(5-chloro-1'H,3H-spiro[1-benzofuran-2,4'-piperidin]-1'-yl)-2-hydroxypropyl]oxy}-4-hydroxybenzoyl)-3-(trifluoromethyl)pyrrolidin-3-ol[ No CAS ]
(2S)-1-(5-chloro-1'H,3H-spiro[1-benzofuran-2,4'-piperidin]-1'-yl)-3-(5-[(4-methoxybenzyl)oxy]-2-[3-(trifluoromethyl)pyrrolidin-1-yl]carbonyl}phenoxy)propan-2-ol[ No CAS ]
1-(2-[(2S)-3-(5-chloro-1'H,3H-spiro[1-benzofuran-2,4'-piperidin]-1'-yl)-2-hydroxypropyl]oxy}-4-[(4-methoxybenzyl)oxy]benzoyl)-3-(trifluoromethyl)pyrrolidin-3-ol[ No CAS ]
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