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CAS No. : | 1374603-97-0 | MDL No. : | MFCD29086651 |
Formula : | C12H12F3NO | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | - |
M.W : | 243.23 | Pubchem ID : | - |
Synonyms : |
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Signal Word: | Class: | ||
Precautionary Statements: | UN#: | ||
Hazard Statements: | Packing Group: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With sodium hydrogencarbonate; In acetonitrile; at 20 - 76℃; | Step 1: Synthesis of 2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzaldehyde A flask was charged with <strong>[89763-93-9]2-fluoro-4-(trifluoromethyl)benzaldehyde</strong> (1.0 equiv.), ACN (5.4* Vol), and pyrrolidine (1.0 equiv.) The solution was cooled below 20 C. Solid sodium hydrogen carbonate (2.5 equiv.) was added, and the resulting slurry was heated to 76 C. until the reaction was complete by LC analysis. The batch was cooled and diluted with water (?30* Vol) and EtOAc (?60* Vol), and the aqueous layer was separated and extracted with EtOAc (?30* Vol). The organic layers were combined, washed with water (?30* Vol) and saturated aqueous sodium chloride (?30* Vol), and dried over anhydrous sodium sulfate. The drying agent was removed by filtration, washed with EtOAc (?60* Vol), and the filtrate and rinse were concentrated under reduced pressure to an oil. The oil was diluted with DCM (?13* Vol) and adsorbed onto silica gel (?8* Wt). After removing solvent under reduced pressure, the dried silica gel was loaded onto a Biotage Ultra cartridge, and the product was eluted to provide 2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzaldehyde as a yellow oil in ?85% yield. 1H NMR (300 MHz, Chloroform-d) delta 10.14 (s, 1H), 7.79 (d, J=8.1 Hz, 1H), 7.05-6.99 (m, 2H), 3.42-3.37 (m, 4H), 2.05-2.01 (m, 4H); MS (ESI, m/z): 244.07 [M+H]+. |
79% | With potassium carbonate; In dimethyl sulfoxide; at 90℃;Inert atmosphere; | Example 66: 1,1,1,3,3,3-Hexafluoropropan-2-yl 1-(2-(pyrrolidin-1-yl)-4- (trifluoromethyl)benzyl)-1,8-diazaspiro[4.5]decane-8-carboxylate Step 1: Preparation of 2-(p rrolidin-1- l -4- trifluorometh l benzaldehyde A flask was charged with <strong>[89763-93-9]2-fluoro-4-(trifluoromethyl)benzaldehyde</strong> (6.00 g, 31.2 mmol, 1.00 equiv), pyrrolidine (3.30 g, 46.4 mmol, 1.50 equiv), potassium carbonate (12.9 g, 93.3 mmol, 3.00 equiv), and DMSO (50 mL) under nitrogen. The resulting solution was stirred overnight at 90 ^C and diluted with H2O (20 mL). The mixture was extracted with DCM (3 x 50 mL) and the organic layers were combined, washed with brine (3 x 10 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified on a silica gel column (1:20 EtOAc/petroleum ether) to provide 6.00 g (79% yield) of 2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzaldehyde as a yellow oil. LCMS (ESI, m/z): 244 [M+H]+. |
59% | With potassium carbonate; In dimethyl sulfoxide; at 80℃; | 1003691 A round-bottom flask was charged with <strong>[89763-93-9]2-fluoro-4-(trifluoromethyl)benzaldehyde</strong> (4.80 g,25.0 mmol, 1.00 equiv), pyrrolidine (5.33 g, 75.0 mmol, 3.00 equiv), DMSO (30 mL), and K2C03 (10.4 g, 75.0 mmol, 3.00 equiv). The reaction mixture was stirred overnight at 80 C and quenched with water (30 mL). The resulting solution was extracted with EtOAc (3 x 50 mL) and the organic layers were combined, washed with brine (2 x 50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column to provide 3.60 g (59% yield) of 2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzaldehyde as a brown oil. LCMS (ESI, m/z): 244 [M+H]. |
43% | With sodium hydrogencarbonate; In acetonitrile; at 80℃; | A flask was charged with <strong>[89763-93-9]2-fluoro-4-(trifluoromethyl)benzaldehyde</strong> (4.00 g, 20.8 mmol, 1.00 equiv), ACN (15 mL), pyrrolidine (2.21 g, 31.0 mmol, 1.50 equiv), and sodium bicarbonate (4.37 g, 52.0 mmol, 2.50 equiv). The resulting solution was stirred overnight at 80 C and quenched with water (30 mL). The resulting solution was extracted with EtOAc (3 x 50 mL) and the organic layers were combined, washed with brine (3 x 30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column to provide 2.20 g (43% yield) of 2-(pyrrolidin-l-yl)-4-(trifluorom ethyl )benzaldehyde as a yellow oil. LCMS (ESI, m/z): 244 [M+H]+. |
37% | With potassium carbonate; In dimethyl sulfoxide; at 90℃;Inert atmosphere; | A 250-mL round-bottom flask was charged with 2-fluoro-4- (trifluoromethyl)benzaldehyde (10.0 g, 52.1 mmol, 1.00 equiv), DMSO (50 mL), pyrrolidine (5.55 g, 78.0 mmol, 1.50 equiv), and potassium carbonate (21.6 g, 156 mmol, 3.00 equiv) under nitrogen. The resulting solution was stirred overnight at 90 C and quenched with water (150 mL). The resulting solution was extracted with EtOAc (2 x 250 mL) and the organic layers were combined, washed with brine (2 x 100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column to provide 4.70 g (37% yield) of 2-(pyrrolidin- 1 -yl)-4-(trifluoromethyl)b enzaldehyde as a yellow solid. LCMS (ESI, m/z): 244 [M+H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: 0.5 h / 20 °C / Inert atmosphere 1.2: 20 °C / Inert atmosphere 2.1: trifluoroacetic acid / dichloromethane / 18 h / 0 - 20 °C / Inert atmosphere 3.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 2 h / 20 °C / Inert atmosphere 3.2: 2 h / 20 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | j00370J A round-bottom flask was charged with 2-(pyrrolidin-1-yl)-4- (trifluoromethyl)benzaldehyde (243 mg, 1.00 mmol, 1.00 equiv), t-butyl 4-amino-4- methylpiperidine-1-carboxylate (257 mg, 1.20 mmol, 1.20 equiv), MeOH (10 mL), and acetic acid (180 mg, 3.00 mmol, 3.00 equiv). The mixture was stirred for 1 h at 60 C prior to addition of sodium borohydride (152 mg, 4.00 mmol, 4.00 equiv). The reaction mixture was stirred overnight at room temperature and quenched with water (20 mL). The resulting solution was extracted with DCM (3 x 30 mL) and the organic layers were combined, washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column to provide 200 mg (45% yield) of t-butyl 4-methyl-4-((2-(pyrrolidin- 1 -yl)-4-(trifluoromethyl)b enzyl)amino)piperidine- 1 -carboxylate as a yell ow oil. LCMS(ESI, m/z): 442 [M+H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | Stage #1: 1,1,1,3,3,3-hexafluoropropan-2-yl piperazine-1-carboxylate, 2,2,2-trifluoroacetate salt With triethylamine In ethyl acetate at 20 - 25℃; for 1.25h; Large scale; Stage #2: 2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzaldehyde In ethyl acetate at 20 - 25℃; for 3.25h; Inert atmosphere; Large scale; Stage #3: With sodium tris(acetoxy)borohydride In ethyl acetate at 20 - 25℃; Inert atmosphere; Large scale; | 9.c Example 9: Synthesis of Compound I Via TFA Route Step c) via TFA route: A3-TFA (16.2 kg) was charged in a vessel at 20-25° C. followed by EtOAc (57 kg) at 20-25° C. obtaining a suspension. TEA (4.4 kg) was added over 15 min and the mixture was stirred at 20-25° C. for 1 hour. The A5 solution obtained in example 5 (20.5 kg) was added under nitrogen over 15 min at 20-25° C. and the mixture was stirred at 20-25° C. for 3 hours. STAB (9.8 kg) was added in 4 equal portions, waiting about 30 minutes between every portion and the following one while maintaining the temperature between 20 and 25° C. Subsequently, the suspension was stirred for 12 hours, followed by the addition of a further portion of STAB (1.4 kg) and a further stirring period of 2 hours. Subsequently, a further portion of STAB (0.3 kg) was added to the suspension followed by stirring for 2 hours. Purified water (13.5 kg) was added at 20° C. over 2 hours to form a phase separation. The organic phase was diluted with EtOAc (12.3 kg) and washed with purified water (63.2 kg). The organic phase was concentrated under vacuum below 40° C. to approx. 25 l. Methanol (21.4 kg) was added and solution was concentrated under vacuum to approx. 25 l. Methanol (48.2 kg) was added and the solution heated to 48-52° C. Purified water (81.2 kg) was slowly added in approx. 2 hours obtaining a suspension that was stirred at 48-52° C. for 30 minutes, followed by cooling to 20° C. over 3 hours and stirred at 20° C. for 3 hours. Suspension was centrifugated and washed with purified water/methanol mixture (27.1 kg/47.6 kg), the wet solid (18.49 kg) was dried under nitrogen flow for no less than 8 hours in a static drier affording Compound 1 (17.29 kg, 92% yield). 1H-NMR (DMSO-d6): δ(ppm) 1.86-1.89 (4H, t), 2.39 (4H, m), 3.24-3.27 (4H, t), 3.56 (2H, s), 6.53-6.63 (1H, m), 7.01-7.02 (1H, d), 7.09-7.11 (1H, dd), 7.53-7.55 (1H, d). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | Stage #1: 1,1,1,3,3,3-hexafluoropropan-2-yl piperazine-1-carboxylate hydrochloride With triethylamine In ethyl acetate at 20 - 25℃; for 1.25h; Large scale; Stage #2: 2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzaldehyde In ethyl acetate at 20 - 25℃; for 3h; Inert atmosphere; Large scale; Stage #3: With sodium tris(acetoxy)borohydride In ethyl acetate at 20 - 25℃; for 15.5h; Inert atmosphere; Large scale; | 10.c; 11.c Example 10: Synthesis of Compound I Via HCl Route Step c) via HCl route: A3-HCl (12.9 kg, 1.43 wt. %) was charged in vessel at 20-25° C. followed by EtOAc (57 kg) at 20-25° C. obtaining a suspension. TEA (4.4 kg) was added over 15 min and the mixture was stirred at 20-25° C. for 1 hour. Water (102 g) was added to the A5 solution from example 4 (20.5 kg at 44% w/w). The A5 solution was then added under nitrogen over 15 min at 20-25° C. and the mixture was stirred at 20-25° C. for 3 hours. STAB (9.8 kg) was added in 4 equal portions waiting about 30 minutes between every portion and the following one while maintaining the temperature between 20-25° C. The suspension was stirred for 15 hours. Purified water (13.5 kg) was added at 20° C. over 2 hours to obtain a phase separation. The organic phase was diluted with EtOAc (12.3 kg) and washed with purified water (63.2 kg). The organic phase was concentrated under vacuum below 40° C. to approx. 25 l. Methanol (21.4 kg) was added and solution was concentrated again under vacuum to approx. (25 l). Methanol (48.2 kg) was added and the solution was heated to 48-52° C. Purified water (81.2 kg) was slowly added over approx. 2 hours obtaining a suspension that was stirred at 48-52° C. for 30 minutes then cooled to 20° C. over 3 hours and stirred at 20° C. for approx. 3 hours. Suspension was centrifugated and washed with a purified water/methanol mixture (27.1 kg/47.6 kg). The wet solid (18.33 kg) was dried under nitrogen flow in a static drier for about 8 hours affording Compound 1 (17.33 kg, yield 92%). 1H-NMR (DMSO-d6): δ(ppm) 1.86-1.89 (4H, t), 2.39 (4H, m), 3.24-3.27 (4H, t), 3.56 (2H, s), 6.53-6.63 (1H, m), 7.01-7.02 (1H, d), 7.09-7.11 (1H, dd), 7.53-7.55 (1H, d). |