| 93% |
Stage #1: t-butyl 4-hydroxy piperidine-1-carboxylate With sodium hydride In ISOPROPYLAMIDE at 0℃; for 0.5h;
Stage #2: 4-Fluoronitrobenzene In ISOPROPYLAMIDE at 0 - 20℃; |
105 Reference example 105; 4-(1-t-Butoxycarbonylpiperidin-4-yloxy)nitrobenzene
To a solution of 1-t-butoxycarbonyl-4-hydroxypiperidine (50.1 g) in N,N-dimethylacetamide (550 ml) was added sodium hydride (10.5 g) with stirring under ice-cooling, and the resulting mixture was stirred at the same temperature for 30 minutes.. At the end of this time, to the reaction mixture was added dropwise a solution of 4-fluoronitrobenzene (42.2 g) in N,N-dimethylacetamide (100 ml) with stirring at the same temperature, and the resulting mixture was furthermore stirred at room temperature overnight.. After stirring, to the reaction mixture was added water and the resulting mixture was extracted with ethyl acetate.. The extract was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated in vacuo.. The residue obtained was purified by chromatography on a silica gel column using a mixed solvent of hexane and ethyl acetate (13:7) as the eluent to afford the title compound (75.1 g, yield: 93%) as a pale yellow solid. 1H NMR (400MHz, CDCl3) δ ppm: 1.43 (9H, s), 1.76 (2H, m), 1.91 (2H, m), 3.34 (2H, m), 3.65 (2H, m), 4.56 (1H, m), 6.91 (2H, d, J=9.0), 8.15 (2H, d, J=9.0). |
| 89% |
Stage #1: t-butyl 4-hydroxy piperidine-1-carboxylate With sodium hydride In N,N-dimethyl acetamide at 0℃; for 0.25h; Inert atmosphere;
Stage #2: 4-Fluoronitrobenzene In N,N-dimethyl acetamide at 0 - 20℃; for 4h; Inert atmosphere; |
7 Tert-Butyl 4-(4-nitrophenoxy)piperidine-1-carboxylate 11
4.2.7 Tert-Butyl 4-(4-nitrophenoxy)piperidine-1-carboxylate 11 In an oven dried round bottom flask equipped with a magnetic stirring bar and under nitrogen atmosphere, NaH 60% in mineral oil (1.76 g, 44.0 mmol) was washed with hexane (3 * 20 mL) and dried at the high vacuum pump. The flask was filled again with nitrogen and placed in an ice bath; dry N,N'-dimethylacetamide (DMA, 130 mL) and 9 (N-Boc-4-hydroxypiperidine, 8.16 g, 40 mmol) were added in this order and stirred vigorously for 15 min. A solution of 1-fluoro-4-nitrobenzene 10 (5.5 mL, 52.24 mmol) in 20 mL of dry DMA was then added in one portion (a moderate but prolonged heat evolution was observed) and the reaction mixture was stirred at room temperature for 4 h. Hereafter, the reaction was quenched with a saturated solution of NH4Cl (100 mL) and diluted with EtOAc (200 mL); the phases were separated and the organic extract was washed with brine (3 * 100 mL), dried over MgSO4 and evaporated in vacuo. The crude brown oil was purified by column chromatography on silica gel (Hex/EtOAc 5:1) to give 11.42 g (35.4 mmol, 89% yield) of 11 as a bright yellow powder (m. p. = 100-102 °C). 1H NMR (400 MHz, CDCl3) δ = 8.21-8.17 (m, 2H); 6.97-6.93 (m, 2H); 4.60 (sept, J = 3.5 Hz, 1H); 3.72-3.66 (m, 2H); 3.41-3.34 (m, 2H); 1.99-1.92 (m, 2H); 1.82-1.74 (m, 2H); 1.47 (s, 9H) ppm. 13C NMR (100 MHz, CDCl3) δ = 162.8; 155.1; 141.8; 126.4, 115.7, 80.2, 73.3; 40.8 (broad); 30.6; 28.8 ppm. IR (KBr) ν = 2954.2, 1698.2, 1590.8, 1509.3, 1412.9, 1340.5, 1262.3 cm-1. GCMS (EI) m/z = 322 [M+·], 266 [M- isobutylene]+ ·, 249 [M- iBuO]+, 222 [M- isobutylene - CO2]+ ·, 184 [M- PhNO2, - H2O]+ ·, 128 [M- PhNO2, - H2O - isobutylene]+ ·, 84 [M- PhNO2, - H2O - isobutylene - CO2]+ ·. |
| 85% |
Stage #1: t-butyl 4-hydroxy piperidine-1-carboxylate With sodium hydride In N,N-dimethyl acetamide at 0℃; for 0.5h;
Stage #2: 4-Fluoronitrobenzene In N,N-dimethyl acetamide at 20℃; |
136 Preparation of N-(3-(2-((4-((1-(2-hydroxyethyl)piperidin-4-yl)oxy)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide
To a solution of tert-butyl 4-hydroxypiperidine-l-carboxylate (603 mg, 3 mmol, 1 eq.) in DMA (10 mL) cooled at 0 °C was added NaH (180 mg, 4.5 mmol, 1.5 eq.) in small portions and the resulting mixture was stirred at 0 °C for 30 min. Then l-fluoro-4- nitrobenzene (423 mg, 3 mmol, 1 eq.) was added slowly. The mixture was stirred at r.t.overnight. The mixture was poured into ice-water (100 mL), extracted with EA (3x20 mL) and the organic layers were combined, washed with brine (60 mL), dired over Na2S04, concentrated and purified via column chromatography (PE/EA=2/1) to afford tert-butyl 4-(4- nitrophenoxy)piperidine-l-carboxylate (818 mg, 85%) as a yellow solid. |
| 83% |
Stage #1: t-butyl 4-hydroxy piperidine-1-carboxylate With potassium <i>tert</i>-butylate In tetrahydrofuran at 20℃; for 0.25h;
Stage #2: 4-Fluoronitrobenzene In tetrahydrofuran at 20℃; for 4h; |
23.1 Step 1 : tert-butyl 4-(4-nitrophenoxy)piperidine-1 -carboxylate
To a stirred solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (7.1 g, 35.5 mmol, commercially available) in THF (50 ml.) was added potassium tert-butoxide (5.9 g, 52.6 mmol) at room temperature. The reaction mixture was stirred at room temperature for 15 min and 1-fluoro-4-nitrobenzene (5.0 g, 35.5 mmol) was added at room temperature. The reaction mixture was stirred at room temperature for 4 h. The reaction mixture was poured into water (50 ml_). The aqueous layer was extracted with ethyl acetate (2 x 80 ml_). The combined organic phase was dried over anhydrous Na2SC>4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with 12% EtOAc in hexane to afford the title product as a yellow solid (9.5 g, 83%). |
| 81% |
Stage #1: t-butyl 4-hydroxy piperidine-1-carboxylate With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; for 0.75h;
Stage #2: 4-Fluoronitrobenzene In N,N-dimethyl-formamide at 0 - 20℃; |
N-(tert-Butoxycarbonyl)-4-(4-nitrophenoxy)piperidine (15)
N-(tert-Butoxycarbonyl)-4-hydroxypiperidine (1.0 g,4.97 mmol) was dissolved in anhydrous DMF (5 mL) and cooled to0 C. NaH (60%, 300 mg, 7.5 mmol) was added portionwise in15 min, and then the mixture was stired for a further 30 min atambient temperature. The mixture was then cooled to 0 C, and asolution of 4-fluoronitrobenzene 14 (771 mg, 5.5 mmol) in DMF(10 mL) was added dropwise. The reaction mixture was stirredovernight at ambient temperature. After completion of the reaction,water was added, and the aqueous layer was extracted withEtOAc. The combined organic layers were washed with brine, driedover Na2SO4 and evaporated to afford 1.3 g 15 as a pale-yellow solid,yield 81%. 1H NMR (500 MHz, CDCl3): d 8.22 (d, J 9.0 Hz, 2H), 6.97(d, J 9.0 Hz, 2H), 4.63e4.59 (m, 2H), 3.73e3.68 (m, 2H), 3.41e3.36(m, 2H), 1.99e1.94 (m, 2H), 1.82e1.76 (m, 2H), 1.48 (s, 9H). ESI-MS:m/z 323.2 [MH]. |
| 79% |
Stage #1: t-butyl 4-hydroxy piperidine-1-carboxylate With sodium hydride In N,N-dimethyl acetamide at 20℃;
Stage #2: 4-Fluoronitrobenzene In N,N-dimethyl acetamide at 20℃; |
|
| 78% |
With sodium hydride In tetrahydrofuran at 20℃; for 14h; |
305
To a solution of 4-fluoronitrobenzene (1.41g, 10 mmol) in THF (50 mL) was added N- Boc-4-hydroxypiperidine (2.01g, 10 mmol) and sodium hydride (60% in mineral oil, 583mg, 14.5 mmol). The mixture was stirred at room temperature for 14 hrs. After purification through flash column chromatography, 4-(4-nitro-phenoxy)-piperidine-l- carboxylic acid tert-butyl ester (2.5 Ig, 78% yield) was obtained as a solid. This nitro compound was hydrogenated to the corresponding amine and coupled with 2-phenyl-5- trifluoromethyloxazole-4-carboxylic acid to give 4-{4-[(2-phenyl-5-trifluoromethyl- oxazole-4-carbonyl)-amino]-phenoxy}-piperidine-l-carboxylic acid tert-butyl ester. LC- MS showed a single peak with a retention time of 4.08 min. LRMS calcd for C27H28F3N3O5 (M+ 1) 532.20, obsd 532.1 |
| 77% |
Stage #1: t-butyl 4-hydroxy piperidine-1-carboxylate With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; for 0.75h; Inert atmosphere;
Stage #2: 4-Fluoronitrobenzene In N,N-dimethyl-formamide at 20℃; for 14h; Inert atmosphere; |
|
| 77% |
Stage #1: t-butyl 4-hydroxy piperidine-1-carboxylate With sodium hydride In N,N-dimethyl-formamide at 20℃; Cooling with ice;
Stage #2: 4-Fluoronitrobenzene In N,N-dimethyl-formamide at 20℃; Cooling with ice; |
1.1 Production of 4-(4-piperidinyl)oxy-N-tert-butoxycarbonyl-1-nitrobenzene
Example 1-1 Production of 4-(4-piperidinyl)oxy-N-tert-butoxycarbonyl-1-nitrobenzene In a nitrogen atmosphere, a dimethylformamide solution (50 mL) of N-tert-butoxycarbonyl-4-piperidinol (10.0 g, 49.7 mmol) was cooled with ice, and sodium hydride (3.0 g, 75 mmol, as 60% content) was added thereto little by little, and stirred at room temperature for 30 minutes. The reaction mixture was again cooled in an ice bath, and a dimethylformamide solution (10 mL) of 4-fluoronitrobenzene (7.71 g, 55 mmol) was dropwise added thereto, and stirred at room temperature for 15 hours. Water (15 mL) was added to it to stop the reaction, and the solvent was evaporated off at 50° C. under reduced pressure. Water (120 mL) was added to the residue, extracted with ethyl acetate (120 mL*2), and the organic layer was washed twice with distilled water, and dried with anhydrous sodium sulfate. After filtered, the filtrate was concentrated under reduced pressure, and the resulting yellow solid was washed in a mixed solvent of isopropyl ether/hexane (1/4) under stirring. The solid was taken out through filtration, and dried under reduced pressure to obtain 4-(4-piperidinyl)oxy-N-tert-butoxycarbonyl-1-nitrobenzene (12.4 g, 77%) as a pale yellow solid. ESI m/z: 345.2 [M+Na]+ 1H-NMR (400 MHz, CDCl3, δ ppm): 1.48 (9H, s), 1.75-1.83 (2H, m), 1.93-2.00 (2H, m), 3.35-3.42 (2H, m), 3.67-3.73 (2H, m), 4.58-4.63 (1H, m), 6.96 (2H, d, J=9.3 Hz), 8.20 (2H, d, J=9.3 Hz). |
| 77% |
Stage #1: t-butyl 4-hydroxy piperidine-1-carboxylate With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; for 0.5h;
Stage #2: 4-Fluoronitrobenzene In N,N-dimethyl-formamide at 0 - 20℃; for 15h; |
1-1 Production of 4-(4-piperidinyl)oxy-N-tert-butoxycarbonyl-1-nitrobenzene
Production of 4-(4-piperidinyl)oxy-N-tert-butoxycarbonyl-1-nitrobenzene In a nitrogen atmosphere, a dimethylformamide solution (50 mL) of N-tert-butoxycarbonyl-4-piperidinol (10.0 g, 49.7 mmol) was cooled with ice, and sodium hydride (3.0 g, 75 mmol. as 60 % content) was added thereto little by little, and stirred at room temperature for 30 minutes. The reaction mixture was again cooled in an ice bath, and a dimethylformamide solution (10 mL) of 4-fluoronitrobenzene (7.71 g, 55 mmol) was dropwise added thereto, and stirred at room temperature for 15 hours. Water (1 5 mL) was added to it to stop the reaction, and the solvent was evaporated off at 50°C under reduced pressure. Water (120 mL) was added to the residue, extracted with ethyl acetate (120 mL x 2), and the organic layer was washed twice with distilled water, and dried with anhydrous sodium sulfate. After filtered, the filtrate was concentrated under reduced pressure, and the resulting yellow solid was washed in a mixed solvent of isopropyl ether/hexane (1/4) under stirring. The solid was taken out through filtration, and dried under reduced pressure to obtain 4-(4-piperidinyl)oxy-N-tert-butoxycarbonyl-1-nitrobenzene (12.4 g, 77 %) as a pale yellow solid. ESI m/z: 345.2 [M +Na]+ 1H-NMR (400 MHz, CDCl3, δ ppm): 1.48 (9H, s), 1.75-1.83 (2H, m), 1.93-2.00 (2H, m), 3.35-3.42 (2H, m), 3.67-3.73 (2H, m), 4.58-4.63 (1H, m), 6.96 (2H, d, J=9.3 Hz), 8.20 (2H, d. J-9.3 Hz). |
| 62% |
Stage #1: t-butyl 4-hydroxy piperidine-1-carboxylate With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.5h;
Stage #2: 4-Fluoronitrobenzene In N,N-dimethyl-formamide; mineral oil at 25℃; for 16h; |
14.2 Step 2: tert-butyl 4-(4-nitrophenoxy)piperidine-1-carboxylate (56)
To a stirred solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (55) (2.0 g, 9.9 mmol) in DMF (20 mL) was added NaH (0.5 g, 11.9 mmol, 60% in mineral oil) at 0° C. The resulting slurry was stirred for 30 min at 0° C. and followed by the addition of 1-fluoro-4-nitrobenzene (1.7 g, 11.9 mmol). The resulting mixture was stirred at 25° C. for 16 h and then quenched with water (60 mL) and extracted with EA (2×20 mL). The combined organic phase was washed with brine (2×30 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography (silica gel, PE/EA=20:1-10:1) to afford the titled compound 56 (2.0 g, 62%) as a pale-yellow solid. 1H-NMR (400 MHz, CDCl3) δ=8.20 (d, J=9.2 Hz, 2H), 6.95 (d, J=9.2 Hz, 2H), 4.65-4.53 (m, 1H), 3.78-3.60 (m, 2H), 3.46-3.31 (m, 2H), 2.05-1.89 (m, 2H), 1.88-1.69 (m, 2H), 1.47 (s, 9H). |
| 47% |
Stage #1: t-butyl 4-hydroxy piperidine-1-carboxylate With potassium <i>tert</i>-butylate In tetrahydrofuran at 0℃; for 0.5h;
Stage #2: 4-Fluoronitrobenzene In tetrahydrofuran at 23℃; for 5h; |
|
| 13% |
With tetrabutylammomium bromide; potassium hydroxide In water at 35℃; |
87.1 tert-butyl 4-(4-nitrophenoxy)piperidine-1- carboxylate
To a suspension of tert-butyl 4-hydroxypiperidine-1-carboxylate (3.00 g, 14.91 mmol) and 1-fluoro-4- nitrobenzene (3.89 g, 27.6 mmol) in aqueous potassiumhydroxide (25% solution by weight) (21.84 mL, 97 mmol)was added tetrabutylammonium bromide (0.625 g, 1.938mmol) and the resulting mixture stirred at 35 °Covernight. The reaction mixture was allowed to cool to room temperature and the precipitated solid isolated by filtration, washed with water (2 x 20 mL) and sucked dry. The residue was purified by Biotage chromatography (silica 50g cartridge, cyclohexane:ethyl acetate,gradient elution from 100:0 to 80:20) to give the title compound as an off-white solid (611 mg, 13%) . ‘H NMR (300 MHz, CDC13) : 3 8.20 (dt, 2H), 6.95 (dt, 2H), (sep, 1H), 3.70 (ddd, 2H), 3.38 (ddd, 2H), 1.90-2.04 (m, 2H),1.72-1.86 (m, 2H), 1.47 (s, 9H) . LCMS (Method C): =1.78 mi m/z = 345 [M+Na]. |
|
With sodium hydride In tetrahydrofuran |
|
|
In water; dimethyl sulfoxide |
17.1 4-(4-Nitrophenoxy)piperidine-1-carboxylic Acid tert-Butyl Ester
Step 1 4-(4-Nitrophenoxy)piperidine-1-carboxylic Acid tert-Butyl Ester To a solution of 4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (38.28 g) and 4-fluoronitrobenzene (26.84 g) in dimethyl sulfoxide (326 ml) was added 60% sodium hydride (7.99 g) under nitrogen atmosphere and with ice-cooling, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, water was added and the mixture was extracted with ethyl acetate and washed with water. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to give the title compound (52.384 g). 1H-NMR (δ ppm, CDCl3) 1.48 (s, 9H), 1.80 (m, 2H), 1.96 (m, 2H), 3.39 (m, 2H), 3.70 (m, 2H), 4.61 (m, 1H), 6.96 (d, J=9.3 Hz, 2H), 8.20 (d, J=9.3 Hz, 2H). |
|
Stage #1: t-butyl 4-hydroxy piperidine-1-carboxylate With sodium hydride In DMF (N,N-dimethyl-formamide) at 0℃; for 0.5h; Heating / reflux;
Stage #2: 4-Fluoronitrobenzene In DMF (N,N-dimethyl-formamide) for 3h; |
8.A Preparation 8 Compounds of Formula (HH)
A. A slurry of hexane-washed sodium hydride (3 g, 75 mmol) in dimethyl formamide (80 mL) was stirred as a solution of N-(t-butoxycarbonyl)4-hydroxypiperidine (10 g, 50 mmol) in dimethyl formamide (10 mL) was added dropwise. Slight heating was used to initiate reaction, but the reaction needed to be cooled in an ice bath to control the reaction rate. Approximately 30 min after the addition was complete, solid 4-fluoro-1-nitrobenzene (7.4 g, 52 mmol) was added at once. The reaction was stirred for about 3 hours. The reaction was poured into ice water. The pH of the resulting liquid was adjusted to neutrality with 1 N hydrochloric acid. The resulting solid was isolated by filtration, washed with water, and dried under reduced pressure to give 16 g of 4-(N-(t-butoxycarbonyl)piperidin-4-yl)oxy-1-nitrobenzene, NMR (CDCl3, TMS) δ1.45 (s, 9), 1.72 (m, 2), 1.98 (m, 2), 3.38 (m, 2), 3.68 (m, 2), 4.62 (m, 1), 6.98 (m, 2), 8.19 (m, 2). |
|
Stage #1: t-butyl 4-hydroxy piperidine-1-carboxylate With potassium <i>tert</i>-butylate In <i>tert</i>-butyl alcohol at 50℃;
Stage #2: 4-Fluoronitrobenzene In <i>tert</i>-butyl alcohol for 0.5h; Heating / reflux; |
4.1
Example 4 ; Preparation of Compound 4A To a stirred mixture of potassium tert-butoxide (19 g, 0.169 mol) and compound 8 (32.7 g, 0.162 mol) in tert-butanol (200 mL) at 50° C. was added compound 1 (25.2 g, 0.178 mol) in one portion. After being heated under reflux for 0.5 h, the mixture was cooled to room temperature, diluted with ether and treated with water. The organic phase was separated, washed with water, dried over anhydrous MgSO4, and filtered. The filtrate was concentrated to a solid which was triturated with hexane and filtered to give 42 g of compound 9. |
|
Stage #1: t-butyl 4-hydroxy piperidine-1-carboxylate With sodium hydride In tetrahydrofuran at 0℃; for 0.25h; Inert atmosphere;
Stage #2: 4-Fluoronitrobenzene In tetrahydrofuran at 0 - 20℃; Inert atmosphere; |
|
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