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CAS No. : | 138227-62-0 | MDL No. : | MFCD06200882 |
Formula : | C16H22N2O5 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | UNNMTKGKCWNQNU-UHFFFAOYSA-N |
M.W : | 322.36 | Pubchem ID : | 2794776 |
Synonyms : |
|
Num. heavy atoms : | 23 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.56 |
Num. rotatable bonds : | 6 |
Num. H-bond acceptors : | 5.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 91.43 |
TPSA : | 84.59 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | Yes |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.02 cm/s |
Log Po/w (iLOGP) : | 3.02 |
Log Po/w (XLOGP3) : | 3.16 |
Log Po/w (WLOGP) : | 2.99 |
Log Po/w (MLOGP) : | 1.48 |
Log Po/w (SILICOS-IT) : | 0.17 |
Consensus Log Po/w : | 2.16 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -3.63 |
Solubility : | 0.0762 mg/ml ; 0.000236 mol/l |
Class : | Soluble |
Log S (Ali) : | -4.61 |
Solubility : | 0.00797 mg/ml ; 0.0000247 mol/l |
Class : | Moderately soluble |
Log S (SILICOS-IT) : | -2.89 |
Solubility : | 0.416 mg/ml ; 0.00129 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 2.0 alert |
Leadlikeness : | 0.0 |
Synthetic accessibility : | 2.59 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* 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 |
---|---|---|
99% | With hydrogen In methanol at 20℃; for 4 h; | To a solution of 4-(1-t-butoxycarbonylpiperidin-4-yloxy)nitrobenzene (11.9 g) obtained in reference example 105 in methanol (100 ml) was added palladium on carbon (1.9 g), and the resulting mixture was stirred at room temperature under a hydrogen atmosphere for 4 hours. At the end of this time, the reaction mixture was filtered, and the filtrate was evaporated in vacuo. The residue obtained was purified by chromatography on a silica gel column using a mixed solvent of hexane and ethyl acetate (1:1) as the eluent to afford the title compound (10.7 g, yield: 99 percent) as a pale red solid. 1H NMR (400MHz, CDCl3) δ ppm : 1.46 (9H, s), 1.71 (2H, m), 1.87 (2H, m), 3.27 (2H, m), 3.71 (2H, m), 4.26 (1H, m), 6.63 (2H, d, J=8.5), 6.76 (2H, d, J=8.5). |
95% | With palladium 10% on activated carbon; ammonium formate In methanol at 50℃; Inert atmosphere; Reflux | 4.2.8 Tert-Butyl 4-(4-aminophenoxy)piperidine-1-carboxylate (12) In a round bottom flask equipped with a magnetic stirring bar and under nitrogen atmosphere, product 11 (11.42 g, 35.4 mmol) and ammonium formate (21.5 g, 354 mmol) were dissolved in 210 mL of degassed MeOH and the solution was heated to 50 °C. 10percent w/w Palladium on activated charcoal (1.10 g) was added and the reaction mixture was stirred at 90 °C (oil bath temperature, in order to ensure a round-boiling reflux of the reaction mixture, even after development of water as a coproduct of the hydrogenation) for 5 h. Hereafter, the reaction mixture was filtered through a short plug of celite, washed with DCM (100 mL) and evaporated in vacuo to give 9.28 g (32.2 mmol, 95percent yield) of pure 12 as a brown solid (m. p. = 80-81 °C). 1H NMR (300 MHz, CDCl3) δ = 6.77-6.71 (m, 2H); 6.63-6.58 (m, 2H); 4.24 (sept, J = 3.6 Hz, 1H); 3.73-3.65 (m, 2H); 3.46 (bs, 2H); 3.29-3.21 (m, 2H); 1.90-1.81 (m, 2H); 1.73-1.62 (m, 2H); 1.45 (s, 9H) ppm. 13C NMR (100 MHz, CDCl3) δ = 154.9; 150.0; 140.7, 118.3; 116.4; 79.5; 73.7; 40.7 (broad); 30.8; 28.4 ppm. IR (KBr) ν = 3460.0, 3361.6, 2955.4, 1685.1, 1509.9, 1419.4, 1229.0, 1049.6 cm-1. GCMS (EI) m/z = 291 [M+·], 219 [M- iBuO]+, 192 [M- isobutylene - CO2]+ ·, 184 [M- PhNH2, - H2O]+ ·, 128 [M- PhNH2, - H2O - isobutylene]+ ·, 109 [4-aminophenol]+ ·, 84 [M- PhNH2, - H2O - isobutylene - CO2]+ ·. |
93% | With palladium 10% on activated carbon; hydrogen In methanol at 50℃; | A solution of tert—butyl 4—(4—nitrophenoxy)piperidine—1—carboxylate (611 mg, 1.895 mmol) in methanol (60 mL) washydrogenated by H-Cube (10percent Pd/C cartridge, Full H2, 50°C, 1 mL/min) . The reaction mixture was concentrated to dryness under reduced pressure to give the title compound as a pale pink solid (517 mg, 93percent) . ‘H NMR (300 MHz,CDC13) : 3 6.76 (dt, 2H), 6.63 (dt, 2H), 4.26 (sep, 1H),3.71 (ddd, 2H), 3.45 (br s, 2H), 3.26 (ddd, 2H), 1.80—1.95 (m, 2H), 1.61—1.78 (m, 2H), 1.46 (s, 9H) . LCMS(Method C) : = 0.85 mi m/z = 237 [M_tBu+H]+. |
82.3% | With hydrogen In methanol; ethanol at 22℃; for 2 h; | A mixture of 4-(4-nitro-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester (3.15 g, 9.77 mmol) and 10percent wt palladium on carbon (1.01 g) in anhydrous ethanol-methanol (1:1, 100 mL) is stirred vigorously under hydrogen gas at 22°C for 2 hr. Then the palladium on carbon is removed by filtration. The filtrate is concentrated to give a white solid (2.35 g, 82.3 percent yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | Stage #1: 4-nitro-phenol With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0℃; for 0.166667h; Stage #2: t-butyl 4-hydroxy piperidine-1-carboxylate In tetrahydrofuran at 20℃; for 2.5h; | Preparation of 4-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]oxy}aniline. Triphenylphosphine (1.56 g, 5.96 mmol), diisopropyl azadicarboxylate (1.2 ml, 5.96 mmol) and 4-nitrophenol (691 mg, 4.97 mmol) were dissolved in 20 ml of THF at 0oC; the solution was stirred for 10min and tert-butyl-4-hydroxypiperidine-1-carboxylate (1 g, 4.97 mmol) was added. The mixture was left to warm up to room temperature and stirred for further 30 min. More triphenylphosphine (2.98 mmol), diisopropyl azadicarboxylate (2.98 mmol) and tert-butyl-4- hydroxypiperodine-1-carboxylate (2.98 mmol),were added to the reaction, and the mixture was left stirring 2 h. Water was added and the reaction was extracted with Et2O and the organics were washed with brine. The solid was filtered out and the solvent was removed in vacuo. The crude was purified by flash chromatography with 20 % of ethyl acetate in cyclohexane to isolate tert-butyl 4-(4-nitrophenoxy)piperidine-1-carboxylate (1.63 g, 99% yield). MS found for C16H22N2O5 as (M+H)+ 323.20. |
77% | With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran at 20℃; for 21h; | |
67.3% | With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 20℃; for 18h; | 370.1 [Step 1] Tert-butyl 4-(4-nitrophenoxy)piperidine- l -carboxylate [4964] A solution of 4-nitrophenol ( 1.000 g, 7.189 mmol), tert-butyl 4-hydroxypiperidine- l-carboxylate ( 1.736 g, 8.626 mmol) and triphenylphosphinet- riphenylphosphine (2.263 g. 8.626 mmol) in tetrahydrofuran (30 mL) was mixed at the room temperature with diisopropyl azodicarboxylate (DIAD, 1.698 mL, 8.626 mmol). The reaction mixture was stirred at the same temperature for 18 hr, and concentrated under the reduced pressure. The concentrate was purified and concentrated by column chromatography (Si02, 24 g cartridge; ethyl acetate / hexane = 0 % to 10 ) to give tert-butyl 4-(4-nitrophenoxy)piperidine- l -carboxylate as pale yellow solid ( 1 .560 g. 67.3 %). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With hydrogen;palladium on activated charcoal; In methanol; at 20℃; for 4h; | To a solution of 4-(1-t-butoxycarbonylpiperidin-4-yloxy)nitrobenzene (11.9 g) obtained in reference example 105 in methanol (100 ml) was added palladium on carbon (1.9 g), and the resulting mixture was stirred at room temperature under a hydrogen atmosphere for 4 hours. At the end of this time, the reaction mixture was filtered, and the filtrate was evaporated in vacuo. The residue obtained was purified by chromatography on a silica gel column using a mixed solvent of hexane and ethyl acetate (1:1) as the eluent to afford the title compound (10.7 g, yield: 99 %) as a pale red solid. 1H NMR (400MHz, CDCl3) delta ppm : 1.46 (9H, s), 1.71 (2H, m), 1.87 (2H, m), 3.27 (2H, m), 3.71 (2H, m), 4.26 (1H, m), 6.63 (2H, d, J=8.5), 6.76 (2H, d, J=8.5). |
95% | With palladium 10% on activated carbon; ammonium formate; In methanol; at 50℃;Inert atmosphere; Reflux; | 4.2.8 Tert-Butyl 4-(4-aminophenoxy)piperidine-1-carboxylate (12) In a round bottom flask equipped with a magnetic stirring bar and under nitrogen atmosphere, product 11 (11.42 g, 35.4 mmol) and ammonium formate (21.5 g, 354 mmol) were dissolved in 210 mL of degassed MeOH and the solution was heated to 50 C. 10% w/w Palladium on activated charcoal (1.10 g) was added and the reaction mixture was stirred at 90 C (oil bath temperature, in order to ensure a round-boiling reflux of the reaction mixture, even after development of water as a coproduct of the hydrogenation) for 5 h. Hereafter, the reaction mixture was filtered through a short plug of celite, washed with DCM (100 mL) and evaporated in vacuo to give 9.28 g (32.2 mmol, 95% yield) of pure 12 as a brown solid (m. p. = 80-81 C). 1H NMR (300 MHz, CDCl3) delta = 6.77-6.71 (m, 2H); 6.63-6.58 (m, 2H); 4.24 (sept, J = 3.6 Hz, 1H); 3.73-3.65 (m, 2H); 3.46 (bs, 2H); 3.29-3.21 (m, 2H); 1.90-1.81 (m, 2H); 1.73-1.62 (m, 2H); 1.45 (s, 9H) ppm. 13C NMR (100 MHz, CDCl3) delta = 154.9; 150.0; 140.7, 118.3; 116.4; 79.5; 73.7; 40.7 (broad); 30.8; 28.4 ppm. IR (KBr) nu = 3460.0, 3361.6, 2955.4, 1685.1, 1509.9, 1419.4, 1229.0, 1049.6 cm-1. GCMS (EI) m/z = 291 [M+·], 219 [M- iBuO]+, 192 [M- isobutylene - CO2]+ ·, 184 [M- PhNH2, - H2O]+ ·, 128 [M- PhNH2, - H2O - isobutylene]+ ·, 109 [4-aminophenol]+ ·, 84 [M- PhNH2, - H2O - isobutylene - CO2]+ ·. |
93% | With palladium 10% on activated carbon; hydrogen; In methanol; at 50℃; | A solution of tert-butyl 4-(4-nitrophenoxy)piperidine-1-carboxylate (611 mg, 1.895 mmol) in methanol (60 mL) washydrogenated by H-Cube (10% Pd/C cartridge, Full H2, 50C, 1 mL/min) . The reaction mixture was concentrated to dryness under reduced pressure to give the title compound as a pale pink solid (517 mg, 93%) . ?H NMR (300 MHz,CDC13) : 3 6.76 (dt, 2H), 6.63 (dt, 2H), 4.26 (sep, 1H),3.71 (ddd, 2H), 3.45 (br s, 2H), 3.26 (ddd, 2H), 1.80-1.95 (m, 2H), 1.61-1.78 (m, 2H), 1.46 (s, 9H) . LCMS(Method C) : = 0.85 mi m/z = 237 [M_tBu+H]+. |
88% | With palladium 10% on activated carbon; hydrogen; In tetrahydrofuran; methanol; at 20℃; for 14h; | A solution of tert-butyl 4-(4-nitrophenoxy)piperidine-l-carboxylate (8.0 g, 24.8 mmol) in MeOH (100 mL) and THF (20 mL) was purged with nitrogen, followed by the addition of Pd/C 10% wet catalyst (0.7 g) to the solution. The mixture was purged with hydrogen and stirred under a hydrogen atmosphere at room temperature for 14 h. The catalyst was removed by filtration through diatomaceous earth and the filter cake was washed with EtOAc (3x30 mL). The filtrates were evaporated under vacuum to afford the crude product. The residue was purified by flash chromatography over silica gel (EtO Ac- heptane gradient from 5% to 60%). Pure fractions were combined, concentrated, and dried under high vacuum to give compound lb (6.4 g, 88%). NMR (300 MHz, Chloroform- d delta 1.46 (s, 9H), 1.57 - 1.77 (m, 2H), 1.78 - 1.94 (m, 2H), 3.10 - 3.33 (m, 2H), 3.35 (s, 2H), 3.60 - 3.79 (m, 2H), 4.19 - 4.34 (m, 1H), 6.62 (d, J = 8.7 Hz, 2H), 6.75 (d, J = 8.7 Hz, 2H). MS m/z 193.0 (M+H-Boc)+. |
82.3% | With hydrogen;palladium 10% on activated carbon; In methanol; ethanol; at 22℃; for 2h; | A mixture of 4-(4-nitro-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester (3.15 g, 9.77 mmol) and 10% wt palladium on carbon (1.01 g) in anhydrous ethanol-methanol (1:1, 100 mL) is stirred vigorously under hydrogen gas at 22C for 2 hr. Then the palladium on carbon is removed by filtration. The filtrate is concentrated to give a white solid (2.35 g, 82.3 % yield). |
palladium-carbon; In tetrahydrofuran; ethanol; hexane; | Step 2 4-(4-Aminophenoxy)piperidine-1-carboxylic Acid tert-Butyl Ester 4-(4-Nitrophenoxy)piperidine-1-carboxylic acid tert-butyl ester (53.687 g) was hydrogenated using 7.5% palladium carbon (8.05 g) in a mixture of tetrahydrofuran (215 ml) and ethanol (215 ml) at 3 atm over 3 hours. After completion of the reaction, the reaction mixture was filtered through celite and the solvent was evaporated. Hexane was added to the obtained residue, and the obtained solid was collected by filtration and dried under reduced pressure to give the title compound (42.157 g). 1H-NMR (delta ppm, CDCl3) 1.46 (s, 9H), 1.71 (m, 2H), 1.86 (m, 2H), 3.27 (m, 2H), 3.71 (m, 2H), 4.26 (m, 1H), 6.63 (d, J=8.7 Hz, 2H), 6.76 (d, J=8.7 Hz, 2H). | |
carbon palladium; In ethanol; dichloromethane; | Step 2 Synthesis of 1-t-butoxycarbonyl-4-(4-aminophenoxy)piperidine: 2.74 g (8.5 mmol) of 1-t-butoxycarbonyl-4-(4-nitrophenoxy)piperidine was dissolved in 20 ml of ethanol. 20 mg of 10 % palladium/carbon was added to the solution, and they were stirred at room temperature in 1 atm. hydrogen atmosphere for 3 hours. Palladium/carbon was removed by the suction filtration. The filtrate was once concentrated and then treated with dichloromethane as extractant in an ordinary manner to obtain the title compound. Yield: 2.59 g (8.02 mmol) (94 %). H-NMR (CDCl3) delta 1.47 (9H, s), 1.63-1.75 (2H, m), 1.82-1.93 (2H, m), 3.22-3.32 (2H, m), 3.68-3.78 (2H, m), 4.71-4.80 (1H, m), 6.63 (2H, d), 6.76 (2H, d) | |
palladium; In tetrahydrofuran; ethanol; | Reference Example 3 4-(1-tert-Butoxycarbonylpiperidin-4-yloxy)aniline 4-(1-tert-Butoxycarbonylpiperidin-4-yloxy)nitrobenzene (11.87 g) was dissolved in a mixture of 150 ml of ethanol and 150 ml of tetrahydrofuran, and 780 mg of 10 % palladium on carbon was added to the solution. The mixture was stirred at atmospheric pressure under a hydrogen atmosphere at room temperature for 5 hours. The insoluble material was removed by filtration and the filtrate was concentrated under reduced pressure to give 9.75 g of 4-(1-tert-butoxycarbonylpiperidin-4-yloxy)aniline. 1H-NMR(CDCl3) delta ppm: 1.46 (9H, s), 1.60-1.77 (2H, m), 1.80-1.95 (2H, m), 3.20-3.80 (6H, m), 4.21-4.30 (1H, m), 6.58-6.67 (2H, m), 6.72-6.80 (2H, m) | |
With hydrogen;palladium 10% on activated carbon; In methanol; ethanol; water; under 2223.8 Torr; | C. A slurry of 4-(N-(t-butoxycarbonyl)piperidin-4-yl)oxy-1-nitrobenzene (15.1 g, 46.8 mmol) in absolute ethanol (500 mL) and methanol (200 mL) was purged with nitrogen, treated with 10% palladium on carbon (1.2 g, 50% water by wt.) and placed on a Parr Hydrogenator under 43 psi of hydrogen gas. The catalyst was removed by filtration. Solvent removal under reduced pressure gave a solid after drying. Purification by flash silica gel chromatography using a step gradient of 50 to 85% ethyl acetate in hexane gave 11.7 g of 4-(N-(t-butoxycarbonyl)piperidin-4-yl)oxybenzenamine, NMR (CDCl3, TMS) delta1.45 (s, 9), 1.7 (m, 2), 1.86 (m, 2), 3.25 (m, 2), 3.68 (m, 2), 4.25 (m, 1), 6.63 (m, 2), 6.76 (m, 2). | |
With hydrogen;50percent Raney nickel (Ra-Ni) (aqueous slurry); In ethanol; N,N-dimethyl-formamide; under 1965.21 Torr; for 0.5h; | A suspension of compound 9 (20 g, 0.062 mol) in DMF (40 mL) and EtOH (130 mL) was mixed with a half-teaspoonful of 50% Raney Nickel (aqueous slurry) and hydrogenated at 38 psi for 0.5 h. The spent catalyst was filtered off, and the filtrate was concentrated to a solid which was triturated with ether-hexane (1:2) and filtered to produce 17 g of compound 10. | |
With palladium 10% on activated carbon; hydrogen; In ethanol; at 20℃; for 18h; | [4967] A solution of tert-butyl 4-(4-nitrophenoxy)piperidine- 1 -carboxylate ( 1 .560 g, 4.839 mmol) in ethanol ( 100 mL) was slowly added dropwise at the room temperature with 10 -Pd/C (200 mg), stirred at the same temperature under the hygdrogen atmosphere (H: balloon) for 18 hr, filtered through a celite pad to remove solids, and concentrated under the reduced pressure. The concentrate was purified and concentrated by column chromatography (Si02, 24 g cartridge; ethyl acetate / hexane = 0 % to 50 %) to give tert-butyl 4-(4-aminophenoxy)piperidine- l-carboxylate as brown oil ( 1 .420 g, 100.4 %). | |
With hydrogen; | 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- <n="229"/>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 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With potassium <i>tert</i>-butylate In tetrahydrofuran at 20℃; for 0.0833333h; Inert atmosphere; | 1.A STEP A: tert-But l 4-(4-nitrophenoxy)piperidine-l-carboxylate, la To a solution of l-fluoro-4-nitrobenzene (5.26 g, 37.26 mmol) in THF (135 mL) at room temperature under nitrogen, was added l-Boc-4-hydroxypiperidine (5.0 g, 24.84 mmol). Potassium t-butoxide (5.58 g, 49.7 mmol) was added portionwise and the mixture was stirred at room temperature for 5 min. The crude mixture was poured onto water and extracted with EtOAc. The organic layer was dried over MgS04, filtered, and concentrated to dryness. The residue was purified by flash chromatography over silica gel (EtO Ac- heptane gradient from 5% to 30%). Pure fractions were combined, concentrated, and dried under high vacuum to give compound la (8.0 g, 99%). MS m/z 266.9 (M+H-tBu)+. |
98% | With potassium <i>tert</i>-butylate In dimethyl sulfoxide at 20℃; for 2h; | |
97.5% | With potassium hydroxide In water at 35℃; for 17h; | 1 4-Hydroxy-1-piperidine-1-carboxylic acid tert-butyl ester (6.04 g, 30 mmol) is dissolved in 1-fluoro-4-nitrobenzene (7.83 g, 55.5 mmol). Then an aqueous potassium hydroxide solution (25% wt, 44 mL) is added, followed by addition of tetrabutylammonium bromide (1.26 g). The reaction mixture is stirred at 35°C for 17 h The yellow solid is collected by filtration, washed with water (4 x 50 mL). A yellow powder is obtained (9.43 g, 97.5 % yield). |
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; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | Stage #1: (trimethylsilyl)methylmagnesium chloride; tert-butyl 4-(4-nitrophenoxy)piperidine-1-carboxylate In tetrahydrofuran; diethyl ether at -5℃; Stage #2: With 2,3-dicyano-5,6-dichloro-p-benzoquinone In tetrahydrofuran; diethyl ether at 0℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: H2 / Pd/C / ethanol; tetrahydrofuran / 3 h / 20 °C / 2280 Torr 2: aq. NaHCO3 / tetrahydrofuran / 1 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: H2 / Pd/C / ethanol; tetrahydrofuran / 3 h / 20 °C / 2280 Torr 2: aq. NaHCO3 / tetrahydrofuran / 1 h / 20 °C 3: NaH / dimethylformamide / 2 h / 20 °C 4: NaOH / tetrahydrofuran; ethanol / 1 h / 50 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: H2 / Pd/C / ethanol; tetrahydrofuran / 3 h / 20 °C / 2280 Torr 2: aq. NaHCO3 / tetrahydrofuran / 1 h / 20 °C 3: NaH / dimethylformamide / 2 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1: H2 / Pd/C / ethanol; tetrahydrofuran / 3 h / 20 °C / 2280 Torr 2: aq. NaHCO3 / tetrahydrofuran / 1 h / 20 °C 3: NaH / dimethylformamide / 2 h / 20 °C 4: NaOH / tetrahydrofuran; ethanol / 1 h / 50 °C 5: 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline / CHCl3 / 3 h / 20 °C 6: AcOH / 96 h / 90 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 9 steps 1: H2 / Pd/C / ethanol; tetrahydrofuran / 3 h / 20 °C / 2280 Torr 2: aq. NaHCO3 / tetrahydrofuran / 1 h / 20 °C 3: NaH / dimethylformamide / 2 h / 20 °C 4: NaOH / tetrahydrofuran; ethanol / 1 h / 50 °C 5: 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline / CHCl3 / 3 h / 20 °C 6: AcOH / 96 h / 90 °C 7: aq. Na2CO3 / tetrahydrofuran / 12 h / 20 °C 8: EDC; HOBt / dimethylformamide / 15 h / 20 °C 9: H2 / Pd/C / tetrahydrofuran / 7 h / 20 °C / 2280 Torr |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 9 steps 1: H2 / Pd/C / ethanol; tetrahydrofuran / 3 h / 20 °C / 2280 Torr 2: aq. NaHCO3 / tetrahydrofuran / 1 h / 20 °C 3: NaH / dimethylformamide / 2 h / 20 °C 4: NaOH / tetrahydrofuran; ethanol / 1 h / 50 °C 5: 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline / CHCl3 / 3 h / 20 °C 6: AcOH / 96 h / 90 °C 7: aq. Na2CO3 / tetrahydrofuran / 12 h / 20 °C 8: EDC; HOBt / dimethylformamide / 15 h / 20 °C 9: H2 / Pd/C / tetrahydrofuran / 7 h / 20 °C / 2280 Torr |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 9 steps 1: H2 / Pd/C / ethanol; tetrahydrofuran / 3 h / 20 °C / 2280 Torr 2: aq. NaHCO3 / tetrahydrofuran / 1 h / 20 °C 3: NaH / dimethylformamide / 2 h / 20 °C 4: NaOH / tetrahydrofuran; ethanol / 1 h / 50 °C 5: 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline / CHCl3 / 3 h / 20 °C 6: AcOH / 96 h / 90 °C 7: aq. Na2CO3 / tetrahydrofuran / 12 h / 20 °C 8: EDC; HOBt / dimethylformamide / 15 h / 20 °C 9: H2 / Pd/C / tetrahydrofuran / 7 h / 20 °C / 2280 Torr |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 9 steps 1: H2 / Pd/C / ethanol; tetrahydrofuran / 3 h / 20 °C / 2280 Torr 2: aq. NaHCO3 / tetrahydrofuran / 1 h / 20 °C 3: NaH / dimethylformamide / 2 h / 20 °C 4: NaOH / tetrahydrofuran; ethanol / 1 h / 50 °C 5: 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline / CHCl3 / 3 h / 20 °C 6: AcOH / 96 h / 90 °C 7: aq. Na2CO3 / tetrahydrofuran / 12 h / 20 °C 8: EDC; HOBt / dimethylformamide / 15 h / 20 °C 9: H2 / Pd/C / tetrahydrofuran / 7 h / 20 °C / 2280 Torr |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 9 steps 1: H2 / Pd/C / ethanol; tetrahydrofuran / 3 h / 20 °C / 2280 Torr 2: aq. NaHCO3 / tetrahydrofuran / 1 h / 20 °C 3: NaH / dimethylformamide / 2 h / 20 °C 4: NaOH / tetrahydrofuran; ethanol / 1 h / 50 °C 5: 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline / CHCl3 / 3 h / 20 °C 6: AcOH / 96 h / 90 °C 7: aq. Na2CO3 / tetrahydrofuran / 12 h / 20 °C 8: EDC; HOBt / dimethylformamide / 15 h / 20 °C 9: H2 / Pd/C / tetrahydrofuran / 7 h / 20 °C / 2280 Torr |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 7 steps 1: H2 / Pd/C / ethanol; tetrahydrofuran / 3 h / 20 °C / 2280 Torr 2: aq. NaHCO3 / tetrahydrofuran / 1 h / 20 °C 3: NaH / dimethylformamide / 2 h / 20 °C 4: NaOH / tetrahydrofuran; ethanol / 1 h / 50 °C 5: 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline / CHCl3 / 3 h / 20 °C 6: AcOH / 96 h / 90 °C 7: aq. Na2CO3 / tetrahydrofuran / 12 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 9 steps 1: H2 / Pd/C / ethanol; tetrahydrofuran / 3 h / 20 °C / 2280 Torr 2: aq. NaHCO3 / tetrahydrofuran / 1 h / 20 °C 3: NaH / dimethylformamide / 2 h / 20 °C 4: NaOH / tetrahydrofuran; ethanol / 1 h / 50 °C 5: 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline / CHCl3 / 3 h / 20 °C 6: AcOH / 96 h / 90 °C 7: aq. Na2CO3 / tetrahydrofuran / 12 h / 20 °C 8: EDC; HOBt / dimethylformamide / 15 h / 20 °C 9: H2 / Pd/C / tetrahydrofuran / 7 h / 20 °C / 2280 Torr |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: H2 / Pd/C / ethanol; tetrahydrofuran / 3 h / 20 °C / 2280 Torr 2: aq. NaHCO3 / tetrahydrofuran / 1 h / 20 °C 3: NaH / dimethylformamide / 2 h / 20 °C 4: NaOH / tetrahydrofuran; ethanol / 1 h / 50 °C 5: 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline / CHCl3 / 3 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 14 steps 1.1: H2 / Pd/C / ethanol; tetrahydrofuran / 3 h / 20 °C / 2280 Torr 2.1: aq. NaHCO3 / tetrahydrofuran / 1 h / 20 °C 3.1: NaH / dimethylformamide / 2 h / 20 °C 4.1: NaOH / tetrahydrofuran; ethanol / 1 h / 50 °C 5.1: 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline / CHCl3 / 3 h / 20 °C 6.1: AcOH / 96 h / 90 °C 7.1: aq. Na2CO3 / tetrahydrofuran / 12 h / 20 °C 8.1: EDC; HOBt / dimethylformamide / 15 h / 20 °C 9.1: H2 / Pd/C / tetrahydrofuran / 7 h / 20 °C / 2280 Torr 10.1: Et3N / CHCl3 / 18 h / 20 °C 11.1: H2S; pyridine; Et3N / 12 h / 20 °C 12.1: MeI / acetone; methanol / 1 h / Heating 12.2: NH4OAc / ethanol / 3 h / 75 °C 13.1: TFA / CHCl3 / 0.08 h / 20 °C 14.1: aq. NaOH / 5 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 14 steps 1.1: H2 / Pd/C / ethanol; tetrahydrofuran / 3 h / 20 °C / 2280 Torr 2.1: aq. NaHCO3 / tetrahydrofuran / 1 h / 20 °C 3.1: NaH / dimethylformamide / 2 h / 20 °C 4.1: NaOH / tetrahydrofuran; ethanol / 1 h / 50 °C 5.1: 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline / CHCl3 / 3 h / 20 °C 6.1: AcOH / 96 h / 90 °C 7.1: aq. Na2CO3 / tetrahydrofuran / 12 h / 20 °C 8.1: EDC; HOBt / dimethylformamide / 15 h / 20 °C 9.1: H2 / Pd/C / tetrahydrofuran / 7 h / 20 °C / 2280 Torr 10.1: Et3N / CHCl3 / 18 h / 20 °C 11.1: H2S; pyridine; Et3N / 12 h / 20 °C 12.1: MeI / acetone; methanol / 1 h / Heating 12.2: NH4OAc / ethanol / 3 h / 75 °C 13.1: TFA / CHCl3 / 0.08 h / 20 °C 14.1: aq. NaOH / 5 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 8 steps 1: H2 / Pd/C / ethanol; tetrahydrofuran / 3 h / 20 °C / 2280 Torr 2: aq. NaHCO3 / tetrahydrofuran / 1 h / 20 °C 3: NaH / dimethylformamide / 2 h / 20 °C 4: NaOH / tetrahydrofuran; ethanol / 1 h / 50 °C 5: 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline / CHCl3 / 3 h / 20 °C 6: AcOH / 96 h / 90 °C 7: aq. Na2CO3 / tetrahydrofuran / 12 h / 20 °C 8: EDC; HOBt / dimethylformamide / 15 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 13 steps 1.1: H2 / Pd/C / ethanol; tetrahydrofuran / 3 h / 20 °C / 2280 Torr 2.1: aq. NaHCO3 / tetrahydrofuran / 1 h / 20 °C 3.1: NaH / dimethylformamide / 2 h / 20 °C 4.1: NaOH / tetrahydrofuran; ethanol / 1 h / 50 °C 5.1: 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline / CHCl3 / 3 h / 20 °C 6.1: AcOH / 96 h / 90 °C 7.1: aq. Na2CO3 / tetrahydrofuran / 12 h / 20 °C 8.1: EDC; HOBt / dimethylformamide / 15 h / 20 °C 9.1: H2 / Pd/C / tetrahydrofuran / 7 h / 20 °C / 2280 Torr 10.1: Et3N / CHCl3 / 18 h / 20 °C 11.1: H2S; pyridine; Et3N / 12 h / 20 °C 12.1: MeI / acetone; methanol / 1 h / Heating 12.2: NH4OAc / ethanol / 3 h / 75 °C 13.1: TFA / CHCl3 / 0.08 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 13 steps 1.1: H2 / Pd/C / ethanol; tetrahydrofuran / 3 h / 20 °C / 2280 Torr 2.1: aq. NaHCO3 / tetrahydrofuran / 1 h / 20 °C 3.1: NaH / dimethylformamide / 2 h / 20 °C 4.1: NaOH / tetrahydrofuran; ethanol / 1 h / 50 °C 5.1: 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline / CHCl3 / 3 h / 20 °C 6.1: AcOH / 96 h / 90 °C 7.1: aq. Na2CO3 / tetrahydrofuran / 12 h / 20 °C 8.1: EDC; HOBt / dimethylformamide / 15 h / 20 °C 9.1: H2 / Pd/C / tetrahydrofuran / 7 h / 20 °C / 2280 Torr 10.1: Et3N / CHCl3 / 18 h / 20 °C 11.1: H2S; pyridine; Et3N / 12 h / 20 °C 12.1: MeI / acetone; methanol / 1 h / Heating 12.2: NH4OAc / ethanol / 3 h / 75 °C 13.1: TFA / CHCl3 / 0.08 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 8 steps 1: H2 / Pd/C / ethanol; tetrahydrofuran / 3 h / 20 °C / 2280 Torr 2: aq. NaHCO3 / tetrahydrofuran / 1 h / 20 °C 3: NaH / dimethylformamide / 2 h / 20 °C 4: NaOH / tetrahydrofuran; ethanol / 1 h / 50 °C 5: 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline / CHCl3 / 3 h / 20 °C 6: AcOH / 96 h / 90 °C 7: aq. Na2CO3 / tetrahydrofuran / 12 h / 20 °C 8: EDC; HOBt / dimethylformamide / 15 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 8 steps 1: H2 / Pd/C / ethanol; tetrahydrofuran / 3 h / 20 °C / 2280 Torr 2: aq. NaHCO3 / tetrahydrofuran / 1 h / 20 °C 3: NaH / dimethylformamide / 2 h / 20 °C 4: NaOH / tetrahydrofuran; ethanol / 1 h / 50 °C 5: 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline / CHCl3 / 3 h / 20 °C 6: AcOH / 96 h / 90 °C 7: aq. Na2CO3 / tetrahydrofuran / 12 h / 20 °C 8: EDC; HOBt / dimethylformamide / 15 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 13 steps 1.1: H2 / Pd/C / ethanol; tetrahydrofuran / 3 h / 20 °C / 2280 Torr 2.1: aq. NaHCO3 / tetrahydrofuran / 1 h / 20 °C 3.1: NaH / dimethylformamide / 2 h / 20 °C 4.1: NaOH / tetrahydrofuran; ethanol / 1 h / 50 °C 5.1: 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline / CHCl3 / 3 h / 20 °C 6.1: AcOH / 96 h / 90 °C 7.1: aq. Na2CO3 / tetrahydrofuran / 12 h / 20 °C 8.1: EDC; HOBt / dimethylformamide / 15 h / 20 °C 9.1: H2 / Pd/C / tetrahydrofuran / 7 h / 20 °C / 2280 Torr 10.1: Et3N / CHCl3 / 18 h / 20 °C 11.1: H2S; pyridine; Et3N / 12 h / 20 °C 12.1: MeI / acetone; methanol / 1 h / Heating 12.2: NH4OAc / ethanol / 3 h / 75 °C 13.1: TFA / CHCl3 / 0.08 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 14 steps 1.1: H2 / Pd/C / ethanol; tetrahydrofuran / 3 h / 20 °C / 2280 Torr 2.1: aq. NaHCO3 / tetrahydrofuran / 1 h / 20 °C 3.1: NaH / dimethylformamide / 2 h / 20 °C 4.1: NaOH / tetrahydrofuran; ethanol / 1 h / 50 °C 5.1: 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline / CHCl3 / 3 h / 20 °C 6.1: AcOH / 96 h / 90 °C 7.1: aq. Na2CO3 / tetrahydrofuran / 12 h / 20 °C 8.1: EDC; HOBt / dimethylformamide / 15 h / 20 °C 9.1: H2 / Pd/C / tetrahydrofuran / 7 h / 20 °C / 2280 Torr 10.1: Et3N / CHCl3 / 18 h / 20 °C 11.1: H2S; pyridine; Et3N / 12 h / 20 °C 12.1: MeI / acetone; methanol / 1 h / Heating 12.2: NH4OAc / ethanol / 3 h / 75 °C 13.1: TFA / CHCl3 / 0.08 h / 20 °C 14.1: aq. NaOH / 5 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 8 steps 1: H2 / Pd/C / ethanol; tetrahydrofuran / 3 h / 20 °C / 2280 Torr 2: aq. NaHCO3 / tetrahydrofuran / 1 h / 20 °C 3: NaH / dimethylformamide / 2 h / 20 °C 4: NaOH / tetrahydrofuran; ethanol / 1 h / 50 °C 5: 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline / CHCl3 / 3 h / 20 °C 6: AcOH / 96 h / 90 °C 7: aq. Na2CO3 / tetrahydrofuran / 12 h / 20 °C 8: EDC; HOBt / dimethylformamide / 15 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 13 steps 1.1: H2 / Pd/C / ethanol; tetrahydrofuran / 3 h / 20 °C / 2280 Torr 2.1: aq. NaHCO3 / tetrahydrofuran / 1 h / 20 °C 3.1: NaH / dimethylformamide / 2 h / 20 °C 4.1: NaOH / tetrahydrofuran; ethanol / 1 h / 50 °C 5.1: 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline / CHCl3 / 3 h / 20 °C 6.1: AcOH / 96 h / 90 °C 7.1: aq. Na2CO3 / tetrahydrofuran / 12 h / 20 °C 8.1: EDC; HOBt / dimethylformamide / 15 h / 20 °C 9.1: H2 / Pd/C / tetrahydrofuran / 7 h / 20 °C / 2280 Torr 10.1: Et3N / CHCl3 / 18 h / 20 °C 11.1: H2S; pyridine; Et3N / 12 h / 20 °C 12.1: MeI / acetone; methanol / 1 h / Heating 12.2: NH4OAc / ethanol / 3 h / 75 °C 13.1: TFA / CHCl3 / 0.08 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 8 steps 1: H2 / Pd/C / ethanol; tetrahydrofuran / 3 h / 20 °C / 2280 Torr 2: aq. NaHCO3 / tetrahydrofuran / 1 h / 20 °C 3: NaH / dimethylformamide / 2 h / 20 °C 4: NaOH / tetrahydrofuran; ethanol / 1 h / 50 °C 5: 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline / CHCl3 / 3 h / 20 °C 6: AcOH / 96 h / 90 °C 7: aq. Na2CO3 / tetrahydrofuran / 12 h / 20 °C 8: EDC; HOBt / dimethylformamide / 15 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 14 steps 1.1: H2 / Pd/C / ethanol; tetrahydrofuran / 3 h / 20 °C / 2280 Torr 2.1: aq. NaHCO3 / tetrahydrofuran / 1 h / 20 °C 3.1: NaH / dimethylformamide / 2 h / 20 °C 4.1: NaOH / tetrahydrofuran; ethanol / 1 h / 50 °C 5.1: 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline / CHCl3 / 3 h / 20 °C 6.1: AcOH / 96 h / 90 °C 7.1: aq. Na2CO3 / tetrahydrofuran / 12 h / 20 °C 8.1: EDC; HOBt / dimethylformamide / 15 h / 20 °C 9.1: H2 / Pd/C / tetrahydrofuran / 7 h / 20 °C / 2280 Torr 10.1: Et3N / CHCl3 / 18 h / 20 °C 11.1: H2S; pyridine; Et3N / 12 h / 20 °C 12.1: MeI / acetone; methanol / 1 h / Heating 12.2: NH4OAc / ethanol / 3 h / 75 °C 13.1: TFA / CHCl3 / 0.08 h / 20 °C 14.1: aq. NaOH / 5 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 14 steps 1.1: H2 / Pd/C / ethanol; tetrahydrofuran / 3 h / 20 °C / 2280 Torr 2.1: aq. NaHCO3 / tetrahydrofuran / 1 h / 20 °C 3.1: NaH / dimethylformamide / 2 h / 20 °C 4.1: NaOH / tetrahydrofuran; ethanol / 1 h / 50 °C 5.1: 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline / CHCl3 / 3 h / 20 °C 6.1: AcOH / 96 h / 90 °C 7.1: aq. Na2CO3 / tetrahydrofuran / 12 h / 20 °C 8.1: EDC; HOBt / dimethylformamide / 15 h / 20 °C 9.1: H2 / Pd/C / tetrahydrofuran / 7 h / 20 °C / 2280 Torr 10.1: Et3N / CHCl3 / 18 h / 20 °C 11.1: H2S; pyridine; Et3N / 12 h / 20 °C 12.1: MeI / acetone; methanol / 1 h / Heating 12.2: NH4OAc / ethanol / 3 h / 75 °C 13.1: TFA / CHCl3 / 0.08 h / 20 °C 14.1: aq. NaOH / 5 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 10 steps 1: H2 / Pd/C / ethanol; tetrahydrofuran / 3 h / 20 °C / 2280 Torr 2: aq. NaHCO3 / tetrahydrofuran / 1 h / 20 °C 3: NaH / dimethylformamide / 2 h / 20 °C 4: NaOH / tetrahydrofuran; ethanol / 1 h / 50 °C 5: 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline / CHCl3 / 3 h / 20 °C 6: AcOH / 96 h / 90 °C 7: aq. Na2CO3 / tetrahydrofuran / 12 h / 20 °C 8: EDC; HOBt / dimethylformamide / 15 h / 20 °C 9: H2 / Pd/C / tetrahydrofuran / 7 h / 20 °C / 2280 Torr 10: Et3N / CHCl3 / 18 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 10 steps 1: H2 / Pd/C / ethanol; tetrahydrofuran / 3 h / 20 °C / 2280 Torr 2: aq. NaHCO3 / tetrahydrofuran / 1 h / 20 °C 3: NaH / dimethylformamide / 2 h / 20 °C 4: NaOH / tetrahydrofuran; ethanol / 1 h / 50 °C 5: 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline / CHCl3 / 3 h / 20 °C 6: AcOH / 96 h / 90 °C 7: aq. Na2CO3 / tetrahydrofuran / 12 h / 20 °C 8: EDC; HOBt / dimethylformamide / 15 h / 20 °C 9: H2 / Pd/C / tetrahydrofuran / 7 h / 20 °C / 2280 Torr 10: Et3N / CHCl3 / 18 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 10 steps 1: H2 / Pd/C / ethanol; tetrahydrofuran / 3 h / 20 °C / 2280 Torr 2: aq. NaHCO3 / tetrahydrofuran / 1 h / 20 °C 3: NaH / dimethylformamide / 2 h / 20 °C 4: NaOH / tetrahydrofuran; ethanol / 1 h / 50 °C 5: 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline / CHCl3 / 3 h / 20 °C 6: AcOH / 96 h / 90 °C 7: aq. Na2CO3 / tetrahydrofuran / 12 h / 20 °C 8: EDC; HOBt / dimethylformamide / 15 h / 20 °C 9: H2 / Pd/C / tetrahydrofuran / 7 h / 20 °C / 2280 Torr 10: Et3N / CHCl3 / 18 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 13 steps 1.1: H2 / Pd/C / ethanol; tetrahydrofuran / 3 h / 20 °C / 2280 Torr 2.1: aq. NaHCO3 / tetrahydrofuran / 1 h / 20 °C 3.1: NaH / dimethylformamide / 2 h / 20 °C 4.1: NaOH / tetrahydrofuran; ethanol / 1 h / 50 °C 5.1: 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline / CHCl3 / 3 h / 20 °C 6.1: AcOH / 96 h / 90 °C 7.1: aq. Na2CO3 / tetrahydrofuran / 12 h / 20 °C 8.1: EDC; HOBt / dimethylformamide / 15 h / 20 °C 9.1: H2 / Pd/C / tetrahydrofuran / 7 h / 20 °C / 2280 Torr 10.1: Et3N / CHCl3 / 18 h / 20 °C 11.1: H2S; pyridine; Et3N / 12 h / 20 °C 12.1: MeI / acetone; methanol / 1 h / Heating 12.2: NH4OAc / ethanol / 3 h / 75 °C 13.1: TFA / CHCl3 / 0.08 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 13 steps 1.1: H2 / Pd/C / ethanol; tetrahydrofuran / 3 h / 20 °C / 2280 Torr 2.1: aq. NaHCO3 / tetrahydrofuran / 1 h / 20 °C 3.1: NaH / dimethylformamide / 2 h / 20 °C 4.1: NaOH / tetrahydrofuran; ethanol / 1 h / 50 °C 5.1: 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline / CHCl3 / 3 h / 20 °C 6.1: AcOH / 96 h / 90 °C 7.1: aq. Na2CO3 / tetrahydrofuran / 12 h / 20 °C 8.1: EDC; HOBt / dimethylformamide / 15 h / 20 °C 9.1: H2 / Pd/C / tetrahydrofuran / 7 h / 20 °C / 2280 Torr 10.1: Et3N / CHCl3 / 18 h / 20 °C 11.1: H2S; pyridine; Et3N / 12 h / 20 °C 12.1: MeI / acetone; methanol / 1 h / Heating 12.2: NH4OAc / ethanol / 3 h / 75 °C 13.1: TFA / CHCl3 / 0.08 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: H2 / 10 percent Pd/C / methanol / 760 Torr 2: pyridine | ||
Multi-step reaction with 2 steps 1: 98 percent / H2 / 10 percent Pd/C / ethanol / 15 h / 20 °C 2: 79 percent / pyridine / 15 h / 3 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: H2 / 10 percent Pd/C / methanol / 760 Torr 2: NaBH(OAc)3; AcOH / CH2Cl2 | ||
Multi-step reaction with 2 steps 1: 98 percent / H2 / 10 percent Pd/C / ethanol / 15 h / 20 °C 2: 79 percent / NaB(OAc)3H / CH2Cl2; acetic acid / 0.75 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: H2 / 10 percent Pd/C / methanol / 760 Torr 2: pyridine 3: Cs2CO3 / dimethylformamide | ||
Multi-step reaction with 3 steps 1: 98 percent / H2 / 10 percent Pd/C / ethanol / 15 h / 20 °C 2: 79 percent / NaB(OAc)3H / CH2Cl2; acetic acid / 0.75 h / 20 °C 3: 90 percent / pyridine / 15 h / 3 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1.1: H2 / 10 percent Pd/C / methanol / 760 Torr 2.1: NaBH(OAc)3; AcOH / CH2Cl2 3.1: pyridine 4.1: NH2OH / ethanol 5.1: acetic anhydride; acetic acid 5.2: H2 / 10 percent Pd/C / methanol / 760 Torr 6.1: TFA / CH2Cl2 | ||
Multi-step reaction with 4 steps 1.1: 98 percent / H2 / 10 percent Pd/C / ethanol / 15 h / 20 °C 2.1: 79 percent / NaB(OAc)3H / CH2Cl2; acetic acid / 0.75 h / 20 °C 3.1: 62 percent / pyridine / 15 h / 3 °C 4.1: HCl gas / ethanol; CHCl3 / 30 h / 5 °C 4.2: ammonium acetate / ethanol; CHCl3 / 16 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: H2 / 10 percent Pd/C / methanol / 760 Torr 2: NaBH(OAc)3; AcOH / CH2Cl2 3: pyridine | ||
Multi-step reaction with 3 steps 1: 98 percent / H2 / 10 percent Pd/C / ethanol / 15 h / 20 °C 2: 79 percent / NaB(OAc)3H / CH2Cl2; acetic acid / 0.75 h / 20 °C 3: 62 percent / pyridine / 15 h / 3 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | Stage #1: tert-butyl 4-(4-nitrophenoxy)piperidine-1-carboxylate With trifluoroacetic acid at 20℃; for 1h; Stage #2: With sodium hydroxide In water; ethyl acetate | 1.2 Production of 4-(4-piperidinyl)oxy-1-nitrobenzene Example 1-2 Production of 4-(4-piperidinyl)oxy-1-nitrobenzene 4-(4-Piperidinyl)oxy-N-tert-butoxycarbonyl-1-nitrobenzene (10.9 g, 33.8 mmol) was dissolved in trifluoroacetic acid (30 mL), and stirred at room temperature for 1 hour. The excessive trifluoroacetic acid was evaporated off under reduced pressure, and ethyl acetate (150 mL) and aqueous 2 N sodium hydroxide solution (100 mL) were added to the residue. (In this stage, the aqueous layer was confirmed to have a pH of at least 9.) The resulting mixture was extracted twice with ethyl acetate, and the organic layer was washed with aqueous 1 N sodium hydroxide solution and saturated saline in that order, and dried with anhydrous sodium sulfate. After filtered, the organic layer was concentrated, and the residue was dried under reduced pressure to obtain 4-(4-piperidinyl)oxy-1-nitrobenzene (7.5 g, quantitative) as a brown oil. ESI m/z: 223.1 [M+H]+ 1H-NMR (400 MHz, CDCl3, δ ppm): 1.70-1.79 (2H, m), 2.03-2.09 (2H, m), 2.23 (1H, brs), 2.77-2.83 (2H, m), 3.14-3.20 (2H, m), 4.49-4.55 (1H, m), 6.95 (2H, d, J=9.3 Hz), 8.19 (2H, d, J=9.3 Hz). |
100% | Stage #1: tert-butyl 4-(4-nitrophenoxy)piperidine-1-carboxylate With trifluoroacetic acid at 20℃; for 1h; Stage #2: With sodium hydroxide In water; ethyl acetate | 1-2 Production of 4-(4-piperidinyl)oxy-1-nitrobenzene Production of 4-(4-piperidinyl)oxy-1-nitrobenzene 4-(4-Piperidinyl)oxy-N-tert-butoxycarbonyl-1-nitrobenzene (10.9 g. 33.8 mmol) was dissolved in trifluoroacetic acid (30 mL), and stirred at room temperature for 1 hour. The excessive trifluoroacetic acid was evaporated off under reduced pressure, and ethyl acetate (150 mL) and aqueous 2 N sodium hydroxide solution (100 mL) were added to the residue. (In this stage, the aqueous layer was confirmed to have a pH of at least 9.) The resulting mixture was extracted twice with ethyl acetate, and the organic layer was washed with aqueous 1 N sodium hydroxide solution and saturated saline in that order, and dried with anhydrous sodium sulfate. After filtered, the organic layer was concentrated, and the residue was dried under reduced pressure to obtain 4-(4-piperidinyl)oxy-1-nitrobenzene (7.5 g, quantitative) as a brown oil. ESI m/z: 223.1 [M+H]+ 1H-NMR (400 MHz, CDCl3, δ ppm): 1.70-1.79 (2H, m), 2.03-2.09 (2H, m), 2.23 (1H, brs), 2.77-2.83 (2H, m), 3.14-3.20 (2H, m), 4.49-4.55 (1 H, m), 6.95 (2H, d, J-9.3 Hz), 8.19 (2H, d, J- 9.3 Hz). |
99% | With trifluoroacetic acid at 20℃; for 1h; |
96% | With trifluoroacetic acid In dichloromethane at 20℃; for 8h; | Preparation of 4-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]oxy}aniline. tert-butyl 4-(4-nitrophenoxy)piperidine-1-carboxylate (1.63 g, 4.97 mmol) was dissolved in a mixture of DCM (25 mL) and TFA (5 mL). The reaction was left stirring at room temperature 8 h, then the mixture was concentrated in vacuo and the residue was passed through an SCX cartridge eluting with NH37N in MeOH. The solvent was removed in vacuo to give 4- (4-nitrophenoxy)piperidine (1.062 g, 96% yield). MS found for C11H14N2O3 as (M+H)+ 222.93. |
92% | With trifluoroacetic acid In dichloromethane at 20℃; | 4-(4-Nitrophenoxy)piperidine (16) A mixture of 15 (1 g, 3.1 mmol) in CH2Cl2 (10 mL) was addedtrifluoroacetic acid (2.5 mL), and stirred overnight at ambient temperature. The mixture was concentrated to dryness and theresiduewas partitioned between ethyl acetate (20 mL) and 2.0 mol/L NaOH (20 mL). The combined organic layers were washed withbrine, dried over Na2SO4, and concentrated to afford 665 mg 16 aspale-yellow liquid, yield 92%. 1H NMR (500 MHz, CDCl3): d 8.21 (d,J 9.0 Hz, 2H), 6.96 (d, J 9.0 Hz, 2H), 4.56e4.52 (m, 2H), 3.21e3.16(m, 2H), 2.86e2.82 (m, 2H), 2.11e2.06 (m, 2H), 1.81e1.74 (m, 2H).ESI-MS: m/z 223.1 [MH]. |
87% | ||
With trifluoroacetic acid In dichloromethane at 20℃; for 0.5h; | 1.A Tert-butyl 4-(4-nitrophenoxy)piperidine-1 -carboxylate (3.10mmol, 1g) was dissolved in dichloromethane (10ml_). Trifluoroacetic acid (3ml_) was added and the reaction was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under vacuum and purified by SCX chromatography to afford the title compound (600mg). MS (ESI) m/z 223.3 [M+H]+ | |
With trifluoroacetic acid In dichloromethane at 0℃; for 3h; | 3.2.8. General Procedure for the Synthesis of 4-(4-Nitrophenoxy)piperidine (11) A mixture of 9 (5.0 mmol), 4-nitrophenol 10 (5.5 mmol), and K2CO3 (10.0 mmol) in DMF (15 mL) was heated to 100 °C for 10 h. After the reaction was completed, the K2CO3 was removed by filtration. The filtrate was poured into ice water and extracted with DCM, saturated NaHCO3, and brine, and the combined organic layer was dried with MgSO4. Finally, the solvent was removed under reduced pressure to give the crude. A solution of the above crude solid (1.0 mmol) in 1 mL TFA/DCM (v/v = 1/1) was stirred for 3 h at 0 °C, then allowed to warm to room temperature. After the reaction was completed, the solvent was removed under reduced pressure. The residue was slowly made alkaline with 2 N NaOH, then the precipitate formed was collected by filtration and washed with water to afford the crude product 11 without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | In tetrahydrofuran; 4-HYDROXYPIPERIDINE; water; ethyl acetate | 63 63.1 1,1-dimethylethyl 4-(4-nitrophenoxy)-1-piperidinecarboxylate: 63.1 1,1-dimethylethyl 4-(4-nitrophenoxy)-1-piperidinecarboxylate: A solution of 2.01 g (10 mmol) of N-Boc-4-hydroxypiperidine (prepared in a standard fashion starting from commercial 4-hydroxypiperidine) in 10 ml of dry THF is added dropwise to a solution of 1.23 g (11 mmol) of tBuO-K+in 10 ml of dry THF in a three necked flask, under an inert atmosphere, cooled by an ice bath. After agitation for 30 minutes at 0° C., a solution of 1.06 ml (10 mmol) of 4-fluoronitrobenzene in 10 ml of dry THF is added dropwise. The reaction mixture is agitated for 5 hours at 23° C. and finally poured into 25 ml of a water+ice mixture. The product is extracted using 50 ml of ethyl acetate. After decantation, the organic phase is washed twice with 25 ml of water and 25 ml of salt water. The organic solution is dried over magnesium sulphate, followed by filtration and concentration of the filtrate under vacuum to produce a residue which is purified on a silica column (eluant: heptane/ethyl acetate: 8/2). The pure fractions are collected and evaporated under vacuum. The expected product is obtained in the form of a pale yellow powder with a yield of 47%. Melting point: 97-98° C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | In 1,4-dioxane; diethyl ether | 13.C Preparation of tetrahydro-N-hydroxy-4-[[4-(4-nitrophenoxy)-1-piperidinyl]sulfonyl]-2H-pyran-4-carboxamide Part C: Preparation of 4-(4-nitrophenoxy)piperidine, monohydrochloride. To a slurry of the substituted BOC piperidine from part B (6.44 g, 20 mmol) in 1,4-dioxane (5 mL) was added 4 N HCl dioxane solution (20 mL). After two hr at ambient temperature the reaction was concentrated in vacuo. The residue was slurried in diethyl ether and vacuum filtration of the resulting precipitate provided the hydrochloride salt as a light yellow solid (5.2 g, 100%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | In hexane; N,N-dimethyl acetamide | R.4 4-(1-t-Butoxycarbonylpiperidin-4-yloxy)nitrobenzene Reference Example 4 4-(1-t-Butoxycarbonylpiperidin-4-yloxy)nitrobenzene To a suspension of sodium hydride (2.2 g) washed with hexane in N,N-dimethylacetamide (150 ml) was added 1-t-butoxycarbonyl-4-hydroxypiperidine (10.1 g) in an ice bath and the mixture was stirred at room temperature for 2 hours. To the reaction mixture was added 4-fluoronitrobenzene over 20 minutes, and the dark brown reaction solution was stirred for 4 hours. To the reaction mixture was added saturated aqueous ammonium chloride in order to stop the reaction. The resulting mixture was extracted with t-butyl methyl ether three times and the extractant was washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by chromatography on a silica gel column using hexane/ethyl acetate=2/1 as an eluant to give the desired compound (11.9 g, yield 74%) as a pale yellow solid. 1H NMR (400 MHz, 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). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | palladium; In methanol; hexane; | Reference Example 5 4-(1-t-Butoxycarbonylpiperidin-4-yloxy)aniline To a solution of 4-(1-t-butoxycarbonylpiperidin-4-yloxy)nitrobenzene (11.9 g) in methanol (100 ml) was added palladium on carbon (1.9 g) and the mixture was stirred under a hydrogen atmosphere at room temperature for 4 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by chromatography on a silica gel column using hexane/ethyl acetate=1/1 as an eluant to give the desired compound (10.7 g, yield 99%) as a pale red solid. 1H NMR (400 MHz, CDCl3) delta ppm: 1.46 (9H, s), 1.71 (2H, m), 1.87 (2H, m), 3.27 (2H, m), 3.71 (2H, m), 4.26 (1H, m), 6.63 (2H, d, J=8.5), 6.76 (2H, d, J=8.5). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; sodium hydrogencarbonate In ethanol; water | 12.1 4-[4-(4-Methylpentylamino)phenyloxy]piperidine fumarate STR67 (1) 1-Acetyl-4-(4-nitrophenyloxy)piperidine (13.2 g) obtained in Example 1, (1) was dissolved in a mixed solvent of ethanol (40 ml) and conc. hydrochloric acid (40 ml), followed by heating with stirring at 100° C. for 15 hours. After the solvent was distilled off, water (100 ml) was added and to the mixture were added solid sodium bicarbonate (12.6 g) and di-tert-butyl-dicarbonate (16.4 g), followed by stirring at room temperature for 8 hours. The solution was extracted with ethyl acetate, the extract was dried over anhydrous magnesium sulfate and then the solvent was distilled off. The residual oily compound was separated and purified by silica gel column chromatography (developing solvent: dichloromethane) to obtain 1-tert-butyloxycarbonyl4-(4-nitrophenyloxy)piperidine (13 g). NMR (CDCl3) δ: 1.50 (9H, s), 1.5-2.2 (4H, m), 3.2-3.9 (4H, m), 4.50-4.80 (1H, m), 6.9-7.1 (2H, m), 8.15-8.35 (2H, m) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triphenylphosphine In tetrahydrofuran; ethyl acetate; toluene | 196.1 Synthesis of 1-t-butoxycarbonyl-4-(4-nitrophenoxy)piperidine: Step 1 Synthesis of 1-t-butoxycarbonyl-4-(4-nitrophenoxy)piperidine: 3.02 g (15.0 mmol) of 1-t-butoxycarbonyl-4-hydroxypiperidine, obtained by the t-butoxycarbonylation of 4-hydroxypiperidine with di-t-butyl dicarbonate in an ordinary manner, 2.09 g (15.0 mmol) of 4-nitrophenol and 4.72 g (18.0 mmol) of triphenylphosphine were dissolved in 50 ml of tetrahydrofuran. 7.84 g (18.0 mmol) of diethyl azodicarboxylate (40 % solution in toluene) was added to the solution at room temperature, and they were stirred at room temperature overnight. After the treatment with ethyl acetate as extractant in an ordinary manner, the crude product was obtained. This product was purified by the silica gel column chromatography to obtain the title compound. Yield: 2.74 g (8.5 mmol) (57 %). H-NMR (CDCl3) δ 1.50 (9H, s), 1.75-1.86 (2H, m), 1.92-2.03 (2H, m), 3.36-3.43 (2H, m), 3.67-3.75 (2H, m), 4.58-4.64 (1H, m), 6.98 (2H, d), 8.20 (2H, d) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | In tetrahydrofuran; 4-HYDROXYPIPERIDINE; water; ethyl acetate | 63 63.1 1,1-dimethylethyl 4-(4-nitrophenoxy)-1-piperidinecarboxylate 63.1 1,1-dimethylethyl 4-(4-nitrophenoxy)-1-piperidinecarboxylate A solution of 2.01 g (10 mmol) of N-Boc-4-hydroxypiperidine (prepared in a standard fashion starting from commercial 4-hydroxypiperidine) in 10 ml of dry THF is added dropwise to a solution of 1.23 g (11 mmol) of tBuO-K+ in 10 ml of dry THF in a three necked flask, under an inert atmosphere, cooled by an ice bath. After agitation for 30 minutes at 0° C., a solution of 1.06 ml (10 mmol) of 4-fluoronitrobenzene in 10 ml of dry THF is added dropwise. The reaction mixture is agitated for 5 hours at 23° C. and finally poured into 25 ml of a water+ice mixture. The product is extracted using 50 ml of ethyl acetate. After decantation, the organic phase is washed twice with 25 ml of water and 25 ml of salt water. The organic solution is dried over magnesium sulphate, followed by filtration and concentration of the filtrate under vacuum to produce a residue which is purified on a silica column (eluant: heptane/ethyl acetate: 8/2). The pure fractions are collected and evaporated under vacuum. The expected product is obtained in the form of a pale yellow powder with a yield of 47%. Melting point: 97-98° C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 10h; | A mixture of 9 (5.0 mmol), 4-nitrophenol 10 (5.5 mmol), and K2CO3 (10.0 mmol) in DMF (15 mL) was heated to 100 C for 10 h. After the reaction was completed, the K2CO3 was removed by filtration. The filtrate was poured into ice water and extracted with DCM, saturated NaHCO3, and brine, and the combined organic layer was dried with MgSO4. Finally, the solvent was removed under reduced pressure to give the crude. A solution of the above crude solid (1.0 mmol) in 1 mL TFA/DCM (v/v = 1/1) was stirred for 3 h at 0 C, then allowed to warm to room temperature. After the reaction was completed, the solvent was removed under reduced pressure. The residue was slowly made alkaline with 2 N NaOH, then the precipitate formed was collected by filtration and washed with water to afford the crude product 11 without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With hydrogenchloride In methanol at 20℃; for 1h; | 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 HC1 in MeOH (20 mL) was added tert-butyl 4-(4- nitrophenoxy)piperidine-l-carboxylate (818 mg, 2.5 mmol). The resulting mixture was stirred at r.t. for 1 h. The mixture was concentrated to afford 4-(4-nitrophenoxy)piperidinehydrochloride (760 mg, 100%) as a yellow solid. |
With hydrogenchloride In ethanol; water at 25℃; for 4h; | 14.3 Step 3: Step 3: 4-(4-nitrophenoxy)piperidine hydrochloride (57) To a stirred solution of tert-butyl 4-(4-nitrophenoxy)piperidine-1-carboxylate (56) (2.0 g, 6.2 mmol) in EtOH (10 mL) was added concentrated HCl aqueous solution (10 mL). The resulting mixture was stirred at 25° C. for 4 h and then concentrated to afford the titled compound 57 (1.6 g, 99%) as a yellow solid. MS (ESI): [M+H]+=222.9. |
Tags: 138227-62-0 synthesis path| 138227-62-0 SDS| 138227-62-0 COA| 138227-62-0 purity| 138227-62-0 application| 138227-62-0 NMR| 138227-62-0 COA| 138227-62-0 structure
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