Structure of 82413-63-6
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CAS No. : | 82413-63-6 |
Formula : | C12H15NO2 |
M.W : | 205.25 |
SMILES Code : | O=CC1=CC=C(CN2CCOCC2)C=C1 |
MDL No. : | MFCD05865107 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
* 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 |
---|---|---|
71% | With hydrogenchloride; In ethanol; water;Heating / reflux; | To a solution [OF 4-HYDRAZINO-1- (3-CHLORO-PHENYL)-1 H-PYRAZOLO] [3, [4-C () PYRIMIDINE] (Intermediates Example S) (38 mg, 0.13 [MMOL)] in [ETOH] (5 mL) were added 2N [HCI] (0.5mL) and [4- (4-DIETHOXYMETHYL-BENZYL)-MORPHOLINE] (39 mg, 0.14 [MMOL).] The reaction mixture was refluxed overnight. The cooled solution was filtered to collect pure product (45 mg, [71%] yield). 'H NMR (400 MHz, DMSO) [812.] 45 (brs, [1 H),] 10.60 (brs, 1H), 8.73 (s, 1H), 8.57 (s, 1H), 8.42 (s, 1 H), 8.37 (s, 1 H), 8.24 (d, 1 H), 7.95 (d, 2H), 7.69 (d, 2H), 7.63 (t, 1 H), 7.45 (d, 1 H), 4.41 (m, 2H), 3.98 (m, 2H), 3.72 (m, 2H), 2.29 (m, 2H), 2.12 (m, 2H) ppm ; ES-MS m/z 448 [(MH+).] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethanol;Heating / reflux; | Example 59 4-(Morpholinomethyl)benzaldehyde 4-(oxazol-5-yl)phenylhydrazone 4-(Morpholinomethyl)benzaldehyde (175 mg) was added to an ethanol solution (10 ml) of 4-(oxazol-5-yl)phenylhydrazine (150 mg), followed by heating overnight under reflux. The solvent was evaporated and the thus obtained residue was washed with diethyl ether to obtain the title compound (165 mg) as a yellow solid. 1H-NMR (400 MHz, DMSO-d6) delta: 2.50 (4H, s), 3.31 (4H, s), 3.58 (2H, t, J=4.6 Hz), 7.14 (2H, d, J=8.6 Hz), 7.33 (2H, d, J=8.6 Hz), 7.44 (1H, s), 7.58 (2H, d, J=8.6 Hz), 7.62 (2H, d, J=8.6 Hz), 7.90 (1H, s), 8.32 (1H, s), 10,56 (1H, s). ESI-MS m/z: 363 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With diisobutylaluminium hydride; In hexane; toluene; at -78℃; for 2h;Inert atmosphere; | A round-bottom flask was charged with 4-(morpholinomethyl)benzonitrile (8.54 g,42.2 mmol, 1.00 equiv) in toluene (50 mL) under nitrogen. Diisobutylaluminum hydride (84.5 mL, 84.5 mmol, 2.00 equiv, 1M in hexane) was added at -78 C and the reaction mixture was stirred for 2 h at -78 C before quenching with saturated NFL1C1 solution (50 mL). The resulting solution was extracted with ethyl acetate (3 x 50 mL) and the organic layers were combined, washed with brine (2 x 50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column to yield 8.50 g (98% yield) of 4-(morpholinomethyl)benzaldehyde. LCMS (ESI, m/z): 206 [M+H]. |
Reference Example 61 4-(Morpholinomethyl)benzaldehyde Diisobutylaluminum hydride (18.9 ml, 0.93 M hexane solution) was added dropwise to a THF solution (60 ml) of 4-(morpholinomethyl)benzonitrile (1.00 mg) at -78C, followed by stirring at the same temperature for 2 hours. Methanol (5.0 ml) was added dropwise to the reaction solution, and concentrated hydrochloric acid (6.7 ml) was subsequently added to the mixture, followed by stirring overnight at room temperature. A saturated aqueous sodium bicarbonate solution was added to the reaction solution, and the resulting precipitate was removed by filtration through celite. The filtrate was extracted with ethyl acetate, washed with water and saturated brine and dried over sodium sulfate. The solvent was evaporated to obtain the title compound (670 mg) as a colorless oil. 1H-NMR (400 MHz, CDCl3) delta: 2.46 (4H, t, J=4.6 Hz), 3.57 (2H, s), 3.72 (4H, t, J=4.6 Hz), 7.52 (2H, d, J=8.3 Hz), 7.84 (2H, d, J=8.3 Hz), 10.00 (1H, s). ESI-MS m/z: 205M+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With manganese(IV) oxide; In dichloromethane; at 20℃; for 72h; | Step 3) 4-Morpholin-4-ylmethyl-benzaldehyde Manganese dioxide (3.28 g, 37.67 mmol) was added to a stirred solution of (4-morpholin-4- ylmethyl-phenyl)-methanol (1.3g, 6.28 mmol) in methylene dichloride (120 mL) at rt and stirred for 72 h. The reaction mixture was filtered through sintered funnel using celite and washed with methylene dichloride (50 mL). The solvent was evaporated under reduced pressure and purifiedby column chromatography (silica gel, 20% EtOAc/Hexanes) to give 4-morpholin-4-ylmethyl- benzaldehyde (1.2 g, 93%) as a white solid. MS calcd. for C12H15N02 [(M+H)?i 206, obsd. |
88% | Protection of the nitrogen at -70 C (COCl)2 (152mg, 1.2mmol) was added to DMSO (156mg, 2.0mmol) in DCM (10 mL), and stirring was continued to maintain a temperature of -70 C for 30 minutes, followed by addition of 4-(morpholinylmethyl)benzyl alcohol (207mg, 1.0mmol) 3mL DCM the solution stirred for 1 hour. Instillation of Et3N (405mg, 4.0mmol), maintaining the temperature at -70 C and stirring was continued for 1 hour was raised to 25 C, dropwise addition of water (10 mL) to quench the reaction, was added NaHCO3 solution (5mL). Liquid separation, the aqueous phase was extracted with 10mLDCM combined organic phase was concentrated after column chromatography (PE:EtOAc = 2:1) as a pale yellow oily product A405A (180mg, yield: 88%). | |
81% | To a solution of 4-bromoethyl-benzoic acid ethyl ester (4.0 g, 16.46 mmol) in THF (30 mL), morpholine (2.87 g, 32.92 mmol) was added and the reaction mixture was stirred for 48 h at room temperature. The reaction mixture was diluted with water and the product was extracted with ethyl acetate. The combined organic layers were washed with water, brine, and dried over Na2SO4. The solvent was removed to give 3.4 g of crude product in 83% yield.LAH (0.571 g, 15.05 mmol) was added to a 3-neck dry flask and THF (50 mL) was added on cooling. A solution of 4-morpholin-4-ylmethyl)-benzoic acid ethyl ester (3.0 g, 12.04 mmol) in THF (10 mL) was added slowly on cooling. After completion of addition, the reaction mixture was heated at reflux for 3 h. The reaction mixture was cooled to 0 C. and a 10% NaOH solution was added carefully followed by water. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water, brine and dried over Na2SO4. The solvent was removed to give (4-morpholin-4-ylmethyl phenyl)methanol (2.0 g, 80%). To the 3-flask anhydrous CH2Cl2 (100 mL) was added and cooled to -78 C. Oxalyl chloride (1.47 g, 11.59 mmol) and DMSO (1.5 g, 19.32 mmol) were added at -78 C. The reaction mixture was stirred for 15 min at -78 C. A solution of (4-morpholin-4-ylmethyl phenyl)methanol (2.0 g, 9.66 mmol) in CH2Cl2 (10 mL) was added at -78 C. and the mixture was stirred at -78 C. for 1 h. Then, Et3N (3.9 g, 38.64 mmol) was added. The reaction mixture was allowed to come at room temperature. Water was added and the organic layer was isolated. The aqueous layer was extracted with CH2Cl2. The combined organic layers were washed with water, brine and dried over Na2SO4. Then solvent was removed to give crude 4-morpholin-4-ylmethyl benzaldehyde (1.6 g, 81%).To a solution of 2-amino-4,6-dimethoxy-benzamide (150 mg, 0.76 mmol) and 4-morpholin-4-ylmethyl benzaldehyde (156 mg, 0.76 mmol) in N,N-dimethyl acetamide (10 mL), NaHSO3 (150 mg, 0.84 mmol) and p-TSA (174 mg, 0.91 mmol) were added and the reaction mixture was heated at 150 C. for 5 h. The reaction mixture was cooled to room temperature, water was added and the mixture was neutralized with NaHCO3. The solvent was removed under reduced pressure to give the crude product, which was purified by column chromatography to give 5,7-dimethoxy-2-(4-(morpholinomethyl)phenyl)quinazolin-4(3H)-one, which was converted to the hydrochloride salt (165 mg, 51%). Selected data: MS (ES) m/z: 382.07; MP 206-208 C. (at decomposition). |
With oxalyl dichloride; dimethyl sulfoxide; In dichloromethane; at -78℃; for 1h; | To the 3-flask anhydrous CH2Cl2 (100 mL) was added and cooled to -78 C. Oxalyl chloride (1.47 g, 11.59 mmol) and DMSO (1.5 g, 19.32 mmol) were added at -78 C. The reaction mixture was stirred for 15 min at -78 C. A solution of (4-morpholin-4-ylmethyl phenyl)methanol (2.0 g, 9.66 mmol) in CH2Cl2 (10 mL) was added at -78 C. and the mixture was stirred at -78 C. for 1 h. Then, Et3N (3.9 g, 38.64 mmol) was added. The reaction mixture was allowed to come at room temperature. Water was added and the organic layer was isolated. The aqueous layer was extracted with CH2Cl2. The combined organic layers were washed with water, brine and dried over Na2SO4. Then solvent was removed to give crude 4-morpholin-4-ylmethyl benzaldehyde (1.6 g, 81%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With toluene-4-sulfonic acid; sodium hydrogensulfite; In N,N-dimethyl acetamide; at 150℃; for 5h; | To a solution of 4-bromoethyl-benzoic acid ethyl ester (4.0 g, 16.46 mmol) in THF (30 mL), morpholine (2.87 g, 32.92 mmol) was added and the reaction mixture was stirred for 48 h at room temperature. The reaction mixture was diluted with water and the product was extracted with ethyl acetate. The combined organic layers were washed with water, brine, and dried over Na2SO4. The solvent was removed to give 3.4 g of crude product in 83% yield.LAH (0.571 g, 15.05 mmol) was added to a 3-neck dry flask and THF (50 mL) was added on cooling. A solution of 4-morpholin-4-ylmethyl)-benzoic acid ethyl ester (3.0 g, 12.04 mmol) in THF (10 mL) was added slowly on cooling. After completion of addition, the reaction mixture was heated at reflux for 3 h. The reaction mixture was cooled to 0 C. and a 10% NaOH solution was added carefully followed by water. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water, brine and dried over Na2SO4. The solvent was removed to give (4-morpholin-4-ylmethyl phenyl)methanol (2.0 g, 80%). To the 3-flask anhydrous CH2Cl2 (100 mL) was added and cooled to -78 C. Oxalyl chloride (1.47 g, 11.59 mmol) and DMSO (1.5 g, 19.32 mmol) were added at -78 C. The reaction mixture was stirred for 15 min at -78 C. A solution of (4-morpholin-4-ylmethyl phenyl)methanol (2.0 g, 9.66 mmol) in CH2Cl2 (10 mL) was added at -78 C. and the mixture was stirred at -78 C. for 1 h. Then, Et3N (3.9 g, 38.64 mmol) was added. The reaction mixture was allowed to come at room temperature. Water was added and the organic layer was isolated. The aqueous layer was extracted with CH2Cl2. The combined organic layers were washed with water, brine and dried over Na2SO4. Then solvent was removed to give crude <strong>[82413-63-6]4-morpholin-4-ylmethyl benzaldehyde</strong> (1.6 g, 81%).To a solution of 2-amino-4,6-dimethoxy-benzamide (150 mg, 0.76 mmol) and <strong>[82413-63-6]4-morpholin-4-ylmethyl benzaldehyde</strong> (156 mg, 0.76 mmol) in N,N-dimethyl acetamide (10 mL), NaHSO3 (150 mg, 0.84 mmol) and p-TSA (174 mg, 0.91 mmol) were added and the reaction mixture was heated at 150 C. for 5 h. The reaction mixture was cooled to room temperature, water was added and the mixture was neutralized with NaHCO3. The solvent was removed under reduced pressure to give the crude product, which was purified by column chromatography to give 5,7-dimethoxy-2-(4-(morpholinomethyl)phenyl)quinazolin-4(3H)-one, which was converted to the hydrochloride salt (165 mg, 51%). Selected data: MS (ES) m/z: 382.07; MP 206-208 C. (at decomposition). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33% | With sodium dithionite; In ethanol; water; at 80℃; for 20h; | To a mixture of 2-[4-(2-amino-5-chloro-3-nitro-pyridin-4-yl)-piperazin-1-yl]-N-thiazol-2-yl-acetamide (0.044 g, 0.11 mmol) and EtOH (4.0 ml) was added <strong>[82413-63-6]4-morpholin-4-ylmethyl-benzaldehyde</strong> (0.029 g, 0.14 mmol) followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.44 ml, 0.44 mmol). The reaction mixture was stirred at 80 C. for 20 h, then allowed to cool to room temperature and concentrated in vacuo. The resulting residue was absorbed on silica, and the free-running powder was placed on a 10 g isolute silica column. Elution with a gradient of methanol (0 to 6%) in ethyl acetate/dichloromethane (v:v; 1:1) afforded a yellow solid. The title compound was obtained as a pale yellow solid after trituration with diethyl ether (0.020 g, 33%); 1H-NMR (500 MHz, DMSO-d6) 2.38 (br s, 4H) and 3.59 (t, J=4.5 Hz, 4H) (morpholine N(CH2)2 and morpholine O(CH2)2), 2.78 (br s, 4H, piperazine N(CH2)2), 3.40 (s, 2H) and 3.53 (s, 2H) (C6H4CH2N and NCH2CO), 3.75 (br s, 4H, piperazine N(CH2)2), 7.24 (d, J=3.5 Hz, 1H, thiazole-H), 7.48 (m, 3H, 3,5-C6H4- and thiazole-H), 8.12 (d, J=9.7 Hz, 2H, 2,6-C6H4-), 8.15 (s, 1H, imidazo[4,5-b]pyridine 5-H), 11.89 (s, 1H, CONH), 13.46 (br s, 1H, imidazo[4,5-b]pyridine N-H);LC (Method B)-MS (ESI, m/z): Rt=2.50 min-553, 555 [(M+H)+, Cl isotopic pattern]. ESI-HRMS: Found: 553.1903, calculated for C26H30ClN8O2S (M+H)+: 553.1901. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39% | With sodium dithionite; In ethanol; water; at 80℃; for 20h; | To a mixture of 5-chloro-4-[4-(5-methyl-isoxazol-3-ylmethyl)-piperazin-1-yl]-3-nitro-pyridin-2-ylamine (0.031 g, 0.09 mmol) and EtOH (3.0 ml) was added <strong>[82413-63-6]4-morpholin-4-ylmethyl-benzaldehyde</strong> (0.025 g, 0.12 mmol) followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.36 ml, 0.36 mmol). The reaction mixture was stirred at 80 C. for 20 h, then allowed to cool to room temperature and concentrated in vacuo. The resulting residue was absorbed on silica, and the free-running powder was placed on a 10 g isolute silica column. Elution with a gradient of methanol (0 to 7%) in ethyl acetate/dichloromethane (v:v; 1:1) afforded a yellow solid. The title compound was obtained as a yellow solid after trituration with diethyl ether (0.018 g, 39%); 1H-NMR (500 MHz, DMSO-d6) 2.38 (br s, 4H) and 3.58 (t, J=4.8 Hz, 4H) (morpholine N(CH2)2 and morpholine O(CH2)2), 2.40 (s, 3H, isoxazole 5-CH3), 2.63 (br s, 4H, piperazine N(CH2)2), 3.53 (s, 2H) and 3.60 (s, 2H) (C6H4CH2N and NCH2 isoxazole), 3.70 (br s, 4H, piperazine N(CH2)2), 6.25 (s, 1H, isoxazole 4-H), 7.47 (d, J=8.2 Hz, 2H) and 8.13 (d, J=8.2 Hz, 2H) (3,5-C6H4- and 2,6-C6H4-), 8.11 (s, 1H, imidazo[4,5-b]pyridine 5-H), 13.48 (br s, 1H, imidazo[4,5-b]pyridine N-H);LC (Method B)-MS (ESI, m/z): Rt=2.38 min-508, 510 [(M+H)+, Cl isotopic pattern]. ESI-HRMS: Found: 508.2229, calculated for C26H31ClN7O2 (M+H)+: 508.2228. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
14% | With sodium dithionite; In ethanol; water; at 80℃; for 20h; | To a mixture of 5-bromo-3-nitro-4-(4-pyridin-3-ylmethyl-piperazin-1-yl)-pyridin-2-ylamine (0.047 g, 0.12 mmol) and EtOH (3.5 ml) was added <strong>[82413-63-6]4-morpholin-4-ylmethyl-benzaldehyde</strong> (0.032 g, 0.16 mmol) followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.48 ml, 0.48 mmol). The reaction mixture was stirred at 80 C. for 20 h, then allowed to cool to room temperature and concentrated in vacuo. The residue was absorbed on silica gel, the free-running powder was placed on a 10 g isolute silica column, and elution of the column with a gradient of methanol (2 to 12%) in ethyl acetate/dichloromethane (v:v; 4:1) afforded a yellow solid which was triturated with diethyl ether. The precipitate was collected by filtration, and was successively washed with diethyl ether, water, and diethyl, then dried in vacuo (0.009 g, 14%). 1H-NMR (500 MHz, DMSO-d6) 2.38 (br t, 4H) and 3.59 (t, J=4.6 Hz, 4H) (morpholine N(CH2)2 and morpholine O(CH2)2), 2.62 (br s, 4H, piperazine N(CH2)2), 3.67 (br s, 4H, piperazine N(CH2)2), 3.53 (s, 2H) and 3.62 (s, 2H) (NCH2-pyridyl and C6H4CH2), 7.39 (dd, J=5.3, 7.1 Hz, pyridine 5-H), 7.47 (d, J=7.7 Hz, 2H) and 8.14 (d, J=8.0 Hz, 2H) (3,5-C6H4 and 2,6-C6H4), 7.78 (d, J=7.5 Hz, 1H, pyridine 4-H), 8.23 (s, 1H, imidazo[4,5-b]pyridine 5-H), 8.50 (dd, J=1.6, 4.7 Hz, 1H, pyridine 6-H), 8.56 (d, J=1.6 Hz, 1H, pyridine 6-H), 13.48 (br s, 1H, imidazo[4,5-b]pyridine N-H);LC (Method B)-MS (ESI, m/z): Rt=1.94 min-548, 550 [(M+H)+, Br isotopic pattern]. ESI-HRMS: Found: 548.1776, calculated for C27H31BrN7O (M+H)+: 548.1773. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | With sodium dithionite; In ethanol; water; at 80℃; for 20h; | To a mixture of 5-chloro-3-nitro-4-(4-pyridin-3-ylmethyl-piperazin-1-yl)-pyridin-2-ylamine (0.031 g, 0.09 mmol) and EtOH (3.0 ml) was added <strong>[82413-63-6]4-morpholin-4-ylmethyl-benzaldehyde</strong> (0.025 g, 0.12 mmol) followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.36 ml, 0.36 mmol). The reaction mixture was stirred at 80 C. for 20 h, then allowed to cool to room temperature and concentrated in vacuo. The resulting residue was absorbed on silica, and the free-running powder was placed on a 10 g isolute silica column. Elution with a gradient of methanol (2 to 13%) in ethyl acetate/dichloromethane (v:v; 4:1) afforded a yellow solid. The title compound was obtained as a pale yellow solid after trituration with diethyl ether (0.014 g, 30%); 1H-NMR (500 MHz, DMSO-d6) 2.38 (br s, 4H) and 3.59 (t, J=4.5 Hz, 4H) (morpholine N(CH2)2 and morpholine O(CH2)2), 2.62 (br s, 4H, piperazine N(CH2)2), 3.53 (s, 2H) and 3.61 (s, 2H) (NCH2-pyridyl and C6H4CH2N), 3.71 (br s, 4H, piperazine N(CH2)2), 7.39 (dd, J=5.30, 8.2 Hz, pyridine 5-H), 7.47 (d, J=8.2 Hz, 2H) and 8.12 (d, J=8.7 Hz, 2H) (3,5-C6H4- and 2,6-C6H4-), 7.78 (d, J=6.9 Hz, 1H, pyridine 4-H), 8.14 (s, 1H, imidazo[4,5-b]pyridine 5-H), 8.50 (dd, J=1.50, 4.6 Hz, 1H, pyridine 6-H), 8.56 (d, J=1.5 Hz, 1H, pyridine 2-H), 13.42 (br s, 1H, imidazo[4,5-b]pyridine N-H);LC (Method B)-MS (ESI, m/z): Rt=1.87 min-504, 506 [(M+H)+, Cl isotopic pattern]. ESI-HRMS: Found: 504.2272, calculated for C27H31ClN7O (M+H)+: 504.2278. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
17% | With sodium dithionite; In ethanol; water; at 85℃; for 24h; | To a mixture of 5-bromo-4-(4-(cyclobutylmethyl)piperazin-1-yl)-3-nitropyridin-2-amine (0.046 g, 0.12 mmol) and EtOH (1.5 mL), was added <strong>[82413-63-6]<strong>[82413-63-6]4-(morpholinomethyl)benzaldehyd</strong>e</strong> (0.028 g, 0.14 mmol) in EtOH (1.3 mL) followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.37 mL, 0.37 mmol). The reaction mixture was heated at 85 C. for 24 h, then allowed to cool to room temperature and the solvents were removed in vacuo. The residue was absorbed on silica gel and purified by column chromatography on a Biotage SP1 system eluting with methanol (2-10%) in dichloromethane. The title compound was isolated as a pale yellow solid after trituration with diethyl ether and (0.011 g, 17%); 1H-NMR (500 Mz, DMSO-d6): delta 1.61-1.74 (m, 2H), 1.76-1.94 (m, 3H), 2.00-2.10 (m, 2H), 2.33-2.45 (m, 6H), 2.52-2.61 (m, 4H, piperazine N(CH2)2), 3.54 (s, 2H, NCH2), 3.59 (t, J=4.5 Hz, 4H), 3.64 (m, 4H), 7.48 (d, J=8.5 Hz, 2H, ArH), 8.14 (d, J=8.5 Hz, 2H, ArH), 8.23 (s, 1H, imidazo[4,5-b]pyridine 5-H), 13.47 (br s, 1H, imidazo[4,5-b]pyridine N-H); LC (Method B)-MS (ESI, m/z) 2.67 min-525/527 [(M+H)+, Br isotopic pattern]; ESI-HRMS: Found: 525.1972, calculated for C28H31BrFN6O (M+H)+: 525.1977. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
29% | With sodium dithionite; In ethanol; water; N,N-dimethyl-formamide; at 85℃; for 24h; | To a mixture of 5-bromo-4-(4-((2-methylthiazol-4-yl)methyl)piperazin-1-yl)-3-nitropyridin-2-amine (0.062 g, 0.15 mmol), EtOH (2.6 mL) and DMF (0.35 mL), 4-(morpholinomethyl)-benzaldehyde (0.034 g, 0.165 mmol) was added followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.45 mL, 0.45 mmol). The reaction mixture was heated at 85 C. for 24 h, then allowed to cool to room temperature and diluted with DCM, and a few drops of aqueous NH3 until complete dissolution was observed. This solution was deposited on two preparative silica TLC plates and eluted with DCM/MeOH (v/v; 96:4) to give the title compound as a pale yellow solid (0.024 g, 29%); 1H-NMR (500 Mz, DMSO-d6): delta 2.33-2.42 (m, 4H), 2.62-2.71 (m, 7H), 3.54 (s, 2H, NCH2), 3.59 (t, J=4.5 Hz, 4H), 3.62-3.74 (m, 6H), 7.32 (s, 1H, thiazole 5-H), 7.47 (d, J=8.0 Hz, 2H, ArH, C6H4), 8.14 (d, J=8.0 Hz, 2H, ArH, C6H4), 8.23 (s, 1H, imidazo[4,5-b]pyridine 5-H), 13.51 (br s, 1H, imidazo[4,5-b]pyridine N-H); LC (Method B)-MS (ESI, m/z) 2.12 min-568/570 [(M+H)+, Br isotopic pattern]. ESI-HRMS: Found: 568.1504, calculated for C26H31N7BrOS (M+H)+: 568.1494. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
18% | With sodium dithionite; In ethanol; water; N,N-dimethyl-formamide; at 85℃; for 24h; | To a mixture of 5-chloro-4-(4-((2-methylthiazol-4-yl)methyl)piperazin-1-yl)-3-nitropyridin-2-amine (0.06 g, 0.19 mmol, 1 eq), EtOH (3.3 mL), and DMF (0.44 mL), 4-(morpholinomethyl)-benzaldehyde (0.043 g, 0.21 mmol, 1.1 eq) was added followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.57 mL, 0.57 mmol). The reaction mixture was heated at 85 C. for 24 h, allowed to cool to room temperature, and diluted with DCM and a few drops of aqueous NH3 until complete dissolution was observed. This solution was deposited on two preparative silica TLC plates and eluted with DCM/MeOH (v/v; 92:8). The title compound was obtained after trituration with diethyl ether as a yellow solid (0.018 g, 18%); 1H-NMR (500 Mz, DMSO-d6): delta 2.35-2.42 (m, 4H), 2.63-2.70 (m, 7H), 3.54 (s, 2H, NCH2), 3.59 (t, J=4.8 Hz, 4H), 3.64 (s, 2H, NCH2), 3.68-3.74 (m, 4H), 7.32 (s, 1H, thiazole 5-H), 7.47 (d, J=8.5 Hz, 2H, ArH, C6H4), 8.10 (s, 1H, imidazo[4,5-b]pyridine 5-H), 8.13 (d, J=8.0 Hz, 2H, ArH, C6H4), 13.43 (br s, 1H, imidazo[4,5-b]pyridine N-H); LC (Method B)-MS (ESI, m/z): Rt=2.25 min-524/526 [(M+H)+, Cl isotopic pattern]; ESI-HRMS: Found: 524.1999, calculated for C26H31ClN7OS (M+H)+: 524.1999; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
3% | With sodium dithionite; In ethanol; dichloromethane; water; at 70℃; for 9h; | To a mixture of 5-bromo-4-[4-(4-chloro-benzyl)-piperazin-1-yl]-3-nitro-pyridin-2-ylamine (0.064 g, 0.15 mmol) and EtOH (6.5 ml) was added <strong>[82413-63-6]4-morpholin-4-ylmethyl-benzaldehyde</strong> (0.038 g, 0.18 mmol) followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.60 ml, 0.60 mmol). The reaction mixture was stirred at 70 C. for 9 h, then allowed to cool to room temperature and concentrated in vacuo. The residue was absorbed on silica gel, the free-running powder was placed on a 10 g isolute silica column and elution with a gradient of methanol (0 to 9%) in ethyl acetate/dichloromethane (v:v; 1:1) afforded a yellow solid. The title compound was obtained as a pale yellow solid after trituration with diethyl ether (0.003 g, 3%). 1H-NMR (500 MHz, DMSO-d6) 2.38 (br s, 4H) and 3.59 (t, J=4.5 Hz, 4H) (morpholine N(CH2)2 and morpholine O(CH2)2), 2.61 (br s, 4H, piperazine N(CH2)2), 3.66 (br s, 4H, piperazine N(CH2)2), 3.54 (s, 2H) and 3.57 (s, 2H) (NCH2-C6H4Cl and C6H4CH2), 7.41 (m, 4H, C6H4Cl), 7.47 (d, J=8.2 Hz, 2H) and 8.14 (d, J=8.2 Hz, 2H) (3,5-C6H4 and 2,6-C6H4), 8.23 (s, 1H, imidazo[4,5-b]pyridine 5-H), 13.48 (br s, 1H, imidazo[4,5-b]pyridine N-H);LC (Method B)-MS (ESI, m/z): Rt=2.41 min-581, 583, 585 [(M+H)+, BrCl isotopic pattern]. ESI-HRMS: Found: 581.1442, calculated for C28H31BrClN6O (M+H)+: 581.1431. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20% | With sodium dithionite; In ethanol; water; at 80℃; for 19h; | To a mixture of 5-bromo-4-[4-(5-methyl-isoxazol-3-ylmethyl)-piperazin-1-yl]-3-nitro-pyridin-2-ylamine (0.044 g, 0.11 mmol) and EtOH (3.5 ml) was added <strong>[82413-63-6]4-morpholin-4-ylmethyl-benzaldehyde</strong> (0.029 g, 0.14 mmol) followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.44 ml, 0.44 mmol). The reaction mixture was stirred at 80 C. for 19 h, then allowed to cool to room temperature and concentrated in vacuo. The resulting residue was absorbed on silica, and the free-running powder was placed on a 10 g isolute silica column. Elution with ethyl acetate/dichloromethane (v:v; 2:3) and then a gradient of methanol (2 to 8%) in ethyl acetate/dichloromethane (v:v; 1:1) afforded a yellow solid. The title compound was obtained as a pale yellow solid after trituration with diethyl ether (0.012 g, 20%); 1H-NMR (500 MHz, DMSO-d6) 2.38 (br s, 4H) and 3.59 (t, J=4.6 Hz, 4H) (morpholine N(CH2)2 and morpholine O(CH2)2), 2.40 (s, 3H, isoxazole 5-CH3), 2.64 (br s, 4H, piperazine N(CH2)2), 3.54 (s, 2H) and 3.60 (s, 2H) (C6H4CH2N and NCH2 isoxazole), 3.67 (br s, 4H, piperazine N(CH2)2), 6.25 (s, 1H, isoxazole 4-H), 7.48 (d, J=8.2 Hz, 2H) and 8.14 (d, J=8.2 Hz, 2H) (3,5-C6H4- and 2,6-C6H4-), 8.23 (s, 1H, imidazo[4,5-b]pyridine 5-H), 13.48 (br s, 1H, imidazo[4,5-b]pyridine N-H);LC (Method B)-MS (ESI, m/z): Rt=2.32 min-552, 554 [(M+H)+, Br isotopic pattern]. ESI-HRMS: Found: 552.1713, calculated for C26H31BrN7O2 (M+H)+: 552.1722. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
3% | With sodium dithionite; In ethanol; dichloromethane; water; at 70℃; for 5h; | To a mixture of 5-bromo-3-nitro-4-[4-(1-phenyl-ethyl)-piperazin-1-yl]-pyridin-2-ylamine (0.060 g, 0.15 mmol) and EtOH (6.0 ml) was added <strong>[82413-63-6]4-morpholin-4-ylmethyl-benzaldehyde</strong> (0.039 g, 0.19 mmol) followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.60 ml, 0.60 mmol). The reaction mixture was stirred at 70 C. for 5 h, then allowed to cool to room temperature, and concentrated in vacuo. The residue was absorbed on silica gel, the free-running powder was placed on a 10 g isolute silica column and elution with a gradient of methanol (0 to 9%) in ethyl acetate/dichloromethane (v:v; 1:1) afforded a yellow solid which was triturated with diethyl ether. The precipitate was collected by filtration, successively washed with diethyl ether, water, diethyl ether, and dried (0.002 g, 3%). 1H-NMR (500 MHz, DMSO-d6) 1.37 (d, J=6.6 Hz, 3H, CHCH3), 2.38 (br s, 4H) and 3.59 (t, J=4.6 Hz, 4H) (morpholine N(CH2)2 and morpholine O(CH2)2), 2.54 (br s, 2H), 2.63 (br s, 2H) and 3.65 (br s, 4H) piperazine N(CH2)2), 3.50 (q, 1H, CHCH3), 3.57 (s, 2H, C6H4CH2), 7.26 (m, 1H) and 7.37 (m, 4H) (PhH), 7.47 (d, J=8.9 Hz, 2H) and 8.13 (d, J=8.2 Hz, 2H) (3,5-C6H4- and 2,6-C6H4-), 8.22 (s, 1H, imidazo[4,5-b]pyridine 5-H), 13.45 (br s, 1H, imidazo[4,5-b]pyridine N-H);LC (Method B)-MS (ESI, m/z): Rt=2.14 min-561, 563 [(M+H)+, Br isotopic pattern]. ESI-HRMS: Found: 561.1971, calculated for C29H34BrN6O (M+H)+: 561.1977. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
3% | With sodium dithionite; In ethanol; dichloromethane; water; at 70℃; for 9h; | To a mixture of 5-bromo-3-nitro-4-(4-pyridin-4-ylmethyl-piperazin-1-yl)-pyridin-2-ylamine (0.050 g, 0.13 mmol) and EtOH (4.5 ml) was added <strong>[82413-63-6]4-morpholin-4-ylmethyl-benzaldehyde</strong> (0.032 g, 0.16 mmol) followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.50 ml, 0.50 mmol). The reaction mixture was stirred at 70 C. for 9 h, then allowed to cool to room temperature and concentrated in vacuo. The residue was absorbed on silica gel, the free-running powder was placed on a 10 g isolute silica column and elution with a gradient of methanol (0 to 15%) in ethyl acetate/dichloromethane (v:v; 4:1). afforded a yellow solid. This material was triturated with diethyl ether, and the pale yellow precipitate was collected by filtration, successively washed with diethyl ether, water, and diethyl, then dried in vacuo (0.002 g, 3%). 1H-NMR (500 MHz, DMSO-d6) 2.38 (br s, 4H) and 3.59 (t, J=5.0 Hz, 4H) (morpholine protons), 2.63 (br s, 4H, piperazine N(CH2)2), 3.69 (br s, 4H, piperazine N(CH2)2), 3.54 (s, 2H) and 3.62 (s, 2H) (NCH2-pyridyl and C6H4CH2), 7.40 (d, J=4.9 Hz, 2H pyridine 3-H and 5-H), 7.48 (d, J=8.2 Hz, 2H) and 8.14 (d, J=8.2 Hz, 2H) (3,5-C6H4- and 2,6-C6H4-), 8.24 (s, 1H, imidazo[4,5-b]pyridine 5-H), 8.54 (d, J=5.5 Hz, 2H, pyridine 2-H and 6-H), 13.48 (br s, 1H, imidazo[4,5-b]pyridine N-H);LC (Method B)-MS (ESI, m/z): Rt=1.88 min-548, 550 [(M+H)+, Br isotopic pattern]. ESI-HRMS: Found: 548.1785, calculated for C27H31BrN7O (M+H)+: 548.1773. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2.4% | With sodium dithionite; In ethanol; water; N,N-dimethyl-formamide; at 85℃; for 24h; | To a mixture of 5-bromo-4-(4-((2-isopropyloxazol-4-yl)methyl)piperazin-1-yl)-3-nitropyridin-2-amine (0.065 g, 0.15 mmol), EtOH (0.85 mL), and DMF (0.15 mL), was added <strong>[82413-63-6]<strong>[82413-63-6]4-(morpholinomethyl)benzaldehyd</strong>e</strong> (0.040 g, 0.19 mmol) followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.49 mL, 0.49 mmol). The reaction mixture was heated at 85 C. for 24 h, then allowed to cool to room temperature and the solvents were removed in vacuo. The residue was purified by column chromatography on a Biotage SP1 system eluting with methanol (10-30%) in ethyl acetate. The title compound was isolated as a pale yellow solid (0.002 g, 2.4%) after trituration with ether; 1H-NMR (500 Mz, DMSO-d6): delta 1.27 (d, J=7 Hz, 6H, iPr-CH3), 2.38 (m, 4H), 2.65 (m, 4H), 3.05 (m, 1H, iPr-CH), 3.44 (s, 2H, NCH2), 3.54 (s, 2H, NCH2), 3.59 (t, J=4.5 Hz, 4H), 3.66 (m, 4H), 7.47 (d, J=7.5 Hz, 2H, ArH), 7.87 (s, 1H, oxazole 5-H), 8.14 (d, J=8.0 Hz, 2H, ArH), 8.23 (s, 1H, imidazo[4,5-b]pyridine 5-H), 13.49 (br s, 1H, imidazo[4,5-b]pyridine N-H); LC (Method B)-MS (ESI, m/z) 2.43 min-580/582 [(M+H)+, Br isotopic pattern]. ESI-HRMS: Found: 580.2036, calculated for C28H35BrN7O2 (M+H)+: 580.2035. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
7.6% | With sodium dithionite; In ethanol; water; at 85℃; for 24h; | To a mixture of 5-bromo-4-(4-(4-fluorobenzyl)piperazin-1-yl)-3-nitropyridin-2-amine (0.12 g, 0.30 mmol) and EtOH (5 mL), <strong>[82413-63-6]<strong>[82413-63-6]4-(morpholinomethyl)benzaldehyd</strong>e</strong> (0.068, 0.33 mmol) in EtOH (1.8 mL) was added followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.9 mL, 0.9 mmol). The reaction mixture was heated at 85 C. for 24 h, then allowed to cool to room temperature and the solvents were removed in vacuo. The residue was absorbed on silica gel and purified by column chromatography on a Biotage SP1 system eluting with methanol (2-10%) in dichloromethane. The title compound was isolated as a pale yellow solid after trituration with diethyl ether (0.013 g, 7.6%); 1H-NMR (500 Mz, DMSO-d6): delta 2.38 (m, 4H), 2.60 (m, 4H), 3.54 (s, 2H, NCH2), 3.56 (s, 2H, NCH2), 3.59 (t, J=4.5 Hz, 4H), 3.66 (m, 4H), 7.17 (d, J=8.5 Hz, 2H, ArH, C6H4-F), 7.40 (br dd, J=8.5, 6.0 Hz, 2H, ArH, C6H4-F), 7.47 (d, J=8.0 Hz, 2H, ArH), 8.14 (d, J=8.0 Hz, 2H, ArH), 8.23 (s, 1H, imidazo[4,5-b]pyridine 5-H), 13.47 (br s, 1H, imidazo[4,5-b]pyridine N-H); LC (Method B)-MS (ESI, m/z) 2.33 min-565/567 [(M+H)+, Br isotopic pattern]. ESI-HRMS: Found: 565.1725, calculated for C28H31BrFN6O (M+H)+: 565.1727. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With sodium dithionite; In ethanol; water; at 85℃; for 24h; | To a mixture of 5-bromo-3-nitro-4-(4-(thiazol-2-ylmethyl)piperazin-1-yl)pyridin-2-amine (0.088 g, 0.22 mmol) and EtOH (2.5 mL), 4-(morpholinomethyl)-benzaldehyde (0.045 g, 0.24 mmol) in EtOH (2.5 mL) was added, followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.66 mL, 0.66 mmol). The reaction mixture was heated at 85 C. for 24 h, then allowed to cool to room temperature and diluted with DCM and a few drops of aqueous NH3 until complete dissolution was observed. This solution was deposited on two preparative silica TLC plates and eluted with DCM/MeOH (v/v; 96:4) to give the title compound as a solid (0.049 g, 40%); 1H-NMR (500 Mz, DMSO-d6): delta 2.33-2.43 (m, 4H), 2.72-2.79 (m, 4H), 3.54 (s, 2H, NCH2), 3.59 (t, J=4.5 Hz, 4H), 3.70 (t, J=4.5 Hz, 4H), 3.95 (s, 2H, NCH2), 7.48 (d, J=8.5 Hz, 2H, ArH), 7.69 (d, J=3.5 Hz, 1H, thiazole 5-H), 7.75 (d, J=3.0 Hz, 1H, thiazole 4-H), 8.15 (d, J=8.0 Hz, 2H, ArH), 8.24 (s, 1H, imidazo[4,5-b]pyridine 5-H), 13.49 (br s, 1H, imidazo[4,5-b]pyridine N-H); LC (Method B)-MS (ESI, m/z) 2.37 min-554/556 [(M+H)+, Br isotopic pattern]. ESI-HRMS: Found: 554.1341, calculated for C25H29BrN7OS (M+H)+: 554.1338. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39% | With sodium dithionite; In ethanol; water; N,N-dimethyl-formamide; at 85℃; for 24h; | To a mixture of 5-bromo-4-(4-((2-isopropylthiazol-4-yl)methyl)piperazin-1-yl)-3-nitropyridin-2-amine (0.066 g, 0.15 mmol), EtOH (2.6 mL) and DMF (0.35 mL), 4-(morpholinomethyl)-benzaldehyde (0.034 g, 0.165 mmol) was added, followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.45 mL, 0.45 mmol). The reaction mixture was heated at 85 C. for 24 h, then allowed to cool to room temperature and diluted with DCM and a few drops of aqueous NH3 until complete dissolution was observed. This solution was deposited on two preparative silica TLC plates and eluted with DCM/MeOH (v/v; 96:4) to give the title compound as a solid (0.035 g, 39%); 1H-NMR (500 Mz, DMSO-d6): delta 1.33 (d, J=7.0 Hz, 6H, iPr-CH3), 2.34-2.42 (m, 4H), 2.68 (m, 4H), 3.22-3.32 (m, 1H), 3.54 (s, 2H), 3.59 (d, J=4.5 Hz, 4H), 3.62-3.70 (m, 6H), 7.35 (s, 1H, thiazole 5-H), 7.47 (d, J=8.5 Hz, 2H, ArH, C6H4), 8.14 (d, J=8.0 Hz, 2H, ArH, C6H4), 8.23 (s, 1H, imidazo[4,5-b]pyridine 5-H), 13.47 (br s, 1H, imidazo[4,5-b]pyridine N-H); LC (Method B)-MS (ESI, m/z) 2.55 min-596/598 [(M+H)+, Br isotopic pattern]. ESI-HRMS: Found: 596.18.07, calculated for C28H35BrN7OS (M+H)+: 596.1793. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20% | With sodium dithionite; In ethanol; water; N,N-dimethyl-formamide; at 85℃; for 24h; | To a mixture of 5-bromo-3-nitro-4-(4-(thiazol-4-ylmethyl)piperazin-1-yl)pyridin-2-amine (0.045 g, 0.11 mmol), EtOH (2.6 mL) and DMF (0.35 mL), 4-(morpholinomethyl)-benzaldehyde (0.025 g, 0.12 mmol) was added followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.33 mL, 0.33 mmol). The reaction mixture was heated at 85 C. for 24 h, then allowed to cool to room temperature and diluted with DCM and a few drops of aqueous NH3 until complete dissolution was observed. This solution was deposited on two preparative silica TLC plates and eluted with DCM/MeOH (v/v; 96:4) to give the title compound as a off-white solid (0.012 g, 20%); 1H-NMR (500 Mz, DMSO-d6): delta 2.33-2.43 (m, 4H), 2.65-2.73 (m, 4H), 3.54 (s, 2H, NCH2), 3.59 (t, J=4.5 Hz, 4H), 3.64-3.72 (m, 4H), 3.77 (s, 2H, NCH2), 7.47 (d, J=8.0 Hz, 2H, ArH, C6H4), 7.58 (d, J=2.0 Hz, 1H, thiazole 5-H), 8.14 (d, J=8.0 Hz, 2H, ArH, C6H4), 8.23 (s, 1H, imidazo[4,5-b]pyridine 5-H), 9.07 (d, J=2.0 Hz, 1H, thiazole 2-H), 13.46 (br s, 1H, imidazo[4,5-b]pyridine N-H); LC (Method B)-MS (ESI, m/z) 1.95 min-554/556 [(M+H)+, Br isotopic pattern]. ESI-HRMS: Found: 554.1338, calculated for C25H29N7OSBr (M+H)+: 554.1339. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
14.7% | With sodium dithionite; In ethanol; water; N,N-dimethyl-formamide; at 85℃; for 24h; | To a mixture of 5-bromo-4-(4-((1-methyl-1H-imidazol-5-yl)methyl)piperazin-1-yl)-3-nitropyridin-2-amine (0.030 g, 0.076 mmol, 1 eq), EtOH (1.95 mL) and DMF (0.29 mL), 4-(morpholinomethyl)-benzaldehyde (0.017 g, 0.083 mmol, 1.1 eq) was added followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.23 mL, 0.23 mmol). The reaction mixture was heated at 85 C. for 24 h, then allowed to cool to room temperature and diluted with DCM and a few drops of aqueous NH3 until complete dissolution was observed. This solution was deposited on two preparative silica TLC plates and eluted with DCM/MeOH (v/v; 94:6). The title compound was obtained after trituration with diethyl ether as a yellow solid (0.005 g, 14.7%); 1H-NMR (500 Mz, DMSO-d6): delta 2.35-2.41 (m, 4H), 2.55-2.62 (m, 4H), 3.52-3.55 (2 s, 4H, 2NCH2), 3.59 (t, J=4.5 Hz, 4H), 3.62-3.67 (m, 4H), 3.68 (m, 3H, imidazole Me), 6.80 (s, 1H, imidazole 4-H), 7.46 (d, J=8.0 Hz, 2H, ArH, C6H4), 7.57 (s, 1H, imidazole 2-H), 8.13 (d, J=8.0 Hz, 2H, ArH, C6H4), 8.23 (s, 1H, imidazo[4,5-b]pyridine 5-H), 13.47 (br s, 1H, imidazo[4,5-b]pyridine N-H); LC (Method B)-MS (ESI, m/z): R=1.79 min-551/553 [(M+H+), Br isotopic pattern, 100%]; ESI-HRMS: Found: 551.1882, calculated for C26H32N8OBr (M+H)+: 551.1882. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
18% | With sodium dithionite; In ethanol; water; N,N-dimethyl-formamide; at 85℃; for 24h; | To a mixture of 5-bromo-4-(4-((1-methyl-1H-imidazol-2-yl)methyl)piperazin-1-yl)-3-nitropyridin-2-amine (0.105 g, 0.26 mmol, 1 eq) in EtOH (6 mL) and DMF (0.9 mL), 4-(morpholinomethyl)-benzaldehyde (0.060 g, 0.29 mmol, 1.1 eq) was added followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.78 mL, 0.78 mmol). The reaction mixture was heated at 85 C. for 24 h, then allowed to cool to room temperature, and diluted with DCM and a few drops of aqueous NH3 until complete dissolution was observed. This solution was deposited on two preparative silica TLC plates and eluted with DCM/MeOH (v/v; 92:8). The title compound was obtained as a solid after trituration with diethyl ether (0.027 g, 18%); 1H-NMR (500 Mz, DMSO-d6): delta 2.34-2.42 (m, 4H), 2.56-2.64 (m, 4H), 3.53 (s, 2H, morpholine N(CH2)2), 3.56-3.68 (m, 10H), 3.72 (s, 3H, imidazole Me), 6.78 (d, J=1.5 Hz, 1H, imidazole 4-H), 7.11 (d, J=1.5 Hz, 1H, imidazole 5-H), 7.47 (d, J=8.0 Hz, 2H, ArH), 8.13 (d, J=8.0 Hz, 2H, ArH), 8.23 (s, 1H, imidazo[4,5-b]pyridine 5-H), 13.47 (br s, 1H, imidazo[4,5-b]pyridine N-H); LC (Method B)-MS (ESI, m/z): Rt=2.23 min-551/553 [(M+H+), Br isotopic pattern, 100%]. ESI-HRMS: Found: 551.1884, calculated for C26H32BrN8O (M+H)+: 551.1882. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
26% | With sodium dithionite; In ethanol; water; N,N-dimethyl-formamide; at 85℃; for 24h; | To a mixture of 5-bromo-3-nitro-4-(4-(thiazol-5-ylmethyl)piperazin-1-yl)pyridin-2-amine (0.030 g, 0.076 mmol, 1 eq), EtOH (1.95 mL) and DMF (0.29 mL), 4-(morpholinomethyl)-benzaldehyde (0.017 g, 0.083 mmol, 1.1 eq) was added followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.23 mL, 0.23 mmol). The reaction mixture was heated at 85 C. for 24 h, then allowed to cool to room temperature and diluted with DCM and a few drops of aqueous NH3 until complete dissolution was observed. This solution was deposited on two preparative silica TLC plates and eluted with DCM/MeOH (v/v; 94:6). The title compound was obtained as a solid after trituration with diethyl ether (0.022 g, 26%); 1H-NMR (500 Mz, DMSO-d6): delta 2.35-2.41 (m, 4H), 2.61-2.67 (m, 4H), 3.54 (s, 2H, NCH2), 3.59 (t, J=4.8 Hz, 4H), 3.63-3.69 (m, 4H), 3.87 (s, 2H, NCH2), 7.48 (d, J=8.0 Hz, 2H, ArH, C6H4), 7.82 (s, 1H, thiazole H-4), 8.14 (d, J=8.0 Hz, 2H, ArH, C6H4), 8.24 (s, 1H, imidazo[4,5-b]pyridine 5-H), 9.05 (s, 1H, thiazole H-2), 13.47 (br s, 1H, imidazo[4,5-b]pyridine N-H); LC (Method B)-MS (ESI, m/z): Rt=2.10 min-554/556 [(M+H+), Br isotopic pattern, 100%]. ESI-HRMS: Found: 554.1342, calculated for C25H29BrN7OS (M+H)+: 554.1338. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | With sodium dithionite; In ethanol; water; N,N-dimethyl-formamide; at 85℃; for 24h; | To a mixture of 5-chloro-3-nitro-4-(4-(thiazol-4-ylmethyl)piperazin-1-yl)pyridin-2-amine (0.076 g, 0.21 mmol), EtOH (3.6 mL) and DMF (0.49 mL), <strong>[82413-63-6]<strong>[82413-63-6]4-(morpholinomethyl)benzaldehyd</strong>e</strong> (0.047 g, 0.23 mmol, 1.1 eq) was added followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.64 mL, 0.64 mmol). The reaction mixture was heated at 85 C. for 24 h, then allowed to cool to room temperature and diluted with DCM and a few drops of aqueous NH3 until complete dissolution was observed. This solution was deposited on two preparative silica TLC plates and eluted with DCM/MeOH (v/v; 92:8). The title compound was obtained as a solid after trituration with diethyl ether (0.045 g, 42%); 1H-NMR (500 Mz, DMSO-d6): delta 2.38 (m, 4H), 2.68 (m, 4H), 3.53 (s, 2H, NCH2), 3.59 (t, J=4.5 Hz, 4H), 3.71 (m, 4H), 3.76 (s, 2H, NCH2), 7.47 (d, J=8.5 Hz, 2H, ArH, C6H4), 7.58 (d, J=2.0 Hz, 1H, thiazole 5-H), 8.10 (s, 1H, pyridine 6-H), 8.13 (d, J=8.0 Hz, 2H, ArH, C6H4), 9.07 (d, J=2.0 Hz, 1H, thiazole 2-H), 13.44 (br s, 1H, imidazo[4,5-b]pyridine N-H); LC (Method B)-MS (ESI, m/z): Rt=1.85 min-510/512 [(M+H)+, Cl isotopic pattern]; ESI-HRMS: Found: 510.1866, calculated for C25H29ClN7OS (M+H)+: 510.1843. |