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CAS No. : | 863377-22-4 | MDL No. : | MFCD03412095 |
Formula : | C10H14BNO3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | OHGOMHOEZUWGOH-UHFFFAOYSA-N |
M.W : | 207.03 | Pubchem ID : | 4192661 |
Synonyms : |
|
Num. heavy atoms : | 15 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.4 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 61.99 |
TPSA : | 52.93 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -7.15 cm/s |
Log Po/w (iLOGP) : | 0.0 |
Log Po/w (XLOGP3) : | 0.58 |
Log Po/w (WLOGP) : | -1.18 |
Log Po/w (MLOGP) : | -0.29 |
Log Po/w (SILICOS-IT) : | -0.68 |
Consensus Log Po/w : | -0.31 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.65 |
Solubility : | 4.6 mg/ml ; 0.0222 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.26 |
Solubility : | 11.3 mg/ml ; 0.0544 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -1.48 |
Solubility : | 6.86 mg/ml ; 0.0331 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.02 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-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 |
---|---|---|
85% | Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78 - -70℃; for 2 h; Stage #2: at 20℃; Cooling with acetone-dry ice Stage #3: With water; ammonium chloride In tetrahydrofuran; hexane |
To a stirred mixture of 4-(3-bromophenyl) morpholine (16.5g, 0.068mol) in dry THF(300mL) was added n-BuLi (98.1mL, 0.102mol, 1.6M solution in n-hexane) dropwise at -70°C to -78°C. The mixture was stirred at the same temperature for 2h. To this reaction mixture was added tri-isopropyl borate (30.5mL, 0.150mol) dropwise whilst maintaining the temperature. The dry ice-acetone bath was removed and the mixture was allowed to warm to room temperature and stirred at room temperature overnight.The mixture was poured into a saturated solution of ammonium chloride and water added and the reaction mixture was extracted with ethyl acetate. The organic phase was dried (MgS04) and the solvent removed under reduced pressure and below 40°C.The residue was triturated with n-hexane and diethyl ether to afford 3-morpholin-4- ylphenylboronic acid (12g, 85percent) as an off-white solid.Mass: (ES+) 208 (M+H)+ NMR: 5H (d6-DMSO) 3.05 (4H, m), 3.72 (4H, m), 6.95 (1H, d), 7.18 (1H, t), 7.21 (1H, d), 7.38 (1H, br s) and 7.94 (2H, s). |
85% | Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78 - 70℃; Stage #2: at -78 - 20℃; Stage #3: With water; ammonium chloride In tetrahydrofuran; hexane |
To a stirred mixture of 4-(3-bromophenyl)morpholine (16.5g, 0.068mol) in dry THF (300mL) was added n-butyl lithium (98.1mL, 0.102mol, 1.6M solution in n-hexane) dropwise at -70°C to -78°C. The mixture was stirred at same temperature for 2h. To this reaction mixture was added tri-isopropyl borate (30.5mL, 0.150mol) dropwise whilst maintaining the temperature at -70°C to -78°C. The dry ice-acetone bath was removed and the mixture was allowed to warm to room temperature and stirred at room temperature overnight. The mixture was poured into a saturated solution of ammonium chloride and water added and the reaction mixture was extracted with ethyl acetate. The organic phase was dried (MgS04) and the solvent removed under reduced pressure. The residue was triturated with n-hexane and diethyl ether to afford 3-morpholin-4-yl-phenylboronic acid (12g, 85percent) as an off white solid.Mass: (ES+) 208 (M+H)+ NMR: 5H (^-DMSO) 3.05 (4H, m), 3.72 (4H, m), 6.95 (1H, d), 7.18 (1H, t), 7.21 (1H, d), 7.38 (1H, br s) and 7.94 (2H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,2-dimethoxyethane; water; at 80℃; for 72h; | A vial under argon containing Example 125B (35 mg, 0.09 mmol), 3- morpholinophenylboronic acid (21 mg, 0.09 mmol), PdC^dppfVdichloromethane (7 mg, 0.009 mmol) and potassium carbonate (24 mg, 0.18 mmol) in DME (1 mL) and water (0.1 mL) was capped and heated at 800C in a heater shaker for 3 days. The solvent was evaporated under reduced pressure, and the product was purified by reverse-phase HPLC using an acetonitrile/water 0.1percent TFA gradient elution method to afford the title compound as a TFA salt. 1H NMR (500 MHz, DMSOd6) delta ppm 11.52 (s, 1 H) 8.14 (s, 1 H) 7.26 - 7.34 (m, 4 H) 6.98 - 7.12 (m, 5 H) 6.67 - 6.75 (m, 2 H) 5.47 (s, 2 H) 3.57 - 3.73 (m, 4 H) 2.91 - 3.03 (m, 4 H). MS (ESI+) m/z 452.2 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;bis-triphenylphosphine-palladium(II) chloride; In 1,2-dimethoxyethane; ethanol; water; N,N-dimethyl-formamide; at 160℃; for 0.333333h;Microwave irradiation; | Example 4; 3-(lff-BenzimidazoI-2-yl)-5-(3-morpholinopheiiyl)pyrazin-2-aiiime; <n="94"/>Dichlorobis(triphenylphosrhohine)palladium (II) (0.003 g) was added to a mixture of 3-(lH-benzimidazol-2-yl)-5-bromopyrazin-2-amine (0.05 g), <strong>[863377-22-4]3-morpholinophenylboronic acid</strong> (0.041 g), 2M aqueous sodium carbonate solution (0.15 ml) and a 2:7:3:2 mixture of DMF:dimethoxyethane:water:ethanoI (3 ml) and the reaction mixture was heated to 16O0C for 20 minutes in a microwave oven. The reaction was cooled to ambient temperature and filtered and the filtrate was purified by X bridge preparative chromatography. The material so obtained was dried under vacuum. There was thus obtained the title compound (0.0048 g); Mass Spectrum: M+eta+ 373; RT 3.21 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | To a stirred mixture of 4-(3-bromophenyl) morpholine (16.5g, 0.068mol) in dry THF(300mL) was added n-BuLi (98.1mL, 0.102mol, 1.6M solution in n-hexane) dropwise at -70°C to -78°C. The mixture was stirred at the same temperature for 2h. To this reaction mixture was added tri-isopropyl borate (30.5mL, 0.150mol) dropwise whilst maintaining the temperature. The dry ice-acetone bath was removed and the mixture was allowed to warm to room temperature and stirred at room temperature overnight.The mixture was poured into a saturated solution of ammonium chloride and water added and the reaction mixture was extracted with ethyl acetate. The organic phase was dried (MgS04) and the solvent removed under reduced pressure and below 40°C.The residue was triturated with n-hexane and diethyl ether to afford 3-morpholin-4- ylphenylboronic acid (12g, 85percent) as an off-white solid.Mass: (ES+) 208 (M+H)+ NMR: 5H (d6-DMSO) 3.05 (4H, m), 3.72 (4H, m), 6.95 (1H, d), 7.18 (1H, t), 7.21 (1H, d), 7.38 (1H, br s) and 7.94 (2H, s). | |
85% | To a stirred mixture of 4-(3-bromophenyl)morpholine (16.5g, 0.068mol) in dry THF (300mL) was added n-butyl lithium (98.1mL, 0.102mol, 1.6M solution in n-hexane) dropwise at -70°C to -78°C. The mixture was stirred at same temperature for 2h. To this reaction mixture was added tri-isopropyl borate (30.5mL, 0.150mol) dropwise whilst maintaining the temperature at -70°C to -78°C. The dry ice-acetone bath was removed and the mixture was allowed to warm to room temperature and stirred at room temperature overnight. The mixture was poured into a saturated solution of ammonium chloride and water added and the reaction mixture was extracted with ethyl acetate. The organic phase was dried (MgS04) and the solvent removed under reduced pressure. The residue was triturated with n-hexane and diethyl ether to afford 3-morpholin-4-yl-phenylboronic acid (12g, 85percent) as an off white solid.Mass: (ES+) 208 (M+H)+ NMR: 5H (^-DMSO) 3.05 (4H, m), 3.72 (4H, m), 6.95 (1H, d), 7.18 (1H, t), 7.21 (1H, d), 7.38 (1H, br s) and 7.94 (2H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
18% | With copper diacetate; triethylamine; In dichloromethane; for 72h;Molecular sieve; Air conditions; | Intermediate 6: 4-[3-(2-Chloro-pyrimidin-5-yloxy)phenyl]morpholineA mixture of 2-chloro-5-hydroxypyrimidine (12.6 lg, 0.097mol), 3-morpholinylphenyl boronic acid (20. Og, 0.097mol), copper (II) acetate (19.28g, 0.097mmol), triethylamine (47.13mL, 0.34mol) and powdered 4A molecular sieves in dichloromethane (600mL) was stirred under air for 3 days. A calcium chloride guard tube was used to protect the reaction from moisture. The suspension was diluted with dichloromethane, filtered and washed with water and brine. The organic phase was dried (MgS04) and the solvent removed under reduced pressure. The crude product was purified by column chromatography on silica (ethyl acetate:hexane, 1: 1) to afford 4-{3-[(2-chloropyrimidin-5-yl)oxy]phenyl}morpholine (5.0g, 18percent) as colourless oil. Mass: (ES+) 292 (M+H)+ NMR: deltaEta ( 6-DMSO) 3.15 (4H, m), 3.84 (4H, m), 6.50 (1H, d), 6.58 (1H, s), 6.75 (1H, d), 7.28 (1H, t) and 8.35 (2H, s). |
With copper diacetate; triethylamine; In dichloromethane; | Intermediate 9: 4-[3-(2-Chloropyrimidin-5-yloxy)phenyl]morpholineA mixture of 2-chloro-5-hydroxypyrimidine (15g, 0.115mol), 3-morpholinylphenyl boronic acid (24g, 0.115mol), copper (II) acetate (21g, 0.115mol), triethylamine(79.5mL, 0.402mol) and powdered 4A molecular sieves in dichloromethane (600mL) was stirred under air for 3 days. A calcium chloride guard tube was used to protect the reaction from moisture. The suspension was diluted with dichloromethane, filtered and washed with water and brine. The organic phase was dried (MgS04) and the solvent removed under reduced pressure. The crude product was purified by column chromatography on silica (ethyl acetate:hexane 1: 1) to afford 4-[3-(2-chloropyrimidin- 5-yloxy)phenyl]morpholine (8.0g, 24percent) as colourless oil.Mass: (ES+) 292 (M+H)+ NMR: deltaEta ( 6-DMSO) 3.15 (4H, m), 3.84 (4H, m), 6.50 (1H, d), 6.58 (1H, s), 6.75 (1H, d), 7.28 (1H, t) and 8.35 (2H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
22% | With copper diacetate; triethylamine; In dichloromethane; | Intermediate 10: 4-[3-(6-Chloro ridin-3-yloxy)phenyl]morpholineA mixture of 2-chloro-5-hydroxypyridine (2g, 0.0154mol), 3-morpholin-4- ylphenylboronic acid (3.2g, 0.0154mol), copper (II) acetate (2.8g, 0.0154mol), triethylamine (10.8mL, 0.077mol) and powdered 4A molecular sieves in dichloromethane (90mL) was stirred under air for 3 days. A calcium chloride guard tube was used to protect the reaction from moisture. The reaction mixture was diluted with dichloromethane, filtered and washed with water and brine. The organic phase was dried (MgS04) and the solvent removed under reduced pressure. The crude product was purified by column chromatography on silica gel (ethyl acetate :hexane 1: 1) to afford 4-[3-(6-chloropyridin-3-yloxy)phenyl] morpholine (l.Og, 22percent) as colourless oil.Mass: (ES+) 291 (M+H)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydrogencarbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; toluene; at 100℃; for 13.5h; | Example 40Synthesis of 1-{4-[5-(3-morpholin-4-ylphenyl)-2-phenyl-3H-imidazo[4,5-b]pyridin-3-yl]phenyl}cyclobutanamine hydrochlorideStep 1: Synthesis of tert-butyl (1-{4-[5-(3-morpholin-4-ylphenyl)-2-phenyl-3H-imidazo[4,5-b]pyridin-3-yl]phenyl}cyclobutyl)carbamate To a solution of tert-butyl (1-{4-[(6-chloro-3-nitropyridin-2-yl)amino]phenyl}cyclobutyl)carbamate (1 g, 2.4 mmol) in DMSO/MeOH (4:1, 20 mL), were added benzaldehyde (0.32 mL, 3.2 mmol) and sodium dithionite (2.0 g, 9.5 mmol). The mixture was heated at 100° C. for 22 h and 1M-NaOH was added to the mixture with cooling in an ice bath until the pH becomes 9. The mixture was diluted with THF (50 mL) then Boc2O (1.5 g) was added and mixed stirred for 2 h at rt. The mixture was filtered through celite and the water phase was extracted with ethyl acetate (.x.2). The combined organic phase was washed with brine and dried over anhydrous Na2SO4. After evaporation, the residue was purified by silica gel column chromatography (hexane/ethyl acetate, 4:1 to 0:100) to give tert-butyl {1-[4-(5-chloro-2-phenyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]cyclobutyl}carbamate (520 mg) as a white solid (46percent). To a suspension of tert-butyl {1-[4-(5-chloro-2-phenyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]cyclobutyl}carbamate (50 mg, 0.1 mmol) in toluene/ethanol/saturated NaHCO3 (3/3/0.3 mL), were added 3-(4-morphoryl)phenylboronic acid (65 mg, 0.22 mmol) and Pd(PPh3)4 (12 mg, 0.01 mmol). The mixture was heated at 100° C. for 13.5 h. After evaporation under reduced pressure, the residue was purified by silica gel column chromatography (hexane/ethyl acetate, 4:1 to 0:100) to give the titled compound (69 mg) as a white solid. 1H-NMR (CDCl3) delta: 8.17 (1H, d, J=8.6 Hz), 7.78 (1H, d, J=8.6 Hz), 7.62 (3H, d, J=7.4 Hz), 7.54 (3H, t, J=8.0 Hz), 7.42 (2H, td, J=5.6, 3.2 Hz), 7.40-7.37 (1H, m), 7.36-7.31 (3H, m), 6.94 (1H, dd, J=8.0, 1.7 Hz), 3.89 (4H, t, J=4.6 Hz), 3.22 (4H, t, J=4.9 Hz), 2.65-2.32 (4H, m), 2.20-2.11 (1H, m), 1.93-1.90 (1H, m), 1.47-1.19 (9H, m); LC/MS: 602 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In 1,4-dioxane; water; at 80℃; for 2h; | Example 93 8-(3-Morpholinophenyl)-l,6-naphthyridine-2-carboxamide To a suspension of 8-bromo-l,6-naphthyridine-2-carboxamide (0.04 g, 0.16 mmol) and 3- morpholinophenylboronic acid (0.03 g, 0.16 mmol) and cesium carbonate (0.06 g, 0.18 mmol) in dioxane (5 ml) and water (0.5 ml) was added bis(diphenylphosphino)ferrocene- palladium(II)dichloride (0.01 g, 0.01 mmol). The mixture was stirred at 80°C for 2 hours. Removal of the solvent by distillation and chromatography (silica gel, ethyl acetate / heptane = 50:50 to 100:0) and trituration with diethyl ether yielded the title compound as yellow solid (0.04 g, 72percent). MS: m/e = 335.4 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28 mg | With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 3h; | b) 8-Hydroxy-6- (3-morpholinophenyl)guinazolin-4(3H)-one A mixture of (6-bromo-4-oxo-3-(pivaloyloxymethyl)-3 ,4-dihydroquinazolin-8-yloxy)methylpivalate (0.05 g, 0.1 mmol), potassium carbonate (0.03 g, 200 jimol), <strong>[863377-22-4]3-morpholinophenylboronic acid</strong> (0.03 g, 0.15 mmol) and <strong>[863377-22-4]3-morpholinophenylboronic acid</strong> (0.03 g,0.15 mmol) in dimethylformamide (1 ml) was heated to 100 °C for 3 h. The mixture was allowedto cool, and ammonia in methanol (7M, 2 ml, 14 mmol) was added. The solution was stuffed at room temperature overnight. The crude material was filtered and then purified by preparative HPLC (20 to 98 percent acetonitrile / water (0.1 percent formic acid)) to give the desired product (28 mg) as a light brown solid. MS: mle = 324.2 [M+H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In 1,2-dimethoxyethane;Inert atmosphere; | General procedure: General procedure (a): a mixture of bromoacetamide 2a or 10a, arylboronic acid (1.5 equiv), CsF (2.2 equiv) and Pd(PPh3)4 or PEPPSI-iPr (0.1?0.15 equiv) in dry 1,2-dimethoxyethane (DME, 3 mL) was stirred under Ar at 85 °C for 16 h. The reaction mixture was diluted with AcOEt, washed with brine and dried over MgSO4. The solvent was evaporated and the residue purified by flash chromatography (cyclohexane/AcOEt). General procedure (b): same procedure with K2CO3 (1.5 equiv) as base and in DME and H2O as reaction solvent 5/1. General procedure (c): same procedure with K2CO3 (3 equiv) as base and in DME and H2O as reaction solvent 4/1. The reaction mixture was then heated at 125 °C under microwave irradiation for 30 min. General procedure (d): same procedure with K2CO3 (4 equiv) as base, and in DME and H2O as reaction solvent 4/1. The reaction mixture was then heated at 125 °C under microwave irradiation for 30 min. 6.4.1.14 7-tert-Butoxycarbonylamino-4-(3-morpholinophenyl)-5,7,8,9-tetrahydrobenzocyclohepten-6-one (20a) Pale brown solid. Mp 146-147 °C. IR (KBr): 3326, 2970, 2854, 1703, 1600, 1493, 1451, 1366, 1265, 1129, 1165, 1121, 994, 980, 782 cm-1. 1H NMR (CDCl3, 400 MHz): 7.33 (m, 2H, H-3 and H-4'); 7.22 (m, 2H, H-2' and H-5'); 7.17 (dd, J = 6.0 and 2.8 Hz, 1H, H-1); 7.11 (m, 1H, H-2); 6.92 (dd, 1H, J = 8.1 and 1.8 Hz, H-6'); 5.44 (br s, 1H, NH); 4.57 (ddd, 1H, H-7); 3.89 (m, 4H, 2CH2-O); 3.85 (d, 1H, Ha-5); 3.78 (d, 1H, Hb-5); 3.26 (m, 4H, 2CH2-N); 3.08 (m, 1H, Ha-9); 2.97 (ddd, 1H, Hb-9); 2.68 (m, 1H, Ha-8); 1.55 (m, 1H, Hb-8); 1.44 (s, 9H, tBu). J(5a,5b) = 12.1, J(NH,7) = 6.0, J(7,8a) = 7.3, J(7,8b) = 10.8, J(8a,9b) = 9.1, J(8b,9b) = 3.5, J(9a,9b) = 14.6 Hz. 13C NMR (CDCl3, 100 MHz): 205.8 (C(6)); 155.4 (NCO2); 151.3 (C(1')); 143.4 (C(9a)); 142.1 (C(4)); 141.3 (C(3')); 130.5 (C(5')); 130.4 (C(4a)); 129.7 (C(4')); 129.5 (C(1)); 128.8 (C(3)); 127.6 (C(2)); 121.7 (C(2')); 114.6 (C(6')); 80.2 (CMe3); 67.4 (2CH2-O); 61.6 (C(7)); 49.6 (2CH2-N); 43.8 (C(5)); 35.1 (C(8)); 32.0 (C(9)); 28.8 (CMe3). HR-MS (ESI-QTof) calcd for C26H33N2O4 [M+H]+: 437.2435; found: 437.2433. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45%; 10% | With chloro(1,5-cyclooctadiene)rhodium(I) dimer; (R)-2,2'-bis(diphenylphosphanyl)-1,1'-binaphthyl; potassium hydroxide; In 1,4-dioxane; at 95℃; for 1.66667h;Microwave irradiation; | Intermediate 9: Methyl 4-f3-fluoro-3-f2-f5,6,7,8-tetrahvdro-l,8-naphthyridin-2- vi^ethynpyrrolidin-l-ylV3-f3-morpholinophenvnbutanoate. Isomer A and Isomer B). (£)-Methyl 4-(3-fluoro-3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)ethyl)pyrrolidin-l- yl)but-2-enoate (Compound (III), for a preparation see Intermediate 8) (145 mg, 0.334 mmol), ( ?)- BINAP (31 mg, 0.05 mmol), [Rh(COD)CI]2 (10 mg, 0.020 mmol), <strong>[863377-22-4](3-morpholinophenyl)boronic acid</strong> (available from for example CombiBlocks, Manchester Organics or Fluorochem) (259 mg, 1.251 mmol) and 3.8M KOH (0.22 mL, 0.836 mmol) were dissolved in 1,4-dioxane (2 mL) in a microwave vial and the solution was heated in a microwave oven (100 min, 95 °C). The reaction mixture was filtered through celite, washed with EtOAc (10 mL) and concentrated. The reaction mixture was suspended in MeOH (300 pL) and purified by reverse phase chromatography (C18, 40 g, 5 - 95percent MeCN (containing 0.1percent ammonia) in 10 mM ammonium bicarbonate, 20 CV). The appropriate fractions were combined and evaporated to give a diastereomeric mixture of the title Compound (II) (99 mg, 58percent) as a gum. The mixture was dissolved in EtOH (2 mL) and heptane (1 mL) and the diastereoisomers were separated by chiral HPLC on a Chiralcel OD-H column (3 cm x 25 cm) eluting with 30percent EtOH (containing 0.2percent isopropylamine) - 70percent heptane (flow rate=30 mL/min, detecting at 215 nm) to give the two diastereoisomers of the Compound (II). Isomer A (17 mg, 10percent): Analytical chiral HPLC RT=8.0 min, >99.5percent on Chiralcel OD-H column (4.6 mm id x 25 cm) eluting with (30percent EtOH (containing 0.2percent isopropylamine) - heptane, flow rate = 1.0 mL/min, detecting at 215 nm; LCMS (System A) RT=1.21 min, 99percent, ES+ve m/z 511 (M+H)+; *H NMR (400 MHz, CD3OD) delta 7.17 (t, J = 7.5 Hz, 1H), 7.13 (d, 7 = 7.5 Hz, 1H), 6.88-6.84 (m, 1H), 6.76 (d, J = 7.5 Hz, 1H), 6.38 (d, J = 7.5 Hz, 1H), 3.87-3.81 (m, 4H), 3.58 (s, 3H), 3.42- 3.36 (m, 2H), 3.17 - 3.10 (m, 4H), 2.90-2.49 (m, 12H), 2.11-1.84 (m, 6H), 1.38-1.28 (m, 2H). Isomer B (77 mg, 45 percent): Analytical chiral HPLC RT= 17.2 min, >99.5percent on Chiralcel OD-H column (4.6 mm id x 25 cm) eluting with (30percent EtOH (containing 0.2percent isopropylamine) - heptane, flow rate=1.0 mL/min, detecting at 215 nm; *H NMR (400 MHz, CD3OD) delta 7.18 (t, J = 7.5 Hz, 1H), 7.13-7.07 (m, 1H), 6.89-6.77 (m, 2H), 6.74 (d, J = 7.5 Hz, 1H), 6.36 (d, J = 7.5 Hz, 1H), 3.87-3.75 (m, 4H), 3.57 (s, 3H), 3.40-3.34 (m, 2H), 3.28-3.20 (m, 1H), 3.16-3.07 (m, 4H), 2.91-2.74 (m, 4H), 2.74-2.44 (m, 9H), 2.07-1.91 (m, 3H), 1.91-1.80 (m, 2H). The absolute configuration of the two isomers of Intermediate 9 was established subsequently by inference to be for the major isomer (Isomer B) (5)-methyl 4-((5)-3-fluoro-3-(2- (5,6,7/8-tetrahydro-l,8-naphthyridin-2-yl)ethyl)pyrrolidin-l-yl)-3-(3-morpholinophenyl)butanoate and for the minor isomer (Isomer A) (/?)-methyl 4-((5)-3-fluoro-3-(2-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)ethyl)pyrrolidin-l-yl)-3-(3-morpholinophenyl)butanoate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2% | With chloro(1,5-cyclooctadiene)rhodium(I) dimer; water; (R)-2,2'-bis(diphenylphosphanyl)-1,1'-binaphthyl; potassium hydroxide; at 50 - 100℃; for 8h;Microwave irradiation; | Example 7. ( g)-4-((5)-3-Fluoro-3-f2-f5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl)pyrrolidin-l-vn-3- -morpholinophenvnbutanoic acid Into a microwave vial (0.5-2 ml) were added (£)-methyl 4-bromobut-2-enoate (for a preparation see Intermediate 7) (113 mg, 0.634 mmol), (5)-7-(2-(3-fluoropyrrolidin-3-yl)ethyl)- l,2,3,4-tetrahydro-l,8-naphthyridine (for a preparation see Intermediate 5) (166.4 mg, 0.667 mmol), DIPEA (0.233 mL, 1.33 mmol) and dichloromethane (1 mL) at 0°C. The solution was stirred at 0°C for 3 h. LCMS showed reasonable conversion to the alkylated intermediate. The solution was then evaporated under nitrogen. To the microwave vial was added 3.8 M KOH (aq) (0.351 mL, 1.335 mmol, [Rh(COD)CI]2 (15 mg, 0.030 mmol), <strong>[863377-22-4](3-morpholinophenyl)boronic acid</strong> (276 mg, 1.335 mmol) and R-BINAP (50 mg, 0.080 mmol) and the vial placed in the microwave (5 h, 50°C, high power). LCMS showed some conversion and that both the starting material and the boronic acid were still present. The vial was placed in the microwave again (1 h, 70°C). LCMS showed further conversion to the ester and complete protodeborylation of the boronic acid. R-BINAP (50 mg, 0.080 mmol), [Rh(COD)CI]2 (15 mg, 0.030 mmol), <strong>[863377-22-4](3-morpholinophenyl)boronic acid</strong> (276 mg, 1.335 mmol) and 3.8 M KOH (aq) (0.351 mL, 1.33 mmol) were added to the vial and the vial was placed in the microwave (1 h, 85°C). LCMS showed some conversion but to improve the yield further R-BINAP (50 mg, 0.080 mmol), [Rh(COD)CI]2 (15 mg, 0.030 mmol), <strong>[863377-22-4](3-morpholinophenyl)boronic acid</strong> (276 mg, 1.335 mmol) and 3.8 M KOH (aq) (0.351 mL, 1.33 mmol)were added and the vial placed in the microwave again (1 h, 100°C). LCMS showed sufficient conversion and the mixture was passed through celite (10 g, 20 mL MeOH) and the filtrate was evaporated under vacuum. The sample was loaded in MeOH:DMSO (1:1) and purified on a reverse phase (C18) column (30 g) using a 50-95percent MeCN (containing 0.1percent ammonia) in 10 mM ammonium bicarbonate) gradient over 10 CV. The appropriate fractions were combined and evaporated in vacuo to give the required intermediate. To the round bottom flask was added 3.8 M KOH (3.34 mL, 12.69 mmol) and the solution suspended in tetrahydrofuran (2 mL) (stirred over night, 25°C). LCMS showed minimal conversion to the carboxylate. 1 M LiOH (aq) (3.34 mL, 3.34 mmol)was added and the reaction stirred at 25°C. 2M HCI (aq) (8.34 mL, 16.68 mmol)was added to the reaction mixture and it was then loaded onto a pre-wetted SCX column (10 g, pre wet with 1 CV MeOH, then 1 CV MeCN) and then washed with 2 CV MeCN followed by 2 CV NH3 in MeOH. The appropriate fraction was evaporated under reduced pressure. The sample was dissolved in 10:10:1 MeOH:DMSO:H20 (2.4 mL) and purified by MDAP (conducted on an XBridge Ci8 column (typically 100 mm x 30 mm i.d. 5 pm packing diameter) at ambient temperature, eluting with a gradient of acetonitrile - 10 mM aqueous ammonium bicarbondate adjusted to pHIO with ammonia solution). The solvent was evaporated under a stream of nitrogen to give the required product as a mixture of diastereoisomers. The mixture was separated by preparative chiral HPLC on a Daicel Chiralpak AS column (20 mm x 250 mm) eluting with 50percent EtOH in heptane at a flow rate of 15 mL/min, detecting at 215 nm. The solvent was evaporated from fractions containing the minor, later eluting isomer to give the title compound (7 mg, 2percent). Analytical chiral HPLC RT=8.15 min on a Daicel Chiralpak AS column (4.6 mm x 25 cm) eluting with 50percent EtOH in heptane, flow rate=1.0 mL/min, detecting at 215 nm; LCMS (System C) RT=0.76 min, 98.9percent, ES+ve /77/z497 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
6%; 27% | With chloro(1,5-cyclooctadiene)rhodium(I) dimer; potassium hydroxide; In 1,4-dioxane; at 95℃; for 1.66667h;Microwave irradiation; | Intermediate 14. Methyl i/n-4-(( g)-3-fluoro-3-f2-f5,6,7,8-tetrahydlro-l,8-naphthyridin- 2-yl)ethyl)pyrrolidin-l-yl)-3-(3-morpholinopheny0butanoate and methyl ( S)-4-(( /-3- fluoro-3-(2-f5,6,7,8-tetrahvdro-l,8-naphthyridin-2-vnethyl)pyrrolidin-l-vn-3-f3- morpholinophenyl)butanoa ( (/?,£)-Methyl 4-(3-fluoro-3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)ethyl)pyrrolidin-l- yl)but-2-enoate (for a preparation see Intermediate 13) (429 mg, 0.988 mmol), [Rh(COD)CI]2 (29.7 mg, 0.060 mmol), <strong>[863377-22-4](3-morpholinophenyl)boronic acid</strong> (716 mg, 3.46 mmol) and 3.8 M KOH (0.647 mL, 2.46 mmol) were dissolved in 1,4-dioxane (2 mL) and the solution was heated in a microwave reactor (high power, 100 min, 95 °C). The reaction mixture was filtered through celite, washed with EtOAc (10 mL) and concentrated. The reaction mixture was suspended in MeOH (300 muIota_) and purified by reverse phase chromatography (C18, 40 g) eluting with a gradient of 30-85percent MeCN (containing 0.1percent ammonia) in 10 mM aqueous ammonium bicarbonate, 30 CV). The appropriate fractions were combined and evaporated to give the product as a mixture of diastereoisomers (214 mg, 42percent yield). The mixture was separated by preparative chiral HPLC on a Chiralcel OD-H column (30 mm x 25 cm) eluting with 30percent EtOH (containing 0.2percent isopropylamine) in heptane, flow rate=30 mL/min, detecting at 215 nm to give the two diastereoisomers of the title compound Isomer 1 Methyl ( -4-(( ?)-3-fluoro-3-(2-(5,6,7/8-tetrahydro-l,8-naphthyridin-2- yl)ethyl)pyrrolidin-l-yl)-3-(3-morpholinophenyl)butanoic acid (29 mg, 6percent) LCMS (System B) RT=0.54 min, ES+ve m/z 511 (M+H)+; Analytical chiral HPLC RT=7.5 min, >99.5percent on a Chiralcel OD-H column (4.6 mm x 25 cm) eluting with 30percent EtOH containing 0.2percent isopropylamine-heptane, flow-rate 1 mL/min. Isomer 2 Methyl (5)-4-(( ?)-3-fluoro-3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl)pyrrolidin-l-yl)-3-(3-morpholinophenyl)butanoic acid (138 mg, 27percent): LCMS (System B) RT=0.57 min, ES+ve m/z 511 (M+H)+; Analytical chiral HPLC RT=13.9 min, >99.5percent on a Chiralcel OD-H column (4.6 mm chi 25 cm) eluting with 30percent EtOH containing 0.2percent isopropylamine-heptane, flow-rate 1 mL/min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
5% | With chloro(1,5-cyclooctadiene)rhodium(I) dimer; water; potassium hydroxide; In 1,4-dioxane; at 50℃; for 2h;Inert atmosphere; | Example 8. (/?)-4-(f/?)-3-Fiuoro-3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- vnethyl)pyrrolidin-l-yl 3-f3-morpholinophenvnbutanoic acid (/?,£)-Methyl 4-(3-fluoro-3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)ethyl)pyrrolidin-l- yl)but-2-enoate (for a preparation see Intermediate 13) (110 mg, 0.253 mmol) was dissolved in 1,4- dioxane (2 mL) under nitrogen. (3-Morpholinophenyl)boronic acid (157 mg, 0.760 mmol) was then added to the reaction mixture. [Rh(COD)CI]2 (13.4 mg, 0.027 mmol) was dissolved in 1,4-dioxane (1 mL) and nitrogen was bubbled through for 2 min. This dark red solution was added to the main reaction flask. 3.8 M KOH (aq) (0.2 mL, 0.76 mmol) was added, then the reaction mixture was heated to 50°C for 1 h. LCMS showed some conversion to the product. The reaction mixture was stirred at 50°C for 1 h. LCMS showed no further conversion to the product. The reaction mixture was cooled and filtered through celite. The column was washed with EtOH (10 mL). The solution was evaporated under reduced pressure then suspended in 1 M LiOH (aq) (1 mL, 1 mmol) and 1,4- dioxane (1 mL). The reaction mixture was stirred overnight. LCMS showed conversion to the product. The reaction mixture was acidified with 2 M HCI (aq) (0.5 mL). The crude mixture was loaded onto an SCX cartridge and eluted with 2M NH3 in MeOH. The ammoniacal fractions were evaporated and the crude mixture was suspended in MeOH (1 mL). The material was purified by reverse phase chromatography on a C18 column (30 g) eluting with a gradient of 5 - 70percent MeCN (containing 0.1percent ammonia) in 10 mM ammonium bicarbonate, 10 CV). The appropriate fractions were combined and evaporated. The residue was purified by chiral HPLC on a Daicel Chiralpak AS column (20 mm x 25 cm) eluting with 50percent EtOH in heptane at a flow rate of 15 mL/min and detecting at 215 nm. The solvent was evaporated from fractions containing the later eluting isomer to give the title compound (6 mg, 5percent). Analytical chiral HPLC RT=26.5 min on a Daicel Chiralpak AS-H column (4.6 mm x 25 cm) eluting with 50percent EtOH in heptane, flow rate=1.0 mL/min, detecting at 215 nm; LCMS (System A) RT=0.81 min, 100percent, ES+ve /n/ 497 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
27% | With bis(norbornadiene)rhodium(l)tetrafluoroborate; potassium hydroxide; In 1,4-dioxane; at 100℃; for 1h;Microwave irradiation; | Synthesis of authentic (A)-4-(3-morpholinophenyl)dihydrofuran-2(3A/)-one (Compound XXIV) for comparison with compound (XXIII). A solution of bis(norbornadiene)rhodium (I) tetrafluoroborate (available from Aldrich) (18.70 mg, 0.05 mmol) and <strong>[863377-22-4](3-morpholinophenyl)boronic acid</strong> (1035 mg, 5.00 mmol) in 1,4-dioxane (10 mL) was treated with furan-2(5 /)-one (0.142 mL, 2.0 mmol) and KOH solution (3.8 M, 1.053 mL, 4.00 mmol). The resulting solution was heated to 100°C for 1 h in a microwave reactor. The reaction was allowed to cool and concentrated in vacuo to give a brown oil. The residue was purified by chromatography (50 g KPNH cartridge) eluting with a gradient of 0-50percent EtOAc in' cyclohexane over 45 min. The relevant fractions were concentrated in vacuo to give (R)-4-(3- morpholinophenyl)dihydrofuran-2(3 )-one (compound XXIV) (132 mg, 27percent) as a white solid: LCMS (System C) RT= 0.82 min, 100percent, ES+ve /77/z248 (M+H)+; [-]D22 = -28.3 (c = 1.70 in CHCI3); Chiral HPLC RT= 23.4min, 94percent, RT=25.4 min 6percent on a Chiralpak ID column (25 cm chi 4.6 mm) eluting with 20percent isopropanol-heptane, flow-rate 1 mL/min, detecting at 215 nm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tetrakis(triphenylphosphine) palladium(0); sodium hydrogencarbonate; In ethanol; toluene; at 100℃;Inert atmosphere; | Step 3 tert-butyl (1-(4-(2-(2-aminopyridin-3-yl)-5-(3-morpholinophenyl)-3H-imidazo[4,5-b]pyridin-3-yl)phenyl)cyclobutyl)carbamatetert-butyl (1-(4-(2-(2-aminopyridin-3-yl)-5-chloro-3H-imidazo[4,5-b]pyridin-3-yl)phenyl)cyclobutyl)carbamate (1 eq.) was suspended in a mixture of ethanol and toluene, 10 mL/mmol respectively. A solution of NaHCO3 sat. was added (3 mL/mmol). The reaction mixture was degassed with nitrogen for 30 min. Pd(PPh3)4 (0.05 eq.) and the boronic acid (1.1 eq.) were added to the reaction mixture. Subsequently it was heated to 100° C. overnight under nitrogen. After cooling down to room temperature it was diluted with dichloromethane (20 mL/mmol) and water (10 mL/mmol). The organic phase was separated and washed with brine (10 mL/mmol) and dried over Na2SO4. After filtration the solvent was removed in vacuo. The crude residue was purified by silica gel chromatography (3-20percent methanol in ethyl acetate). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69.8 mg | The compound obtained in Example 1b (80.0 mg),an aqueous solution of <strong>[863377-22-4]3-(morpholino)phenylboronic acid</strong> (463 mg) (3 mL) solution ofsodium carbonate (50.8 mg) (1 mL), and the mixture was stirred at room temperature for 5 minutes. [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) dichloromethanecomplex (13.1 mg) was added at a microwave reactor and allowed to react for 1 hour at 130 °C. The reaction mixture was cooled to room temperature and extracted with water was addedethyl acetate. The organic layer was washed with water and saturated brine, dried overanhydrous sodium sulfate, and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound(69.8 mg) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In water; N,N-dimethyl-formamide; at 140℃;Microwave irradiation; | General procedure: A mixture of 6-bromo-4-phenylquinazolin-2(1H)-one (200 mg, 0.66 mmol, 1 eq.), DMF (1.5 mL), H2O (0.6 mL), 4-pyridylboronic acid (106 mg, 0.864 mmol, 1.3 eq.), Pd(PPh3)4 (53 mg, 0.046 mmol, 0.07 eq.), and sodium carbonate (162 mg, 1.52 mmol, 2.3 eq.) in a microwave vessel (2 ? 5 mL) was heated in the microwave at 140 °C for 4 - 24 min. After completion of the reaction (monitored by LC/MS), the mixture was allowed to cool to room temperature, and H2O (8 mL) was added. The resulting precipitate was collected by vacuum filtration and washed with H2O and diethyl ether to afford the crude product as a solid. The crude product was dissolved in a minimal amount of 1,4-dioxane (1 - 10 mL) and any insoluble material was removed by vacuum filtration. A solution of HCl in dioxane (4.0 M) was then added dropwise until a precipitate was formed. The resulting precipitate was collected by vacuum filtration. All Suzuki reactions followed this general procedure, using the appropriate boronic acid, unless otherwise noted. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
13% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In water; N,N-dimethyl-formamide; at 140℃;Microwave irradiation; | General procedure: A mixture of 6-bromo-4-phenylquinazolin-2(1H)-one (200 mg, 0.66 mmol, 1 eq.), DMF (1.5 mL), H2O (0.6 mL), 4-pyridylboronic acid (106 mg, 0.864 mmol, 1.3 eq.), Pd(PPh3)4 (53 mg, 0.046 mmol, 0.07 eq.), and sodium carbonate (162 mg, 1.52 mmol, 2.3 eq.) in a microwave vessel (2 ? 5 mL) was heated in the microwave at 140 °C for 4 - 24 min. After completion of the reaction (monitored by LC/MS), the mixture was allowed to cool to room temperature, and H2O (8 mL) was added. The resulting precipitate was collected by vacuum filtration and washed with H2O and diethyl ether to afford the crude product as a solid. The crude product was dissolved in a minimal amount of 1,4-dioxane (1 - 10 mL) and any insoluble material was removed by vacuum filtration. A solution of HCl in dioxane (4.0 M) was then added dropwise until a precipitate was formed. The resulting precipitate was collected by vacuum filtration. All Suzuki reactions followed this general procedure, using the appropriate boronic acid, unless otherwise noted. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With bis(norbornadiene)rhodium(l)tetrafluoroborate; (R)-2,2'-bis(diphenylphosphanyl)-1,1'-binaphthyl; potassium hydroxide; In 1,4-dioxane; water; at 100℃; for 1h;Microwave irradiation; | A solution of [Rh(nbd)2]BF4 (18.70 mg, 0.05 mmol), (R)-BINAP(62.3 mg, 0.1 mmol) and <strong>[863377-22-4](3-morpholinophenyl)boronic acid</strong> 6b(1.035 g, 5.00 mmol) in 1,4-dioxane (10 mL) was treated with 7(0.142 mL, 2.0 mmol) and KOH solution (3.8 M, 1.053 mL,4.00 mmol). The resulting solution was heated to 100 C for 1 hin a microwave reactor, allowed to cool and concentrated in vacuo.The residue was purified by chromatography (50 g KPNH cartridge)eluting with a gradient of 0?50percent EtOAc in cyclohexane over45 min. The relevant fractions were concentrated in vacuo to give(R)-5b (132 mg, 27percent) as a white solid: LCMS (System B)RT = 0.82 min, 100percent, ES+ve m/z 248 (M+H)+; HRMS (ESI) calc?d for C14H18NO3 (M+H)+ 248.1281, found 248.1283. [a]D22 = 28 (c 1.70,CHCl3). Anal. Chiral HPLC RT = 23.4 min, 94percent, RT = 25.4 min 6percent ona Chiralpak ID column (250 mm 4.6 mm) eluting with 20percent isopropanol?heptane, flow-rate 1 mL/min, detecting at 215 nm |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
34% | With 1,10-Phenanthroline; copper diacetate; In N,N-dimethyl-formamide; at 20℃; for 18h; | A mixture of Intermediate F (142 mg, 0.389 mmol), <strong>[863377-22-4](3-morpholinophenyl)boronic acid</strong> (241 mg, 1.17 mmol), Cu(OAc)2 (141 mg, 0.778 mmol) and 1 , 10-phenanthroline (140 mg, 0.778 mmol) was stirred in DMF (3.9 mL) for 18 h at RT before the reaction was diluted with NH4OH (50 mL) and water (50 mL). The resulting mixture was extracted with DCM (5 x 30 mL) using a phase separator, the combined organic phases were concentrated in vacuo and the residue was purified by flash chromatography (28 g KP-NH, 0-100percent EtOAc in cyclohexane, then 0-15percent MeOH in EtOAc; then 40 g GraceResolv silica, 0-15percent MeOH in DCM) to give the title compound (70 mg, 34percent) as a pale pink solid after lyophilisation. LCMS (Method A): RT = 1.18 min, m/z = 526, 528 [M+H]+. 1 H NMR (500 MHz, DMSO-d6): 5 8.07 (s, 1 H), 7.41 (t, J = 8.1 Hz, 1 H), 7.10 (ddd, J = 8.6, 2.6, 0.9 Hz, 1 H), 6.96 (t, J = 2.2 Hz, 1 H), 6.82 (ddd, J = 7.7, 1.9, 0.8 Hz, 1 H), 6.78 (s, 1 H), 4.92 (s, 1 H), 4.01 (s, 2H), 3.95 (dt, J = 13.2, 4.2 Hz, 2H), 3.77 - 3.71 (m, 4H), 3.27 - 3.04 (m, 6H), 1.56 - 1.47 (m, 2H), 1.42 - 1.36 (m, 2H), 1.21 (s, 3H), 0.80 - 0.74 (m, 2H), 0.55 - 0.48 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
11.2% | With 2,6-dimethylpyridine; lauric acid; copper diacetate; In toluene; at 20℃; for 48h; | To a solution of 3-( orpholino)phenyiboronic acid (124 mg, 0,6 mmol) and Cu(OAc)2 (15.6 mg. 008 mmol) in toluene (10 rnL) were added 2,6-Lutidine (42.8 rng, 0.4 mmol). Laurieacid (8.0 mg, 0.04 mmol) and compound A3 (300 mg, 0.4 mmol) The mixture was stirred under air atmosphere for two days at room temperature. The mixture was concentrated and the residue was purified by column chromatography on silica gel (MeOH/DCM = 1120) and prep-HPLC to afford compound 45 (40 mg, yield 1 1.2percent) as white solid. Partial 1F1 NMR (CDCIs, 400 MHz): ?7.94-7.89(m, 2H), 7.48 (dd,J::: 8.8 Hz, 2H) 7.27-7.20(ni. 2H), 6.78(s, 1H, 4.91 (s, IH), 4.76-4.67 (m, 1Ff), 4.47-4.42 (m, 1Ff), 4.39-4.31 (rn, 1H, 3.69-3.62 (in.1H), 3.58-3.44 (in, 15H), 3.36-3.25 (in, 2H), 3.21-3.09 (ni, 2H), 2.70 (5, 3H), 2.64-2.49 (in,3H). 234-217 (rn, I 1H). 1.33-116 (m, 2H), 0.91-0.80 (m, 4H). LCMS: rn/z 88& 4 [M-t-HJ. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45.2 mg | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 1,2-dimethoxyethane; water; at 130℃; for 0.25h;Microwave irradiation; | The compound (40.0 mg) obtained in Example 1b, [3- (morpholin-4-yl) phenyl] boronic acid (28.8 mg), aqueous solution (0.5 mL) of sodium carbonate (29.5 mg) was added to a solution of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (7.57 mg) in 1,2-dimethoxyethane (1.5 mL) and microwave The reaction was carried out in a reaction apparatus at 130 ° C. for 15 minutes. After cooling the reaction solution to room temperature, water was poured and extracted three times with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (45.2 mg) As a colorless amorphous solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33.8 mg | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 1,2-dimethoxyethane; water; at 130℃; for 0.75h;Microwave irradiation; | The compound obtained in Example 3b (35.0 mg), In 1 of [3-(morpholine-4-yl) phenyl] boron acid (21.7 mg) and a [1 and 1' -bis (diphenylphospino) ferrocene] dichloropalladium (II) dichloromethane complex (2.85 mg), and 2-dimethoxyethane (1.5 mL) solution, The aqueous solution (0.5 mL) of sodium carbonate (22.2 mg) was added, and it was made to react for 45 minutes at 130 degrees C with a microwave reaction apparatus. Water was poured out after cooling reaction mixture to a room temperature, and ethyl acetate extracted 3 times. The mark compound (33.8 mg) was obtained as a red amorphous solid by refining the residue obtained by distilling off the bottom solvent of decompression after drying with anhydrous sodium sulfate in the doubled organic layer with silica gel column chromatography (ethyl acetate/dichloromethane). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30.4 mg | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; water; at 130℃; for 0.5h;Microwave irradiation; | A mixture of the compound obtained in Example 5e (35.0 mg), [3- (morpholin-4-yl) phenyl] boronic acid (20.8 mg) and tetrakistriphenylphosphine palladium (5.48 mg) An aqueous solution (0.5 mL) of sodium carbonate (21.3 mg) was added to a solution of 2-dimethoxyethane (1.5 mL), and the mixture was reacted at 130 ° C. for 30 minutes in a microwave reactor. After cooling the reaction solution to room temperature, water was poured and extracted three times with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / dichloromethane) to give the title compound (30.4 mg) As a light brown amorphous solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
26.8 mg | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 1,2-dimethoxyethane; water; at 130℃; for 0.5h;Microwave irradiation; | The compound obtained in Example 11b (35.0 mg), In 1 of [3-(morpholine-4-yl) phenyl] boron acid (23.7 mg) and a [1 and 1' -bis (diphenylphospino) ferrocene] dichloropalladium (II) dichloromethane complex (6.24 mg), and 2-dimethoxyethane (1.5 mL) solution, The aqueous solution (0.5 mL) of sodium carbonate (24.3 mg) was added, and it was made to react for 30 minutes at 130 degrees C with a microwave reaction apparatus. Water was poured out after cooling reaction mixture to a room temperature, and 1 time, ethyl acetate, and two dichloromethanes extracted. The mark compound (26.8 mg) was obtained as a colorless solid by refining the residue obtained by distilling off the bottom solvent of decompression after drying with anhydrous sodium sulfate in the doubled organic layer with silica gel column chromatography (ethyl acetate/dichloromethane). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
34.8% | A mixture of N-(3-bromo-7-quinolyl)-2-methyl-pyrazole-3-carboxamide (50 mg, 147.96 mol, 1 eq), <strong>[863377-22-4](3-morpholinophenyl)boronic acid</strong> (30.63 mg, 147.96 mol, 1 eq), Pd(dppf)Cl2 (32.48 mg, 44.39 mumol, 0.3 eq), Cs2CO3 (144.63 mg, 443.88 mumol, 3 eq) in 1,4-dioxane (4 mL) and H2O (1 mL) was degassed and purged with N2 for 3 times. The mixture was stirred at 90° C. for 3 h under N2 atmosphere. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (20 mL*3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue which was purified by preparative HPLC (column: Phenomenex Gemini 150*25 mm*10 um; mobile phase: [water (0.05percent HCl)-ACN]; B percent: 25percent-55percent, 9 min), followed by lyophilization to yield 2-methyl-N-[3-(3-morpholinophenyl)-7-quinolyl]pyrazole-3-carboxamide (26.88 mg, 51.41 mumol, 34.8percent yield, 100.0percent purity, 3HCl) as a yellow solid. 1H NMR (400 MHz, CD3OD) delta ppm 9.56 (d, J=1.7 Hz, 1H), 9.47 (s, 1H), 9.21 (s, 1H), 8.42 (d, J=9.3 Hz, 1H), 8.16-8.09 (m, 2H), 7.92 (d, J=7.6 Hz, 1H), 7.80-7.74 (m, 1H), 7.73-7.67 (m, 1H), 7.60 (d, J=2.0 Hz, 1H), 7.17 (d, J=2.2 Hz, 1H), 4.23 (s, 3H), 4.15-4.08 (m, 4H), 3.76-3.66 (m, 4H); ES-LCMS m/z 414.2 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.52 mg | With potassium phosphate; tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 110℃;Sealed tube; | To a solution of 3-bromo-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo [1,5-a]pyrimidine-2-tert-butoxycarbonylamino (30 mg) in a mixture of DME/water (V/V = 1/1) were added <strong>[863377-22-4](3-morpholinylphenyl)boronic acid</strong> (15 mg), potassium phosphate (26 mg) and tetra(triphenylphosphine) palladium (1.4 mg) in a sealed-tube reaction. The reaction mixture was purged with nitrogen gas, warmed to 110C and reacted overnight. Then, an appropriate amount of water was added thereto, and the resulting mixture was extracted with ethyl acetate. The combined organic phase was washed with a saturated saline solution, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo, and the residue was purified and separated by thin layer chromatography to afford the title compound (1.52 mg). 1H NMR (400 MHz, CDCl3) delta 8.22 (brs, 1H), 7.05 (m, 2H), 6.91-6.89 (m, 2H), 6.77-6.75 (m, 2H), 5.83 (brs, 1H), 5.33 (brs, 1H), 4.53-4.14 (m, 2H), 4.00-3.63 (m, 5H), 3.19 (m, 4H), 2.44 (m, 1H), 2.08-2.01 (m, 3H). m/z = 477[M+1]+. |
Tags: 863377-22-4 synthesis path| 863377-22-4 SDS| 863377-22-4 COA| 863377-22-4 purity| 863377-22-4 application| 863377-22-4 NMR| 863377-22-4 COA| 863377-22-4 structure
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